Carbon‒Carbon Bond Activation of Ketones

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Review

Carbon‒Carbon Bond Activation of Ketones Lin Deng1 and Guangbin Dong1,* C
C bond activation has emerged as an increasingly useful approach for constructing complex molecular scaffolds through unusual bond-disconnection strategies. As a common versatile functional group, ketones provide an excellent handle and platform for C
C bond activation reactions. Utilizing strain-release, carbon-monoxide-extrusion, and directing-group (DG) approaches, diverse transformations of various ketones have been developed in the past few decades through cleavage of their a C
C bonds. This review highlights the development of C
C bond-activation strategies for both strained and less strained ketones with a focus on transition-metal (TM)-catalyzed approaches.

General Considerations for C
C Bond Activation of Ketones Carbon
carbon (C
C) and carbon
hydrogen (C
H) bonds constitute most organic compounds. Complementary to the late-stage C
H functionalization that modifies existing scaffolds, C
C bond activation provides unique opportunities for constructing backbones of organic molecules. However, realizing general and practical C
C bond activation methods has still been challenging. First, compared with C
H bonds that mostly exist on the surface, C
C bonds are normally ‘buried’ inside a molecule. In addition, with less s character, C
C s bonds are typically more directional than C
H bonds, which could hamper their interactions with a catalyst. For example, even when metal insertion into a C
C bond is more thermodynamically favorable, C
H bond activation can still be preferred kinetically [1,2]. Thus, steric hindrance and directionality have represented the main obstacles for C
C bond activation. Moreover, the resulting relatively weak metal
carbon bonds, compared with the corresponding metal
hydrogen bonds, could become another difficulty for breaking C
C bonds [3]. Nevertheless, despite these challenges, the field of C
C bond activation has undergone significant progress in the past two decades, especially with the advance of TM catalysis and the development of new strategies.

Highlights C
C bond activation methods have found increasing importance in complex-molecule synthesis. A number of different approaches for C
C bond activation of ketones have been developed. Complex bridged, fused, and spirocyclic ring systems have been constructed through activation of strained ketones. Synthetically useful transformations with less strained ketones have started to appear.

Ketones, as one of the most versatile and readily available functional groups, provide an excellent handle and platform for C
C bond activation reactions. Broadly, there are two major reaction modes to activate a C
C bonds of ketones (Figure 1). The first involves the oxidative addition (see Glossary) of a low-valency TM into C
C bonds. Such a process can take place either directly or with the help of a DG, which consequently forms a relatively stable acyl- or iminyl-metal bond. The other reaction mode involves a b-carbon elimination pathway, which starts with a 1,2-addition of a nucleophile to the carbonyl moiety, followed by elimination of a carbon substituent from the resulting alkoxide intermediate. In both pathways, C
C bonds are converted to new C
TM bonds that can undergo further bond-forming events. This review was inspired by many excellent reviews and book chapters on the topic of C
C bond activation in the past [4–8]. It focuses on using ketones as the direct substrates mediated or catalyzed by TMs reported until October 2019. The content is divided into two sections: highly strained ketones and less strained ketones. Not aiming to be comprehensive, the review intends to emphasize key milestones and more recent advances in the field, hoping to provide some insight and/or inspiration for future development. Note that C
C bond cleavage reactions through oxidative [9], radical, or photochemical [10] approaches are beyond the scope of this review.

C
C Bond Activation of Highly Strained Ketones Benefitting from ring-strain release and forming stable acyl-metal bonds, highly strained ketones can easily undergo C
C bond cleavage. Thus, numerous established C
C bond activation reactions involve strained ketones. To be specific, highly strained ketones here mainly refer to cyclopropenones (by contrast, cyclopropanones are unstable), cyclobutenones, and cyclobutanones.

1Department of Chemistry, University of Chicago, Chicago, IL 60637, USA

*Correspondence: [email protected]

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Pathway A: Oxidative Addition

(A)

O n

[M ]

Glossary

(B)

O

N [Mn+II]

N n

DG

[M ]

DG [Mn+II]

Pathway B: -Carbon Elimination n O [M ]

O n

[M ] Nu

Nu

O Nu: nucleophile

Nu [Mn]

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Figure 1. Two Major Mechanistic Pathways for C
C Bond Activation of Ketones. DG, directing group; M, transition metal.

Cyclopropenones Cyclopropenones, with roughly 70 kcal/mol strain energy [11], show special stability due to the resonance structure of a cyclopropenylium cation, which is the smallest member of the Hu¨ckel aromatic systems (Figure 2A). The chemical behavior of cyclopropenones is largely related to the polarized carbonyl moiety and the large ring strain [12]. Consequently, they have been found to undergo facile C
C bond cleavage reactions. This section focuses on the TM-mediated C
C activation of cyclopropenones. The existence of metallacyclobutenone intermediates from cyclopropenones was originally proposed by Bird and coworkers in the decomposition of diarylcyclopropenones with complexes of Fe and Co as early as 1967 [13]. However, isolation of metallacyclobutenones was not reported until 1972 by Baddley and coworkers [14]. Insertion of stoichiometric platinum(0) into the C
C bond of diphenylcyclopropenone afforded the corresponding platinacyclobutenone complex 1 in 60% yield at room temperature, which was confirmed by X-ray crystallography (Figure 2B). In 1990, rhodium(I) complexes were also found to react with the C
C bond of cyclopropenones, giving transRh(PPh3)2(CO)Cl and alkyne products through proposed intermediate 2 in high yields by Stang and coworkers (Figure 2B) [15]. In addition to the use of stoichiometric TMs, several catalytic transformations have been developed. First, in 1972, Noyori and coworkers reported a Ni-catalyzed dimerization of cyclopropenones to form symmetrical benzoquinones (Figure 2C) [16]. Baba later disclosed a [3+2] coupling between cyclopropenones and ketenes to form cyclopentadienones, taking advantage of metallacyclobutenone intermediates 3 [17]. Later in 2006, Wender disclosed a rhodium(I)-catalyzed [3+2] cycloaddition of cyclopropenones with alkynes forging cyclopentadienones through a similar pathway (Figure 2D) [18]. The general mechanism of the cycloaddition reactions starts with oxidative addition of Rh(I) into the acylcarbon bond of cyclopropenones to give a rhodacyclobutenone intermediate; the subsequent alkyne migratory insertion followed by reductive elimination delivers the five-membered ring product. Recently, the cycloaddition partners have been greatly enriched [19,20] and other types of downstream transformations, such as cross couplings [21], copolymerizations [22], s-bond metathesis [23], and C
H activations [24,25], have been incorporated as summarized in Figure 2E.

