Update to 2012 Bode Research Group //ethz.ch/content/dam/ethz/special-interest/... · The reaction...

Update to 2012 Bode Research Group http://www.bode.ethz.ch/

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Topic: Catalytic C-H functionalization

1 Introduction, definitions The term “C-H functionalization” describes the transformation of a C-H bond (of whatever kind) into a C-X bond, where X is any useful functional group. This field of research has gained a lot of attention in the past years, and many different catalytic systems have been developed and studied.

Suggested Reading:

Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62 (11), 2439-2463. Crabtree, R.H. “The organometallic chemistry of the transition metals”, 5th Ed., Wiley, 2009.

Crabtree, R. H. J. Chem. Soc. Dalton Trans. 2001, (17), 2437-2450.

Definitions: - “C-H Activation” The replacement of a C-H bond by a C-M bond, where M is a transition metal. “Activation” in this sense means the replacement of a relatively unreactive C-H bond with a C-M bond, which can much more easily functionalized. A C-H activation followed by a reaction from C-M to C-X is therefore a key part of a C-H functionalization.

Shilov, A. E.; Shul'pin, G. B. Chemical Reviews 1997, 97 (8), 2879-2932.

- “C-H Functionalization” A general term describing the transformation of a C-H bond into a C-X bond. This expression is not very well defined (which leads to problems) and most general. In the following, this term is used for a C-H activation followed by a transformation to a C-X bond. In this way, a C-H functionalization has to run via an intermediate C-M bond (M = transition metal) as described for a C-H activation.

Kakiuchi, F.; Chatani, N. Advanced Synthesis & Catalysis 2003, 345 (9-10), 1077-1101.

Ritleng, V.; Sirlin, C.; Pfeffer, M. Chemical Reviews 2002, 102 (5), 1731-1769. Note: A Friedel-Crafts alkylation or acylation is therefore not a C-H activation (or C-H functionalization), as it is defined by an electrophilic aromatic substitution mechanism, even though the products obtained are similar in the sense that a C-H bond has been transformed to a C-C bond. (The terminolgy “C-H functionalization” does not specifically exclude these reactions types, which showcases the problems associated with the expression “C-H functionalization”). - “C-H Oxidation” A very general term denoting the replacement of a C-H bond by any C-X bond where X is more electronegative than H. Therefore, almost all of the C-H functionalizations discussed below are also C-H oxidations.

Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62 (11), 2439-2463. - “C-H Oxygenation, Amination, Halogenation, Borylation, etc.” The replacement of a C-H bond through C-H activation (i.e. intermediate C-M species) to a C-O, C-N, C-Hal, C-B bond. C-H oxygenation should be used instead of C-H oxidation as this definition is much more narrow

H X"C-H functionalization"

H M"C-H activation"

M = transtion metal

H M"C-H activation"

M = transtion metal

X

"C-H functionalization"


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and descriptive.

Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62 (11), 2439-2463. - “C-H Insertion” The reaction of a electron-deficient species such as a carbene or a nitrene or a corresponding (metal)-carbenoid or –nitrenoid that inserts between the C and the H atom of a C-H bond.

Doyle, M.P., Duffy, R., Ratnikov, M., Zhou, L. Chem. Rev. 2010, 110, 704-724 1.1 Bond Strengths Some selected bond strengths.

Bond Bond Strenth (in kcal/mol) Bond Bond Strenth

(in kcal/mol) CMethyl-H 105 C-C (in ethane) 90

CIsopropyl-H 99 C-O (in MeOH) 92 Ctertbutyl-H 97 C-N (in MeNH2) 85

Callyl-H 89 C-F (MeF) 115 Cphenyl-H 113 C-Cl (MeCl) 84

HCC-H (ethyne) 133 C-Br (MeBr) 72 C-I (MeI) 58

Blanksby, S.J., Ellison, G.B. Acc. Chem. Res. 2003, 36, 255-263.

1.2 Problems and Challenges associated with C-H functionalization - Reactivity: Most of the C-H bonds are stronger than the corresponding C-X bonds (see table in section 1.1), therefore a C-H functionalization is thermodynamically unfavoured. Possible solution(s): Use of transition metal catalysts to lower the activation barrier - Chemoselectivity: Once the desired C-X bond is formed, this bond itself has a lower bond strength than the C-H bond before, and over-reactions such as catalyst inhibition can occur. Secondly, the introduction of a C-X bond might change the reactivity of a whole molecule (for example by changing the electron density of an aromatic system), it is important to suppress overreaction. Possible solutions: Running the reaction to low conversion, employ excess of substrate over oxidant, carry out intra- vs intermolecular reactions, use deactivating functional groups, catalyst design. - Regioselectivity: In most molecules, more than one C-H bond of a certain type, and more than one type of C-H bond exist. Therefore, a catalyst should exert high selectivity towards one particular type of C-H bond. Possible solutions: Use weak or activated C-H bonds (allylic, benzlic), use coordinating (directing) groups, try to achieve intramolecular reactions via 5- or 6-membered transition states, catalyst design. - Stereoselectivity: The conversion of a C-H bond to a C-X bond can create a stereogenic center. In this case, the selective installation of a desired stereoisomer represents another challenge. Possible solutions: Development of chiral catalysts.

Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62 (11), 2439-2463.

