Organometallics II (Lecture 12) 1 Alternative methods for ...

OC II (FS 2019) Prof. Morandi, Prof. J. W. Bode http://www.bode.ethz.ch/

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Organometallics II (Lecture 12)

1 Alternative methods for the synthesis of organometallic reagents Reagents containing C–M bonds are often used as substrates in various cross-coupling reactions. If they are not commercially available (e.g. complex or unstable molecules) they have to be synthesized.

1.1 Directed ortho-Lithiation (Aromatic) C–H bonds can be deprotonated in presence of strong bases, for example n-BuLi:

Usually, a mixture of regioisomers is obtained. This can be altered if the substrate contains a directing metallation group (DMG), or directing group:

Most commonly, DMGs are ethers, tertiary amines or tertiary amides (free alcohols or primary/secondary amines/amides would get deprotonated and coordinate their own Li+ instead of directing BuLi):

MPd

X

M = -B(OH)2, -B(OR)2, -BR2, -BF3 Suzuki-Miyaura -SnR3 Stille -SiR3 Hiyama

X = I; Br; Cl; OTf etc.

R

n-BuLiH

H

RLi

H

+

RH

Li

mixture of regioisomers

DMGH

H

n-BuLi

DMGH

H

LiBu

Complexation between Lewis-basic DMGand Lewis-acidic Li+

DMGLi

H

- C4H10

ortho-selective lithiation

DMG:O

RN

R

R'N R

O

R'


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Example:

1.2 Trapping of Organometallic Nucleophiles

1.2.1 Synthesis of Isolable Boron and Tin Reagents Even if you are used to see metallic compounds as nucleophiles, M–X reagents can also act as electrophiles since they have a leaving group that can easily be cleaved. Additions of strong carbon nucleophiles (RLi or RMgX) to M–X is a useful way of preparing new carbon-metal bonds. The identity of X depends on the metal and the desired products.

Note: Organotin reagents are highly toxic and should be handled with caution!

1.3 Cross-Coupling of M–M bonds 1.3.1 Miyaura Arylboronic Ester Synthesis (B–B cross-coupling) This reaction is analogous to the Suzuki cross-coupling, except that the nucleophile contains a B–B bond rather than a C–B bond. This method benefits from its mild reaction conditions and that no formation of strongly nucleophilic carbanions is required.

OH

Me

n-BuLi

OH

LiBu

MeO

Li

- C4H10

Me

Br2

OBr

Me

MeI

OMe

Me

CO2

OCOOH

Me

HCO2Et

OCHO

MeB(OiPr)3

OB(OiPr)2

Me

B OMeMeOMeO PrMgBr OMe

BPr OMe

OMe

H3O

B PrHOHO

B PrMeOMeO

HO OHB Pr

OO

- MeO-

+ MeO-

RMgBr ClSnBu3

RSnBu3 Li ClSnBu3 SnBu3


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J. Org. Chem., 1995, 60, 7508

This method can be used to synthesize chiral allylboronic esters:

Note: the chiral allylboronic esters are used in stoichiometric asymmetric allylation of carbonyls (see OCIII). 1.3.2 Synthesis of Organotin Compounds for the Stille Cross-Coupling This is the tin analogue of the Miyaura cross-coupling, using a Sn–Sn reagent. In situ prepared organotin species can be directly used for Stille cross-coupling.

1.4 Hydrometallation/Carbometallation 1.4.1 Preparation of alkyl or alkenyl metal species using M–H-type reagents:

Hydroboration: Due to steric reasons 9-BBN is more selective than BH3:

OB

OBO

O O

MeO

O

MeO

O

O

MeO

MeOBr

Pd0 BO

O O

MeO

O

MeO

BrMe3Sn SnMe3

PdoLnSnMe3

R' R2BH R'BR

RR''

Br

Pd0R'

R''

BH3 BH2HB

HB

9-BBN

OMe Cl

B B B

BBB

THF•BH3:

9-BBN: 99.9 0.1 98 298.9 1.1

94 6 82 18 60 40


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The uncatalyzed hydroboration of alkynes with catecholborane affords stereospecific and regioselective monohydroboration products. The reaction proceeds in a stereospecific cis manner (due to the cyclic transition state) with the boron being attached regioselectively at the less hindered carbon atom of the triple bond (Anti-Markovnikov product, E-alkene product).