Cyclobutenones Compared with cyclopropenones, four-membered ring ketones, including cyclobuten(di)ones and cyclobutanones, have been extensively studied in C
C activation. Early studies focused on the more strained cyclobuten(di)ones and the related benzocyclobutenones. In general, they can serve

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Decarbonylation: an organic reaction of a carbonyl compound in which the two groups attached to the carbonyl connect to each other with the loss of CO. Directing group (DG): a substituent on a molecule that can coordinate to metals and direct the metal to the proximity of the reaction site. Migratory insertion: a process in which an anionic ligand and a neutral ligand in a metal complex combine to generate a new coordinated anionic ligand. Oxidative addition: a process in which a metal is inserted into a covalent bond and the oxidation state and coordination number of the metal are both increased by two. Ring strain: a type of ground-state destabilization in ring systems that arises from distorted bond angles (Baeyer strain), torsional eclipsing interactions (Pitzer strain), and interactions of substituents on nonadjacent atoms (transannular strain). Transmetalation: a process in which a ligand is transferred from one metal center to another. b-Carbon elimination: a process in which a carbon substituent b to the metal center is cleaved to form a metal-alkyl or -aryl species and the corresponding unsaturated unit. b-Hydrogen elimination: a process in which a hydrogen atom b to the metal center is cleaved to form a metal hydride species and the corresponding unsaturated unit.

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(A) The Resonance Structure of Cyclopropenones O

(B) Stoichiometric C C Bond Activation of Cyclopropenones

O

O

O

DCM, r.t.

Pt(PPh3)4 R

R

R

Ph

R

Ph3P

10 min

Ph

Ph3P

1, 60%

O R1

14 mol% Ni(cod)2

R1

benzene 15–20oC, 48 h

R1

Noyori (1972)

R1

R1 O R1 = Ph, 51% R1 = n-propyl, 43%

Ph

O R4 30 mol% Ni(CO)4

R2

R5

O

1 mol% [Rh(CO)2Cl]2

2

toluene, 80oC

3

R

R

[Rh]

R2

Rh 3

R3

R6

R9 N

R2

Rh R3

Rh

R2

H

2-Py N

O

R6

O

O

O

R7 R8 Sun (2018)

R

R7

2

Ph3P

R

Rh

OC R

Cl PPh3

R = Ph, 90% R = n-propyl, 61%

R

R8

R11

O R9

R

N R10 [Ag]

13

R -CH3 [Rh] R14 Si R15

O N 2-Py H [Rh]

H R5 R6

R7

R13

7

O R7

R8

8

R Li (2014 & 2017) O R8 R7 Si

R15 R14 Zhao (2018)

[Pd]

Chatani (2019)

5

R6

O

R10

35–99% O

O

Cl Rh Ph3P R

Stang (1990)

11HO

R R5 22 examples

5

R O

R

50oC - PPh3

R

3

Wender (2006) R

R

4

O

2

R

Ph

Ph R2 = R3 = Ph R4 = Ph, 83% R4 = Et, 85%

R6

Rh(PPh3)3Cl

Ph3P

(E) Recent Developments of Ring-Opening Reactions of Cyclopropenones

Ph

Baba (1976)

benzene

O

O

DMF 50–60oC, 3.5 h

R3

O

R1

(D) [3+2] Cycloaddition of Cyclopropenones O

2 PPh3

Ph Ph

Baddley (1972)

(C) Self-Dimerization of Cyclopropenones O

Pt

O

O

R12 R8 Wu (2018)

R12B(OH)2

R7

[Pd]

[Pd] copolymerization

R8 Nozaki (2019)

R3 Trends in Chemistry

Figure 2. Cyclopropenones and Their C
C Bond-Cleavage Reactions Promoted by Transition Metals (TMs). (A) Illustration of the origin of the special stability of cyclopropenones. (B) Selected stoichiometric insertion of metals into cyclopropenones. (C) The first catalytic cycloaddition reaction of cyclopropenones. (D) Summary of representative [3+2] cycloaddition of cyclopropenones catalyzed by TMs. (E) Summary of recent examples of the ring-opening reactions of cyclopropenones. Note: The dates in figure represent the years of publication and are not references.

as either a four-carbon or a three-carbon synthon depending on whether decarbonylation is involved (Figure 3A). Benzocyclobutenediones were first reported by Kemmitt and coworkers to undergo stoichiometric C
C bond cleavage by Pt(PPh3)4 to yield the unsymmetrical insertion product 4 (Figure 3B) [26]. Liebeskind and coworkers showed that cobalt and Wilkinson’s catalysts are also capable of breaking the C
C bond of benzocyclobutenediones, but giving the symmetrical insertion product 5 or 6 after an extended reaction time [27,28]. Similarly, Wilkinson’s catalyst can undergo oxidative addition to cyclobutenones and benzocyclobutenones with good efficiency. When benzocyclobutenones were employed, 8 was found to be the thermodynamically favored product (Figure 3C) [29]. By contrast, when cyclobutenones reacted with (h5-C9H7)Co(PPh3)2, h4-vinylketene complexes were formed as mixtures of E/Z isomers (Figure 3C) [30].

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(A)Four-membered Ring Ketones as three- or four-Carbon Synthons [Mn] R1 ‘3-carbon synthons’

1

R

[Mn+II]

R2

R3

R2

CO

[Mn] ‘4-carbon synthons’

O

(D) C

O

R1

C Bond Cleavage of Benzocyclobutenones at Room Temperature

[Mn+II] R2

R3

2 1

O

H

N

Rh

R3

N

8

benzene

B Rh

r.t., 2 h

P(t-Bu)2 n

(B) Stoichiometric Insertion of Transition Metals into Cyclobutenediones O O

Pt Ph3P

4 70%

benzene, r.t. PPh3 Kemmitt (1973) Co(PPh3)3Cl PhCl, 110oC Liebeskind (1980)

t-Bu O Pd

Co Cl O 5 90%

1

O

Co R1 O C toluene 3 R2 100oC to reflux R

PPh3

6 O 93%

5 examples

Liebeskind (1990)

PhCl, 60–90 oC 5–18 h Liebeskind (1990)

99%

(E) Catalytic C–C Bond Cleavage of Cyclobutenediones R1O

O

O

R

O

O

O

PPh3 Rh

5 h 7/8 = 1/2 5 d 7/8 = 1/30

O

1 2

PPh3 R3 4 examples

R2

THF, 160oC 20 h Mitsudo (2000)

O

O 5 examples 46–75%

O

(F) Catalytic C–C Bond Cleavage of Cyclobutenones: Synthesis of Phenols R5 2

PPh3 Rh Cl

1

O

OH

R6

R8 or

O

Cl

R3

4

R4

PPh3

7

or

R1O

5 mol% Ru3(CO)12 15 mol% PEt3, 3 atm CO

Rh Cl

PPh3

Liebeskind (1990)

3 2

O

4

PHPh3

71–92% Rh(PPh3)3Cl PhCl, reflux

t-Bu

C C N Pd O

r.t., 7 h Murakami (2017)

PPh3 PPh3

Me Me

N

R2

17–81% O

O

R1

Rh(PPh3)3Cl

R3

R2

Me Me

benzene

Rh Cl

(C) Stoichiometric Insertion of Transition Metals into Cyclobutenones Co(PPh3)2 R

C N

Me Me t-Bu 2

O

N

53% (93% NMR yield)

5h 110oC PPh3

B

Nozaki, Murakami (2013)

Rh(PPh3)3Cl O PhCl, 10 min Rh O 110oC Ph3P PPh3 Cl Liebeskind (1985) 85%

O

N

O

O

Pt(PPh3)4

t-Bu t-Bu P O N B Rh N P t-Bu t-Bu

P(t-Bu)2 H

R7

R5

cat. [Rh] or [Ni]