1.3 Advantages of C-H functionalization reactions - The starting materials are cheap and easily accessible - Reactions are very atom economical

C HR

RR

M CR'R'

C CR

RR

R'R'

H

metal carbene

"C-H Insertion"


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- no further functional group transformations are required (compare to cross coupling reactions, where functionalities of both coupling partners have to be installed) - Reactions are cost effective 2 Historical background

2.1 Seminal work on stoichiometric C-H activation In the following are some early examples of C-M-bond forming reactions, i.e. C-H activation reactions.

The first reported C-H activation was the reaction of azobenzene with nickelocene.

Kleiman, J. P.; Dubeck, M. J. Am. Chem. Soc. 1963, 85 (10), 1544-1545.

C-H activation of naphthalene with Ru complexes.

Chatt, J.; Davidson, J. M. J. Chem. Soc. 1965, 843-855.

Intramolecular C-H activation with Pt complexes leading to cyclometallated compounds.

Cheney, A.J.; Mann, B.E.; Shaw, L.; Slade, R.M. J. Chem. Soc. Chem. Commun. 1970, 1175-1176.

Ibers, J.A.; DiCosimo, R.; Whitesides, G.M. Organometallics 1982, 13-20. Foley, R.; DiCosimo, R.; Whitesides, G.M. J. Am. Chem. Soc. 1980, 6713-6725.

Alkane dehydrogenation represents a special case of C-H activations. In this example by Crabtree, the cyclopentadienyl ligand (Cp) can be made from cyclpentane by C-H activation. It is vital to add a hydrogen scavenger (in this case dimethylbutene) for the reactions to occur. The initial step was proposed to be a oxidative addition of a C-H bond of cyclpentane.

Crabtree, R. H.; Mihelcic, J. M.; Quirk, J. M. J. Am. Chem. Soc. 1979, 101 (26), 7738-7740.

NN Ni 135 ºC N

N

Ni

25%

RuPP P

P

H

PRu

P PP

P P =Me2P

PMe2

PtP(tBu)2Cl

(tBu)2P Cl

Me

Me

LiBr

heat

PtP(tBu)2Br

(tBu)2P

Me

Shaw

PtEt3PEt3P

cyclohexane, heatPt

Et3PEt3P Me

Me

MeMeMe Me

Whitesides

[IrH2(acetone)2(PPh3)2]+

3.0 eq.

IrH PPh3PPh3


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2.2 Seminal work on catalytic C-H functionalization

These are some early examples where catalytic C-H to C-C bond transformations have been achieved, therefore, they are all examples of C-H functionalization. (For a historical overview, see: Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35 (10), 826-834.) Zirconocene complexes were found to catalyze the alkylation of pyridine under relatively mild conditions.

Jordan, R. F.; Taylor, D. F. J. Am. Chem. Soc. 1989, 111 (2), 778-779.

Ru-catalyzed acylation of pyridine. Note that the reaction only occurred in the presence of a CO atmosphere, no direct C-H functionalization with the olefin was observed.

Moore, E. J.; Pretzer, W. R.; O’Connell, T. J.; Harris, J.; Labounty, L.; Chou, L.; Grimmer, S. S. J. Am. Chem. Soc. 1992,

114, 5888-5890.

The first example of a direct C-H olefin coupling (Murai reaction). Very high yields and regioselectivties could be achieved through this first usage of a directing group to make use of chelation control in the intermediate Ru complex. Note that the coupling partners chosen lack the ability to facilitate a beta-hydride elimination reaction.

Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N. Nature 1993, 366 (6455), 529-531.

First examples of catalytic activation and functionalization of C-H bonds at sp3 centers. For the reaction to occur, aromatic iodides had to be employed. In the absence of I, the C-H functionalization was not observed. The second example with the activation of the tert-butyl groups demonstrates that the presence of a heteroatom as directing group is not required.

NCp2Zr

N N

5.0 mol%

H2 (1 atm)

CH2Cl2, rt

NBu

NBu

O1.3 mol% Ru3(CO)12

CO atmosphere

pyridine as solvent150 ºC

65%linear/branched 93:7

R"

O

R Y

Y = Si(OEt)3, Ph, tBu, CH2SiMe3

2.0 mol% RuH2(CO)(PPh3)3

toluene, relfuxR"

O

RY

proposed intermediate: O

R'

RRuH


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Dyker, G. Angew. Chem. Int. Ed. 1992, 31 (8), 1023-1025.

Dyker, G. Angew. Chem. Int. Ed. 1994, 33 (1), 103-105.

The Shilov system: Catalytic homogeneous alkane oxidation with Pt(II) complexes. This catalyst has been found to facilitate H/D exchange in alkanes as well as chlorination and oxygenation. The catalyst prefers terminal CH3 carbons of alkane chains (even over allylic and benzylic position), suggesting that the reaction does not run via a radical or electrophilic mechanism, but an organometallic C-H activation mechanism. As terminal oxidant, Pt(IV) complexes are used (for alternatives, see below).

The mechanism is believed to run via an intial interaction of the Pt(II) complex to give an alkane complex. This is then converted to a Pt-alkyl complex (whose existence has been shown for alkyl=Me), however, it is not known whether this step runs via a direct oxidative addition followed by deprotonation or, alternatively, via direct deprotonation of the Pt-alkane complex. The Pt(II) complex is then oxidized to a Pt(IV) complex by the terminal oxidant [PtCl6]2. After loss of one chloro-ligand, the resulting complex can be seen as an alkyl fragment bearing a terminal PtCl4 leaving group. Nucleophilic attack by a chloride ion (or, alternatively, water) results in the chlorinated or hydroxylated product, respectively.

