reactions for organic synthesis non-metathesis · pdf filereactions for organic synthesis...
TRANSCRIPT
Reactions for Organic Synthesis
Tristan Lambert
MacMillan Group Meeting
May 23, 2002
Non-Metathesis Ruthenium-Catalyzed
I. Properties of Ruthenium
II. Reductions
III. Oxidations
IV. Isomerizations
V. C-C bond forming reactions
Murahashi, Chem. Rev., 1998, 2599.
Trost, Toste, Chem. Rev., 2001, 2067.
Properties of Ruthenium
Ru4d75s1
Ruthenium has the widest range of accessible oxidation states of any element in the periodic table
Ru(CO)42- RuO4
Ru-II RuVIIIRu0
Ruthenium complexes of each oxidation state can assume several coordination geometries
Oxidation Coordinationnumber Geometry Examples
Ru0
RuII
RuIII
RuVI
RuVII
RuVIII
5
5
6
6
4
4
4
trigonal bipy. Ru(CO)5
trigonal bipy. RuHCl(PPh3)3
octahedral
octahedral [Ru(NH3)5Cl]2+
tetrahedral RuO42-
tetrahedral RuO4-
tetrahedral RuO4
state
Cotton, 5th Ed.
Ru complexes are generally characterized as
having high electron transfer ability, high Lewis
acidity, low redox potentials, and the ability to
stabilize reactive species such as oxometals,
metallacycles, and metal carbene complexes.
The wide range of oxidation states, coordination
geometries, and tunable properties result in the
ability of Ru complexes to catalyze a remarkable
range of chemical transformations
RuCl2CO(PR3)3
Regioselective Reduction of Unsymmetrical Cyclic Anhydrides
O
Me
Me
O
O
O
Me
Me
O
O
Me
Me
O
RuCl2(PPh3)3
2 mol%
reducing agent
reducing agent
LiAlH4
A B
yield % A : B
70
72
1 : 19
9 : 1H2
Morand and Kayser, J.C.S., Chem. Comm., 1976, 314.
O
MeO
MeO
OMe
OMe
O
O
O
MeO
MeO
OMe
OMe
O
Ru2Cl4(dppb)3
H2 (15 atm), 160 oC
88%
Ikariya, Tetrahedron Lett., 1986, 365.
Asymmetric Hydrogenation of Prochiral Olefins
MeO
CO2H
MeO
Me
CO2HRu(OAc)2[(S)-BINAP]
cat.
H2 (135 atm)
(S)-naproxen
97% eeNoyori, J. Org. Chem., 1987, 3176.
O
O
O
Me
O
{RuCl[(S)-BINAP] (benzene)} Cl
0.1 mol%
H2 (100 atm)
Et3N
92% eeTakaya, J. C. S., Chem. Comm., 1992, 1725.
O O
O
Me
Me
O O
O
Me Me
MeRu(OCOCF3)2[(R)-BINAP]
0.5 mol%
H2 (20 atm)
95% ee
Bruneau and Dixneuf, J. Org. Chem., 1996, 8453.
NCHO
MeO
MeO
OMe
OMe
NMe
MeO
MeO
OMe
OMe
(R)-laudanosine >99.5% ee
Ru(OAc)2[(R)-BINAP]
1 mol %
H2 (4 atm)
LiAlH4
Noyori, JACS, 1986, 7117.
Enantioselective Reduction of Ketones
MeOH
ORuCl2[(R)-BINAP]
0.5 mol%
H2 (93 atm) MeOH
OH
100% yield
92% ee
MeNMe2
O 0.1 mol%
H2 (50 atm)Me
NMe2
OH
72% yield
96% ee
Ru(OAc)2[(S)-BINAP]
NTs
HNTs
84% ee
Ru(OAc)2[(S)-BINAP]
5 mol%
80% yield
Charette, Tetrahedron Lett., 1996, 6669.
Noyori, JACS, 1988, 629.
Me Me
O O
Me Me
OH OH{Ru2[(R)-BINAP]2Cl4}NEt3
0.15 mol %
H2 (80 atm)
100% yield
99% ee
Me OMe
O O
Me OMe
OH ORuCl2[(R)-BINAP]
0.05 mol %
H2 (100 atm)
99% yield
99% ee
Noyori, JACS, 1988, 629.