OH R6 R5

OH R7

R5

R8

or

Liebeskind (1991) Kondo (2007)

R3

7

R R3 R4 R4 13 examples 43–76%

R6

R3 5 examples 40–65%

8 reflux

(G) Catalytic C–C Bond Cleavage of Cyclobutenones: 3 or 4-Carbon Synthons

(H)Catalytic C–C Bond Cleavage of Cyclobutenones: with Cyclopropanes or Cyclobutanes R10

O

R11 H

5 mol% Rh(PPh3)3Cl or 5 mol% [Rh(CO)2Cl]2

H n

13 R12 R

o

toluene, 60–120 C

R10

R9

O n

R11

Liebeskind (1993)

R13 R12

n = 1 or 2 7 examples 30–90%

R9 4 examples 67–84%

5 mol% [Rh(CO)2Cl]2 R9 Ar atmosphere toluene, 110oC -CO

R9

Mitsudo (2004)

O 5 mol% [Rh(CO)2Cl]2 30 atm CO toluene, 110oC Harrity (2015)

O R9 R9 4 examples 78–94%

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Figure 3. C
C Bond Cleavage Reactions of Cyclobutenediones and Cyclobutenones. (A) Four-membered ring ketones can serve as three- or four-carbon synthons. (B) Stoichiometric insertion of transition metals (TMs) into cyclobutenediones. (C) Early studies on stoichiometric insertion of TMs into cyclobutenones. (D) Room temperature insertion of TMs into benzocyclobutenones. (E) TMcatalyzed C
C bond cleavage of cyclobutenediones. (F) Catalytic C
C bond cleavage of cyclobutenones followed by insertion of olefins or alkynes. (G) Cyclobutenones as three- or four-carbon synthons in catalytic C
C bond cleavage reactions. (H) Ring expansion of cyclopropyl- or cyclobutylsubstituted cyclobutenones through catalytic C
C bond cleavage. Note: The dates in figure represent the years of publication and are not references.

With the development of new ligands, the high reaction temperature is no longer necessary for C
C bond cleavage of benzocyclobutenones. In 2013, Nozaki, Murakami, and coworkers observed cleavage of the C1
C8 bond in benzocyclobutenones at room temperature with a rhodium(I) complex coordinating to a PBP pincer ligand (Figure 3D) [31]. Later, in 2017, Murakami reported the selective C1
C2 bond cleavage of benzocyclobutenones using a palladium(0)-isocyanide complex at room temperature (Figure 3D) [32]. Due to the labile vicinal dicarbonyl moiety, the catalytic C
C bond activations of cyclobutenediones often involve decarbonylation; thus, they typically serve as three-carbon synthons. Mitsudo and coworkers disclosed a ruthenium-catalyzed decarbonylative C
C bond activation of

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cyclobutenediones followed by coupling with alkenes (Figure 3E) [33]. Similar reactions could also occur intramolecularly [34]. By contrast, (benzo)cyclobutenones, with increased stability, can be used as either three- or four-carbon synthons in catalytic transformations. Liebeskind and Huffman reported the first nickel-catalyzed coupling between cyclobutenones and alkynes via C
C bond cleavage for the synthesis of multisubstituted phenols (Figure 3F) [35]. Similar reactivity using alkynes or olefins as coupling partners was discovered by Kondo in 2007 using a rhodium catalyst [36]. In 2015, Harrity investigated the regioselectivity in the nickel-catalyzed system and extended the insertion partner to alkynylboronates [37]. Meanwhile, Mitsudo and coworkers reported the direct and decarbonylative coupling between cyclobutenones and norbornene controlled by a CO atmosphere (Figure 3G) [38]. In addition to cycloaddition reactions, Liebeskind and Huffman reported a rhodium-catalyzed ring expansion of cyclopropyl- or cyclobutyl-substituted cyclobutenones, which provides a unique approach to access medium-size rings (Figure 3H) [39]. Benzocyclobutenones are readily prepared from benzyne [2+2] cycloaddition and other methods [40]; systematic studies have been performed to investigate their catalytic transformations via C
C bond activation. A series of intramolecular carboacylation of benzocyclobutenones with unsaturated coupling partners have been developed. The general mechanistic pathway starts with oxidative addition of TMs into the benzocyclobutenone C
C bond, followed by intramolecular migratory insertion of coupling partners and reductive elimination. The so-called ‘cut-and-sew’ strategy allows convenient access to diverse complex molecular scaffolds that could be of biological interest [41]. In 2012, the Dong group reported the rhodium-catalyzed intramolecular carboacylation of olefins through C
C bond activation of benzocyclobutenones [42], and excellent enantioselectivity was obtained using DTBM-segphos as the ligand [43,44]. Liu, Dong and coworkers later found through density functional theory (DFT) calculation that the C
C bond cleavage first occurs at the C1
C8 position, and then the CO extrusion and reinsertion occurs to afford the formal C1
C2 cleavage intermediate [45]. In addition, decarbonylative couplings between benzocyclobutenones and olefins afforded unusual spirocycles [46]. The reaction path features a CO extrusion after migratory insertion of the olefin followed by b-hydrogen elimination. Both direct insertion products and decarbonylative insertion products were obtained when alkynes were used as coupling partners [47]. Polarized 2p units, such as C=O and C=N bonds, are also viable coupling partners and cationic rhodium(I) complexes are privileged catalysts (Figure 4A) [48,49]. In addition, ring expansion reactions to lessstrained five-membered rings from benzocyclobuteneones and cyclobutenones have also been developed through catalytic C
C activation [50]. TMs other than rhodium have also been explored as catalysts. The same team disclosed that Co2(CO)8/P(3,5-C6H3(CF3)2)3 can successfully catalyze the cut-and-sew reaction between benzocyclobutenones and alkynes (Figure 4B) [51]. Coupling partners other than unsaturated bonds can also react with benzocyclobutenones efficiently. Murakami and coworkers developed the insertion of silacyclobutanes into benzocyclobutenones catalyzed by a palladium(0)-isocyanide complex (Figure 4C) [32,52]. Recently, Krische and coworkers disclosed a Ru-catalyzed C1
C8 bond cleavage of benzocyclobutenones followed by insertion of diones (generated by dehydrogenation of diols) (Figure 4D) [53]. Excellent enantioselectivity was observed in this transformation when (R)-segphos was used [54]. Catalytic C
C bond activation of benzocyclobutenones can also proceed through a b-carbon elimination pathway. Martin and coworkers reported that nickel(0) can catalyze the intermolecular insertion of dienes or diphenylacetylene into various benzocyclobutenones after selective cleavage of the C1
C2 bond (Figure 4E) [55]. The proposed mechanism started with a Ni(0)-mediated oxidative cyclization of benzocyclobutenones and 1,3-dienes, followed by b-carbon elimination and reductive elimination. This approach provides a unique strategy to access eight-membered rings.

Cyclobutanones Compared with cyclobutenones, saturated cyclobutanones possess less ring strain. Nevertheless, significant effort has been made to develop C
C activation of cyclobutanones given its potential in forging complex ring systems and quaternary carbon centers.