1.4.2 Hydrostannation Hydrostannation reactions are initiated by catalytic AIBN and proceed via a radical mechanism. A main regioisomer is formed where tin adds to the terminal carbon to generate a higher substituted radical intermediate. The Z-product is favored in most cases.

1.4.3 Hydrozirconation Hydrozirconation is most commonly performed using stoichiometric amounts of Schwartz reagent. The intermediate alkyl or alkenyl zirconium can be trapped by electrophiles or used for transmetallation to form new C–M bonds.

1.4.4 Hydroalumination Alkenes can be treated directly with alkyl aluminium species in the presence of a Zr-catalyst to form new C–Al bonds.

Ph

O

OBH

Ph

BOOH

PhB O

OH HydrolysisPh

HB(OH)2H H

H H

OTHP

Bu3SnHAIBN

80 °C OTHPBu3Sn

H

N N

NC

CN

CN2 N2

CNH SnBu3

OTHP Bu3Sn

H

OTHP

HSnBu3

Bu3Sn OTHP

AIBN

MeMe

CN

H

Bu3SnBu3Sn

Bu3Sn

Zr ClH

Schwartz reagent

R Cp2ZrHClR

HZrCp2Cl

ER E

MXR M M = Al, B, Cu, Ni, Pd, Sn, Zn

E = I2, Br2, D2O, CO etc

orR

Me

i-Bu3Al

Cl2ZrCp2 (cat.)AlBu2

ZrCp

CpCl

Cl ZrCp

Cp ClMe

Me

Hβ-hydride

elemination R

Me Me-Al(iBu)2Cl

Al(iBu)2Cl

Me

ZrCp

CpH

ClZr

Cp

Cp ClR

i-Bu3Al

ZrCp

CpCl

Cl

Bu2AlR


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2 Cross-Coupling Reactions Proceeding through formal C-H functionalization

2.1 Sonogashira Coupling The coupling between aryl-vinyl halides/triflates and terminal alkynes is called Sonogashira cross-coupling. It is related to the ‘normal’ Pd-catalyzed cross-coupling reactions (e.g. the same elementary steps occur), but there are some important differences: Not only is a catalytic amount of Pd(0) required, but also a Cu(I) salt in most cases. Instead of a metal-vinyl or metal-aryl species (such as aryl boronic acids), a terminal alkyne is used as a reaction partner. Finally, a stoichiometric amount of base (usually an amine base like Et2NH) is crucial to deprotonate the activated alkyne (see catalytic cycle).

2.1.1 Catalytic Cycle There are two catalytic cycles involved in the Sonogashira reaction:

• Step 1: Cu(I) coordinates to the terminal alkyne, rendering its proton more acidic. • Step 2: The proton is removed by the base (in this example Et2NH) and a copper acetylide is formed. • Step 3: Transmetalation: The acetylide is transferred onto palladium, forming a trans-alkynyl/vinyl(aryl)-

palladium(II) complex. • Step 4: Isomerization to the corresponding cis-complex. • Step 5: Reductive elimination: The product is eliminated from the cis-complex (en-yne or aryl-yne), forming a

palladium(0) complex. • Step 6: Oxidative addition: The palladium(0) complex inserts in the sp2-X bond, completing the catalytic cycle.

2.1.2 Applications The stereochemical information of the olefin is conserved:

The Sonogashira coupling is, due to its relatively mild conditions and chemoselectivity, widely employed in organic synthesis, for example in natural product synthesis.

X + H R[Pd(0)], [Cu(I)]

Et2NHR

X = Cl, Br, I, OTf

Et2NH2+X-+

Cu+X-H R2

Cu+X-

H R2

Et2NH

Et2NHH+X- Cu R2 Pd LLX

Pd LL

R

PdLL

R

R

Pd0L2

XOxidative Addition

Transmetallation

Reductive elimination

Copper cycle Palladium cycle

1

2

3

4

5

6

MeBr H R

[Pd(PPh3)4][CuI]

Et2NH Me R

H R

[Pd(PPh3)4][CuI]

Et2NHMe

BrMe

R


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Tetrahedron 2003, 59, 7509-7513.

