Ruthenium in Organic Synthesis

O O
R1
R1 R2
R2 Ru
•

R1
H
Ru
O

R2
Ru R1
•
Ru
O

R2

H O
R1 Ru
H R2

Ernie Cruz
Literature Presentation
02 February 2004
147 Noyes

Ruthenium in Organic Synthesis: Outline

I. Regioselective Reductions

II. Oxidations

III. C-C bonds

A. Ruthenacycle Intermediates
B. Heteroatom Additions to Alkynes
C. C-H Activation
D. Diazo Compounds

IV. Appendix: Preparation of Ruthenium Catalysts

Trost Noyori Ley Murahashi

Reviews

Murahashi Chem. Rev. 1998, 98, 2599.

Trost and Toste Chem. Rev. 2001, 101, 2067.
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 Properties of Ruthenium

Ruthenium has the widest range of oxidation states of any element

Ru(CO)42- Ru(CO)5 RuO4

-2 0 +8

Ruthenium complexes can adopt several coordination geometries

Oxidation Coordination
State number Geometry Example
Ru(0) 5 trig. bipy. Ru(CO)5

Ru(II) 5 trig. bipy. RuHCl(PPh3)3

6 octahedral RuCl2CO(PR3)3
Ru(III) 6 octahedral [Ru(NH3)5Cl]2+
Ru(VI) 4 tetrahedral RuO42-
Ru(VII) 4 tetrahedral RuO4-

Ru(VIII) 4 tetrahedral RuO4

Range of reactivity due to properties of Ru complexes:

1. High electron transfer ability
2. High Lewis acidity
3. Low redox potentials
4. Stabilities of reactive metallic species such as oxometals, metallacycles, and metal carbene complexes

Regioselective Reductions

cat. RuHCl(PPh3)3
1 atm H2, 25 °C
benzene-ethanol
J. Chem. Soc. Chem. Comm. 1967, 305.

O O

cat. RuCl2(PPh3)3
100 atm H2, 50 °C
benzene
(94%) O
O
Bull. Chem. Soc. Jpn. 1975, 48, 2852.

O
O cat. RuCl3/P(m-C6H4SO3Na)3 cat. RuCl2(PPh3)3
OH
20 atm H2, 35 °C OH 12 atm H2, 180 °C O
H O
toluene, buffer O (99%)
97% conversion
99% selectivity
Organometallics 1991, 10, 2126. J. Organomet. Chem. 1982, 231, 79.

O cat. RuCl2(PPh3)3
O O
24 atm H2, 100 °C
O (72%) 9:1
O
LAH
1:19
O (70%)
J. Chem. Soc. Chem. Comm. 1976, 314.
2
 Alcohol Oxidation-Reductive Amination

R1R2CHOH + (Ru) (R1R2C=O)(Ru)(H2)

R1 R1
H cat. Ru
N R4 (R1R2C=O)(Ru)(H2) + R3R4NH (R1R2C=NR3R4)+(Ru)(H)- + H2O
R2 OH R3 R4 R2 N
R3 (R1R2C=NR3R4)+(Ru)(H)- R1R2CHNR3R4

catalyst amine alcohol product % y ield

RuH2(PPh3)4 C8H17NH2 C7H15OH C7H15NHC8H17 92

RuCl2(PPh3)3 PhNH2 C3H7OH PhN(C3H7)2 88

RuCl3·nH2O· CH3OH 99
P(OBu)3

N N
H

Ru(cod)(cot) C2H5OH 85

N NH2 N NHC2H5

OH
RuCl2(PPh3)3 100

NH2 N
H

Murahashi TL 1982, 229.

Tetrapropylammonium Perruthenate (TPAP) Oxidations

[RuO4]- is a milder oxidant than RuO4; can cleave some C=C bonds
[RuO4]- salts with large organic cations are soluble in organic solvents
Water inhibits catalyst turnover; use molecular sieves
TPAP catalytic (5 mol %) with suitable co-oxidants; NMO most effective
Wide tolerance of functional groups
1. Double bonds, polyenes, enones, halides, cyclopropanes, epoxides, and acetals
2. Esters, amides, lactones, amines, peroxides, and catechols
3. Protecting groups: SEM, MOM, BOM, MEM, trityl, silyl, benzyl, PMB, THP, acetate, and benzoate
4. Piperidines, pyrroles, indoles, furans, thiophenes, and pyridines are unreactive

O TBDPSO
O
H H
O
H
O O O
H
OTBDPS
O OBn
70%
85% 88% 96%

OH O
O O O
OH O
90%
98%
OH OH OH

O O O O

O O O O

Panek JACS 2002, 124, 12806.