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(A) Cut-and-Sew Reactions of Benzocyclobutenones Catalyzed by Rhodium Complexes O

R5

n

R5 R1

OH

Dong (2014)

Dong (2014)

n

X

R4

R1

5 mol% [Rh(CO)2Cl]2 10 mol% P(C6F5)3 3 THF, 130oC R

R1

8

R2

X

m

(D) Insertion of Diols into Benzocyclobutenones Catalyzed by Ruthenium

n

R

O R

R1

R17

HO

R19

7.5 mol% Co2(CO)8 36 mol% P(3,5-C6H3(CF3)2)3

(E) Ni-Catalyzed C

14 examples 37–74% 81– 95% ee

O R3 R2

Dong (2018)

R7

OH R9

20 examples 48–96%

19 examples 53–95% >20:1 dr

R

4

R

Martin (2015)

O

R7

1

tolune, 25 C 0.5–16 h

R5

O Ni R1

R

7 2R

R

R5 R6

o

R

R3

13 examples 81–98%

R O 2

-[Ni]

R4

Et

Me Me

R4

10 mol% Ni(cod)2 20 mol% P(4-CF3C6H4)3

6

[Ni]

R11 or

R8

1,4-dioxane, 110oC, 15 h

R19 R17 OH

C Bond Cleavage via -Carbon Elimination Pathway

O

O

O OH R18

2 mol% Ru3(CO)12 6 mol% dppp R16 m-xylene 150oC

O

R1

20 mol% pyridine N-oxide 10

R9 R

R18

OMe

O

O

HO

R16

(B) Cut-and-Sew Reactions of Benzocyclobutenones Catalyzed by Cobalt

8

O

7

N

Dong (2016)

R11

R13 O 10 examples 66–94%

Krische (2017 & 2018)

N

6 mol% (R)-xyl-binap 1,4-dioxane, 110oC R6 O

R12

Murakami (2017 & 2018)

R2 18 examples 56–90%

10 mol% Rh(cod)2BF4 6 mol% (R)-xyl-sdp

THF, 150 C OH Dong, Xu (2018) O

O R13 R Si R15

2 1

R12

R7

o

via

14

R1

Dong (2014)

MeO

5 mol% [Rh(cod)(MeCN)2]BF4 6 mol% dppf

23 examples 60–90%

n

O

O R6 O

X

m

2 1

R6

O

R5

R15 R14 Si

2 mol% CpPd( -allyl) Me Me 8 mol% t-Bu CN toluene, 100oC

n

12 examples 23–83%

R4

5 mol% [Rh(cod)Cl]2 12 mol% dppb or (R)-DTBM-segphos THF or 1,4-dioxane R1 O 130–133 oC 14 examples 35–94% Dong (2012 & 2018) 92–99% ee n

(C) Cut-and-Sew Reactions of Benzocyclobutenones Catalyzed by Palladium

O

7.5 mol% [Rh(cod)Cl]2 18 mol% DTBM-segphos xylene, reflux R1

5 mol% [Rh(cod)Cl]2 12 mol% dppp 1,4-dioxane, 130oC

R2 14 examples 23–93% X

R5

R4 Ni

4

Ni R7

R1 R2

O

R7

R1 R

2

O

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Figure 4. Catalytic C
C Bond Activation of Benzocyclobutenones. (A) Summary of ‘cut-and-sew’ reactions of benzocyclobutenones catalyzed by rhodium. (B) Cut-and-sew reactions of benzocyclobutenones catalyzed by cobalt. (C) The s-bond metathesis reaction between benzocyclobutenones and silacyclobutanes catalyzed by palladium. (D) Insertion of diols into benzocyclobutenones catalyzed by ruthenium. (E) Catalytic C
C bond activation of benzocyclobutenones via the b-carbon elimination pathway. Note: The dates in figure represent the years of publication and are not references.

Murakami, Ito, and coworkers reported the first decarbonylation of cyclobutanones on refluxing substrate 9 with stoichiometric Wilkinson’s catalyst. The generation of stable trans-Rh(PPh3)2(CO)Cl was crucial for the high efficiency (Figure 5A) [56,57]. In 2013, Murakami and coworkers disclosed that an electron-rich rhodium(I) PBP complex underwent oxidative addition into cyclobutanone 10 and afforded the decarbonylation product 11 at room temperature (Figure 5B) [31]. The catalytic C
C bond activation of cyclobutanones can also proceed through either an oxidative addition or b-carbon elimination pathway. Concurrent with their discovery of stoichiometric decarbonylation, Amii, Murakami, and Ito disclosed a rhodium-catalyzed ring-opening hydrogenolysis of cyclobutanones [56]. Shortly afterwards, the same group reported the rhodium-catalyzed decarbonylation of cyclobutanones to generate two types of products through ligand control (Figure 5C) [57]. Similar to benzocyclobutenones, cut-and-sew reactions of cyclobutanones can proceed smoothly to generate various bridged or fused ring systems. For example, Murakami and coworkers disclosed the racemic cut-and-sew reactions between cyclobutanones and olefins to generate [3.2.1] bridged rings (Figure 5D) [58]. In 2014, Cramer and coworkers further developed the highly enantioselective version of this reaction with a significantly extended substrate scope (Figure 5D) [59,60]. Due to the competing decarbonylation reactions (Figure 5C), to apply the discovered reactivity to substrates beyond the styrene-tethered cyclobutanones (Figure 5D) (e.g. longer linkers, aliphatic

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(A) Stoichiometric Decarbonylation of Cyclobutanones using Wilkinson's Catalyst H

O

1

Rh(PPh3)3Cl

8

+

toluene, reflux, 41 h

H Ph 9

(C) Catalytic C

(B) Stoichiometric Decarbonylation of Cyclobutanones at Room Temperature

H Rh

Cl H

PPh3

OC

H Ph 99%

Murakami, Ito (1994)

Ph3P

N

Rh

N

benzene

B Rh

r.t., 72 h

P(t-Bu)2 n

N

B

N Ph

R1

50 atm H2 2.5–5 mol% [Rh(cod)Cl]2

OH

R1

6–12 mol% dppe THF or toluene, 140oC then NaBH4

Murakami (2013)

(F) Catalytic Cut-and-Sew of Cyclobutanones to Forge Fused-Ring Systems

Me 9 examples 71–87%

R12

1,4-dioxane, 125oC

X

O

2.5 mol% [Rh(cod)Cl]2 2.5 mol% [Rh(cod)Cl]2 5 mol% dppp 10 mol% AsPh3 xylene, reflux xylene, reflux R R2 reductive elimination -H elimination R2 R2 = n-C16H33, 99% R2 = n-C16H33, 68% Murakami, Ito (1996) -(CH2)4CO2Ph, 70% -(CH ) CO Ph, 86%

O

5 mol% [Rh(CO)2Cl]2 16 mol% PMe2Ph

O

Murakami, Ito (1994) Me

Ph 10

C Bond Activation of Cyclobutanones via Hydrogenolysis or Decarbonylation O

t-Bu t-Bu P N B Rh CO N Ph Ph P 11 t-Bu t-Bu 79% 81%

O

P(t-Bu)2 H

R10

22 examples 33–89%

X

Dong (2018)

