Organoruthenium Chemistry 03/02/19• Current market price: $266/ozt, or $8.55/g Aldrich price:...

Organoruthenium ChemistryDongmin Xu Baran Group Meeting03/02/19

Rutheniumd8 second-row transition metalSilvery-white, metallic appearancePossible oxidation states: -2 to +8Toxicity not well studied except RuO4Density = 12.45 g/cm3, m.p. = 2334 °C (8th in metals)6th rarest element in Earth’s crust (after Os, Rh, Ir, Re, Pd)

• Named after Ruthenia, a Latin word that refers to Russia• Ru has 7 natural stable isotopes, along with 34 radioisotopes• Global production ~12 tons per year; projected world reserve ~5000 tons - Mostly as byproduct of copper, nickel, or platinum mining• Current market price: $266/ozt, or $8.55/g Aldrich price: $112/g (200 mesh powder, 99.9% trace metal basis)• Percentage of Ru in mined platinum group metal mixture varies greatly - e.g. 11% in South Africa vs. 2% in certain parts of Russia• Parker 51 fountain pen has a 14K gold nib tipped with 96.2% Ru and 3.8% Ir

Fun Facts:

Important events in the history of Ru:• 1650s: Platinum alloy (contains Pt, Ru, Os, Rh, Pd, Ir) was discovered• 1844: Karl Ernst Claus discovered ruthenium by dissolving crude Pt with aqua regia and examining the residues• 1953: Djerassi discovered the oxidizing capability of RuO4• 1965: Allen and Senoff reported an unprecedented [Ru(NH3)5(N2)]X2 complex• 1987: TPAP was first synthesized by Ley and Griffith• 1992: Grubbs et al reported the first Ru carbene catalyst for olefin metathesis

• Adding 0.1% Ru to titanium increases its corrosion resistance by 100 times• Hardening of Pt and Pd; used in manufacture of jewelry and electrical contacts• Ru-Mo superconductors

Applications:

d8, second-row, variable ox. states and geometries = versatile reactivity• Hydrogenation• Oxidation• Ruthenacycle mediated reactions• Addition to Ru π complexes• Ru vinylidene mediated reactions• C-H activation• Metathesis• Olefin isomerization• Cyclopropanation• Radical addition• Ru-catalyzed click reaction• Cross coupling

Useful Reviews:• Murahashi, Chem. Rev. 1998, 2599.• Trost, Chem. Rev. 2001, 2067.• Alcaide, Chem. Rev. 2009, 3817.• Ru-catalyzed olefin metathesis: Grubbs, Chem. Soc. Rev., 2018, 4510. Hoveyda, JOC, 2014, 4763.• Photoredox: MacMillan, Chem. Rev. 2013, 5322.NOT covered in this group meeting:• Reactions using Ru as a Lewis acid• Photochemistry

Hydrogenation:Chemoselective hydrogenation with H2:

RuCl2(PPh3)3 (cat.)

In the appendices:• Syntheses of common Ru complexes

“Compared to Rh, Ir, and Co, ruthenium complexes generally have less effective catalytic activities for hydrogenation of simple alkenes.”

H2 (100 atm), 50 °C94%

O

Me

OMe

O

Me

OMe

Tsuneda, Bull. Chem. Soc. Jpn. 1973, 279.

RuCl2(CO)(PPh3)3 (cat.)

H2 (14 atm), 158 °C95%

[Ru], ZrO2, ZnSO4 (aq)“bilayer catalytic system”

H2 (50 atm), 150 °C>60%

• Developed by Asahi Chemical Co., Japan• >50000 tons annually

Nagahara, Rev. J. Surf. Sci. Technol. Avant-Garde 1992, 951.

Fahey, JOC 1973, 80.


Transfer hydrogenation:

OtBu

RuCl2(PPh3)3(1 mol%)

MeOH, 150 °C, 5 h78%

tBu OH(cis:trans = 1:4)

M

MH2

R OH

R

O

HA

AH2Pros: homogeneous reaction avoids hazardous H2 no pressurization neededCons: limited scope lower efficiency than direct [H] no universal proton donor (screening needed)

N

Maitlis, J. Organomet. Chem. 1984, c7RuCl2(PPh3)3(0.25 mol%)

HCOOH, 180 °C, 6 h76%

Watanabe, Bull. Chem. Soc. Jpn. 1984, 2440.