Shilov, A. E.; Shul'pin, G. B. Chem. Rev. 1997, 97 (8), 2879-2932.

Suggested reading: Crabtree, R. H. J. Chem. Soc. Dalton Trans. 2001, (17), 2437-2450.

In order to circumvent the use of Pt(IV) complexes, Pt-diazine complexes have been developed as catalysts for methane oxidation, employing H2SO4 as the terminal oxidant. The product of this reaction is is MeSO3H, in which the SO3-group is believed to prevent the product from overoxidation. It is remarkable that the catalytic Pt complexes are stable under the reaction conditions.

IOMe

O

MeO

MeO

4.0 mol% Pd(OAc)24.0 eq. K2CO31.0 eq. Bu4NBr

DMF, 100 ºC

90%

I2.0 mol% Pd(OAc)2

4.0 eq. K2CO31.0 eq. Bu4NBr

DMF, 100 ºC

75%

RMe

cat. [PtCl4]2-stoich. [PtCl6]2-

R

H2C

Clor

R

H2C

OH

in presence ofH2O

PtClCl

Cl Cl

2-

RMe

PtClCl

Cl H

-

R

-Cl-

PtClCl

Cl CH2

2-

R

-H+

PtClCl

Cl CH2

-

R

H

oxidativeaddition

-H+

oxidation[PtCl6]2-

PtClCl

Cl CH2

2-

R

Cl

Cl

-Cl-

PtClCl

Cl CH2

-

R

Cl

Cl-

R

H2C

Cl


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Periana, R.A.; Taube, D.J.; Gamble, S.; Taube,H.; Satoh, T.; Fujii, H. Science 1998, 280, 560-564

3 Mechanistic Considerations In general, the different mechanisms for C-H activation are divided into two classes: Inner sphere (or organometallic) mechanisms and outer sphere (or coordination) mechanisms. The differences lie in the way the metal catalysts interact with the C-H bond to be activated. Note: These mechanisms are just dealing with the different ways for C-H activation, the follow-up mechanisms leading to C-H functionalization can be very different and do not necessarily depend on which C-H activation pathway has been taken. For an overview of some possible C-H functionalization mechanisms, see section 4.1.1. - Inner sphere (organometallic) mechanism This mechanism involves two discrete steps, namely the cleavage of a C-H bond first, leading to a metal-alkyl or metal aryl (C-M) species. Secondly, this intermediate undergoes functionalization towards M-X. The formation of the organometallic C-M species is the defining factor of this mechanism. This C-M species governs all follow-up reaction with respect to regio- and stereoselectivity. Generally, inner sphere mechanism have a tendency to prefer less hindered C-H bonds, since they avoid radical or electrophilic steps. Since organometallic species are generally oxidation-labile, reactions via inner sphere mechanisms normally employ no or very weak oxidants.

- Outer sphere (coordination) mechanism This mechanism involves a activated ligand of the metal complex, which is directly involved in the C-H activation/C-H functionalization reaction. The general steps are: 1. Formation of a high oxidation state metal complex with and activated ligand X (generally oxo-, nitrene or carbine species). This M-X complex then undergoes a reaction with the C-H bond to be functionalized. This reaction can run via a direct insertion mechanism or H-abstraction (radical rebound). These secondary reactions already comprise the C-H functionalization reaction. In contrast to the inner sphere mechanisms, no distinct organometallic species has to be present and that the substrate to be functionalized does not directly interact with the metal catalyst (instead, it reacts with the activated ligand). Note: In practice, direct insertion and radical rebound steps are hard to distinguish. Generally, and in contrast to inner sphere mechanisms, outer sphere mechanisms comprise some radical or cationic character at the C to be activated, therefore leading to a higher selectivity towards weaker C-H bonds (tertiary, allylic, benzylic or alpha to heteroatoms).

Crabtree, R. H. J. Chem. Soc. Dalton Trans. 2001, (17), 2437-2450. Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62 (11), 2439-2463.

CH4

N N

NNPt

Cl

Clcat.

H2SO4, 180 ºCCH3OSO3H

72%

H [M]

cat. [M]

C-H bond cleavage Functionalization X

cat. [M]oxidant

oxidation/activation[M]=X

H

direct insertion

radical rebound

H[M] X

functionalization

•[M] X

H•

XH


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4 C-C bond formation 4.1 Sp2 C-H functionalization C-C Bond forming processes via sp2-sp2 coupling are among the most studied C-H functionalizations. 3 distinct strategies can be used to overcome the inherent lack of regioselectivity of these reactions: - Take advantage of the intrinsic reactivity of the substrate (in particular for heterocycles) - Use of intramolecular reactions - Use of directing groups able to coordinate the metal (nowadays, much attention is focused on “removable” directing groups). Some relevant directing groups

4.1.1 Direct arylation Formation of aryl-aryl bond is usually called ‘‘direct arylation’’. For a general review see ACIE, 2009, 48, 9792-9826.

4.1.1.1 Direct arylation with pseudohalides Direct arylations with easily accessible pseudohalides, does not require oxidants and expensive organometallic reagents and had, therefore, the greatest impact on bi(hetero)aryl syntheses thus far. Early examples:

Ames, Tetrahedron 1982, 38, 383-387

N

R

NR'

R

O

R

N

R

O NH

R

OOMe

pyridines ketones imines/oximes oxazolines hydroxamic acids

HO O

R

N+

R

NO2

R

carboxylic acids nitro N-oxides

O-

MR

R'X catalyst

M= SnR3, B(OR)2 MgX...

