Download Heck Reaction

M.C. White, Chem 253
Cross-Coupling -132-
Week of October 18 , 2004
Heck Reaction
The Heck Reaction:
L2Pd IIX2 cat.
H
+
R'X
R'
+
Base
R
Base H+
X-
R
Heck is stereoselective
for E olefin formation
Heck Org. React. 1982 (27) 345.
Olefin:
Increasing the db substitution dramatically decreases the
rate of intermolecular Heck reactions:
Base:
2o or 3o amine, NaOAc,
K2CO3, KHCO3, KOAc
>
>
X- +HNEt3
reductive
elimination
H
LPd(II)
X
R
R'
R
H
L
R'
Pd II
X
L
L
H
R
PdII
Pd
X
R'X oxidative
addition
L2Pd 0
β -hydride
elimination (cis)
H
L
Et2N
X
R'
R
H
+
PdII
L
R'
Catalyst:
Pd(II) sources often used: Pd(OAc) 2 ,
PdCl2PR3, PdCl2(CH3CN)
Pd (0) sources: Pd(PPh 3) 4, Pd(dba)2+ PR3
NEt3
R
H
The base may serve a dual
purpose: reducing the Pd(II)
precatalyst to Pd(0) and promoting
reductive elimination of the
PdH(X) intermediate by shifting
the equilibrium towards Pd(0).
L2Pd IIX2
Neutral mechanism: coordination of olefin via
dissociation of a neutral ligand. Thought to operate
when X = strong σ-donor (i.e.Cl, Br or I). When aryl
or vinyl halides are used, bidentate ligands can result
in a partial or complete suppression of the reaction.
The reaction is stereoselective for the E
olefin because the corresponding TS
leading to the cis olefin involves
energetically unfavorable R'/R eclipsing
interactions.
R' = aryl, heterocyclic,
vinyl, benzyl
X = Br, I, OTf, Cl
L
reversible β-hydride elimination
can lead to olefin isomerization
when R= alkyl
H
X
R'
R
H
II
Pd
X
II
L
R'
internal
rotation
R
H
cis migratory also known as: olefin insertion,
insertion carbopalladation
Pd II
X
L
M.C. White, Chem 253
Cross-Coupling -133-
Week of October 18, 2004
Heck Reaction
L2Pd II(X)2
Cationic mechanism: coordination of olefin via
dissociation of a weakly associated anionic ligand.
Thought to operate when X = OTf, OAc or when
Ag or Tl salts (AgY or TlY; Y= CO3, OTf, OAc)
are used that are capable of halide abstraction
(metathesis- see Structure & Bonding -12-)
NEt3
+
HNO3
R
Faster dissociation of the olefin
leads to less β-hydride elimination.
LPd
R'
R
PdII
L
R'
H
R
H
H
R'
PdII
L
Pd
NO3-
Br
II
L
L
AgNO3
β -hydride
elimination (cis)
AgBr
+
H
L
internal
rotation
R
H
+
NO3-
L
cis migratory
insertion
PdII
L
Pd II
L
NO3-
R'
R'
R
+
H
Cabri Acc. Chem. Res. 1995 (28) 2.
Beletskaya Chem. Rev. 2000 (100) 3009
R'
L
+
Pd II
L
X
H
NO3-
R
H
H
R'Br oxidative
addition
L2Pd 0
(II)
R
Et2N
L
Halide abstraction additives minimize db isomerization
O
Ph
O
O
N
I
Pd(OAc)2 (10 mol%)
Ph
N
Ph
O
Ph
N
N
PPh3 (20 mol%)
CH3CN, 80oC
1st product formed
First example:Overman JOC 1987 (52) 4133.
Grigg TL 1991 (32) 687.
Pd-H insertion product I
none
TlOAc (1.2 eq)
AgOAc (1.2 eq)
1: 2: 5
1: 0: 0
1: 0: 0
Pd-H insertion product II
M.C. White, Chem 253
Cross-Coupling -134-
Week of October 18, 2004
Heck: Regioselectivity of migratory insertion
with neutral Pd complexes
α
PdII(OAc)2 1 mol%
PPh3 2 mol%
H
Br (I)
+
or
NEt3 or
TMED (tetramethylethylene diamine)
R
R
R
β
100%
100%
CO2Me
100%
CN
Ph
100%
99%
80%
C4H9
20%
CO2Me
60% 40%
Ph
N
OCH3
100%
1%
O
For intermolecular Heck reactions with neutral Pd complexes and unactivated or electron-poor alkenes, the regioselectivity for R' insertion is under steric
control, resulting in substitution at the less sterically hindered position. In contrast, with neutral Pd complexes and electron-rich alkenes (e.g. heteroatom
substituted olefins), the regioselectivity of R' insertion is under electronic control, resulting in substitution α to the electron-donating group.
Heck Org. React. 1982 (27) 345.
Heck JACS 1974 (96) 1133.
Hallberg Tetrahedron 1994 (50) 285.
M.C. White, Chem 253
Cross-Coupling -135-
Week October 18, 2004
Heck: Regioselectivity of migratory insertion
with cationic Pd complexes
R'
α
Pd II(OAc)2
P(dppp)
R'
H
OTf
+
R
R
or Ar-X + TlOAc
β
100%
CO2Me
R'
NEt3 or iPr2NEt
R
100%
or
20%
60% 40%
CN
Ph
100%
C4H9
N
100%
5% 95%
OH
OAc
100%
O-n-Bu
80%
O
For intermolecular Heck reactions with cationic Pd complexes, the regioselectivity for R' insertion is predominantly under electronic control for all
substrate classes. Coordination of the olefin π-system to a cationic Pd complex results in an increase in polarization of the C=C bond, and selective
migration of the aryl moiety onto the carbon with lower charge density is observed.