Noyori, JACS, 1987, 5856.
Cl
Ru
HP
P
O
O OMe
Me
H
Ru
ClP
P
O
OMe
OMe
S
favored
unfavored
P
P= (R)-BINAP
Me Me
R
Dynamic Kinetic Resolution of !-Keto Esters
R1 OR3
O O
R2
R1 OR3
O O
R2
R1 OR3
OH O
R2
R1 OR3
OH O
R2
H2
Ru-BINAP
H2
Ru-BINAP
acyclic
syn-favored
cyclic
anti-favored
If equilibration is faster than hydrogenation, high ee's can be obtained
Me OMe
O O
NHCOMe
Me OMe
OH O
NHCOMeH2 (100 atm)
RuBr2[(R)-BINAP]
O O
OMe
OH O
OMe
RuCl(C6H6)-
[(R)-BINAP]Cl
H2 (100 atm)
98% ee
93% ee
99 : 1 syn : anti
1 : 99 syn : antiNoyori, JACS, 1989, 9134.
Ru
H
X
OP
P
OOMe
Ru
H
X
OP
P
O
Me
O
H
N
H
Me
O
Me
OMe
O O
OMe
OH O
H2 (100 atm)
RuBr2[(R)-BINAP]Ph Ph
NHBoc NHBoc
0.5 mol%
0.1 mol%
99% ee
0.2 mol%
> 99 : 1 syn : anti
4-Substituted !"keto-esters can be used as well
Noyori, Tetrahedron Lett., 1988, 6327.
Directed Hydrogenation of Allylic and Homoallylic Alcohols
Me
Me Me
OH
Me
Me Me
OH
Me
Me Me
OH
Me
Me Me
OH
Ru[(S)-BINAP]
Ru[(S)-BINAP]
Ru[(R)-BINAP]
geraniol
nerol
(R)-citronellol
(S)-citronellol
98% ee, 97% yield0.2 mol% cat.
Noyori, JACS, 1987, 1596.
Me
Me Me
Me
Me MeRu[(S)-BINAP]
OH OH
Olefins allylic to alcohols can be selectively and asymmetrically hydrogenated
Homoallylic alcohols similarly under slightly more forcing conditions
0.5 mol%
(100 atm H2)
(30 atm H2)
Homo homoallylic alcohols and higher analogs are inert
Me
Me Me
OH no rxnRu[(S)-BINAP]
0.5 mol%
(100 atm H2)
P
P
Ru
O
O
O
O
CH3
CH3
Ph2
Ph2
(R)-homocitronellol
96% yield
92% ee
Ru[(R)-BINAP]
homogeraniol
Oxidation of Diols to Lactones
HOOH
OO
180 oC, acetone
99% yield
HONMe
OHMeN O
O
RuH2(PPh3)4
RuH2(PPh3)4
2 mol%
2 mol%
180 oC, acetone
95% yield
OH
OH O
O
H
H
RuH2(PPh3)4
2 mol%
180 oC, acetone
90% yield
HO OH
Me
MeO
O
O
O
MeMe
MeMe
RuH2(PPh3)4
2 mol%
20 oC, toluene 99.6% yield
0.4% yield
Nozaki, JOMC, 1994, 473, 253.
Saburi and Yoshikawa, JOC, 1986, 2034
Murahashi, JOC, 1987, 4319.
OH
OHO
O[RuCl((S)-BINAP)-
60 oC, toluene 61% yield
23% ee
(C6H6)]Cl
0.2 mol%
H2NOH
NH
O140 oC, DME
RuH2(PPh3)4
2 mol%
hydrogen
acceptor
Murahashi, SynLett, 1991, 693.
Reactions can be performed intermolecularly to form esters and amides
59% yield
PhCH=CHCOCH3
PhCH=CHCOCH3
Oxidative Cleavage of Olefins
O
OAc
AcO
OAc
OCHO
CO2H
OAc
AcO
OAc
97% yield
0.2 mol% RuO2
NaIO4, CCl4-H2O N
CO2Et
Me NCHO
CO2H
CO2Et
Me
0.2 mol% RuO2
NaIO4, CCl4-H2O
96% yield
Torii, JOC, 1985, 4980.