NH

Oxidation:Ley-Griffith oxidation: TPAP, NMORuO4 oxidation: often generated in situ with cat. RuCl3/RuO2 and NaIO4

nBunBu

RuCl3 (2 mol%)- Oxidative cleavage of olefins

H

O

17%

(+ 80% unreacted SM)

OH

O

88%Sharpless, JOC, 1981, 3936

• Sluggish reaction due to formation of insoluble Ru-carboxylate complexes• Addition of MeCN causes rapid decomplexation of carboxylates and restores catalytic activity of Ru

NaIO4CCl4-H2O

RuCl3 (2 mol%)NaIO4

CCl4-H2O-MeCN

“To our disadvantage, we organic chemists too often ignore even the most ele-mentary aspects of the coordination chemistry of the metals we employ ascatalysts or reactants” – Barry Sharpless

- Olefin dihydroxylation

RuCl3 (7 mol%)NaIO4

EtOAc-H2O-MeCN0.5 - 3 min

OH

OHShing, ACIEE 1994, 231258%

• Low yield if diol too water-soluble; cleavage in the aqueous phase by NaIO4- Olefin epoxidation

PhPh

N NMe

Me Me

Me

NaIO4CH2Cl2-H2O

RuCl3 (cat.)Ph

PhO

H

H

90%

Eskenazi, J. Chem. Soc. Chem. Commun. 1985, 1111.

- α-oxidation of ethers

- Oxidation of allenes and alkynes- Oxidation of 1° and 2° alcohols- Degradation of aromatic rings to carboxylic acid- C-H oxidationOxidation via oxoruthenium species

C9H19 OMeRuO2 (cat.)

NaIO4CCl4-H2O-MeCN

C9H19 OMe

OO Ph

O

83% 85%Sharpless, JOC 1981, 3936

• Generation of Ru oxo species from peroxyacids Run + ROOOH * Can also be generated under aerobic conditions

Run+1 O OR O Run+2

MeRuCl3 (cat.)

AcOOHDCM-H2O-MeCN

MeO

OH

67%Mechanism:

RuVO O

RuIV

HH2O

then β-Helim.

O

OH

Murahashi, JOC 1993, 2929.

O

Me

CO2H

(if NaIO4 is used)

91%

(If no H2O, get epoxidation instead)


Ruthenacycle Mediated Transformations:

Alkyne + simple olefin: formal ene reaction

R+RuClCp(cod)

EtO2CRDMF, 100 °C

Trost, JACS 1995, 615.

Mechanism:

R2

R1 R4

R3

Ru RuR1

R2 HaR3

R4

HbHb

β-H elim. R2 HaR3

R4R1

RuH

cyclo-metalation R.E.

PDT

• Only Hb can easily adopt syn conformation with Ru• Thus, olefins with allylic protons yield 1,4-dienes, or a formal ene reaction• Sterics determines branched vs. linear selectivity - TMS/TES alkynes give excellent regioselectivity

50%(R = COCH3)(6:1 branched:linear)

Ph H + OH

EtO2C 33

RuClCp*(cod)

DMF, 100 °CPh

H

O

85%(3:1 branched:linear)

- When no allylic protons are present:

Alkyne + norbornene: formal [2+2]

+ R3 CpRu(MeCN)3PF6R1

R2

R1R3

R2+ R3R1

R2A B

R1 R2 R3 A:B Yield

TsHN TMS

TMS

TMS

TES

HO

MeO

nBu

>98:2

>98:2

>98:2

>98:2

78%

79%

61%

88%

CO2Me7

n-pentyl

Me

O

OAc

Ph

Ph

+ CO2Me4% Ru(cod)(cot)

pyridine, 80 °CPh

Ph

CO2Me85%

RuR1

R2 H R3

R4

β-H elim. R2 R3

R1

RuH

R.E.PDT

R4

Wantanabe, Chem. Soc. Chem. Commun. 1991, 598.

Dérien, J. Chem. Soc. Chem. Commun. 1994, 2551

• Ru forced to eliminate with endocyclic hydride• Higher energy process, not observed when allylic protons are present

CO2Me

CO2Me

+RuH2(CO)[PR3]

(cat.)

PhH, 80 °C CO2Me

CO2Me

RuR1

R2 H R3

R4

β-H elim. R2 R3

R1

RuHR4slower

R.E.

faster

R2

R1 R4

R3

• Exocyclic β-H elimination will result in unfavorable anti-Bredt olefin• Steric bulk of norbornene accelerates reductive elimination, outcompetes endocyclic β-H elimination

RuH2(CO)[PR3](cat.)