X= Cl, Br, I, OSO2R...

R

R'M X

HR

R'Z catalyst

Z= pseudohalide or organometallic

R

R'

"Classical" cross-coupling

Direct arylation

X

NNBr

Et3N, MeCN150°C

CO2Et

X

NN

X= O Yield= 15%X= NH Yield= 55%

Pd(OAc)2 (cat.)

In a “classical” cross coupling, an aryl (pseudo)halide reacts with an organometallic partner C-H activation can be used to replace one or both of the reaction partners


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With heterocycles:

Ohta, Chem. Pharm. Bull. 1989, 37, 1477-1480

Plausible mechanisms

Evidences for different types of mechanisms have been obtained, depending on the nature of the reaction partners. While for heterocycles and electron-rich π–nucleophilic aromatics, SEAr mechanism (Friedel-Crafts type reaction) predominates; strong evidences for Concerted Metalation Deprotonation (CMD) have been obtained in other cases.

Fagnou, JACS 2008, 130, 10848-10849

The use of strained alkene norbornene as a temporary covalent linker, has been developed by Catellani for chemo and regio selective direct arylation of ortho-C-H bonds in aryl iodides with aryl bromides as reaction partners.

N N

N

NEt

Et

Cl N

NEt

Et

Pd(PPh3)4

KOAcDMA

reflux, 12h

PdX H

SEAr

ConcertedMetalationDeprotonation

Heckreaction

oxidativeaddition

PdH

X-

PdX

HB

XPdH

PdX H

S SAr

Pd(OAc)2PCy3HBF4

ArBr

PivOH (30 mol%)K2CO3, DMA, 100˚C

[Pd] Ar-Br

[Pd] BrAr

[Pd] OArO

tBu

tBu

O

OH

K2CO3 KHCO3

tBu

O

OKKBr

[Pd]H

Ar

OO

tBu

‡[Pd]Ar

tBuO

OH

[Pd]Ar

[Pd]O

OH

tBu

Ar

Ar

In-situ generated pivalate has been shown to help the C-H activation by stabilizing the Pd and abstracting hydrogen (CMD).


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Catellani, JACS 2004, 126, 78-79

Aryl iodonium salts have also been investigated for direct arylation. In this case, a Pd(II)/Pd(IV) cycle is operating. Oxidation of the stable Pd(II) intermediate to unstable Pd(IV) enable reductive elimination.

with heterocycles:

for a review see: Sanford, Inorg. Chem. 2007, 46, 1924-1935

4.1.1.2 Direct arylation with an organometallic partner (oxidative arylation) Direct arylations with an organometallic partner have been less studied because they require a terminal oxidant and because organometallic partners are expensive and difficult to prepare. They were first developed by Yu, using Pd as a catalyst but can also be carried out with Cu, Rh, Ru, Fe… Organometallic partners: B(OH)2, BF3K, SnR3, ZnX… Benzoic acids as directing groups:

Yu, JACS 2006, 128, 12634-12635

Pyridine directing groups

IMe

BrCO2Me

CO2Me

Pd(OAc)2norbornène

K2CO3DMF, 150°C, 24h

IMe

BrCO2Me

CO2Me

Pd0

PdII

MeMe

PdII

Me

PdII CO2Me

Me

PdIVBr

CO2Me

Me

PdII

-CO2Me

Me

PdII

CO2Me

Me

MeO2C

Me

CO2Me

CO2Me

NH

I Ar

BF4N

Ar

72-88% (sole product)

Pd(OAc)2 5% mol.

AcOH12h, 100-120°C

NPdII

L L

NPdIV

Ar L

PdII-H+

L

-PdII

BF4

-MesI

Cl I

BF490%

IMesPd(OAc)2 5% mol.

AcOH12h, 25°C

NCl

NCl

Pd(OAc)2benzoquinoneK2HPO4Ag2CO3

COOHMe

BOO

t-BuOH, 120°C, 3h

CO2HMe

63%


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Studer, OL 2008, 10, 129-131

Oxygen as terminal oxidant

Yu, JACS 2008, 130, 17676-17677

Iron as catalyst, imine DG

Nakamura, ACIE 2009, 48, 2925-2928

4.1.1.3 Dehydrating arylation This method his highly desirable because neither of the partners have to be pre-functionalized. Nowadays, intramolecular and homo couplings are well established. However, regioselectivity in intermolecular cross-dehydrogenative arylation reactions represents a major obstacle. Early examples:

Itatani, Angew. Chem. Int. Ed. 1974, 13, 471-472

Sequential C-N coupling/oxidative arylation

NPhB(OH)2

[{RhCl(C2H4)2}2] 5 mol. %P[p-(CF3)C6H4]3 20 mol.%TEMPO 6.0 eq.

1,4-dioxane/t-BuOH (10:1)130˚C, 9h

N

Ph

N

PhPh

50% 18%

L2RhITEMPOArB(OH)2

(TEMPO)B(OH)2

L2RhIAr

(TEMPO)2RhIIIAr

L

L

N L

(TEMPO)2RhIIIAr

L

N

TEMPOH

N

(TEMPO)RhIIIAr

L

NAr

L

Pd(OAc)2 (10 mol. %)BQ (0.5 eq.)K2HPO4 (1.5 eq.)O2 (20 atm)

t-BuOH, 100˚C, 24h

CO2HOBF3K CO2HO

69%

MgBr

OTf

NAr

OMe OTf

O O

[Fe(acac)3] (10 mol%)dtbpy (10 mol%)ZnCl2.TMEDA (5 eq.)