O
Me
H
O
Me
HO
MeO
1. NaIO4, RuCl3
CH3CN / CCl4 / H2O
2. CH2N2
85% yield
OH
H
MeO2C
MeO2C
OH
H1. NaIO4, RuCl3
CH3CN / CCl4 / H2O
2. CH2N2
85% yield
Ghatak, Synthesis, 1983, 746.
Oxidative cleavage of aromatic rings
ORu
O
OO
reactions proceed through
a cyclic ruthenium (VI) diester
In reactions where carboxylic acids are
generated, the addition of CH3CN has
a dramatic effect on rate and efficiency
due to the disruption of insoluble Ru-
carboxylate species
Sharpless, JOC, 1981, 3936.
Oxidation of Ethers, Amines, and Alkanes
Oxidation of !-methylenes of ethers and amines
Me Me
O Ph
Me Me
O Ph
O
0.2 mol% RuO2, NaIO4
CH3CN / CCl4 / H2O
85% yield
Schuda, Tetrahedron Lett., 1983, 3829.
N
Boc OTBS
N
Boc OTBS
O
cat. RuO2, NaIO4
CCl4 / H2O
90% yield
Tanaka, Chem. Pharm. Bull., 1986, 3879.
Amides can be oxidized in a similar manner to imides
MeMe
Me
Me
H
MeMe
Me
Me
OH
0.2 mol% RuCl3, NaIO4
CH3CN / CCl4 / H2O
69% yield
Waegell, Tetrahedron Lett., 1989, 5271
JOC, 1992, 5523.
Oxidation of unactivated alkanes
OAc OAc
O20 mol% RuCl3
CH3CN / CCl4 /
71% yieldMe
Me
Me
Me
Me
Me
O
NaIO4
H2O
20 mol% RuCl3
CH3CN / CCl4 /
NaIO4
H2O
OAc OAc
57% yield
Yamada, Chem. Lett., 1985, 1385.
Tetrapropylammonium Perruthenate (TPAP) Oxidations
O
OTBDPS
O
Me
Me
Yield %
Product
70
N
O
TMS
Me
Me
O73
O
O
HN
Me
TBSO
86
O
O O
78
(0)
RuO4 (RuVIII, d0) is a powerful, nonselective oxidant.
Perruthenate ion, [RuO4]- (RuVII, d1) is a milder oxidant
though it will still cleave some C=C bonds. Disproportionates
in aqueous solution below pH = 8.
Salts of the anion with large, organic cations are soluble in
organic solvents and are much milder and selective oxidants.
The tetrapropylammonium salt is the easiest to prepare.
R1 R2
OH
R1 R2
O(n-Pr4N)(RuO4)
NMO, 4Å mol sieves
CH2Cl2, rt
Water retards catalyst turnover so mol sieves are required
Although [RuO4]- is an overall 3e- oxidant, studies suggest
the oxidation process is of the 2e- type.
Ru(VII) + 2e- Ru(V)
Ru(VI) + Ru(IV)
Ru(VI) + 2e- Ru(IV)
(Swern)
(35)
AcO
R
Me
Me
Me
Me
HO
Yield %Product
93
NBoc
MOMO H
92
O
Me
O
73
HOC3H7
OH
OC3H7O
76
Review: Ley, Synthesis, 1994, 639 and ref. therein.
2Ru(V)
Oxidation of 3 o Amines to Iminium Ions
R1
NCH3
R2
R1
NCH2OOtBu
R2
RuCl2(PPh3)3
cat.
tBuOOH
rt
H+ R1
N
R2
+
N
Me
Me
Br
NH
Me
BrRuCl2(PPh3)3
3 mol%
tBuOOH
1.
2. H3O+
84% yield
NR
Me
RuCl2(PPh3)3
3 mol%
tBuOOH
1.
2. HXN
R
X
Ph
Mechanism:
R1 R2
NR3 R4
R1 R2
NR3 R4+
Ru(OH)
R1 R2
NR3 R4
OORRu
H2O
Demethylation of anilines
Iminium ion intermediate can be trapped
R = H, X = OH
R = C3H7, X = ClMurahashi, JACS, 1988, 8256.
Murahashi, JACS, 1988, 8256.
N
Me
Me
RuCl2(PPh3)3
3 mol%
tBuOOH
1.