RR R

RFe(CO)3

then CAN

RR

RR

RR

iterative synthesis of ladderanes

Alkyne + olefin + CO: formal Pauson-Khand

EtMeO2C

MeO2C

Ru3(CO)12

CO (1 atm)DMF, 140 °C

R

RO

Etvia

Ru

OEt

Mitsudo, JACS 1997, 6187

Warrener, JACS 1994, 3645

Mitsudo, JOC 1979, 449287%


Norbornene + propargyl alcohol: facile cyclopropanation Homo Diels-Alder:

Formal [6+2] cycloaddition (stoichiometric):

[2+2+2] alkyne trimerization:

Enone-allene cycloetherification/amination:

OH+

Me

OCp*Ru(MeCN)3PF6

RuII

RuIV OH

RuIV OH

•

RuIV

HO

OH

R.E.

β-OHelim.1,2-M.I.

Me

O

Takahashi, Chem Lett 1997, 1273

MeOH, rt (quant.)

Takahashi, Bull. Chem. Soc. Jpn. 1999, 2475

•BnHN

+

+

O

Ph

O

10% CpRu(MeCN)3PF6

15% CeCl3•7H2ODMF, 60 °C

Cy

O

Ph

O

NBn

10% CpRu(MeCN)3PF6

15% TiCl4DMF, 60 °C

•

OHO

H

HH

72%

3

62%

Trost, JACS 1999, 10842Trost, JACS 2000, 12007

EtO2C +

RuClCp(cod)(cat.)

MeOH, reflux91%

CO2Et

Mechanism:Ru

R

RuR

migratoryinsertion

reductiveelimination

R

Trost JACS 1993, 8831

Ru(nbd)

0 °C

acetylene

Ru Ru 67%

reductiveelimination

Formal [5+2] cycloaddition:

RuII

R.E.

R

RuIV

R

1,2-insertion

RuIVR

R

Trost JACS 2000, 2379

Itoh, Chem. Lett. 1983, 499

MeO2C

MeO2C

Me+

nBu

H

Cp*Ru(cod)Cl(1 mol%)DCE, rt

85%93:7 A:B

Me Me

A BItoh, Chem. Commun. 2000, 549

nBu

nBuviaRu

R

O

Nun


Cycloisomerization of dienynes:

Murai, JACS 1998, 9104

E E

E

E

(E = CO2Et)

[RuCl2(CO)3]2

MePh, 80 °C, 4 h84%

H

H

HH

E

E

E

E

Mechanism?

Addition to Ru π Complexes

Addition to alkynes:With halide:

CpRu X

Rvs.

CpRu

R

+

X–

anti-metalation

syn-metalation

Addition to π-allylruthenium complexes:

R

X

LnRuX

R

LnRu

LnCpRu

covalentcomplex

ioniccomplex

R'

O

R'

O

R R'

OX

X R'

OR

C6H13

+Me

OH

10%CpRu(cod)ClSnCl4, Me4NCl

DMF, 60 °C

10%CpRu(MeCN)3PF6

LiBr, SnBr4

acetone, 60 °C

Cl

C6H13

Me

O

C6H13

Br

Me

O

- Rationale for E/Z selectivity:

88%, 1:6.6 E:Z

72%, >15:1 E:Z

Trost, JACS 1999, 1988.Trost, JACS 2000, 360

(Z) (E)

With water:

acetone, rt

10%CpRu(MeCN)3PF6

CSA, H2O

acetone, rt

5%CpRu(MeCN)3PF6

EtO2C

EtO2C Me

PhO

Ph

OEtO2CEtO2C

O

Ph

OEtO2CEtO2C

Me75%

60%Mechanism?

Trost, JACS 2000, 5877.With carboxylic acid:

With CO2:

HHO

MeMe Me(dppe)Ru

2 Me

Me OPhCO2H, 70 °C

O Ph

OOHMeMe

O

O Ph

OHMe

Me

68%

Picquet, J. Chem. Soc., Chem. Commun.1997, 1201

• MeCN is a strong ligand, thus more ionic X–

HnPrHN PPh3, CO2

Toluene, 100 °C

Ru(cod)(cot)O N

OnPr

Mitsudo, TL 1987, 4417

Ru(CO)3Br

PhCHOEt3N

CO2Me

Na

MeO2C

CO2Me

CO2Me

Ph

OH

55%

70%

• Ambiphilic nature of Ru π-allyl complexesWatanabe, Organometallics 1995, 1945


Addition to Ru vinylidene complexes:

Ru

Cp

ClPh3P

Ph3PR

– PPh3Ru

Cp

Ph3PCl •

R

Generation of vinylidene species:

Ru

Cp

ClPh3P

R

1,2-hydrideshift

Quenched with O nucleophiles:

NCO2tBu

+ OH

Me

10%CpRu(PPh3)2Cl

(solvent)NH4PF6100 °C N

CO2tBu

O

Me

44%Mechanism:

Ru

Cp

Ph3PCl •

R

• Analogous to Corey-Fuchs

OH

R' Ru

Cp

Cl •R

O

R'

H

Ru

Cp

ClO

R

R'

metalla-Claisen Ru

Cp

ClO

R

R'

reductiveelimination R

O

R'

Quenched with C nucleophiles:Trost, JACS 1990, 7809

• RuLn RuLn

H

O

5% RuCl2(cymene)PPh3

NH4PF6, CH2Cl289%

OMerlic, JACS 1996, 11319

[Ru] 1,3RuLn

H

R.E.

C-H ActivationOrtho C-H activation:

O Ph

TMS

+O

TMSPh

76%, 2:1 E:Z

RuH2(CO)(PPh3)3

NtBu

+Si(OEt)3 Ru3(CO)12

N

75%

CF3 CF3tBu

Si(OEt)3

• Other possible directing groups: nitrile, ester, oxazoline• Other possible transformations: allylation, acylation, sulfonation, etc.

N+

Br 2.5% [RuCl2(C6H6)]2 NPh

95%

Murai, Organomet. Chem. 1995, 151

Murai, Chem. Lett. 1998, 1053

Useful review: Dixneuf, Chem. Rev. 2012, 5879.

MeMe

Inoue, Org. Lett. 2001, 2579

Meta C-H activation:Useful review: Frost, Chem. Soc. Rev., 2017, 7145

2-py

OMe

[RuCl2(p-cymene)]2(2.5 mol %)

Piv-Val-OH (30 mol %)

K2CO3, dioxane100 °C, 20 h

78%

N

MeO

O

Me

+ O Me

BrAckermann, JACS 2015, 13894

2-py

+ NBS[RuCl2(p-cymene)]2

(5 mol %)DMA, 80 °C, 24 h

52%Me

NBr

MeHuang, ACIE 2015, 15284


Principles of σ-activation:

RuIIAr

RCO2 OO

R

NH

RCO2H

RuIIAr

O2CRN

RuIIAr

O2CRN

R

R

RuIIRuIIIX

R

•

N

RRCO2H

RuIIAr

O2CRN

R

RuIIIXRCO2K

RuII

KBrRCO2H

X

sp3 C-H activation:

Me

Me

NC

RuH2(dmpe)2(cat.)

d6-benzene140 °C

NH

Me98%Mechanism? Jones, JACS 1986, 5640

Olefin Metathesis

PhNO2 + CO +

Ru3(CO)12(cat.)ligand

160 °C

NHPh

59%

Ligand =NN p-tolylp-tolyl

• in situ reduction of PhNO2 to aniline by CO, followed by allylic C-H amination

Cenini, JACS 1996, 11964

Ru

MesN N

RuS

S

MesN NMes

O R

R

i-PrO

OO

NO +−

MesN NMes

Ru

Oi-PrCl

Cl

Ru

PPh3

PPh3

ClCl

Ph

Ph PCy3

RuPh Cl

Cl

PCy3

MesN NMes

RuPh Cl

Cl

PCy3

Ru-1First Grubbs catalyst

“Grubbs 0”1992

Ru-2Grubbs I

1995

Ru-3Grubbs II

(Mes = 1,3,5-mesityl)1999

Ru-4Hoveyda-Grubbs II

2000

Ru-5Grubbs Z-selective

catalyst2011

Ru-6Hoveyda catechothiolate

Z-selective catalyst2013

Key players in this field:

Major OM catalysts:

Other notable events:• 1955: First instance of olefin metathesis, Ti-catalyzed ROMP of norbornene, was discovered by chemists at Du Pont• 1965: First Ru-catalyzed ROMP with RuCl3•nH2O was reported• 1971: Chauvin proposed the [2+2] mechanism• 1987: Schrock reported a tungsten alkylidene complex for OM• 2009: First example of Z-selective OM was reported by Schrock and Hoveyda

H2O +


General mechanism:

M

R1 R2 [2+2]

M

R1 R2 cyclo-reversion

M+ + R1 R2

• Homo- vs. cross-metathesis• Reversibility of OM complicates Z:E selectivity; post-metathesis isomerization

Principles of Z-selective olefin metathesis:• Step #1: Force a syn metallocyclobutane intermediate!