Cabri Acc. Chem. Res. 1995 28, 2-7.
Cabri JOC 1992, 57, 1481-1486.
Cabri Tet. Lett. 1991 32:14, 1753-1756.
M.C. White, Chem 253
Cross-Coupling -136-
Week of October 18, 2004
Intramolecular Heck: “exo-trig” vs “endo-trig” cyclization
exo-trig
endo-trig
Pd
L
Pd
X
L
Pd(L)n(X)
X
Pd(L)n(X)
For the formation of small rings (5,6, or 7 membered rings)
conformational effects dominate and the exo-trig mode of
cyclization is generally preferred.
In contrast, for the formation of macrocyclic structures
(>9-membered rings), steric effects dominate and the endo-trig
mode of cyclization is generally preferred.
CO2CH3
CO2CH3
N
Pd(OAc)2
N
n
Ph 3 P, Et 3 N
I
H
86%
O
N
O
H
H
N
I
CO2CH3
N
Pd(OAc)2
O
O
O
O
O
Pd(OAc)2
Tri-o-tolphosphine O
Et3 N, CH 3 N
N
O
n
O
CO2CH3
O
I
Ph 3 P, Et 3 N
H
74%
Overman JOC 1987 52 4130-4133.
O
n=3, 29%
n=5, 24%
n=7, 38%
Stocks Tet. Lett. 1995 36:36 6555-6558.
M.C. White/ M.W. KananChem 253
Cross-Coupling -137-
Week of October 18, 2004
Tandem Heck: construction of adjacent quaternary C centers
O
I
O
O
Bn
Bn
N
N
O
I
O
O
Pd(PPh3)2Cl2 (10 mol%)
BnN
Et3N, DMA, 100°C
NBn
O
O
Pd(PPh3)2
90%
β -hydride
elimination
oxidative addition
O
O
O
The stereochemistry of the acetonide controls
the Heck cyclizations such that only a single
stereoisomer is observed. Despite the steric
congestion of the olefins in the two
cylcizations (tetra- and tri-substituted), the
overall transformation proceeds efficiently.
O
Bn
BnN
I
I
N
Pd
PPh 3O
BnN
NBn
O
olefin insertion
O
O
O
I
BnN
PdIL O
O
β -hydride
elimination
O
O
Bn
N
BnN
O
Overman JACS 1999 (121) 7702.
O
O
Bn
HN
I
oxidative
addition
PdLI
O
olefin insertion
O
O
I
Pd
BnN
O
L
N
Bn
M.C. White/M.W. Kanan Chem 253
Cross-Coupling -138-
Week of October 18, 2004
Intramolecular Mizoroki-Heck to construct a quaternary
carbon center
OMOM
TfO
OBOM
OMOM
P
Pd2(dba)3 (15 mol%)
OBOM
Pd 0
P
oxidative addition
TfO
-
OH
O
OH
dppb (40 mol%)
Et3N, DMAc, 120°C
84%
H
O
H
OMOM
reductive elimination
OBOM
+
P
Pd
OMOM
P
OBOM
Pd
P
In the initial insertion intermediate, there is no β-hydrogen to enable elimination of
OH
O
H
P
PdII and regeneration of olefin. Et3N serves as a hydride donor, generating an
H
O
OH
H
+
Et2 N
alkyl-hydrido species that reductively eliminates to release the desired product.
OMOM
OBOM
OMOM
OBOM
+
P Pd
P
OMOM
OH
OBOM
OBOM
O
H
olefin insertion
+
P Pd
P
Hirama Org. Lett. 2002 (4) 1627.
O
H
Et2 N
Pd
P
P
Et3N
OH
b-hydride
elimination
OH
H
+
OMOM
OH
Et3 N +
P Pd
P
O
H
O
H
M.C. White/Q.Chen Chem 253
Cross-Coupling -139-
Week of October 18, 2004
Tandem Heck-Hiyama Coupling
OEt
I
EtO
O
O
10% Pd(OAc)2, 20% dppp
R
Et 3N (5 eq), H2O (2 eq),
DMF, 80 °C
O
R
Si
iPr iPr R = n-Hex
Pd(dppp)
Isoprostanes &
Neuroprostanes
O
73%
OH
Si
iPr iPr
reductive
elimination
oxidative addition
I OEt
(dppp)Pd
R
Si
iPr iPr
OEt
Following olefin insertion, there is no syn hydrogen available for
β-hydride elimination. Instead, this intermediate is proposed to
undergo a hydroxide-promoted, intramolecular Hiyama-type
transmetalation followed by reductive elimination to yield the
desired product.
O
Pd(dppp), I
O
R
O
OEt
olefin
insertion
OEt
O
O
intramolecular
transmetalation
OH
I
Pd
(dppp) O
Si
iPr iPr
Quan, L. G.; Cha, J.K. JACS 2002, ASAP.
I
R
Pd
OH
(dppp) O
Si
iPr iPr
R
Pd
OH
(dppp) O
I
Si
iPr iPr
M.C. White, Chem 253
Hydrogenation -140-
Week of October 18, 2004
Wilkinson’s Catalyst
Wilkinson's original report:
Ph3P
PPh3
Rh(I)
P h3P
Investigations into the reactivity of (PPh3)RhCl
uncovered its high activity as a homogeneous
hydrogenation catalyst. This was the first
homogeneous catalyst that compared in rates
with heterogeneous counterparts.
