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M.C. White, Chem 253 Cross-Coupling -132- Week of October 18 , 2004
Heck ReactionThe Heck Reaction:
H
R
+ R'XL2PdIIX2 cat.
Base
R'
R
R' = aryl, heterocyclic, vinyl, benzylX = Br, I, OTf, ClBase:
2o or 3o amine, NaOAc,
K2CO3, KHCO3, KOAc
+ Base H+ X-
The base may serve a dualpurpose: reducing the Pd(II)precatalyst to Pd(0) and promoting reductive elimination of thePdH(X) intermediate by shiftingthe equilibrium towards Pd(0).
Catalyst:Pd(II) sources often used: Pd(OAc)2 , PdCl2PR3, PdCl2(CH3CN)Pd (0) sources: Pd(PPh3)4, Pd(dba)2+ PR3
Increasing the db substitution dramatically decreases therate of intermolecular Heck reactions:
> >
Olefin:
Heck is stereoselective for E olefin formation
Heck Org. React. 1982 (27) 345.
L2PdIIX2
NEt3
Et2N+
L2Pd0
PdIIR'
LX
R
cis migratoryinsertion
oxidativeaddition
PdII
XL
R
H
R'
LPd(II)H
X
PdII
R'
L
L
X
R'X
ββββ-hydrideelimination (cis)
X- +HNEt3
reductiveelimination
PdII
LX
Neutral mechanism: coordination of olefin viadissociation of a neutral ligand. Thought to operatewhen X = strong σ-donor (i.e.Cl, Br or I). When arylor vinyl halides are used, bidentate ligands can result in a partial or complete suppression of the reaction.
L
R'
R
HH
H
internalrotation
PdIIH
XL
R
R'
R
R
The reaction is stereoselective for the Eolefin because the corresponding TSleading to the cis olefin involvesenergetically unfavorable R'/R eclipsing interactions.
PdII
XL
H
H
H
reversible β-hydride elimination can lead to olefin isomerizationwhen R= alkyl
R'
R
also known as: olefin insertion, carbopalladation
M.C. White, Chem 253 Cross-Coupling -133- Week of October 18, 2004
L2PdII(X)2
NEt3
Et2N+
L2Pd0
PdIIR'
LL
R
cis migratoryinsertion
oxidativeaddition
PdII
LL
R
H
R'
LPd(II)H
PdIIR'
L
L
Br
R'Br
ββββ-hydrideelimination (cis)
HNO3
PdII
LL
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-)
R'
R
HH
H
internalrotation
PdIIH
LL
R
R'
R
R
+
NO3-+
NO3-
+
NO3-
+
NO3-
PdII
XL
H
H
H
R'
R
Faster dissociation of the olefin leads to less β-hydride elimination.
AgNO3
AgBr
Heck Reaction
N
PhO
I
Halide abstraction additives minimize db isomerization
N
O
Ph N
O
PhN
O
PhPd(OAc)2 (10 mol%)
PPh3 (20 mol%)
CH3CN, 80oC
none TlOAc (1.2 eq)AgOAc (1.2 eq)
1: 2: 51: 0: 01: 0: 0
1st product formed Pd-H insertion product I Pd-H insertion product II
First example:Overman JOC 1987 (52) 4133.Grigg TL 1991 (32) 687.
Cabri Acc. Chem. Res. 1995 (28) 2.Beletskaya Chem. Rev. 2000 (100) 3009
M.C. White, Chem 253 Cross-Coupling -134- Week of October 18, 2004
Heck: Regioselectivity of migratory insertionwith neutral Pd complexes
Heck Org. React. 1982 (27) 345.Heck JACS 1974 (96) 1133.Hallberg Tetrahedron 1994 (50) 285.
H
R
Br (I)
CO2Me CN Ph C4H9
R
CO2Me Ph N
O
OCH3
+
PdII(OAc)2 1 mol%PPh3 2 mol%
NEt3 or
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. heteroatomsubstituted olefins), the regioselectivity of R' insertion is under electronic control, resulting in substitution α to the electron-donating group.
TMED (tetramethylethylene diamine)ββββ
100% 100% 100% 100%99%
1%
80%
20%
60% 40%
αααα
100%
or
R
M.C. White, Chem 253 Cross-Coupling -135- Week October 18, 2004
Heck: Regioselectivity of migratory insertionwith cationic Pd complexes
Cabri Acc. Chem. Res. 1995 28, 2-7.Cabri JOC 1992, 57, 1481-1486.Cabri Tet. Lett. 1991 32:14, 1753-1756.
H
R
OTf
CO2Me CN Ph C4H9 N
O
OH
R
OAc
R'
O-n-Bu
+
PdII(OAc)2
P(dppp)
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 olefinπ-system to a cationic Pd complex results in an increase in polarization of the C=C bond, and selectivemigration of the aryl moiety onto the carbon with lower charge density is observed.