ClCl (2 eq.)

THF, 0˚C, 20h88%

Pd(OAc)22,4-pentanedioneN2/O2 (1:1 50 atm.)

150°C, 5hO O


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Ohno, Chem. Commun. 2007, 4516-4518

First intermolecular examples:

Fagnou, Science 2007, 316, 1172-1175

Homocoupling Intermolecular dehydrogenative homocoupling of heteroarene is one of the most useful tools for the preparation of symmetrically substituted 1,1’-binaphtyls.

Katsuki, JACS 2009, 131, 6082-6083

4.2. Other couplings involving sp2 C-H activation Alkene-arene coupling (Fujiwara Moritani reaction) Also called oxidative Heck coupling, this reaction has been applied to a wide range of arenes and alkenes. It can be catalyzed by Pd, Ru… See section 2.2 for early examples With (2-pyridyl)sulfonyl as removable DG

Carretero, ACIE 2009, 48, 6511-6515.

H

OTfPd[0]

H2N

H

PdII

OTf

MeO2C

OMe

H

PdII

HN

OMe

CsOTf + CsHCO3

Cs2CHO3

MeO2C

HN

MeO2C

OMe

Pd0

H2N

OMe

CsOTf + CsHCO3

Cs2CO3

HN

MeO2C

OMePdIIX

HX

OMeHN

MeO2C PdXH

OMe

HN

MeO2CPdIIX2

O2 H2O

Buchwald-HartwigDehydrogenative

arylation

MeO NH2

OTf

CO2MeNH

1) Pd(OAc)2 XPhos Cs2CO3 PhMe, 100˚C, 1.5h

2) O2 ACOH, 80˚C, 22h

68%

MeO2C

OMe

- HX

N

Ot-Bu

Pd(TFA)2 5% mol.AgOAcPivOH

110°C, 3hN

Ot-Bu

84%solvent

I

OH

I

OH

I

OH

(R)

Cat* (4 mol%)air

PhMe, 60˚C, 96h

77% (96% ee)

N

PhO

Ph Ph

NHH

FeO

Ph

O2

Cat*:

NS

NCO2Me N

SN

CO2Me[Pd(CH3CN)2Cl2] 10% mol.Cu(OAc)2 2 eq.

DMA110˚C, 8h

75%

OO

OO

Zn NH4Cl

THF, rt NH

CO2Me

NS

NO

O

PdLnvia


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Selective functionalization of indoles In this case, the nature of the solvent influences the regioselectivity of the reaction. C-H activation occurs first at C3 position but under acidic conditions and with a weekly coordinating solvent, Pd can migrate at C2 (thermodynamically more stable) prior to functionalization.

Gaunt, ACIE, 2005, 44, 3125

With enaminone

Glorius, Angew. Chem. Int. Ed. 2008, 47, 7230-7233

Aldehydic C-H bond functionalization Transition metals are known to activate aldehydic C-H bonds and this type of C-H activation has been used in oxidative coupling to prepare ketones.

Li, JACS, 2010, 132, 8900-8902

The proposed mechanism involves Cu insertion into the aldehydic C-H bond as the rate limiting step (kH/kD = 2.4). A Friedel-Craft mechanism as also been ruled out by complementary experiments. 4.2 Sp3 C-H functionalization 4.2.1 Via C-H activation Sp3 C-H activation has been less studied because C(sp3)-H bonds lack π-orbitals to interact with the metal center. Pd(II)/Pd(0) catalysis: Hydroxamic acids as directing groups (easily converted to esters, amides or alkanes), O2 as terminal oxidant, sp2 and sp3 boronic acids can be used.

Yu, JACS 2008, 130, 7190-7191

Pd(0)/Pd(II) catalysis: Amides as directing group, no oxidant needed

NH

R

Pd(OAc)2 10 mol%

Cu(OAc)2DMF-DMSO

70˚C

R

Pd(OAc)2 20 mol%

tBuOOBzdioxane-AcOH

70˚C

NH

RNH

R

NH

O

OH

NH

OOPd(OAc)2 5% mol.

CuOAc (3eq.)K2CO3

DMF, 140°C, 15 min. 70%

N

O

O

HCuCl2 10 mol %

THF, 100˚C1 atm O2

NH

O

O

N

CuIICl2

CuII

OO

Cl

N

O

O

H O2

N

CuIII

O

OCl

NO

O

CuICl

O2

Pd(OAc)2 10 mol % BQ (0.5 eq.)K2CO3

20 atm O2, 20 atm N2tBuOH, 80°C, 48h

NH

OOMe

B(OH)2

NH

OOMe

75%


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Yu, JACS 2009, 131, 9886-9887

Recent application: With 2-aminothioanisole as DG:

Baran, JACS, 2011, ASAP

Amide substrate (Ir catalysis) sp3 C-H activation, followed by Heck type reaction and isomerization promoted by norbornene.