Ley Synthesis 1994, 7, 639 and ref. therein.
3
 Ruthenacyclopentane: Allene and Vinyl Ketone Coupling

O O
Ru catalyst
R1
• R2 R2
cocatalyst
R1

O O
R1
R1 R2
R2 Ru
•

O
O
Ru R1 Ru
H R2
• R2
R1

H O
R1 Ru
H R2

JACS 1999, 121, 4068.

Ruthenacyclopentane: Allene and Vinyl Ketone Coupling

O O
O O
AcO 10% CpRu(COD)Cl
AcO
• 15% CeCl3
O PhH, 80 oC
DMF, 60 oC
(81%)

O
O O CO2H
H H
O HCl, MeOH O
H
AcO 72% yield 2 steps
H H
O O

Role of CeCl3 cocatalyst unknown; may activate enone

Variety of allenes coupled to methyl or phenyl vinyl ketone
in good yields (53-81%)

JACS 1999, 121, 4068.

4
 Ruthenacyclopentane: Allene and Vinyl Ketone Coupling

O O
Ru catalyst Nu
HNu • R n
n cocatalyst R

Nu O
HNu O
n
R n
Ru R

•
H+

O
O
HNu Ru
Ru n R
Nu R
n

O Unclear whether nucleophilic

Ru addition occurring onto !- or "-
H+ HNu bound allylruthenium intermediate
n R

Alcohols: JACS 1999, 121, 10842.

Amines: JACS 2000, 122, 12007.

Ruthenacyclopentane: Allene and Vinyl Ketone Coupling

allene Product Yield

O
X • X=O 82%
X X = NBn 73%

O
X • X=O 74%
X X = NBn 67%

O
X • X=O 70%
X Ph X = NBn 62%

H
O
• X=O 68%
X = NBn 90%
X X
H
H
O
• X=O 67%
X = NBn 71%
X
H
X

Ru catalyst: 10% CpRu(CH3CN)3PF6

Cocatalyst:
-Alcohols require 15% CeCl3
-Amines use 15% TiCl4 or MeAlCl2

5
 Ruthenacyclopentene: Alkyne and Alkene Coupling--An Alder-Ene Reaction

R2 Ru catalyst
R2 or R1 R2
cocatalyst R1
R1

R2
R2
R1
or Ru
R1 R2
R1

R1 Ru Ru Ru R1
H H Ru
R2 R2 R2
R1 R1 R2
H
R1 Ru R2
The reaction usually favors H
formation of the more substitued
carbon of the alkyne.
H
Ru R2
H

R1
JACS 1993, 115, 4361; JACS 1995, 117, 615.

Ruthenacyclopentene: Alkyne and Alkene Coupling--An Alder-Ene Reaction

OH OH OH
OH OH OH
10% CpRu(COD)Cl
CO2CH3 CO2CH3 CO2CH3
20% NH4PF6
MeOH, reflux
(65%) CO2t-Bu
CO2t-Bu
12.5:1, A:B CO2t-Bu

A B

OH
n-Bu 10% CpRu(COD)Cl n-Bu
(65%) n-Bu OH
OH
1:9.9 A:B
A B

CH3O2C
4 10% CpRu(COD)Cl CH3O2C
4
acetone, rt
Isolated as a single regioisomer
(88%)
TMS
TMS

JACS 1993, 115, 4361; JACS 1995, 117, 615.

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Application in Total Synthesis: The Proposed Structure of Amphidinolide A

O
1. 10% Cp*Ru(CH3CN)3PF6
O O
O OH

O OFmoc O

2. Piperidine
O O
O O
Cycloisomerization: 76% yield
brsm as 3.5:1 mixture of branched
and unbranched isomers

O
O
HO
O O
O O
O 1. 10% CpRu(CH3CN)3PF6
HO
O 2. H +

HO
O
OH
O
Proposed structure of amphidinolide A;
58% yield for cycloisomerization

Trost JACS 2002, 124, 12420.