ββββ
100% 100% 60% 20%
80%
100%
αααα
40% 100% 95% 100%5%
or Ar-X + TlOAc
NEt3 or iPr2NEt
R'
R
R'or
M.C. White, Chem 253 Cross-Coupling -136- Week of October 18, 2004
PdL X
Pd(L)n(X)
exo-trig
PdL X
endo-trig
Pd(L)n(X)
For the formation of small rings (5,6, or 7 membered rings) conformational effects dominate and the exo-trig mode ofcyclization 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.
NO
I
O
O
N
O
O
O
Pd(OAc)2 N
OO
O
N
O
O
O
n
nTri-o-tolphosphineEt3N, CH3N
n=3, 29%n=5, 24%n=7, 38%
Stocks Tet. Lett. 1995 36:36 6555-6558.
I
CO2CH3Pd(OAc)2
Ph3P, Et3N
CO2CH3
H86%
H
N
I
CO2CH3Pd(OAc)2
Ph3P, Et3N
H
NCO2CH3
H
74%
Overman JOC 1987 52 4130-4133.
Intramolecular Heck: “exo-trig” vs “endo-trig” cyclization
M.C. White/ M.W. KananChem 253 Cross-Coupling -137- Week of October 18, 2004
Tandem Heck: construction of adjacent quaternary C centers
N
O O
N
OO
Bn BnI IBnN
O
NBnO
OO
Pd(PPh3)2Cl2 (10 mol%)
Et3N, DMA, 100°C
90%
BnN
O
OO
N
IBn
O
PdI
PPh3
BnN
O
OO
PdIL O
N
BnI
H
BnN
O
OO
N
I
O
Bn
BnN
O
NBnO
OOPdLI
BnN
O
NBnO
OO
PdI
L
The stereochemistry of the acetonide controls the Heck cyclizations such that only a singlestereoisomer is observed. Despite the stericcongestion of the olefins in the twocylcizations (tetra- and tri-substituted), theoverall transformation proceeds efficiently.
Pd(PPh3)2
oxidative addition
olefin insertion
β-hydrideelimination
oxidativeaddition
olefin insertion
β-hydrideelimination
Overman JACS 1999 (121) 7702.
M.C. White/M.W. Kanan Chem 253 Cross-Coupling -138- Week of October 18, 2004
Pd0P
P
TfO OMOM
HO
OH
OBOM
Pd OMOM
HO
OH
OBOMP
P
OMOMOBOM
OH
HO
PdPP
OMOM
OBOM
OH
HO
PdP
P
TfO-
Et3N
PdP
P
Et3N
OMOM
OBOM
OH
HO
OMOM
OBOM
OH
HO
Et2N
PdP
P
H
PdP
P
H
OMOM
OBOM
OH
HO
OMOM
OBOM
OH
HO
Pd2(dba)3 (15 mol%)
dppb (40 mol%)Et3N, DMAc, 120°C
+
+
+ +
+
oxidative addition
olefin insertion
b-hydride elimination
reductive elimination
In the initial insertion intermediate, there is no β-hydrogen to enable elimination of
PdII and regeneration of olefin. Et3N serves as a hydride donor, generating an
alkyl-hydrido species that reductively eliminates to release the desired product.
Hirama Org. Lett. 2002 (4) 1627.
84%
Et2N+
Intramolecular Mizoroki-Heck to construct a quaternary carbon center
M.C. White/Q.Chen Chem 253 Cross-Coupling -139- Week of October 18, 2004
Tandem Heck-Hiyama Coupling
O
O
OEt
I
SiR
iPriPr
OSi
OH
iPr iPr
O
EtO
R
O
O
OEt
SiR
iPriPr
(dppp)PdI
O
OSi
R
iPr iPr
Pd(dppp)
OEt
IOH
O
OSi
R
iPr iPr
Pd(dppp)
OEt
IOH
O
OSi
I
iPr iPr
Pd(dppp)
OEt
OHR
10% Pd(OAc)2, 20% dpppIsoprostanes &Neuroprostanes
73%Pd(dppp)
Pd(dppp), I
Following olefin insertion, there is no syn hydrogen available for β-hydride elimination. Instead, this intermediate is proposed toundergo a hydroxide-promoted, intramolecular Hiyama-typetransmetalation followed by reductive elimination to yield thedesired product.
Et3N (5 eq), H2O (2 eq), DMF, 80 °C
oxidative addition
olefininsertion
intramoleculartransmetalation
reductiveelimination
R = n-Hex
Quan, L. G.; Cha, J.K. JACS 2002, ASAP.
M.C. White, Chem 253 Hydrogenation -140- Week of October 18, 2004
Wilkinson’s CatalystWilkinson's original report:
Ph3P
Rh(I)Ph3P PPh3
Cl
cat.