Cl
cat.
H2 (1 atm), benzene, rt
quantitative
Ph3P
Functionality tolerated
O
O
O
OR
C
N
OH
O
NO2
R
Rh(I)
Ph3P
Compatibility with carbonyl
groups indicates that the metal
hydride intermediate is primarily
covalent in character (lacks
hydridic properties characteristic
of strongly ionic M-H). See
Structure & Bonding pg. 28.
PPh3
H
Cl
cat.
H
H2: D2 (1:1)
50%
D
D
Minimal H/D scrambling in the product is
indicative of formation of a dihydrometal
intermediate that transfers both of its hydrido
ligands to the unsaturated substrate.
43.9% H
D
6.1%
Ethylene is not hydrogenated under these conditions but...stoichiometric hydrogen transfer from preformed dihydride complex occurs.
Ph3P
Rh(I)
Ph3P
Data indicates that formation
of an ethylene/ Rh(Cl)(PPh3)3
complex inhibits hydrogen
activation by the complex.
This implies that dihydride
formation precedes olefin
complexation in the catalytic
cycle.
PPh 3
H
Cl
Ph3P
cat.
H
Rh(III)
H2 (1 atm), benzene, rt
Cl
rt
+
PPh3
Ph3P
Rh(I)
Ph3P
PPh 3
+
Cl
PPh 3
The stereochemical outcome of this experiment indicates that the mechanism involves stereospecific cis hydrometallation of the unsaturated substrate
followed by stereospecific reductive elimination from the resulting alkenyl (or alkyl) hydrido species.
Ph3P
H
HO 2C
H
CO2H
Rh (I)
Ph3P
PPh 3
Ph3P
D
D
Cl
D2 (1 atm), benzene
20oC
Ph3P
H
HO 2C
H
CO2H
meso compound
major product observed
Wilkinson J. Chem. Soc. (A) 1966, 1711.
Rh(I)
C 3H7
CH3
PPh3
Cl
H 2 (50 atm), benzene
20oC
H
H
+ hexane
C 3H7
CH3
cis- hexene: trans-hexene
(>20:1)
M.C. White, Chem 253
Hydrogenation -141-
Week of October 18, 2004
Wilkinson: substrate selectivity
Ph3P
Rh(I)
P h3P
+
unsaturated
substrate
PPh3
Cl
1 mol%
H2 (1 atms.), benzene, rt
unsaturated substrate
+
saturated
substrate
rate of hydrogenation of
competition
unsaturated substrate
figure = rate of hydrogenation of
1-octene
competition figure
NC
14.7
HO
9.1
HO
3.4
2.6
EtO
1.8
C 3H7
,
also 1-heptyne, 1-octyne
C 4H 9
1.7
1.0
also, 1-decene, 1-dodecene
cyclohexene
Unsaturated substrates containing functionality are
hydrogenated more rapidly than their unfunctionalized
counterparts. The effect is suggested to result from polar
functional group assisted olefin coordination to the
catalyst.
Terminal alkynes are hydrogenated more rapidly than
terminal alkenes. This selectivity may be enhanced by use
of acidic alcohol co-solvents (e.g. in benzene/
2,2,2-trifluoroethanol, 1-hexyne: 1-octene (12:1).
Terminal alkenes between C6-C12 are hydrogenated at the
same rate. The same is observed for terminal alkynes. An
increase in carbon chain length does not appear to affect
olefin/catalyst interaction.
0.92
Conjugated dienes are reduced slower than isolated alkenes.
1,3-cyclooctadiene
C 2H5
0.75
C2H5
0.71
C 2H5
C 3H7
0.69
C3H7
0.54
C3H7
Internal and branched alkenes (alkynes) are hydrogenated
slower than terminal alkenes (alkynes). These differences are
rationalized in terms of steric effects on olefin interaction
with the catalyst and have been used to effect selective
alkene hydrogenations in polyene compounds.
0.17
C 3H7
Candlin Faraday Discuss. Chem. Soc. 1968 (46) 60.
M.C. White, Chem 253
Hydrogenation -142-
Week of October 18, 2004
Wilkinson hydrogenation: classic dihydride mechanism
PPh3
Rh
P h3P
(I)
Ph3P
oxidative
addition
H2
PPh3
Rh(I)
Cl
Ph3P
Cl
H
H
Ph3P
strong π-acids (e.g. ethylene) bind
tightly to the electron rich Rh
center and inhibit hydrogenation
Rh(I)
Rh(I)
Ph3P
PPh3
PPh 3
Cl
H2
Cl
Rh(I)
Ph3P
S
H
oxidative
addition
PPh3
Rh(I)
H
H2
Rh(III)
Ph3P
Cl
coordinatively unsaturated
complex reacts w/ H2 10 4 x
faster than Rh(Cl)PPh3
Ph3P
H
PPh3
Cl
H
Rh(III)
Ph3P
PPh3
Cl
S
R
reductive
elimination
R
Rh (III)
Rh(III)
Cl
H
H
PPh3
Ph3P
Cl
+PPh 3 -PPh3
-PPh3
catalytic cycle
Cl
solution structure
determined by NMR.
PPh3
+PPh 3
Ph3P
PPh3
Rh(III)
H
PPh3
Intermediates observed by NMR or as isolated
solids in the reaction system. Formation of
these "side-products" results in a reduction in
the rate of hydrogenation.