2.2 Pd-Catalyzed Direct Arylation The aim is to convert C–H into a C–Y group, whereby Y is any of a wide range of useful functionalities (e.g. aryl-, HO-, NH2- etc.) This strategy aims to replace activated reactant molecules (R–Br, R–OTf or R–M) by simpler R–H-type molecules thus making processes less expensive, and “greener” with increased atom and step economy.

2.2.1 Pd(0)/Pd(II) Cycle

Step 1: The Phosphine ligands reduce PdII to Pd0. Step 2: Oxidative addition into C–Br bond. Step 3: Ligand (anion) exchange. Step 4 (new elementary step): concerted metallation deprotonation (CMD) –pentafluorobenzene is a very electron poor substrate that has a relatively low pKa (for aromatic C–H) especially when coordinated to a metal species. Step 5: reductive elimination. Reminder Pd(II) reduction to Pd(0) in presence of phosphine ligands.

AcO OAc

BrO

OMeO

H

[Pd(OAc)2], PtBu3, [CuI], DIPEA

AcO OAc

OO

OMe O

O

O

MeOHO

Sonogashira cross-coupling

Cicerfuran

Proposed mechanism

Pd0Ln ArBr

Ar-PdII-Br

K2CO3

KBr

Ar-PdII

KO

O

OF

FF

F

FH

Pd PR3R3PO

OO

F

F

FF

F

H

F

FF

F

FPdIIAr

F

FF

F

FAr

F

FF

F

FH

ArBr

Pd(OAc)2, SPhos, PivOH, K2CO3

F

FF

F

FAr

PdII(OAc)2 PR3 PdIIOAcR3P ligand

exchangeR3P

OAc

OPR3O

PdII

OAc

PR3

AcO

Pd0-R3PO-Ac2O

OMe

OMe

P


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3 Catalytic Functionalization of Alkenes 3.1 Hydroformylation Hydroformylation is the conversion of olefins to aldehydes by addition of an extra carbon atom. It is the most important reaction for the industrial synthesis of aldehydes. It is also one of the most commonly applied homogenous catalysis on industrial scale with worldwide production capacities of about 6 million tons per year (2002). Product distribution can be controlled by choice of a suitable catalyst. Typical catalysts for hydroformylation reactions are e.g. HCo(CO)4 or HRh(CO)2(PR3)2.

3.2 Wacker Oxidation The Wacker oxidation# (or Wacker process) is used to synthesize aldehydes and ketones from the corresponding alkenes. The reaction is catalytic in palladium(II) and copper(II) and requires a stoichiometric oxidant, most commonly oxygen gas or simply air is used. The most important application of a Wacker oxidation is the synthesis of acetaldehyde, which is done on a billion ton scale per year.

Unlike the hydroformylation process, there is no chain extension. # Good to know: The reaction is named after the German chemical company Wacker, not after a chemist. 3.2.1 Tsuji-Wacker oxidation The Tsuji-Wacker reaction is a very useful extension of the Wacker process which is more relevant to organic synthesis. In this process, a wide variety of easily accessible terminal alkenes can be transformed into the corresponding methyl ketones in the presence of water as nucleophile and Cu/O2 or benzoquinone as a stoichiometric oxidant to reoxidize the Pd(0) generated through the process. This reaction has found broad application in organic synthesis, including natural product synthesis.

migratoryinsertion

R CO H2 R H

O

R

H OHH

HCoCO

OCOC CO1/2 Co2(CO)8

H2

HCoCO

OC CO

-CO+CO

HCoCO

OCOC

R

COCoCO

OCR

CoCO

OCOC CO

R

COCoCO

OCO

CoCOH CO

H COO

R

RH2

CO

R

COCoCO

OCR

Me

H

OR

Me

O

H Rn-Aldehyde

i-Aldehyde

H

H

migratoryinsertion

oxidative addition

H2C CH2

[PdCl2][CuCl2]