H2 (1 atm), benzene, rtquantitative
Investigations into the reactivity of (PPh3)RhCl uncovered its high activity as a homogeneoushydrogenation catalyst. This was the firsthomogeneous catalyst that compared in rateswith heterogeneous counterparts.
Wilkinson J. Chem. Soc. (A) 1966, 1711.
O
C N NO2O R
O
OR
O
OH
Functionality tolerated
Ph3P
Rh(I)Ph3P PPh3
Cl
Cl
Rh(III)
Ph3P H
PPh3
H
PPh3
Ph3P
Rh(I)Ph3P PPh3
Cl
Data indicates that formationof an ethylene/ Rh(Cl)(PPh3)3 complex inhibits hydrogenactivation by the complex.This implies that dihydrideformation precedes olefincomplexation in the catalyticcycle.
cat.
H2 (1 atm), benzene, rt
Ethylene is not hydrogenated under these conditions but...stoichiometric hydrogen transfer from preformed dihydride complex occurs.
+ rt +
Ph3PRh(I)
Ph3P PPh3
ClC3H7 CH3
CH3C3H7
H H
Compatibility with carbonylgroups indicates that the metalhydride intermediate is primarily covalent in character (lackshydridic properties characteristicof strongly ionic M-H). SeeStructure & Bonding pg. 28.
H2 (50 atm), benzene
20oCcis- hexene: trans-hexene
(>20:1)
+ hexaneCO2HHO2C
Ph3PRh(I)
Ph3P PPh3
Cl
D2 (1 atm), benzene
20oC
H H D D
HO2CH H
CO2H
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.
meso compoundmajor product observed
Ph3P
Rh(I)Ph3P PPh3
Clcat.
H2: D2 (1:1)
H
H
50% D
D
43.9% H
D
6.1%
Minimal H/D scrambling in the product isindicative of formation of a dihydrometalintermediate that transfers both of its hydrido ligands to the unsaturated substrate.
M.C. White, Chem 253 Hydrogenation -141- Week of October 18, 2004
Ph3P
Rh(I)Ph3P PPh3
Cl1 mol%
H2 (1 atms.), benzene, rt
+unsaturated
substrate
+saturatedsubstrate
competition figure =
rate of hydrogenation ofunsaturated substrate
rate of hydrogenation of1-octene
Wilkinson: substrate selectivity
Candlin Faraday Discuss. Chem. Soc. 1968 (46) 60.
HO
HO
EtO
C3H7 ,
C4H9
C2H5C2H5
C2H5
also 1-heptyne, 1-octyne
also, 1-decene, 1-dodecene
C3H7C3H7
C3H7
C3H7
NC
unsaturated substrate competition figure
14.7
9.1
3.4
1.8
1.7
2.6
0.92
0.75
0.71
0.69
0.54
0.17
1.0
cyclohexene
1,3-cyclooctadiene
Terminal alkenes between C6-C12 are hydrogenated at the same rate. The same is observed for terminal alkynes. Anincrease in carbon chain length does not appear to affectolefin/catalyst interaction.
Internal and branched alkenes (alkynes) are hydrogenatedslower than terminal alkenes (alkynes). These differences are rationalized in terms of steric effects on olefin interactionwith the catalyst and have been used to effect selectivealkene hydrogenations in polyene compounds.
Unsaturated substrates containing functionality arehydrogenated more rapidly than their unfunctionalizedcounterparts. The effect is suggested to result from polar functional group assisted olefin coordination to thecatalyst.
Terminal alkynes are hydrogenated more rapidly thanterminal 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).
Conjugated dienes are reduced slower than isolated alkenes.
M.C. White, Chem 253 Hydrogenation -142- Week of October 18, 2004
Wilkinson hydrogenation: classic dihydride mechanism
Ph3P
Rh(I)
Ph3P PPh3
Cl
H2
Ph3P
Rh(III)H PPh3
Cl
H
PPh3
oxidative addition
-PPh3
Ph3P
Rh(I)S PPh3
Cl
solution structuredetermined by NMR.
Ph3P
Rh(III)H PPh3
Cl
H
R
+PPh3
Ph3P
Rh(III)PPh3
Cl
H
S
R migratory insertion
RDS
Ph3P
Rh(III)H PPh3
Cl
H
S
-PPh3+PPh3
H2
reductive elimination
oxidative addition
catalytic cycle
coordinatively unsaturatedcomplex reacts w/ H2 104 x faster than Rh(Cl)PPh3
Ph3P
Rh(I)
PPh3
Cl
strong π-acids (e.g. ethylene) bind tightly to the electron rich Rhcenter and inhibit hydrogenation
Ph3P
Rh(I)Ph3P Cl
Cl
Rh(I)PPh3
PPh3
Ph3P
Rh(I)
Ph3P Cl
Cl
Rh(III)
H
H
PPh3
PPh3
H2
Intermediates observed by NMR or as isolatedsolids in the reaction system. Formation ofthese "side-products" results in a reduction inthe rate of hydrogenation.