Ph3P
PPh3
migratory
insertion
RDS
Cl
S
Halpern Chem. Comm. 1973 629.
Halpern J. Mol. Catal. 1976 (2) 65.
Halpern Inorg. Chim. Acta. 1981 (50) 11.
M.C. White, Chem 253
Hydrogenation -143-
Week of October 18, 2004
Wilkinson: site selectivity
Site selective hydrogenation: sterics
O
O
Pd/C
acetone, H2 (1 atm), rt
75%
ketone activated
cis-disubstituted
O
O
O
Ph3P
O
tetrasubstituted
Rh(I)
Ph3P
highly active heterogeneous
catalysts often cannot achieve
high levels of selectivity.
H
Rh(I)
Ph3P
PPh3
PPh3
Cl
Chlorotris(triphenylphosphine)rhodium I
Cl
1 mol%
H2 (1 atm), benzene/EtOH, rt
95%
Strem catalog 2001-2003
1g = $42
O
Ph3P
O
O
Pedro JOC 1996 (61) 3815.
Site selective hydrogenation: sterics and electronics
H3 CO
H3 CO
H
O
O
H
O
trisubstituted
O
HO
CH(CH3 )C2 H5
O
HO
O
O
MeO
CH(CH3 )C2H5
H
O
H
O
O
MeO
cis-disubstituted
Ph3P
O
conjugated
diene
OH
O
Rh (I)
PPh3
Ph3P
Cl
~30 mol%
H 2 (1 atm), tol, rt
92%
H
trisubstituted
O
O
O
OH
H
only site of
hydrogenation
O
H
Fisher J. Med. Chem. 1980 (23) 1134. Ivermectin
H
OMe
OMe
cis vs. trans-disubstituted olefins:
O
cis-disubstituted
O
CO2Me
Ph3P
Rh(I)
CO2Me
PPh3
Ph3P
HO
trans-disubstituted
OAc
PGE 2
Cl
cat.
H2 (1 atm), benzene/acetone, rt
80%
HO
OAc
PGE 1
Schneider JOC 1973 (38) 951.
M.C. White, Chem 253
Hydrogenation -144-
Week of October 18, 2004
Wilkinson: diastereoselectivity
Ph3P
Rh(I)
PPh3
Ph3P
Cl
1 mol%
H2 (1 atm.), benzene/EtOH, rt
H
Me
R = H : 73% endo
R = Me : 92% endo
Me
R
R
R
endo
Rationale for observed diastereoselectivity:
Olefin binds the catalyst from the least
sterically hindered exo face. Subsequent cis
hydrometallation of the exo face followed
by stereospecific reductive elimination of
the alkyl metal hydrido intermediate results
in overall cis addition of H2 to the least
sterically hindered exo face of the olefin.
exo
H
H
H
Ph3P
Ph3P
Rh(III)
PPh3
Cl
H
Rh(III)
PPh3
ClR
vs.
Rousseau J. Mol. Cat. 1979 (5) 163.
Jardine Prog. Inorg. Chem. 1981 (28) 63.
R
olefin complexation and
hydrogenation from sterically
less hindered face
BnO
OMOM
BnO
OBn
Ph3P
Rh(I)
PPh 3
BnO
P h3P
Cl
30 mol%
H2 (1 atm.), tol, rt
83%
OMOM
BnO
OBn
Lowary OL 2000 (2) 167.
M.C. White, Chem 253
Hydrogenation -145-
Week of October 18, 2004
Wilkinson: directing group effects
Ph3P
OH
Rh(I)
PPh3
Ph3P
Cl
0.04 mol%
H 2 (6.8 atm, 100psi), benzene, 50oC
OH
no reaction
Ph3P
trisubstituted
MeO
K+ B -
Ph3P
Rh(I)
note: when Pd/C was used
a mixture of cis and trans
isomers resulted
PPh3
H
Cl
0.04 mol%
MeO
H 2 (6.8 atm, 100psi), benzene, 50oC
cis isomer (exclusive)
68%
PPh3
O -K+
O
H
Rh
PPh3
H
H
trisubstituted
MeO
The slow reaction without the alkoxide is
attibuted to the steric hinderance of the
tri-substituted double bond, which renders it less
able to coordinate to the Rh. The protonated
alcohol is not a strong enough nucleophile to
associatively displace the anionic chloride ligand.
Base-assisted formation of the alkoxide results in
effective displacement of the chloride ligand and
thus directs olefin complexation from the same
face.
Thompson JACS 1974 (96) 6232.
Jardine Prog. Inorg. Chem. 1981 (28) 63.
M.C. White, Chem 253
Hydrogenation -146-
Week of October 18, 2004
Schrock- Osborn /Crabtree: Cationic catalysts
Diene ligated cationic catalysts mode of activation:
PCy3
Ir(I)
+
+
H
(PF 6-)
Ir(III)
H2
N
PCy3
(PF 6- )
H
cis-oxidative
addition
cis-migratory
insertion
N
diene ligated
catalyst precursor
+
Ir(III)
PCy3
(PF 6- )
H
N
+
S
Ir(I)
S
PCy3
+
(PF 6- )
repeat
Ir(I)
N
S
PCy3
(PF 6- )
cis-reductive
elimination
N
solvated active catalyst
Crabtree Acc Chem Res 1979 (12) 331.