O2 H3C

O

H


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3.3 Olefin Metathesis The 2005 Nobel Prize in Chemistry was awarded to Grubbs, Schrock, and Chauvin for their pioneering work in the area of olefin metathesis. In 1971, Yves Chauvin (Institut Français du Pétrole) proposed a mechanism for olefin metathesis that was later proven correct. The mechanism involves metallocarbenes, species with an M=C double bond, as key intermediates. E. O. Fisher described an example of such a species, [W(CO)5{C(CH3)(OCH3)}], in 1964. An olefin coordinates to the metal atom of the metallocarbene, which leads to the formation of a metallocyclobutane intermediate, another key intermediate, via a [2+2] cycloaddition process that is followed by a related [2+2] cycloreversion, forming a new metallocarbene and a new olefin. The new metallocarbene then re-enters the catalytic cycle.

The term olefin metathesis covers all reactions that proceed by the exchange of carbene or alkylidene groups between alkenes and a metal catalyst. This mechanistic insight enabled the development of well-defined homogeneous metathesis catalysts which are active at room temperature.

R + H2O R Me

O

RPd(II)X2

Pd(II)X2oxid.

Pd(0) R.E. X–Pd(II)–H β-H elimination

cat. Pd(II)

oxidant

Pd(II)X

R

HOH2O

- HX

oxidant: cat. Cu/O2 or benzoquinone

MR1

Chauvin mechanism of

olefin metathesis

M

R1

R1

R2

M

R2

R1CH=CHR2

M

R2

R1

R2

R1CH=CHR2

2 R1CH=CHR2Catalyst R1CH=CHR1

R2CH=CHR2CHR1

CHR1

CHR2

CHR2


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Structure and Activities Grubbs-type catalysts are based on d6 Ru(II) complexes. These are generally less reactive than W and M-based catalysts. However, Grubbs' Ru catalysts are air and moisture stable in the solid state and display remarkable tolerance to various organic functional groups. Several generations of Grubbs catalysts have been developed over the years, showing increasing activity and stability. Replacing the PCy3 ligand by a chelating 2-isopropoxy benzylidene group yielded catalysts with even higher activity, known as Hoveyda-Grubbs catalysts.

Selected Applications of RCM in Synthesis of Complex Molecules

Ring-closing metathesis is one of the most powerful applications of metathesis in organic synthesis. Nearly any ring size from 5 to macrocycles, including medium sized rings, can be accessed readily from the cyclization of a diene. Many functional groups are tolerated.

Ti W Mo Ru

L

Ru

PCy3

Cl R

Cl

RFO

Mo

N

R

Ar

RFORFO

W

N

R

Ar

RFOTi

Cp

Cp

AcidsAlcohols, WaterAldehydesKetonesEsters, AmidesOlefins

AcidsAlcohols, WaterAldehydesKetonesOlefinsEsters, Amides

AcidsAlcohols, WaterAldehydesOlefinsKetonesEsters, Amides

OlefinsAcidsAlcohols, WaterAldehydesKetonesEsters, Amides

Incr

easi

ng re

activ

ity

Increasing activity

Increasing functional group tolerance

Ru

PCy3

Cl

NN

Ph

ClL

Ru

OCl

Cl

iPr

Ru

NCl

NN

Ph

Cl

Br

N

Br

Ligand: H2IMes (SIMes)

PCy3

Ru

PCy3

Cl Ph

Cl

Grubbs-I Grubbs-II Grubbs-III(applications in ROMP)

L = PCy3, Hoveyda-Grubbs-IL = H2IMes, Hoveyda-Grubbs-II

OTMS

TMSO

H

Me

MeMe G-II

CH2Cl2, reflux

55 %

TMS

MeMe

HMe

TMSO 1) mCPBA, NaHCO3

2) TBAF

MeMe

HMe

TMSO

OH

Poitediol

46 %

NBoc

CO2HHN

CO2tBu

PyBOP

DIPEA

MeCN, rt

81 %

(Amide Bond Formation)

N

N

O

Boc

H CO2tBu

H

H

G-II (5 mol%)

CH2Cl2, D

91 %N

Boc

H

H

N CO2tBu

H


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ACIE, 1997, 36, 166-168

4 Optional Advanced Topics

4.1 Monsanto Acetic Acid Process Scale – over 8 million tons a year of acetic acid derivatives are produced by carbonylation of methanol. The process is 100% atom economic. Methyl iodide is used in catalytic amount as an initiator of the reaction.