Sames, JACS, 2004, 126, 6556-6557

4.2.2 via C-H insertion See the definition in Section 1. Loss of nitrogen provides the driving force for the energetically unfavorable formation of the carbenoid. Even if different metals are known to form and stabilize carbenes (Ru, Ag, Cu…), rhodium and dirhodium species are the most studied to date because of their higher reactivity and versatility. These reactions have been mostly studied in systems capable of intramolecular reactions to overcome regioselectivity issues.

Doyle, Chirality 2002, 14, 169-172

Chemoselectivity is controlled by both steric and electronic factors. The carbenoid has an electronic preference to functionalize C-H bonds in which the carbon can stabilize positive charge build-up (C-H insertion has a partial characteristic of a hydride abstraction). Bulky ligands on the metal species are used to modulate its reactivity and limit concurrent cyclopropanation on unsaturated substrates.

Davies, JACS 1999, 121, 6509-6510

Pd(OAc)2 (10 mol %) L (20 mol %)CsF

3Å MStoluene, 100°C, 24h

NH

OOMe

I

Me

Me

Me

MeO

NH

OOMe

Me

Me

MeO

PCy2

L= cyclohexyl JohnPhos

NH

O

MeS

OMe

O

OMeMeO

MeO I

Pd(OAc)2Ag2CO3, PivOHHFIP, 90˚C

NH

O

MeS

OMe

O

MeOOMe

OMe

52%gram scale

piperarborenine B

N

TBSO

O

H

Ir[(COE)Cl2 5 mol %]IPr 10 mol %

norbornene, hexane, 150˚C N

TBSO

O

N NiPr

iPr

iPr

iPr

Cl-

IPr

N2

OO

Cl

Rh2(4S-MPPIM)4

CH2Cl2, 40˚C

OO

Cl85% yield95% ee

Cl

NH2.HCl

HOOC

(R)-(-)-baclofen.HCl

Rh

NN

OO

BnH2C

CO2Me

Rh

4Rh2(4S-MPPIM)4

NBoc

N2

CO2Me

Ph 1. Rh2(S-biDOSP)2

2. TFA NH

CO2Me

PhH

52% yield86% ee

Ritalin

N

O

ORh

RhO O

O

ORN

R OH H

HHO

H N H

NH

H

R= SO2-p-(C12H25)C6H5

Rh2(S-biDOSP)2

R

R


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A preference for insertion into tertiary over secondary C-H bonds has been observed, insertion into primary C-H bonds are scarce. Insertion occurs with retention of configuration.

Davies, JOC 2003, 68, 6126-6132

Synthetic utility of these reactions remains limited, mainly because of the difficult preparation of diazo compounds other than diazocarbonyls. 4.3 Allylic C-H activation Formation of π-allyl intermediates can occur via a C-H activation pathway and have successfully been trapped by carbon nucleophiles to create C-C bonds.

White, JACS, 2008, 130, 14090-14091

5 C-O bond formation 5.1 C-O bond formation with the aid of directing group Nitrogen containing groups such as pyridines, amides, and oximes could control the regioselectivity in predictable manner. Sanford reported the first example of ligand-directed sp2 C-H bond oxygenation as well as sp3 C-H bond.

Sanford, JACS 2004, 126, 9542

Sanford, OL 2010, 12, 532

5.2 C-O bond formation through allylic C-H bond activation (also see 4.3) White reported the catalytic system enable to control the product distribution (linear / branched) by using different condition. Although ees were moderate, her group also succeeded to develop enanchioselective variant with the combination of achiral Pd catalyst and chiral Cr-salen catalyst.

White, JACS 2004, 126, 1346

White, ACIE 2008, 47, 6448

TBSOOAc

N2p-BrPh

MeO2C

50˚C

OAc

OTBS

p-BrPh CO2Me

92% yield>94% de72% ee

electronically deactivated

siloxy group activation

Rh2(S-DOSP)4

O2NO

OMe

O

OMeNO2

62%linear/branched 4:1

DMBQ (1.5 eq.)AcOH

Dioxane/DMSO (4:1)

SSOO

Ph PhPd(OAc)2 10 mol %

CH3

NMeO Pd (OAc)2 (5 mol%)

PhI(OAc)2

AcOH, 80 ºCN

MeO

OAcH3C

CH3H3C

H3C

H3CH3C

NOH

Br

AcOH / Ac2O (1:1), rt, 2 h;Pd(OAc)2 (5 mol%)PhI(OAc)2, 80 ºC

NOAc

Br

OAc

1) K2CO3, MeOH2) NaHSO3, EtOH/H2O

OBr

OHCH3 CH3

CH3

y.86% y.-80%

OO Pd(OAc)2 (10 mol%)BQ (2 equiv.)

DMSO / AcOH (1:1)MS 4A, air, 40 ºC

OOOAc

y.50%linear/branched : >99:1

Pd cat. (10 mol%)[(Salen)CrIIIF] (10mol%)

AcOH (1.1 equiv.)BQ (2 equiv.)

EtOAc, MS 4A, rt, 48 h

OAcS Pd

SO

PhO

Ph

(OAc)2

PdAcO BQ Cr(F)L* y.78%

62% eelinear/branched= 1:1.5


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5.3 C-O bond formation with Fe-based catalyst and H2O2 as oxidant Fe-based catalyst was reported to recognize subtle differences between electronic / steric natures and existence of directing group even in complex molecules with a lot of C-H bonds, and selectively oxidize the most reactive sp3 C-H bond.