Wilkinson's catalyst
P h3P
Rh (I)
Turnover Frequency (TOF)
PPh3
Ph3P
Cl
benzene/EtOH, 25oC
650
700
13
----
4000
10
----
----
6400
4500
3800
4000
+
Schrock-Osborn catalyst
Rh (I)
PPh3
(PF 6- )
PPh3
CH2Cl2, 25oC
+
Crabtree's catalyst
Ir(I)
PCy3
N
(PF 6- )
CH2Cl2, 25oC
TOF = mol reduced substrate/mol catalyst/h
"Coordinatively"
unsaturated
cationic hydrogenation catalysts
are the most active homogeneous
hydrogenation
catalysts
developed thus far. Use of
weakly coordinating solvents
provides the olefin substrate
with relatively free access to the
metal's reactive site. These
cationic catalysts are also
remarkably selective....
M.C. White, Chem 253
Hydrogenation -147-
Week of October 18, 2004
Cationic catalysts: substrate-directed hydrogenations
+
OH
PCy3
Ir(I)
OH
OH
(PF6 -)
N
2.5 mol%
H
CH2Cl2, H 2 (1 atm), rt
Me
H
Me
Me
98%
The availability of a second "open" coordination
site on the catalyst now makes it possible to bind a
ligating group on the substrate in addition to the
olefin. This "two-point" binding has important
implications on the selectivity of product formation.
The ability of a late metal complex to effectively
bind hard functionality (hydroxyls, ketones, etc...)
is attributed to the lewis acidic properties imparted
on the complex by the overall positive charge.
64:1
Py
Cy3P
Pd/C (EtOH), 1:5 (sterics)
+
H
(PF6-)
Ir(III)
H
OH
Me
Crabtree JOC 1986 (51) 2655.
i-Pr
Other functionalities with lewis basic sites also direct:
Esters:
Ketones:
Ethers
O
CO2Me
Me
Me
Me
above
>99%
Me
Me
H
56:1
Pd/C 1.35:1
Amides:
Me
(±)
124:1
Pd/C 1.26:1
O
N
H
H
Me H
above
5 mol%
O
O
above
>99%
Me
N
For a comprehensive review of cyclic and acyclic
substrate-directed hydrogenations see: Hoveyda,
Evans, and Fu Chem. Rev. 1993 (93) 1307 and
D.A. Evans; Chem 206 notes.
Me
O
above
97%
(±)
O
CO2Me
Me
Me
(±)
999:1
Pd/C 1:4
O
N
N
H
O
>99:1
Pd/C 1:9 (steric approach control)
H
M.C. White/Q. Chen Chem 253
Hydrogenation -148-
Week of October 18, 2004
High catalyst loadings: diminished yields and selectivities
+
OH
Ir( I)
PCy3
(PF6 -)
OH
OH
N
Me
CH2Cl2, H2 (1 atm), rt
H
H
Me
Me
A
A decrease in selectivity is observed at higher catalyst
loadings. It is possible that higher catalyst loadings
promote the formation of dimeric (Crabtree suggested
M-H-M) species that no longer have the "open"
coordination site necessary for providing effective
directing effects in olefin hydrogenation. No
experimental data exists thus far to support this
hypothesis.
Dimished yields are observed with higher catalyst loadings. This can be
rationalized on the basis that higher catalyst loadings promote the irreversible
trimerization of the coordinatively unsaturated catalysts to yield inactive triiridium
hydride bridged complexes. Such complexes have been isolated by Crabtree from
reaction mixtures of more sterically hindered olefins that did not proceed to
completion.
Crabtree Acc. Chem. Res. 1979 (12) 331.
B
yield
selectivity
(ratio A:B)
2.5 mol%
99%
139:1
20 mol%
48%
74:1
Stork JACS 1983 (105) 1072.
Crabtree JOC 1986 (51) 2655.
M.C. White, Chem 253
Hydrogenation -149-
Week of October 18, 2004
Synthetic applications of directed hydrogenations
+
Ph2
P
OH
()n= 3
P
Ph2
O
O
Me
OH
Rh (I)
MOMO
MOMO
(BF4-)
O
[Rh(NBD)(DIPHOS-4)]+BF4-
H
OSEM
MOMO
O
NaH, THF
H2 (800 psi), rt
O
MOMO
Me
H
OSEM
H
O
68%
Paquette OL 2002 (4) 937.
+
Ir(I)
H
H
Me
O
HO
OH
(PF 6-)
HO
HO
Me
N
[Ir(COD)(py)(PCy3)]+PF6-
O
Me
PCy3
H2, CH2Cl2
H
H
Me
10
Me
O
H
HO
Me
O
HO
OH
HO
99% Yield,
d.r. 11:1 at C10
Barriault OL 2001 (3) 1925.
M.C. White, Chem 253
Hydrogenation -150-
Week of October 18, 2004
Mechanism of hydrogenation:bidentate cationic complexes
+
PPh 3
Rh(I)
(PF 6- )
nbd
(norbornadiene)
ring strain results
in more facile
hydrogenation
diphos
+
Ph 2
P
(PF 6-)
Rh(I)
() n= 3
P
Ph 2
PPh3
Schrock-Osborn type catalyst
most commonly used:
[Rh(nbd)(diphos-4)]BF4
Schrock-Osborn catalyst
Halpern's mechanism for cationic Rh(I) catalysts with bidentate
phosphine ligands:
+
Ph2
P
Rh(I)
P
Ph2
H2
MeOH
Ph
CO 2Me
NHAc
stereospecific
reductive
elimination
H
+
Ph2
P
Rh(I)
P
Ph2
+
Ph
Ph
CO 2Me (R)
S
NHAc
S
observed by NMR
H
Ph 2
P
Rh
P
Ph2
Ph2
P
H
R
NH
(III)
P
Ph2
+
O
H Ph
H
S
observed by NMR
stereospecific
cis-migratory
insertion
Ph 2
P
P
Ph 2
Rh(I)
R
O
NH
observed by NMR
Rh (III) R
H
O
+
H Ph
H2
NH
oxidative addition (OA)
RDS
(rate determining step)
Halpern Science 1982 (217) 401.