R11

R10

R12

R11

2

2 4

(G) Intramolecular Coupling of Cyclobutanones via

2

O

5 mol% [Rh(nbd)dppp]PF6 10 mol% BHT

3 examples 72– 89%

o

m-xylene, 135 C, 1.5-3 h racemic Murakami (2002) R

O

3

2.5 mol% [Rh(cod)Cl]2 R4 6 mol% (R)-DTBM-segphos O

5

R

1,4-dioxane, 130oC enantioselective

R7

R6

Cramer (2014)

R

R2

R3

R4 R5 R6 R7

O R1

X 15 examples 39–87%

O

R

R1

R6

R6 5 mol% [Rh(C2H4)2Cl]2 24 mol% L1 1,4-dioxane, 130oC

N R7

O

R1

X

n

Me Me

Me P N Me O

Ph Ph

R1

O H

Si R9 12 8 examples 72–87%

Ko, Dong (2016)

Ph Ph O O O

1,4-dioxane, 170oC - CO

L1

5 mol% Pd(allyl)Cp 20 mol% PMe3 p-xylene, 130oC Murakami (2014)

O

R5

R3 12 examples 64–89% 94.4–99.6% ee

R8 9

R

n

17 examples 48–86%

R7

R1 Si R9

1-Np O P N O 1-Np

13 8 examples 76–87%

O

t-Bu L2

O

R8 R9

R10

X

10 mol% Ni(cod)2 12 mol% L1 mesitylene, r.t.

X

Dong (2016)

X = NTs Dong (2016)

(H) Intermolecular Coupling of Cyclobutanones via

X

Murakami (2014)

O

10 examples 77–97% 80–92% ee

10 mol% Ni(cod)2 R7 12 mol% PPh3 toluene, 100oC

ORh

10 examples 68–92% 77–99% ee

O

R10 X 22 examples 36–92%

R8

R1

Si

10 mol% Pd(allyl)Cp 20 mol% P(Ad)2(n-Bu) p-xylene, 150oC

O

O

R6

O Ni

via

R13 O R9

via

R4

t-Bu

Murakami (2012)

R6

R5

X

R3

R3

hexane, r.t. to 50oC

8

Dong (2015)

9 examples 43–72% 90–99% ee

O

R 5 mol% [Rh(coe)2Cl]2 10 mol% XPhos

Me

O

R5

10 mol% Ni(cod)2 12 mol% L2

R

R6 6

toluene, r.t.

5

Cramer (2014)

Dong (2012)

13 examples 27–76%

3.5 mol% [Rh(cod)(OH)]2 8 mol% (R)-tol-binap

O

R5 2.5 mol% [Rh(cod)Cl]2 R1 6 mol% (R)-DTBM-segphos o 1,4-dioxane, 110 C

n

Rh O

via

R2

Murakami (2007)

O

N NH2 R4 5 mol% [Rh(C2H4)2Cl]2 R3 2 24 mol% P(3,5-C H (CF ) ) R 6 3 3 2 3 1,4-dioxane, 150oC

O OH

R3

R4 1 equiv.

Murakami (2005)

R1

Ar

1,4-dioxane, 100 oC

R4

15 examples 73–96% 96.6–99.6% ee

Bridged-Ring Systems

Me

R1

3

(E) Summary of Catalytic Cut-and-Sew Reactions of Cyclobutanones to Forge R2

(ArBO)3 Ar 3 equiv. H2O 5 mol% [Rh(cod)(OH)]2 O 20 mol% P(t-Bu)3

R1

(D) Catalytic Cut-and-Sew Reactions of Cyclobutanones

-Carbon Elimination

R

R7

R10 NTs 10 examples 55–80% 90–92% ee

-Carbon Elimination

R13

R13 10 mol% Ni(cod)2

O

R8 9

R14 R15 10 mol% Ni(cod)2 20 mol% PCy3

O

O R14

11 R12 20 mol% P(n-Bu)3, 100oC toluene, 90 to 110oC R 12 R15 R11 R R11 R12 Murakami (2005) 13 or 10 mol% IPr, r.t. R 15 examples toluene [Ni] 37–97% 13 examples O R15 Murakami (2006) 32 – 92%

via R11 R12

R14

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Figure 5. C
C Bond Activation of Cyclobutanones. (A) Stoichiometric decarbonylation of cyclobutanones using Wilkinson’s catalyst. (B) Stoichiometric decarbonylation of cyclobutanones at room temperature using a Rh-PBP complex. (C) Catalytic C‒C bond cleavage of cyclobutanones through hydrogenolysis or decarbonylation. (D) Catalytic (enantioselective) ‘cut-and-sew’ reactions of cylcobutanones tethered with olefins. (E) Cut-and-sew reactions of cyclobutanones with different coupling partners to generate bridged-ring systems. (F) Cut-and-sew reactions of cyclobutanones to forge fused-ring systems. (G) Intramolecular coupling of cyclobutanones with different partners through b-carbon elimination. (H) Intermolecular coupling of cyclobutanones with alkynes through b-carbon elimination. Note: The dates in figure represent the years of publication and are not references.

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olefins) was difficult. In 2014, Ko and Dong utilized the aminopyridine cofactor to suppress the decarbonylation side reaction, which enabled the nitrogen-tethered and malonate-tethered cyclobutanones with a broader olefin scope in this reaction [61]. In addition to olefins, Souillart and Cramer disclosed that polar C=O bonds can couple with cyclobutanones to generate the lactone-containing [3.2.1] bridged rings with excellent enantioselectivity [62]. Zhou and Dong later reported that allene can serve as a vinyl carbenoid equivalent to insert into cyclobutanones and generate [4.2.1] bridged rings with high enantioselectivity [63]. Decarbonylative insertion of olefins into cyclobutanones was also achieved when using a bulky XPhos ligand, which provided five-membered bridged bicycles [64]. In 2014, Murakami and coworkers reported palladium-catalyzed intramolecular bond-exchange reactions between C
C and C
Si bonds to generate bicycle 12 or aldehyde 13 (Figure 5E) [65]. The selectivity was determined by the choice of ligands and reaction temperatures. Similar reactivity was observed between cyclobutanones and Si
Si bonds [66]. In addition to forming bridged rings, Dong and coworkers reported that fused rings could also be constructed via the cut-and-sew reaction between a-tethered cyclobutanones and alkynes (Figure 5F) [67]. Besides the oxidative addition pathway, 1,2-addition of a nucleophile to the C=O bond followed by b-carbon elimination represents another common pathway for C
C bond activation of cyclobutanones. In 2005, Murakami and coworkers reported a rhodium-catalyzed ring expansion of cyclobutanones, which involves transmetalation of triarylboroxins followed by migratory insertion into alkynes and then addition to cyclobutanones (Figure 5G) [68]. In addition to triarylboroxins, phenols have been employed as nucleophiles to promote the C
C bond cleavage of cyclobutanones to construct ester linkages intermolecularly [69] or intramolecularly [70,71] (Figure 5G). In addition, nickel(0) catalysts have been found to be privileged in promoting the ring-opening of cyclobutanones through the oxidative cyclization/b-carbon elimination pathway. Ashida and Murakami reported an intramolecular insertion of olefins into cyclobutanones catalyzed by nickel(0) to generate [2.2.2] bridged rings [60], and the enantioselective version of this reaction was achieved later using L2 (Figure 5G) [72,73]. Besides olefins, Zhou and Dong discovered that allenes can also react with cyclobutanones intramolecularly as a two-carbon unit to generate [3.2.2] bicycles with excellent enantioselectivity (Figure 5G) [74]. Moreover, similar reactions can occur intermolecularly. The Murakami group reported the first intermolecular alkyne insertion into cyclobutanones using the Ni(cod)2/PCy3 catalytic system with moderate regioselectivity (Figure 5H) [75]. The same group later disclosed a similar transformation between cyclobutanones and diynes, which afforded the bicyclic eight-membered ketones [76]. Similar to cyclobutanones, azetidin-3-ones [77–82] and oxetan-3-ones [83] have been reported by Louie, Murakami, and Aı¨ssa, independently, to be viable substrates to couple with various alkynes or dienes through nickel catalysis.