2. TiCl4, -78 oCN
Me
H
H
67% (2 steps)Murahashi, SynLett, 1992, 835.
N
CO2Me
N
CO2Me
SiMe3
TiCl4
-78 oC
N
CO2Me
OOtBu
60% yield
RuCl2(PPh3)3
3 mol%
tBuOOH
71% yield
Ru=O
ROOH
ROHROOH
Isomerization of Allylic Alcohols, Amines, and Ethers
R Z R Z
H
Ru
RuHR Z-RuH
MeO RuCl2(PPh3)3
0.1 mol%
200 oCMe
O
Me
Me
Me
CHO
92% yield
Salomon, JOC, 1977, 3360.
NHCOMeMe NHCOMe
RuHCl(PPh3)3
0.5 mol%
80 oC80% yield
all cisStille, JOC, 1980, 2139.
Me OTMS Me OTMSRuH2(PPh3)4
150 oC
100% yield
(E / Z = 45 / 55)
Suzuki, Tetrahedron Lett., 1979, 1415.
OO
C6H13
RuH2(PPh3)4
100 oC
OO
C6H13
BF3 OEt2
-78 oCCHO
C6H13
99% yield
95% yield
OEt
O
n-C5H11
n-C5H11 OEt
O
RuH2(PPh3)4
PBu3, PhMe, reflux
90% yield
Suzuki, Tetrahedron Lett., 1980, 4927.
Ma, Tetrahedron Lett., 1989, 843.
Ru
Coupling of Allenes and Vinyl Ketones to Form Dienes
+ R1
•R2
O
Ru
R2
OR1
•
+
R2
OH
H
R1Ru
+
Ru
+
H R2
O
R1
R1
R2
O
O
R2•R1
Ru cat.
co-catalyst+ R2
O
R1
53-81% yield
•
O
Me10% CpRu(COD)Cl
15% CeCl3DMF, 60 oC
Me
O
O
O
Me
O CO2MeH
H
AcO
AcO
OOO
1.
81%
2. HCl, MeOH
72% (2 steps)
Role of cocatalyst unknown,
possibly activates enone.
Trost, JACS, 1999, 4068.
7H2O
Ru
Coupling of Allenes and Vinyl Ketones: Formation of Cyclic Ethers and Amines
+
•R2
O
Ru
+
R2
O
O
R2•
Ru cat.
co-catalyst+
R2
O
Trost, JACS, 1999, 10842 and 2000, 12007.
nHNu
Nu
n
HNu n
R2
ORu
+
HNu n
R2
ORu
+
HNu n
Nu
H+
R2
ONu
n
H+
n
Nu = OH or NHRn = 1, 2
62-90% yields
OH
•
O
O
O
H
H
H
72% yield
10% CpRu(CH3CN)3PF6
15% CeCl3
DMF, 60 oC
Product Yield
X Me
OX = O 82%
X = NBn 73%
Me
OX = O 74%
X = NBn 67%X
Ph
OX = O 70%
X = NBn 62%X
7H2O
Coupling of Alkenes and Alkynes: Ruthenium Catalyzed Alder-Ene Reaction
Ru cat.
co-catalyst
Trost, JACS, 1993, 4361 and 1995, 615.
R2
R1 R1R2 R1 R2
or
Ru
+
R2
Ru
+
R1
Ru
+
R1
R1R2
Ru
+
R2
or R1
H
HR2
Ru
+H
HR2
R1
or
Ru
+
HR1
R2
Ru
+
H
R2
R1
or
R1R2
R1 R2
or
+
Me
Me
OHOH
CO2Me
CO2tBu
Me
Me
OHOH
CO2Me
CO2tBu
10% CpRu(COD)Cl
20% NH4PF6
MeOH, reflux
65% yield, 12.5 : 1 regioisomers
Ru
H
Intramolecular Coupling of Alkenes and Alkynes
Me
MeMe
O
TMS
Me
MeMe
O TMS
Me
O
TMS
Me
Me
O TMS
Me
Me
10% CpRu(CH3CN)3PF6
DMF, rt
10% CpRu(CH3CN)3PF6
DMF, rt
56% yield
8 : 1 A : B
58% yield
1 : 17 A : B
A
B
H
MeMe
Me
H
Ru
H
H H
Me
Me
Olefin geometry of substrate can dictate product distribution
Trost, JACS, 2000, 714.