• Step #2: Controll Z/E selectivity by steric gradient of the catalyst

S

RuS

S

ArN NAr

Cl

Cl

RuS

S

ArN NAr

Cl

Cl

R3

R3

Ru

ArN NAr

SCl

Cl

S

Ru

ArN NAr

SCl

ClR1

R2 R3

R2

R1R3

more favored

R2

R1

R2R1

(major)

(minor)

R2

R2

R1

R1

less favored

vs.M

NHClarge

small

• Some examples:

MesN NMes

Ru

Oi-PrCl

Cl

Cl

Ru

ArN NAr

Cl

R1R2

R1 R2

vs.Ru

ArN NAr

Ar

Cl Cl

Ar R2

R1

syn antihigher energy

stereocontrol possiblelower energy

stereocontrol difficult

S

Ru

ArN NAr

SCl

ClR1

R2

Ar

syn

Ru

ArN NAr

S S

Ar R2

R1

antigeometrically impossible

RuS

S

MesN NMes

O Cl

Clvs.

R1 R2

Ru

MesN N

i-PrO

OO

NO +−

Grubbs & Houk, JACS 2012, 1464

Hoveyda, Organometallics 2016, 543(Boc-Tyr)

HN

NH

HN

NH

CO2Me

O

O Bn

O

HN

NH

NH

CO2Me

BnO

ONH

O(Boc-Tyr)

2 mol% Ru-6, 20 eq.Me Me

THF (0.25 M), rt, 12 hthen 10 mol% Ru-6

THF (50 mM), 35 °C, 24 h72%, >98:2 Z:E

Hoveyda, JACS 2017, 10919

O

O+

Ru-4

Ru-6

Ru-5

Ru-5 (2 mol%)

THF (0.5 M)35 °C, 5 h(4 equiv.)

OO

O

OMe8 8 OMe

O

84%, >95:5 Z:EGrubbs, Chem. Sci. 2014, 501


Other Transformations

Cyclopropanation:

Tandem RCM-Kharash addition:

Photochemistry (NOT covered)

Ru-catalyzed click reaction:

Cross coupling:

Ph OtBu

O

N2

+[Ru] (cat.)

DCM, rt

Ph

CO2tBu Ph CO2tBu

97 : 3 94% ee 87% ee

65% yield

NN

OO

N

iPr iPrRu

Cl

Cl

[Ru] =

Itoh, JACS 1994, 2223.

Useful review: Johansson, Chem. Rev. 2016, 14726.

Ph

Ph N3

+

Ru(OAc)2(PPh3)2RuHCl(CO)(PPh3)3

RuH2(CO)(PPh3)3RuCl2(PPh3)3

Cp*RuCl(PPh3)2Cp*RuCl(cod)

Cp*RuCl(nbd)[Cp*RuCl2]2

NN

N

Ph

Ph NN

NPh

Ph

1,4-disubstituted 1,5-disubstituted

• Mechanistic studies point to the formation of a Ru acetylide complex

HN O

CCl3

5 mol% Grubbs-I

MePh, 155 °C, 2 h

HN O

CCl3

HN

O

Cl ClCl

85%

Snapper, JACS 2005, 16329

HN O

CCl3

5 mol% Grubbs-Istyrene

MePh, 140 °C, 2 h

HN

O

Cl

H

HCl

Ph

Cl 78%, dr = 1:1

Br+ MeMgBr

RuCl2(PPh3)3(cat.)

PhH, 80 °C

Me

Murahashi, JOC 1979, 2408

Tandem RCM-hetero Pauson-Khand:

O N76%

10 mol% Grubbs-IIMePh, 100 °C, 1 h

then NaOMe (20 mol%)CO (7 atm), 180 °C, 30 h

O

O

Py

Snapper, JOC 2011, 3644

Useful review: MacMillan, Chem. Rev. 2013, 5322

RuIIN

N

NN

NN

• Reduction• Oxidation• Radical cyclizations• Cycloadditions• Addition to arenes ……

hvRuIII

N

N

NN

NN

*

eg*

π *

t2g

eg*

π *

t2g

oxidant reductant

Ru(bpy)3+Ru(bpy)3

3+

“It is amazing that so much has been done with only a handful of ruthenium complexes as the actual catalysts. The obvious scope of possibilities for catalyst design strongly reinforces the notion that immense opportunity abounds.’

– Barry M. Trost

Organoruthenium Chemistry 03/02/19• Current market price: $266/ozt, or $8.55/g Aldrich price:...

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