M.C. White, Chem 253
Hydrogenation -151-
Week of October 18, 2004
Mechanism of monodentate cationic complexes
Halpern notes that the hydrogenation mechanism for bidentate ligated cationic complexes where olefin substrate coordination precedes oxidative addition of H 2 may
not be operating for cationic catalysts with monodentate ligands. Schrock-Osborn invoke involvement of the dihydride complex (below) in the principle hydrogenation
pathway for their catalyst. Halpern notes some significant differences in the reactivities towards H2 of the catalysts w/ bidentate and monodentate phosphine ligands.
+
In the absence of olefin substrate, no
further uptake of H 2 can be
detected. The only species observed
by NMR
is
the
cationic,
4-coordinate solvated species.
Ph 2
P
Rh(I)
S
H2
P
Ph 2
Rh (I)
S
+
H
+
Ph2
P
k1
S
Rh(I)
P
Ph 2
H
P
Ph 2
k-1
Ph 2
P
S
only species
observed by NMR
PPh3
Rh(I)
S
H2
PPh3
Rh (I)
PPh3
PPh 3
Rh (III)
H
S
k1
P h3P
S
Ph3P
+
H
+
+
Treatment
of the monodentate
catalyst with H 2 resulted in detection
of the Rh(III)-dihydride complex.
k-1
S
only species
observed by NMR
Halpern JACS 1977 (99) 8055. Schrock & Osborn JACS 1976 (98) 2135.
The Trans Effect:
To explain the difference in reactivities towards H2 of the catalysts, Halpern invokes the trans effect. The trans effect is defined as the
labilization of ligands trans to certain other ligands. The trans effect often arises when a ligand shares an orbital with another ligand of strong
σ-bonding character. Because phosphine forms a strong σ bond with Rh, trans Rh-H bonds formed will be weak because the orbital is not as
available for bonding to H. In the case of the bidentate complex, cis addition of H2 requires that one hydride share an orbital with a phosphine.
Since both hydride and phosphine are strong σ-bonding ligands, the dihydride adduct, once formed, is highly unstable and thus rapidly reverts
back via reductive elimination to the solvated 4-coordinate species. In the case of the monodentate phosphine complex, a H2 adduct can form
where neither H ligand is trans to a phosphine.
Classic example of the trans effect: synthesis of "cis-platinum" a chemotherapeutic agent
Cl
Cl
Pt(II)
Cl
Cl
2NH3
Cl
Pt(II)
Cl
-
NH3
Cl
Cl has a stronger "trans
influence" than NH3
NH3
Cl
Cl
(II)
NH3
Pt
NH3
only the cis
isomer is formed
H 3N
H 3N
Pt(II)
NH3
NH3
2+
Cl
H 3N
H 3N
Pt(II)
Cl
+
Cl
NH3
Cl has a stronger "trans
influence" than NH3
H 3N
Pt(II)
Cl
NH3
Cl
only the trans
isomer is formed
M.C. White, Chem 253
Hydrogenation -152-
Week of October 18, 2004
Asymmetric Hydrogenation
A bidentate, C2 symmetric version of the cationic Schrock-Osborn catalyst affords extraordinarily high levels of
enantioselectivity in the hydrogenation of achiral enamides. This was the first demonstration that a chiral
transition metal complex could effectively transfer chirality to a non-chiral substrate with selectivities that rival
those observed in enzymes. Recall that this led to the 1st commericalized asymmetric process using a chiral
transition metal complex: Monsanto Process for the industrial production of L-DOPA (see Structure and
Bonding, pg. 4)
+
+
Rh(I)
PPh3
MeO
(PF 6- )
Rh(I)
P
(PF 6-)
P
PPh 3
OMe
DIPAMP (common name for
this bidentate chiral phosphine
ligand)
Schrock-Osborn catalyst
CO2H
CO2H
NHAc
Knowles JACS 1975 (97) 2567.
i-PrOH, H 2 (1 atm), rt
>99% yield
NHAc
93% ee
A variety of bidentate chiral phosphines have since been synthesized and used to effect the hydrogenation of aromatic enamides (important substrates for the efficient
generation of amino acids):
H
PPh2
PPh2
PPh2
O
PPh2
NMe2
Fe
PPh2
PPh2
O
PPh2
PPh2
PPh2
PPh2
H
SKEWPHOS (92% ee)
Chiraphos (99% ee)
NORPHOS (95% ee)
BPPFA (93% ee)
DIOP (85% ee)
R
PPh2
P
R
R
PPh2
P
BINAP (100% ee)
R
DuPHOS (99% ee)
H
H
PPh 2
PPh 2
BICP (97% ee)
We'll see these ligands again effecting asymmetry in
a wide assortment of mechanistically unrelated metal
catalyzed reactions with prochiral substrates.
PCy2 "Privileged ligand class": ligands that communicate
asymmetry effectively with a transition state
Fe
PPh2
localized at the metal center, irrespective of the
nature of the transition state.