Ruthenium-catalyzed intramolecular Pauson-Khand reaction
EtO2C
MeEtO2C
2 mol%
DMAc, CO (15 atm)
140 oC Me
O
EtO2C
EtO2C
78% yield
RuLn
Me
EtO2C
EtO2C
H
substrate must be unable to
undergo !-hydride eliminationMitsudo, JACS, 1997, 6187.
H
Ru3(CO)12
Intramolecular [5 + 2] CycloadditionsR
R
10% CpRu(CH3CN)3PF6
acetone, rt
CpRu
+R
R
RuCp
+
RuCp
R +
RuCp
R +
R
10% CpRu(CH3CN)3PF6
acetone, rt
MeO2C
MeO2C
H
H
MeO2C
MeO2C
85% yield
Wender has reported the same reaction
Trost, JACS, 2000, 2379.
using rhodium. However, Ru is ~10 times
cheaper than Rh.
TsN
TMS
OTBDPS
TsN
TMSOTBDPS
H87% yield
CpRu(CH3CN)3PF6
acetone, 50 oC
20 mol%
Addition of Water to Alkynes: Formation of 1,5-Diketones
R1
O
R2
Ru catalyst
H2O R1 R2
O O
Ru
+
Ru
+
R1
Ru
+
OH
R1
Ru
+
O
R1
Ru
+
O
R1
O
R2
R1
O
R2O
Ru
+
O
R2
R1
R1 R2
O O
H+
Mechanism:
+
NC
Ph
O
Ph
OO
NC
5 mol% CpRu(COD)Cl
NH4PF6, In(OTf)3
DMF / H2O 1 : 1, 100 oC
93% yield
Trost, JACS, 1997, 836.
Me
Ph
O
MeO2C
MeO2C
Intramolecular variant is also known
RuCp(CH3CN)3PF6
10% CSA, H2O
Me
OMeO2C
MeO2C
COPh
OMeO2C
MeO2C
Ph
H
H
K2CO3
MeOH
2 : 1 dr69% yield
one diastereomer
75% yield
10 mol%
Trost, JACS, 2000, 5877.
Reconstitutive Addition of Alkynes and Allylic Alcohols
R2
OH
R1 + Ru catalyst R1
O
R2
Ru
Ph3P
Ph3P Cl
Ru •
R1
L
R1
Ru •
R1
L
L
R2
OH
RuL
R1
O
R2
RuL
R1
O
R2
R1
O
R2
R1
PPh3
R2
OH
L
N
CO2tBu
OH
Me
N
CO2tBu
Me
O
10 mol%
CpRu(PPh3)2Cl
NH4PF6
100 oC
44% yield
Trost, JACS, 1990, 7809.
O
MeOH
Me
Me
CO2Me
8
10 mol%
CpRu(PPh3)2Cl
90 oC
15 mol% In(OTf)3
1 eq. TFA, toluene
O
Me
Me
Me
CO2MeO
8
61% yield
Electrophilic Addition to !-Allyl Ruthenium Complexes
!-allyl Ru complexes can exhibit nucleophilic as well as electrophilic behavior
This property is due to the fact that ruthenium can access a wide range of oxidation states
O
Me OAc
OH
Me
OH
Me
1 mol%
Ru3(CO)12, CO
Et3N, CHCl3, rt
55 : 45
64% yield
L
Ru
OAc
LRu
OAc
O RLRu
OR
OAc
LRu
OR
H
Et2N Me+
AcO-
Et3N
R
OH
Watanabe, Organometallics, 1995, 1945.
CO is essential to catalytic activity--no rxn under Argon
Tertiary amine base crucial, dimethylaniline, pyridine, K2CO3
were ineffective (see mechanism)
Generally, only acetate as allylic group gives good yields
O
X
1 mol%
Ru3(CO)12, CO
Et3N, CHCl3, rt
OH
X = OAc
X = Br
X = OCO2Me
87%
39%
38%
X =OH 0%
Watanabe, JOMC, 1989, 369, C51.