--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

4.2 Ziegler-Natta Polymerization The Ziegler-Natta polymerization is a very important process in polymeric chemistry for the polymerization of alkenes, for example propene. It is based on various organometallic catalysts that were first developed by K. Ziegler and G. Natta in the 1950s. The first catalytic system was a mixture of TiCl3 and AlEt3:

Modern catalytic systems, including for example metallocenes, are very efficient catalysts, the loading can go down to 1 g Ti per 150’000 kg polymer. The worldwide production of polypropylene with the Ziegler-Natta-process was 45 billion tons in 2007 (ca. 80 billion CHF). 4.3 Catalytic Hydroboration Catecholborane normally does not react with alkenes without the presence of a catalyst. In the example shown below, Wilkinsons catalyst is used for the reaction. Mechanism: 1) Oxidative addition, 2) Phosphine ligand dissociation and alkene coordination, 3) Migratory insertion in C=C bond, 4) Reductive elimination and catalyst regeneration.

O

O

OMe

HOMe

MeMe

N

SMe

ORO

O

OMe

HOMe

MeMe

N

SMe

OR

Grubbs-I (15 mol%)- C2H4

CH2Cl225 ˚C, 8h

85 %(E/Z) = 1:1.4

Epothilone A

CH3OH

cat. MeIcat. [Rh]

CO, 30 bar180 °C

CH3COOH

RhII CO

CO

RhII CO

CO

CH3

I

RhII COCH3

COI

RhOC

I COCH3COI

I

O

H3C I

O

H3C OH

CH3ICH3OH

HI H2O

oxidative additionrate-determiningstep

reductive elimination

migratory insertion

CO

Men

TiCl3AlEt3 Me Me Me Me

n/4isotactic polypropylene


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4.4 Transition metal-catalyzed Carboalumination Direct carboalumination of non-functionalized alkynes is possible, however, the reaction requires elevated temperatures compared to the catalyzed variant. For this reason Zr-catalysts are typically used to catalyze this reaction. In general, the syn-addition product is observed. The regioselectivity is substrate dependent.

4.5 Transition metal-catalyzed Hydrostannation Regioselectivity is substrate and catalyst dependent, however, this reaction delivers H and Sn from the same side, thus yielding Z-alkene (in respect to R1 and R2).

4.6 C–H Borylation Regioselective C–H activation is possible also for linear alkanes. Note the similarity with the Miyaura cross-coupling with the difference that the C–H has replaced the C–X component.

4.7 Aromatic Borylation

OBH

OBOO oxidation

OH

RhBCl

HO

O

PPh3PPh3

RhCl(PPh3)3

Ph-PPh3

RhBCl

HO

O

PPh3Ph

RhBCl

PPh3O

OPPh3Ph

H

H

RhCl(PPh3)2

H

RAlMe3

RAlMe2

Me

Me3Al Cp2ZrCl2 Me2AlMe

ZrCp2ClCl

R R'

AlMeMeMe ZrCp2Cl

Cl

AlMe

R'R

Me Cl

MeZrCp2Cl

R'

Me

R

AlMe2

Cp2ZrCl2

R R'

R2R1 Bu3SnHPd0 R2

H SnBu3

R1

R1 R2

HBu3Sn

PdLH

LSnBu3 R2R1

SnBu3Pd

R1 R2

HL

LSnBu3Pd

R2 R1

HL

L

reductiveelimination

oxidativeaddition

Me B BO

OO

O

CpRh(4η−C6Me6) BO

OMeH H B

O

O


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H

[Ir(OMe)COD]2, dtbpyB2pin2

80°C, µW

B O

O

Pd0

Ar-IAr

BO

OI

Organometallics II (Lecture 12) 1 Alternative methods for ...

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