White, Science 2007, 318, 783

6 C-N bond formation

6.1 C-N bond formation through C-H insertion Similar to C-H insertion of metal carbenoid into C-H bond(see 4.2.2), metal nitorenoid can insert C-H bond. Breslow investigated several catalysts for intramolecular amination and Rh2(OAc)4 showed the best reactivity.

Breslow, JACS 1983, 105, 6728

Du Bois reported Rh-catalyzed intramolecular C-H amination to form 5 and 6 membered rings, which could be transformed to 1,2- and 1,3-aminoalcohol. Use of simple carbamates and sulfamate esters as nitrene precursors instead of iodoimine made these protocols simpler.

Du Bois, ACIE 2001, 40, 598

Du Bois, JACS 2001, 123, 6935

Du Bois succeeded to apply these methodologies to the total syntheses of complex natural products.

Du Bois, JACS 2003, 125, 11510

Du Bois, JACS 2008, 130, 12630

FeN

N

NCCH3NCCH3

N

N

Fe(S,S-PDP)

OO

CH3

H

O

H3C

HH3C

H

OO

Fe(S,S-PDP) (5*3 mol%)AcOH (50*3 mol%)H2O2 (1.2*3 equiv.)

CH3CN, rtO

O

CH3

H

O

H3C

HH3C

OH

OO

(+)-artemisinin y.54%

H3C

CH3

S H

CH3CH3

NO

O IPh

MLn

CH3CNH3C

CH3

NHSO

O

CH3

CH3

MLnMn(TPP)ClFe(TPP)Cl

[Fe(cyclam)Cl2]ClFeCl3

Rh2(OAc)4

1677421686

yield (%)

O

CO2tBu

H2NO Rh2(OAc)4 (5 mol%)

PhI(OAc)2 (1.4 equiv.)MgO (2.3 equiv.)

CH2Cl2, 40 ºCCO2tBu

O

HN O

y.82%

O

OTBS

SNH2

O O Rh2(oct)4 (2 mol%)PhI(OAc)2 (1.1 equiv.)

MgO (2.3 equiv.)CH2Cl2, 40ºC

O

OTBS

SNH

O O

Hy.75%

O

OO

O CH3CH3

CH3

CH3

OHO

Cl

NH2

O

Rh-nitreneC-H insertion

O

OO

O CH3CH3

CH3

CH3

O

Cl

77% yield

ONH

O

O OHO

OH

OH

OHOHNHHN

H2N

HO

(-)-tetrodotoxin

N NH

NC(O)CCl3

NHH2N

NTces

OTBDPS Rh-catalyzedamination

N NH

NC(O)CCl3

OTBDPSNHHN

NTces

AcO

61% yieldN NH

NHHN

NH2

HOHO

O3SO

O NH2

O

(+)-gonyautoxin 3


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Vinyl azides were found to generate nitorene species in situ, and be inserted into C-H bond intramolecularly.

Driver, JACS 2007, 129, 7500

The reactivity for nitrene C-H bond insertion follows the order 3º > 2º >> 1º bond. Sp2 C-H bond also shows low reactivity. For intermolecular amination, these tendencies become challenges to control regioselectivity among many C-H bonds. Use of directing group is one of the solutions.

Che, JACS 2006, 128, 9048

Au-catalyzed C-H amination of sp2 C-H bond was reported. Although substrate scopes were narrow, this is rare example for the insertion into sp2 C-H bond in intermolecular manner.

He, JACS 2007, 129, 12058

6.2 C-N bond formation through oxidative amination Buchwald reported intramolecular oxidative amidation to form carbazole. Acetyl group on the nitrogen was important to obtain product in high yield. Authors proposed amide-directed C-H activation mechanism.

Buchwald, JACS 2005, 127, 14560

Buchwald also reported benzimidazole formation by Cu-catalyzed oxidative amination. Authors proposed three possible mechanisms, but they didn’t get any mechanistic insights. In this system, alkyl substituted substrate showed lower reactivity.

HN

NBoc

CO2Me

NBoc

N3

CO2MeRh2(O2CC3F7)4 (5 mol%)

toluene, 60 ºCy. 94%

NH3CO Pd(OAc)2 (5 mol%)

H2NCOCH3 (1.2 equiv.)K2S2O8 (5 equiv.)

DCE, 80 ºCN

H3COHN

O

CH3

y.94%

H3C CH3

CH3 AuCl3 (2 mol%)PhI=NNsCH2Cl2, rt

H3C CH3

CH3

NHNs

y.90%

H3C CH3

CH3

AuCl3

H3C CH3

CH3

AuCl2

HCl

H3C CH2

CH3

HAuCl2H3C CH3

CH3

AuCl2PhI=NNs

HCl

H3C CH3

CH3

NHNs

NH

CH3

O Pd(OAc)2 (5 mol%)Cu(OAc)2 (1 equiv.)

O2 (1 atm)toluene, 120 ºC

NO

CH3

y.94%

HN

NH CH3

F

N

HN

H3C

FCu(OAc)2 (15 mol%)AcOH (5 equiv.)

O2DMSO

100 ºC, 18 h

y.89%


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Buchwald, ACIE 2008, 47, 1932

For intermolecular oxidative amination, similar protocols were reported by several groups. Amides, 2º-anilines, 2º-aliphatic amines, and 1º-aliphatic amines can be used in this transformation. On the other hand, scopes for arenes were limited to ones with relatively weak C-H bond.