PPh2
E.N. Jacobsen;
personal communication
JOSIPHOS (96% ee)
E. N. Jacobsen. Chem 153 notes. Spring 2001.
For review on DuPhos: Burk Acc. Chem. Res. 2000 (33) 363.
M.C. White, Chem 253
Hydrogenation -153-
Week of October 18, 2004
Origin of Asymmetric Induction
+
(ClO4-)
H 3C
It was concluded from kinetic measurements that
the minor diastereomer was 580 fold more reactive
towards H2 oxidative addition (recall the RDS at rt).
This factor offsets its lower concentration in
solution and results in a 60:1 product ratio in favor
of the R enantiomer.
P
Rh(I)
P
H 3C
(S,S-CHIRAPHOS)
(R) CO2Et
CO2H
H2 (1 atm), 25oC, MeOH
NHAc
NHAc
N-acetyl-(R)-phenylalanine
>95% ee
stereospecific H migratory insertion /
stereospecific H/C reductive elimination
both to the olefin face bound to Rh
HN
CO 2Me
Rh(I)
Ph O
+
+
(ClO4-)
(ClO4-)
CH3
NH
P
P
P
MeO2 C
H 3C
Rh(I)
CH3
H 3C
P
O Ph
olefin bound
to Rh via its
si-face
olefin bound
to Rh via its
re-face
major diastereomer formed
in solution (identified by NMR
and x-ray crystallography)
minor diastereomer formed
none detected by NMR (must be
less than 5% present in solution)
Halpern Science 1982 (217) 401.
M.C. White/Q. Chen Chem 253
Hydrogenation -154-
Week of October 18, 2004
Crystal structure of major diastereomer
+
(ClO4-)
HN
CO 2Me
Rh(I)
Ph O
CH3
P
P
CH3
olefin bound
to Rh via its
re-face
major diastereomer formed
in solution (identified by NMR
and x-ray crystallography)
Major enantiomer observed upon
exposing crystal to H2:
(R) CO2Et
NHAc
Minor enantiomer observed upon
exposing crystal to H2.
(S) CO2Et
NHAc
N-acetyl-(R)-phenylalanine
>95% ee
Halpern Science 1982 (217) 401.
M.C. White/Q. Chen Chem 253
Hydrogenation -155-
Week of October 18, 2004
Monohydride catalysts: RuClH(PPh3)3
Wilkinson's original report:
"In contrast to the rhodium system, ethanol plays an intimate part in the hydrogenation mechanism; in the
absence of such a co-solvent, hydrogenation is exceedingly slow." Wilkinson Nature 1965 (208) 1203.
RuCl2(PPh3) 2 cat.
H2 (1 atm), benzene:ethanol, rt
quantitative
The active species was identified as the monohydride, thought to form via heterolytic cleavage of
H2, with ethanol acting as a base. The monohydride can also be prepared in 100% benzene if an
equivalent of NEt3 is added. One mole of H 2 is absorbed with respect to Ru and amine
hydrochloride is quantitatively formed. Wilkinson J. Chem. Soc. (A) 1968 3143.
H
RuCl2(PPh3) 3
H2 (1 eq)
NEt3 (1 eq), benzene
Ph3P
PPh3
Ru(II)
+
-
Cl +HNEt3
RuCl(H)(PPh3)3, highly distorted
trigonal bipyramidal. Skapski Chem.
Comm. 1968 1230.
PPh3
Cl
Effect of base on conversion
O
O
RuCl2(PPh3) 2 cat.
H2 (126 atm), base (1 eq)
benzene, 40oC, 6h
O
O
Base
Tsuneda Bull. Chem. Soc. Jpn. 1973 (46) 279.
NEt3
Et2NH
BuNH2
aniline
Ca2CO3
Na 2CO3
none
% Conversion
95.4
95.4
86.5
88.1
95.2
73.0
76.0
+ fully satuturated
products
M.C. White, Chem 253
Hydrogenation -156-
Base promoted heterolytic cleavage:
Week of October 18, 2004
Mechanism of H2 Activation
H
σ-donation>>
π-backbonding
Mn
Mn
heterolytic cleavage
H
σ-complex
generally observed for electrophilic
metals that are in their highest stable
oxidation state within the context of
their ligand framework.
H + BH+
note: there is no
oxidation state
change at the
metal
Example:
+
(BF 4) N
Ir(III)
+
(BF4) -
NH2
L H δ+
N
L
Ir(III)
H
L
NH3+
H
L
H
H
1
2
Complexation of dihydrogen to the electrophilic, cationic
Ir(III) center is predominantly σ-donating in nature.
Donation of electron density from the H-H σ-bond to an
empty Ir orbital leaves the H-H with a partial positive
charge. The pendent NH2 group is thought to act as an
internal base effecting heterolytic cleavage of the acidified
dihydrogen σ-complex via deprotonation.When L = PPh3,
the equilibrium lies far to the right and only the dihydride 2
is observed. When more basic alkyl phosphines are used
(L= PBu3) the equilibrium lies to the left with the H2
complex 1 being observed exclusively by NMR. It was
hypothesized that moving to a more basic phosphine
increases the electron density at the metal center. This
makes the metal a less effective σ-acceptor and attenuates
its ability to effectively acidify the dihydrogen complex.
Crabtree Chem. Commun. 1999 297.
σ-bond metathesis: the base is effectively one of the ligands on the metal
Cl
RuCl2(PPh 3)3
H2
δ+ H
external amine base may still drive the rxn forward
by forming insoluble amine hydrochloride salts
δ−
HCl
RuCl(PPh 3)3
H
σ-bond metathesis
Crabtree The Organometallic Chemistry of the Transition Metals: 3rd Edition; Wiley: New York; 2001.