C
C Bond Activation of Unstrained Ketones Without the benefit of strain-energy release, C‒C bond activation of unstrained ketones is more challenging, consequently requiring appropriate strategies to provide driving forces. Given the recent review on the activation of unstrained C‒C bonds [84], this section focuses on using ketone substrates with updates. According to the different strategies employed, reactions in this section are organized into three categories: direct C‒C bond cleavage, use of permanent DGs, and use of temporary DGs. Note that miscellaneous transformations beyond these three categories are not discussed here due to space constraints.

Direct Decarbonylations Extrusion of carbon monoxide (CO) from ketones can significantly enhance the reaction entropy, and the formation of strong M
CO bonds could in principle provide some enthalpy benefits, thereby realizing a thermodynamically favorable process. However, direct decarbonylation of unstrained ketones is considerably challenging and typically requires somewhat activated substrates and/or stoichiometric metals.

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(A) Stoichiometric Decarbonylation of Diynones

(B) Stoichiometric Decarbonylation of Cyclic Ketones RhCl(CO)(PPh3)2

O + Rh(PPh3)3Cl 1

2

R

R

via

R

1

Muller (1969)

2

R

Ph

R

1

R

R

Ph 57%

O

R2 2

+ RhCl(CO)(PPh3)2

Murakami, Ito (1994)

Rh

1

toluene, reflux

+ Rh(PPh3)3Cl

8 examples 8–93%

O

Rh

O

+

heat

PhCN, 150oC

+ Rh(PPh3)3Cl

O

+ RhCl(CO)(PPh3)2

Murakami, Ito (1994) ~20%

(C) Stoichiometric Decarbonylation of Aromatic Ketones using Rh

(E) Catalytic Decarbonylation of 1,2- and 1,3-Diketones

R3 R4

O

O R

t

+ t t

o

C6D12, 120 C

Bu t

Rh

t

Bu

Brookhart (2004)

Bu

Me

+

R3

4

t

Bu

Bu O tBu C Rh Rh C O

t t

t t

5

R

R

toluene 160oC, 18 h

R2

Bu

17 examples 20–91%

CO

Chatani, Tobisu (2017)

5 mol% [Rh(cod)Cl]2 12 mol% Xantphos

O

PhCl, reflux =

PhEt, 150oC

R2

R3

= aryl

Dong (2013)

Ar

R2

36 examples 12–96%

Dong (2015)

(G) Catalytic Decarbonylation of 1,2-Diketones 5 mol% [Rh(cod)Cl]2 10 mol% dppe

O R R5

R1

6 examples 3–36%

Teranishi (1974)

2.5 mol% [Rh(cod)Cl]2 6 mol% dppf

Bu

1 equiv. Ni(cod)2 1 equiv. IMesMe.HCl 1 equiv. NaOtBu 6

n

(F) Catalytic Decarbonylation of Diynones and Ynones

(D) Stoichiometric Decarbonylation of Aromatic Ketones using Ni O

toluene, reflux

Bu R3

t

R

n

Me

Bu

Bu

Rh

O

2.5 mol% Rh(PPh3)3Cl 1

n = 0, 1

+

Bu

O

R6

4 5

R 16 examples 17–92%

toluene, 110oC Dong (2015)

5 mol% [Rh(cod)Cl]2 10 mol% Xantphos

O R4 O

5

R

PhEt, 136oC Dong (2015)

R4

R5

13 examples 32–94%

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Figure 6. Direct Decarbonylation of Less Strained Ketones. (A) Stoichiometric decarbonylation of diynones. (B) Stoichiometric decarbonylation of less strained cyclic ketones. (C) Stoichiometric rhodium complexmediated decarbonylation of aryl ketones. (D) Stoichiometric nickel complex-mediated decarbonylation of diaryl ketones. (E) Decarbonylation of 1,2and 1,3-diketones catalyzed by Wilkinson’s catalyst. (F) Rhodium-catalyzed decarbonylation of diynones and monoynones. (G) Rhodium-catalyzed monoor double decarbonylation of yn-diones controlled by the reaction conditions. Note: The dates in figure represent the years of publication and are not references.

For reactions involving stoichiometric metals, in 1965 Rusina and Vlcek discovered that refluxing RhCl3 and PPh3 in solvent amounts of cyclohexanone and acetophenone generated Rh(PPh3)2(CO) Cl, although the fate of the ketones was unknown [85]. A clear example of direct decarbonylation of diynones was reported by Mu¨ller and coworkers in 1969 with stoichiometric Wilkinson’s catalyst (Figure 6A) [86,87]. In 1994, Amii, Murakami, and Ito reported two examples of decarbonylation of a 6,5-fused and a 12-membered cyclic ketone also with stoichiometric Wilkinson’s catalyst (Figure 6B) [56]. In 2004, Daugulis and Brookhart employed a bulky CpRh complex to achieve decarbonylation of diaryl ketones and an aryl enone (Figure 6C) [88]. In 2017, Chatani, Tobisu, and coworkers found that the same transformation could be realized with a stoichiometric Ni(0)-NHC complex (Figure 6D) [89]. In the above cases, free CO was not generated, thus forming the strong M–CO bond provided the driving force for the C‒C bond cleavage. For catalytic reactions, in 1974 Teranishi and coworkers reported the first catalytic direct decarbonylation of unstrained 1,2- or 1,3-diketones using Wilkinson’s catalyst (Figure 6E) [90]. In 2013, Dong and coworkers developed the catalytic decarbonylation of diynones and monoynones using rhodium

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(A) Stoichiometric C–C Bond Cleavage with Quinoline Directing Group L N Cl Rh R1

Rh(PPh3)3Cl

[Rh(C2H4)2Cl]2

o

O

L

CH2Cl2, 40 C

then pyridine

N

Suggs (1981)

R1

O

N

N Rh

Cl

Suggs (1984)

L

L = pyridine

R1 = alkynyl L = PPh3

2 examples

(B) Catalytic C–C Bond Cleavage with Quinoline Directing Group

Et

R O 1

N R

2

R3

5 mol% Rh(CO)2(acac) PhCl, 140oC Shi (2012)

R2

R3

R7

R3

PhCl, 140oC

R5

N Me

O

DG

N R

4

[Rh(cod)Cl]2 R O Wang, Liu (2018) dppp, Et3N xylene, 160oC

PhCl, 160oC Dong (2015)