Mori, OL 2009, 11, 1607

Duan, JOC 2011, 76, 5444

Chang, ACIE 2010, 49, 9899

Yu reported intermolecular amination with simple arenes by using O-Bz hydroxylamines as amine source.

Yu, JACS 2011, 133, 7652

7 C-B bond formation 7.1 Bond strength of C-B bond Different from other C-H functionalization such as formations of C-O, C-N, and C-C bond, functionalization of C-H to C-B bond is thermoneutral or thermodynamically favorable process (also see 1.1).

Hartwig, JACS 1996, 118, 4648

The accessible barriers for C-H bond cleavage and C-B bond formation are attributed to the combination of the strong σ-donor properties of the boryl group, and the presence of an unoccupied pz-orbital on boron in a boryl complex. 7.2 Seminal work on catalytic C-H activation / boryration Smith reported the first example of catalytic C-H activation / boryration process with Ir complex. Although this reaction was slow, benzene was used as solvent, and TON was only 3, still it is an important precedent for the feasibility of this catalytic transformation.

HN

N[Cu]OAc

N

HN

H

H

HN

N[Cu]

N

NH [Cu]

N

HN

S

NH +

HN

H3C

Cu(OAc)2 (20 mol%)PPh3 (40 mol%)

O2 (1 atm)xylene, 140 ºC, 20 h

S

NN

CH3y.81%

O

NH + N

H

Cu(OAc)2 (20 mol%)AcOH (2 equiv.)

O2 (1 atm)CH3CN, 70 ºC, 12 h

O

NN

CH3

y.65%

H3C

O

NH +

CH3H2N

Mn(OAc)2 (10 mol%)AcOH (2 equiv.)

aq.TBHP (1.2 equiv.)CH3CN, 70 ºC, 12 h

O

NNH

y.75%

CH3

CH3

CH3

NH

OF

F

FF

CF3

+

O

NOBz Pd(OAc)2 (10 mol%)

AgOAc (1 equiv.)CsF (2 equiv.)

(2 equiv.)

DCE, 130 ºC, 18 h NH

OF

F

FF

CF3

NO

y.85%

H3C H + (RO)2B B(OR)2

104 kcal/mol 104 kcal/molH3C B(OR)2 + H B(OR)2

111 kcal/mol 110 kcal/mol!BDE = -13 kcal/mol

H3C H + H B(OR)2

104 kcal/mol 110 kcal/molH3C B(OR)2 + H H111 kcal/mol 104 kcal/mol

!BDE = -1 kcal/mol


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Smith, JACS 1999, 121, 7696

7.3 Alkane C-H bond boryration Based on his W-mediated system and Re-catalyzed system with photo-irradiation, Hartwig reported Ir-catalyzed thermal system. Steric factor has a major influence on regioselectivity, so that terminal 1º-CH bond reacts selectively. Existence of heteroatom wouldn’t override the regioselectivity to C-H bond adjacent to heteroatoms such as oxygen and nitrogen, but inductive effect has still some influences on the selectivity.

Hartwig, Science 2000, 287, 1995

JACS 2004, 126, 15334

7.4 Aromatic C-H bond boryration Normally the catalysts for alkane C-H boryration showed poor reactivity for aromatic substrates, probably due to unfavorable interaction of substrate with catalyst. Addition of P or N-based ligands was found to increase reactivity of catalyst for aromatic substrates, and Ir/dtbpy complex was reported as a good catalyst for a variety of aromatic substrates including heteroaromatics even at ambient temperature. Similar to aliphatic cases, steric factor is important to determine the regioselectivity. Directing group, however, could control the reaction to be o-selective over steric preferences.

Ishiyama, Hartwig, and Miyaura, ACIE 2002, 41, 3056

Hartwig, JACS 2008, 130, 7534

Extensive mechanistic study revealed that trisboryl complex is important intermediate in this system.

Ishiyama, Miyaura, and Hartwig, JACS 2005, 127, 14263

C6H6 + HBPin

Cp*Ir(PMe3)(H)(BPin)(17 mol%)

150 ºC, 120 h C6H5BPin + H2

y.53%

n-Octane + HBPin

Cp*Ir(!4-C6Me4)(5 mol%)

150 ºC, 25 h + H2

y.88%

H3C BPin

H3C O CH3 + (BPin)2

Cp*Ir(!4-C6Me4)(5 mol%)150 ºC

H3C OBPin

O CH3BPin

4:1

Ar-H + (BPin)2

[Ir(OMe)(cod)]2 (1.5 mol%)dtbpy (3.0 mol%)

hexane, rt Ar-BPin

N N

CH3H3C

H3C H3CCH3

CH3

dtbpy

Cl

I

PinB

Cl

CO2Me

PinBNH

PinB

4 h, 82% 8 h, 80% 0.5 h, 88%

[Ir(cod)Cl]2 (0.25 mol%)dtbpy (0.5 mol%)HBPin (5 mol%)(BPin)2 (1 equiv.)

THF, 80 ºCSiMe2H

F

SiMe2H

F

BPin

IrNN Bpin

BpinBpin

IrNN Bpin

BpinBpin oxidative addition

orsigma bond metathesis

IrNN Bpin

BpinBpin

Ph HIr

NN H

BpinBpin

Ph-BPin

(BPin)2

HBPin

Update to 2012 Bode Research Group //ethz.ch/content/dam/ethz/special-interest/... · The reaction...

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