RuHCl(PPh3)3
M.C. White, Chem 253
Hydrogenation -157-
Week of October 18, 2004
BINAP-Ru complexes: Noyori increases the substrate scope
for asymmetric hydrogenations
The first report: asymmetric hydrogenation of (Z)-enamides
Interestingly, E-enamides are completely unreactive
towards these hydrogenation conditions. No
rationale for this has been presented.
air-sensitive
O
Ph 2
P
H3CO
OAc
H3CO
HO
O
P
Ph 2
NCOCH3
AcO
O
Ru(II)
NCOCH3
AcO
O
O
OAc
(R)-1 (0.5-1 mol%)
HO
EtOH:CH2Cl2 (5:1), H2 (4 atm), 23oC
Noyori JACS 1986 (108) 7117.
Noyori ACIEE 2002 (41) 2008.
NCH3
OCH3
OCH3
H
morphine
92% yield
95% ee
Asymmetric hydrogenation of allylic and homoallylic alcohols:
Tol2
P
P
Tol2
E-olefin
OH
O
O
Ru(II)
regioselectivity: allylic and homoallylic alcohols are
hydrogenated whereas bis homoallylic and higher
analogues are left untouched.
O
O
(S)-1 0.01 mol%
MeOH, H2, 18-20oC
geraniol
97 to >99% yields
OH
(R)-citronellol
allylic olefin geometry may dictate the
stereochemical outcome of the
hydrogenation. Practical consequence:
to obtain high ee's must start with
stereochemically pure olefins.
96% ee
Z-olefin
(S)-1 0.2 mol%
MeOH, H2, 18-20oC
nerol
OH
OH
(S)-citronellol
98% ee
Noyori JACS 1987 (109) 1596.
M.C. White, Chem 253
Hydrogenation -158-
Week of October 18, 2004
BINAP-Ru complexes: Noyori increases the substrate scope
for asymmetric hydrogenations
The first demonstration of high asymmetric induction in the hydrogenation of substrates lacking an acylamino group:
asymmetric hydrogenation of α,β-unsaturated carboxylic acids
CO2H
Ph 2
P
H 3C
(S)
O
Ru
CH3
(II)
H3C
O
P
Ph 2
CO2H
CO2H
O
O
CH3
H2 (4 atm): 91% ee
H2 (101 atm): 50% ee
(S)-1 (0.5-1 mol%)
MeOH, H2,
CO2H
15-30oC
The degree of asymmetric induction is significantly
affected by the H 2 pressure in a substrate specific
manner. The implication of this is that a range of H2
pressures must be screened to achieve optimal
asymmetric induction on a substrate by substrate basis.
No trend was observed and no rationale for the
emperical observation was given.
(S)
Ph
H2 (4 atm): 48% ee
H2 (112 atm): 92% ee
Asymmetric Synthesis of (S)-Naproxen:
CO2H
(S)-1 (0.5 mol%)
MeOH, H2 (135 atm),
H3CO
92% yield
97% ee
CO2H
15-30oC
H 3CO
(S)-Naproxen
Noyori JOC 1987 (52) 3174.
M.C. White, Chem 253
Hydrogenation -159-
Week of October 18, 2004
Mechanism of BINAP-Ru hydrogenation of α,β-unsaturated acids
Ph 2
P
P
Ph 2
O
Ru (II)
O
O
O
1
CO 2H
note: mechanism is valid for both enantiomers of
BINAP. No rationalization for the enantiofacial
selectivity is given.
AcOH
Ph 2
P
CO 2H
P
Ph 2
CO 2H
O
O
Ru (II)
O
H2
O
Heterolytic cleavage of H2
RDS
H+
Ph 2
P
P
Ph 2
O
Ru (II)
Ph 2
P
O
O
P
Ph 2
O
Ph 2
P
protonolysis
P
Ph 2
H+
Ru (II)
O
O
O
H
note: no oxidation
state change to the
metal
O
Ru (II)
O
O
cis-migratory
insertion
O
H
O
Reactions in MeOD
CO2H
H 3C
CH3
D
(S)-1
H2, MeOD
H 3C
H
H
CH3
CO2H
Experiment indicates that the hydrogen α to the acid comes from H2 whereas the β-hydrogen
comes from MeOH. Regio- and stereospecific deuterium incorporation indicates that cis-migratory
insertion of the Ru-H is stereospecific as is cleavage of the Ru-C bond via protonolysis. The lack of
D incorporation into the α position indicates that the rate of H/D exchange between the Ru-H and
solvent is slow.
Halpern JACS 1991 (113) 589.
M.C. White, Chem 253
Hydrogenation -160-
Week of October 18, 2004
Question of the Week
Ru(CH3CO2) 2-[(S)-BINAP] catalyzes the hydrogenation of α-(acylamino)acrylic esters to give the (S) saturated product in >90% ee's.
Propose a mechanism that accounts for the observed mixture of hydrogenation products when the reaction is run in MeOD. Note: your
mechanism need not rationalize the absolute stereochemistry obtained.
CH3
O
Ph
NH
Ph 2
P
P
Ph 2
O
Ru (II)
O
O
Ph
O
O
O
O
CH3
CH3
CH3
NH
Ph
NH
Ph
NH
(S)-1
H
O
MeO
H2 (1 atm), MeOD
H H
O
H
OMe
H H
O
D
OMe
79:14:2
H D
O
H
OMe