21 examples 50–98%

O R5

N Me

R8 N O 5 mol% [Rh(cod)Cl]2 20 mol% AsPh3 1,4-dioxane, 160oC Dong (2016)

Ar

X Rh(cod)2OTf THF, 100oC

DG

R2 R8 N

R

N N

O N

N

O R5

N Me

N

Xu, Wei (2018)

32 examples 47–98%

O

N O R6 X Douglas (2009)

(C) Ru-Catalyzed Directed Deacylation O N

O

Me Me

O N

N

toluene 160oC, 20 h

Me Me

Ru O

O

5 mol% Ru3(CO)12 5 atm CO

R1

O

Me Me R1

N Ru H

Me Me

9 examples 34–96%

Murai (1999)

via

N

1,4-dioxane 150oC, 24 h

R6

X = O, NMe, CH2

R1 Ar

R5

Johnson (2016)

[Rh(C2H4)2Cl]2 toluene, 130oC

Douglas (2009)

23 examples 41–99%

R5

O

N

(F) Ni-Catalyzed Directed Decarbonylation 5

R2

R2 =

O

DG = 3-methyl-2-pyridinyl

10 mol% Ni(cod)2 20 mol% IMes.HCl 50 mol% Cs2CO3

O

N

Rh(PPh3)3Cl CuI, K2CO3 Xylene, 130oC

R3

Shi (2015)

O

R5 B(OH)2 N

3

47 examples 25–90%

R6 R7 5 mol% [Rh(cod)Cl]2

R4

R2 = Et

(E) Rh-Catalyzed Directed Decarbonylative Cyclization with Isatins DG R

N

Wang (2012)

N

40 examples 44–98%

6

[Rh(C2H4)2Cl]2 toluene, 140oC

5 examples

R4 COOH 10 mol% Rh(CO)2(acac)

O

R4 B(OH)2

[Rh(C2H4)2Cl]2 benzene, 100oC

Suggs (1985)

(D) Rh-Catalyzed Directed Decarbonylative Functionalization N

O

6 atm CH2=CH2

O

O or

N

Me Me

Ru R' H + CO

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Figure 7. C
C Bond Activation Using Permanent Directing Groups (DGs). (A) Stoichiometric C
C bond cleavage using quinoline DGs. (B) Catalytic C
C bond cleavage using quinoline DGs. (C) Ru-catalyzed directed deacylative reactions. (D) Rh-catalyzed pyridine-directed C
C bond activation of linear ketones. (E) Rh-catalyzed directed decarbonylative cyclization with isatins. (F) Nicatalyzed directed decarbonylation. Note: The dates in figure represent the years of publication and are not references.

catalysts and bidentate phosphine ligands with a large bite angle, which could be useful for preparing unsymmetrical diynes and internal alkynes (Figure 6F) [91,92]. Later, Whittaker and Dong reported that, through modifying ligands and other reaction parameters, selective mono or double decarbonylation of yn-diones could be achieved (Figure 6G) [93].

Permanent DGs The use of DGs can make a previously intermolecular reaction occur intramolecularly through the proximity effect, therefore significantly reducing the activation barrier for C
C bond cleavage. Permanent DG strategies have been widely applied to pursue this goal. Pioneer work by Cox and Suggs in 1981 employed 8-acylquinoline as the substrates and oxidative addition of Rh to the ketone C
C bonds occurred at low reaction temperatures (Figure 7A) [94,95]. Later, Jun and Suggs successfully developed the catalytic C
C bond activation of the same types of substrates and an alkyl exchange reaction with ethylene was realized (Figure 7B) [96]. Since then, various other transformations with 8-acylquinoline substrates have been achieved involving the C
C bond activation processes (Figure 7B), which include intermolecular and intramolecular carboacylation of olefins by Douglas [97,98], insertion of substituted olefins by Wang and Liu [99], and cross-coupling reactions with organoboronic acids by Wang [85] and Johnson [100,101].

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In addition to quinoline-derived substrates, other DGs have also been used for cleaving C
C bonds. In 1999, Murai and coworkers reported a ruthenium-catalyzed deacylation reaction using oxazoline and pyridine as DGs, which involved oxidative addition to the aryl-carbonyl bond of the substrates (Figure 7C) [102]. Later, Shi and coworkers disclosed an efficient rhodium-catalyzed decarbonylation of aryl ketones with pyridine DGs, in which aryl, alkenyl, and alkyl groups could all be coupled (Figure 7D) [103]. Later, they found that, with a bulkier acyl substituent and additional carboxylic acids as the coupling partner, cross-coupling reactions were realized through a directed C
C bond cleavage and decarboxylation process [104]. In 2015, Zeng and Dong developed a directed rhodium-catalyzed decarbonylative addition of isatins to alkynes as a [5
1+2] transformation (Figure 7E) [105]. When isocyanates were used as the coupling partner, a double-decarbonylation pathway was found to be involved, which gave a [5
2+2] transformation [106]. Recently, the decarbonylation of diaryl ketones was achieved by Xu, Wei, and coworkers using a nickel catalyst and a heterocycle DG (Figure 7F) [107]. In addition, phosphine-based DGs have been reported by Ruhland and coworkers to facilitate stoichiometric insertion of rhodium or nickel into the ketone a-C
C bonds [108,109].

Temporary DGs The chelation-assisted strategy enabled by the use of permanent DGs permits facile C
C bond cleavage of unstrained ketones; however, DG installation and removal are nontrivial for these substrates. It would be more attractive if temporary and catalytic DGs could be employed, which could allow more common ketones to be used as substrates. In 1999, seminal work by Lee and Jun took advantage of reversible imine formation and realized the use of 2-amino-3-picoline as a temporary DG via in situ installation and removal (Figure 8A) [110]. The reaction involved oxidative addition of Rh(I) to the C
C bond, b-hydrogen elimination, and reinsertion with another olefin to realize an alkyl-exchange transformation. Later, Jun and coworkers utilized a catalytic amount of 2-amino-3-picoline for the same transformation, promoted by microwave irradiation [111]. The same group also employed preformed ketimines to realize the same transformation and used imines derived from cyclic ketones with various ring sizes to achieve ring contractions involving consecutive b-hydrogen elimination and Rh-H reinsertion (Figure 8B) [112]. Another challenge for C
C bond activation of unstrained ketones is how to realize constructive and synthetically useful transformations. Besides b-hydrogen elimination, other elemental organometallic processes have also been coupled with the temporary DG-mediated C
C bond activation. In 2016, Dong, Liu, and coworkers reported a rhodium-catalyzed C
C bond activation of 3-arylcyclopentanones using a catalytic amount of 2-aminopyridine as the temporary DG (Figure 8C) [113]. Two regioisomers were obtained from the cleavage of the proximal or distal C
C bond, which leads to the formation of 1-tetralone or 1-indanone derivatives, respectively. A good regioselectivity towards the proximal C
C bond cleavage was obtained in most substrates. Computational studies showed that C
H activation of the arene and the later C
C bond reductive elimination are the turnover-limiting steps, while the oxidative addition into C
C bonds was reversible with a relatively low activation barrier. Later, Dong and coworkers found that the distal C
C bond cleavage could be favored by 6-methyl-2-picoline with the bulkier IPr ligand, which provided 1-indanones as the major products (Figure 8D) [114]. Using arylboronic esters as the coupling partner, Dong and coworkers were able to realize a Suzuki
Miyaura coupling of simple ketones via C
C bond activation (Figure 8E) [115]. Cyclopentanones, acetophenones, 1-indanones, and acetone were suitable substrates. To enable a more constructive two-C
C bond-forming event after cleavage of one C
C bond, in 2018 Dong and coworkers realized an intramolecular acyl transfer reaction using styrene-tethered ketones (Figure 8F) [116]. The reaction involved migratory insertion of the resulting alkyl-Rh intermediate to the olefin and then C
C reductive elimination. Compared with the earlier Jun studies (Figure 8A,B), the use of NHC ligands was found to be critical to inhibit the b-hydrogen elimination pathway. Finally, the cut-and-sew reaction between 1-indanones and ethylene was reported by Dong and coworkers as an efficient way to construct benzo-fused seven-membered rings using ethylene as a two-carbon unit (Figure 8G) [117]. The C(sp2)
C(sp2) bond of 1-indanones was