Ruthenacyclopentene: Intramolecular [5+2] Cycloaddition

R

R Ru catalyst

R
R

Ru

R
RuCp
RuCp
R

RuCp

Ru catalyst: 10 mol % CpRu(CH3CN)3PF6

Solvent: DMF or acetone
Mild conditions: conducted at rt
Bi- and Tricyclic cycloheptadienes formed in
good yields (73-92%)

Trost JACS 2000, 122, 2379.

7
 Ruthenacyclopentene: Intramolecular [5+2] Cycloaddition Examples
"Complete diastereoselectivity is always observed" (Diastereomers are observed for substitution at other allylic position)

MeO2C H
MeO2C 10% CpRu(MeCN)3PF6
MeO2C H acetone, rt MeO2C
(85%) H

TMS Reactions are slower and require

R higher temperatures and catalyst
TMS loadings for formation of [6,7]
15-20% CpRu(MeCN)3PF6 ring systems
TsN TsN
acetone, 50 °C
R H
R = H; 87% yield
R = CH2OTBS; 79%

Regioselectivity controlled by choice of substituents

H
10% Ru 10% Ru MeO2C
MeO2C MeO2C
acetone, rt MeO2C R acetone, rt OTIPS
MeO2C
MeO2C H H (85%) H
(80%)
H

MeO2C 10% Ru MeO2C MeO2C

R
MeO2C H acetone, rt
H R MeO2C MeO2C
H H
R = CH2OTIPS 3:1 mixture of regioisomers

Trost JACS 2000, 122, 2379.

Intramolecular [5+2]: Rationale of Cyclopropane Ring Opening

O

H E E
E R
E R
H H MeO2C
E H
H R
E E
E R
R = CH2OTIPS
E H E E
H R H H

Ru E
H ! = 0° R
Rtrans E
Ru H R = CH2OTIPS
H H Rcis
H E
R
Rcis Rtrans
E
H

H H Rcis
Ru R
Rtrans
Rcis Rtrans
E
Ru Rcis
H Rtrans E
H
H
H R = CH2TIPS
O
! = 0° H H
Rtrans
Ru E
Rcis

E
H

Trost JACS 2000, 122, 2379.

8
 Ruthenacyclopentadiene: [2+2+2] cycloaddition
R R
Ru catalyst

R1
R1

R
Ru
R1

Ru Ru
R

R1

Steric interaction between R-group

and metal center forces the larger
R
group to be situated in the R1-position.
Ru R
R1

R1

Itoh JOC 1998, 63, 9610; Chem. Commun. 2000, 549.

Ruthenacyclopentadiene: [2+2+2] cycloaddition

MeO2C 1% Cp*Ru(COD)Cl MeO2C

O Itoh JOC 1998, 63, 9610.
MeO2C O MeO2C
, 40 °C

(87%)

MeO2C
MeO2C
1% Cp*Ru(COD)Cl MeO2C
Itoh Chem. Commun. 2000, 549.
MeO2C DCE, rt A
(85%)
93:7, A:B MeO2C

MeO2C
B

9
 Heteroatom Additions to Alkynes: Addition of Water
O
Ru catalyst R R'
R R' cocatalyst
H2O O O

R R'

O O R

H+
Ru

O
Ru
Ru
O R'
R
R H2O

H+

Ru
O Ru R' R
O Ru

R O O R OH

R'

Trost JACS 1997, 119, 836.

Heteroatom Additions to Alkynes: Addition of Water

O O O
5 mol % CpRu(COD)Cl
NC NC
Ph NH4PF6, In(OTf)3 Ph
DMF/H2O 1:1, 100 °C
(93%)
Role of indium unclear;
Cl- scavenger? Trost JACS 1997, 119, 836.

O O
OH 5 mol % CpRu(COD)Cl
NH4PF6, In(OTf)3 HO
O DMF/H2O 1:1, 100 °C
(80%)
HO
Trost JACS 1997, 119, 11319.

Intramolecular Variant
O O
10 mol % CpRu(MeCN)3PF6 MeO2C MeO2C H
MeO2C
O O K2CO3
CSA, H2O MeO2C MeO2C
MeO2C MeOH
acetone, rt Ph
Ph Ph (69%)
(75%, 2:1 dr) H
single diastereomer
Trost JACS 2000, 122, 5877.

An alternative mechanism at work?