Activation of Aromatic C-H Bonds: Mechanism
[Ru]
X
X
RuH
R2
R1
X
Ru
HR2
R1
X Ru
R2
R1
H
X
Ru
R1
R2
XR1
R2
or
X
H
Ru
or
Ru
X
H
N
O
D
D
D
D
D
99% D
+ Si(OEt)3
1 mmol 1 mmol1 atm
+CH3CN, 120 oC
N
O
D
D
D
D
D
44% D
Si(OEt)3
39% D
94% recovered 57% recovered
+
(40% theoretical D at each of 5 positions)
Deuterium labelling experiment shows C-H / olefin insertions are reversible
Murai, Pure Appl. Chem., 1997, 589 and JOC, 2000, 1475.
CORu3(CO)12
Activation of Aromatic C-H Bonds: Scope
Me
OMe
Me
OMe
Si(OEt)3
Si(OEt)3
Ru(H)2(CO)(PPh3)3
100% yield
Me
O
Me
O
Si(OEt)3
Si(OEt)3
69% yieldMe
Me
Me
O
Me
O
Si(OEt)3
Si(OEt)3
88% yieldNC
NC
NMe NMe
Si(OEt)3
Si(OEt)3
Ru3(CO)12
100% yield
tBu tBu
1 =
2 =
1
1
1
2
CN
Me Me
Si(OEt)3
Si(OEt)3
97% yield
1
CN
OO
Me
TMS
1
Me TMS
83% yield
Me
O
Me
O
NMe2
(EtO)3Si
NMe2
Si(OEt)3
85% yield
1
Trost, Chem. Rev., 2001, 2067.
NO
Br
NO
Br
Me
O
2, ethylene, CO
80% yield
Hydrometallation Initiated Reactions
Baylis-Hillman type reaction
[Ru] HR1
O
R1
O
CH3
[Ru]
O
R2
R1
O
CH3
O
R2
[Ru]
R1
O OH
R2R1
O
CH3
OH
R2
H3C [Ru]
[Ru]
R1
O OH
R2
Me
O O
Me
iPrOH, 40 oC Me
O OH
Me
83% yield
0.2 mol%
Cycloisomerization of ene-ynes
OMe
CO2Et
CO2Et
MeO
5 mol%RuClH(CO)(PPh3)3
toluene, 110 oC
81% yield
N
O
Me
Ph
CO2Et
H HTBSO
N
O
Me
H HTBSO
Ph
CO2Et
10 mol%
RuClH(CO)(PPh3)3
toluene, 110 oC
44% yield
Matsuda, JOMC, 1989, 377, 347.
Substrate scope is very limited, Rh more effective
Mori, JOC, 1998, 9158. Mori, Org. Lett., 2000, 3245.
RuH2(PPh3)4
Cyclopropanation Using Diazo Esters
Ph
N2
CO2Etcatalyst
CO2Et
CO2EtPh
Ph
+ +
N
N
O
N
O
Ru
Cl
Cl
catalyst yield
A
B
A(%ee) : B(%ee)
73% 91(89) : 8(78)
5 mol%
NN
N N
R
R R
R
Ru
C
O
0.15 mol%
100% 95(91) : 5(27)
R =
N N
O O
Ru
Cl
NO
PhPh
N
N
O
N
O
Ru
Cl
ClCO2R
H
Ph
A 5 mol%
45% 7(15) : 93(97)
Trost, Chem. Rev., 2001, 2067 and ref. therein.
Nishiyama
Katsuki
Stereochemical rational with pybox ligand
Ph
B
As expected, R = tBu gives higher dr and ee
than R = Et
Conclusions
Ruthenium catalyzes a tremendous range of organic transformations including hydrogenation of olefins, carbonyls, and imines;
hydrogen transfer reactions; oxidation of olefins, alcohols, lactols, amines, amides, aromatics, and unactivated C-H bonds;
epoxidations; olefin isomerizations; heteroatom addition to alkynes and nitriles; C-H activation; olefin metathesis and ene-yne
metathesis; metallacycle formation; Pauson-Khand reactions; nucleophilic and electrophilic allylic substitutions; radical reactions;
and cyclopropanations among others.
The field is relatively new and rapidly developing, especially in the area of C-C bond forming reactions. 50% of the articles
sited in Trost, Chem. Rev., 2001, 2067 were published in 1997 or after.
Ruthenium catalyzed chemistry promises to be an area of continuing development through the investigation of catalyst structure
and the recognition and utilization of mechanistic intermediates.