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(A) Rh-Catalyzed C–C Activation for Olefin Exchange R3 10 mol% Rh(PPh3)3Cl 100 mol% DG-NH2 150oC, 48 h

O R1

R3

Jun (1999)

10 examples 13–98% via

R2

R

R1

N Rh

H

R

R1

H

2

Rh

R1

R4 58 examples 20–75%

N

O

Rh

H

H

R

5 mol% [Rh(C2H4)2Cl]2 10 mol% IMes 20 mol% MsOH

O Me

R2

R3

Me R2

100 mol% 2-aminopyridine PhCl, 120oC

R1

(B) Rh-Catalyzed C–C Activation of Unstrained Cyclic Ketones

R1

Dong (2018)

17 examples 28–63%

via

Me N

O

(F) Rh-Catalyzed C– C Activation for Acyl Transfer

N

N

3

R

R2

R3

Me

N

3

20 mol% TsOH.H2O 25 mol% ethyl crotonate 150–200 mol% H2O MeTHF, 140oC, 48 h Dong (2018)

7 examples 64–100%

Me

N

R4

R1

DG-NH2 = 2-amino-3-picoline

N Rh

O

6 mol% [Rh(C2H4)2Cl]2 14 mol% MeIMes 45 mol% 2-amino-3-picoline

O B O

+

R2 Me

N

O

Jun (2006)

2

Me

R1

O R1

(E) Rh-Catalyzed C–C Activation Coupled with Suzuki–Miyaura Coupling

R3 5 mol% Rh(PPh3)3Cl 20 mol% DG-NH2 20 mol% CyNH2 microwave 200oC, 30 min

10 mol% [Rh(coe)2Cl]2 20 mol% PCy3

N (CH2)n

toluene, 150oC, 1 h then H+/H2O

O Me

(CH2)n

Et

N

(CH2)n

N Rh

Me

R2

4 examples 12–82%

Jun (2001)

n = 1, 2, 3

O +

1

R

(C) Rh-Catalyzed C–C Activation of Cyclopentanones proximal

5 mol% [Rh(C2H4)2Cl]2 10 mol% IMes 25 or 50 mol% 2-aminopyridine

O

10 mol% TsOH.H2O 50 mol% H2O 1,4-dioxane, 140 or 150 oC, 48 h

R1 R2

O R2

+

R2

Me R1 major

Dong, Liu (2016)

(G) Rh-Catalyzed [5+2] Cycloaddition

O

Et

29 examples 30–85% up to >10:1

R1

minor

(D) Rh-Catalyzed C–C Activation of Cyclopentanones at Distal Position O

distal

R3 H X

5 mol% [Rh(C2H4)2Cl]2 10 mol% IPr 50 mol% 2-amino-6-picoline 10 mol% TsOH.H2O 10 mol% pyridine, 10 mol% H2O 1,4-dioxane, 140oC, 48 h Dong (2017)

O

100 psi CH2=CH2 5 mol% [Rh(C2H4)2Cl]2 10 mol% IMes 100 mol% 2-amino-3-picoline

R3

20 mol% TsOH.H2O 100 mol% H2O THF, 150oC

R4

R

R

46 examples 33–90%

Dong (2019)

N 19 examples Me 6–92% up to >99:1

Rh

O 4

via

O 3

R3

Me N

R3

X

R4

Trends in Chemistry

Figure 8. Catalytic C
C Bond Activation of Less Strained Ketones Using Temporary Directing Groups (DGs). (A) Olefin exchange of simple ketones enabled by C
C bond cleavage using 2-amino-3-picoline as the temporary DG. (B) Ring contraction of cyclic ketones via catalytic C
C bond cleavage. (C) Proximal C
C bond cleavage of ring-fused cyclopentanones to synthesize 1-tetralones. (D) Distal C
C bond cleavage of 3-arylcyclopentanones to synthesize 1-indanone derivatives. (E) The Suzuki
Miyaura coupling of unactivated ketones with arylboronic esters. (F) Intramolecular acyl transfer with olefins via catalytic C
C bond cleavage. (G) [5+2] Cycloaddition of 1-indanone derivatives with ethylene. Note: The dates in figure represent the years of publication and are not references.

selectively cleaved and the resulting benzocycloheptenone products have been often used as precursors for the synthesis of bioactive compounds containing seven-membered rings.

Concluding Remarks In summary, C
C bond activation of ketones has received considerable attention in the past two decades. A number of different approaches for activation have been conceived and developed. Complex bridged, fused, and spirocyclic ring systems have been constructed through activation of strained ketones. More synthetically useful transformations with less strained ketones have also started to appear. An increasing number of C
C bond activation methods have been applied to complex-molecule synthesis, which often provide unusual strategic bond disconnections compared with conventional approaches.

12

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However, many challenges remain from the viewpoint of practicality for broad use of these C
C bond activation methods. Important questions, such as how to expand the substrate scope, how to use lower reaction temperatures, and how to reduce catalyst loading and costs, remain to be addressed (see Outstanding Questions). Solutions are likely to come from the development of more general and powerful catalyst systems (e.g., new ligands) and the discovery of new activation modes. It is anticipated that efficient, general, and milder catalytic C
C bond activation conditions for both strained and unstrained ketones could be achieved and more diverse transformations would be realized. Given the ubiquity of the ketone function group, we anticipate that C
C bond activation could ultimately be added to the chemist’s toolbox for constructing complex molecular scaffolds in the future.

Acknowledgments We acknowledge NIGMS (2R01GM109054) and the University of Chicago for support of research. We also thank Dr Ying Xia for helpful discussions.

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Outstanding Questions  How can we extend the scope of unstrained ketones that can undergo facile C–C bond activation?  How can milder reaction conditions (e.g., lower reaction temperature) be realized for activation of unstrained ketones?  How can we develop more efficient C–C bond activation methods (e.g., with reduced catalyst loading and costs)?  Can C–C bond activation methods find practical applications in the synthesis of biologically important molecules?

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