10
 Heteroatom Additions to Alkynes: Addition of Water (Alternative Mechanism)

1,5-Diketone product may result O

from hydrolysis of pyran product. R
O R
H2O R' O
R
Ru
O
R' O
R'

Ru
R
O

R'

R R OH
R
Ru Ru Ru
O
O O
R' R' R'

Trost JACS 2000, 122, 5877.

Heteroatom Additions to Alkynes: Addition of Water (Alternative Mechanism)

O
MeO2C
10 mol % CpRu(MeCN)3PF6
O
MeO2C
CSA, H2O
MeO2C acetone, rt Ph
O (93%)
MeO2C
Ph MeO2C
5 mol % CpRu(MeCN)3PF6
O
MeO2C
acetone, rt
(60%) Ph

10 mol % CpRu(MeCN)3PF6, 10 mol %CSA, H2O 5 mol % CpRu(MeCN)3PF6, acetone

O

O
O O 70% yield, 2:1 dr TsN
TsN 89% yield
TsN Ph
Ph Ph

CHO
CHO
O O 85%, 12:1
O
86%, 10:1

51%
O
O
Ph
Ph Trost JACS 2000, 122, 5877.
11
 Aromatic C-H Bond Activation

X X
Ru catalyst
R
R'

X
[Ru] X
R
R'

X X
X
Ru H or
Ru Ru
R H
R'
R'
R

R
X
R
Ru
R'
Requires aid of chelation from ortho- H
coordinating functional group (usually ketone)
R'
Excellent control of regioselectivity for activation
of aromtic C-H at the less hindered ortho-position

Reviewed in Murai Pure Appl. Chem. 1997, 589.

Aromatic C-H Bond Activation

R O
R O
1 mol % RuH2(CO)(PPh3)3 R=H (80%)
R = CF3 (92%)
Si(OEt)3 R = OMe (11%)
Si(OEt)3 R = CH3 (100%)

t-Bu t-Bu
R N R N
R = H (78%)
2 mol % Ru3(CO)12 R = CF3 (75%)
Si(OEt)3 R = F (79%)
R = CH3 (81%)
Si(OEt)3

Si(OEt)3

O
O
1 mol % RuH2(CO)(PPh3)3
Si(OEt)3
toluene, 125 °C
(85%)
N
N

SiMe3

O O
SiMe3 2 mol % RuH2(CO)(PPh3)3

toluene, 125 °C
(85%)

Reviewed in Murai Pure Appl. Chem. 1997, 589.

12
 Cyclopropanation
Ph Ph cat. load A(%ee):B(%ee)
N2 cat. Ru catalyst (mol %) Yield

CO2Et CO2Et Ph CO2Et R = i-Pr

A B
O O 5 73 91(89):8(78)
N Cl
N Ru N
Cl R=H
R
E 5 93 89(90):11(66)
N2
Ln
R E
Ru
R O
N N N
Ln E Ru 5 45 7(15):93(97)
Ln E Ln E Ru N2 O Cl O
Ru Ru
or Ph Ph
R
R R

Ln E
Ru
N2
R R

0.15 100 95(91):5(27)

N CO N R=

R Ru R
N N

Trost Chem. Rev. 2001, 2067 and ref. therein.

Preparation of Ruthenium Catalysts

4. Encylopedia Reagents Org. Syn. 1996, Vol. 6, 4415. 15. Inorg. Synth. 1974, 15, 45.
8. Synthesis 1994, 639; Aldrichimica Acta 1990, 23, 13. 16. JCS Dalton Trans. 1980, 1961.
9. J. Organomet. Chem. 1981, 214, 391. 17. JCS Chem. Comm. 1982, 1388.
10. J.C.S., Dalton Trans. 1975, 1710. 18. JCS Dalton Trans. 1974, 233.
11. J. Organomet. Chem. 1980, 195, 77. 19. Chem. Lett. 1984, 1161.
12. Inorg. Synth. 1970, 12, 237. 20. Organometallics 1988, 7, 2243.
13. JACS 1968, 90, 1089. 21. J. Organomet. Chem. 1986, 314, C46.
14. ACIEE 1995, 4, 2039; JACS 1996, 118, 100.
13
 Conclusion

Wide scope of reactions catalyzed or mediated by Ruthenium complexes

Relatively new area in C-C bond formation;

50% literature cited in Trost's review was published in 1997 or later

"Prospects are clearly bright for more reactions to be discovered." --Trost

14