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
Ph3P
Rh(I)Ph3P PPh3
Cl
Ph3P
Rh(I)Ph3P PPh3
Cl
Strem catalog 2001-20031g = $42
Chlorotris(triphenylphosphine)rhodium IO
O
O
O
O
O
H
O
O
O1 mol%H2 (1 atm), benzene/EtOH, rt
95%
Pd/Cacetone, H2 (1 atm), rt
75%
ketone activatedcis-disubstituted
tetrasubstituted
O
CH(CH3)C2H5
OO
H
OMe
O
O
OH
H3CO
O
OH
MeO
HO
OH
H
conjugateddiene
trisubstituted
trisubstituted
cis-disubstituted
O
CH(CH3)C2H5
OO
H
OMe
O
O
OH
H3CO
O
OH
MeO
HO
OH
H
Ph3P
Rh(I)Ph3P PPh3
Cl~30 mol%
H2 (1 atm), tol, rt92%
only site of hydrogenation
O
HO
CO2Me
OAc
cis-disubstituted
trans-disubstituted
Ph3P
Rh(I)Ph3P PPh3
Cl
H2 (1 atm), benzene/acetone, rt80%
cat.
O
HOOAc
CO2Me
cis vs. trans-disubstituted olefins:
Schneider JOC 1973 (38) 951.PGE2 PGE1
Site selective hydrogenation: sterics
highly active heterogeneouscatalysts often cannot achievehigh levels of selectivity.
Site selective hydrogenation: sterics and electronics
Pedro JOC 1996 (61) 3815.
Fisher J. Med. Chem. 1980 (23) 1134. Ivermectin
M.C. White, Chem 253 Hydrogenation -144- Week of October 18, 2004
Wilkinson: diastereoselectivity
Ph3P
Rh(I)Ph3P PPh3
Cl1 mol%
H2 (1 atm.), benzene/EtOH, rt
Me
H
endo exo
Me
R R R
R = H : 73% endoR = Me : 92% endo
Rationale for observed diastereoselectivity:Olefin binds the catalyst from the leaststerically hindered exo face. Subsequent cis hydrometallation of the exo face followedby stereospecific reductive elimination ofthe alkyl metal hydrido intermediate resultsin overall cis addition of H2 to the leaststerically hindered exo face of the olefin.
ClRh(III)
Ph3P H
PPh3
H
R
vs.
ClRh(III)
Ph3P H
PPh3
H
R
Rousseau J. Mol. Cat. 1979 (5) 163.Jardine Prog. Inorg. Chem. 1981 (28) 63.
BnO
OMOM
OBnBnO
olefin complexation andhydrogenation from sterically less hindered face
Ph3P
Rh(I)Ph3P PPh3
Cl30 mol%
H2 (1 atm.), tol, rt83%
BnO
OMOM
OBnBnO Lowary OL 2000 (2) 167.
M.C. White, Chem 253 Hydrogenation -145- Week of October 18, 2004
Wilkinson: directing group effects
MeO
OH
trisubstituted
Ph3P
Rh(I)Ph3P PPh3
Cl0.04 mol%
H2 (6.8 atm, 100psi), benzene, 50oC
no reaction
Ph3P
Rh(I)Ph3P PPh3
Cl0.04 mol%
H2 (6.8 atm, 100psi), benzene, 50oC
68%
K+ B-
MeO
OH
H
MeO
O-K+
trisubstituted
H
ORh
H
PPh3
H
PPh3
cis isomer (exclusive)
note: when Pd/C was used a mixture of cis and transisomers resulted
Thompson JACS 1974 (96) 6232.Jardine Prog. Inorg. Chem. 1981 (28) 63.
The slow reaction without the alkoxide isattibuted to the steric hinderance of thetri-substituted double bond, which renders it lessable to coordinate to the Rh. The protonatedalcohol is not a strong enough nucleophile toassociatively displace the anionic chloride ligand. Base-assisted formation of the alkoxide results ineffective displacement of the chloride ligand andthus directs olefin complexation from the sameface.
M.C. White, Chem 253 Hydrogenation -146- Week of October 18, 2004
Schrock- Osborn /Crabtree: Cationic catalystsDiene ligated cationic catalysts mode of activation:
Ir(I)PCy3
N
(PF6-) Ir(III)
PCy3
H
(PF6-)
H
N
Ir(III)PCy3
H
(PF6-)
N
+ +
+
SIr(I)
PCy3
N
(PF6-)
+
repeat
SIr(I)
S PCy3
N
(PF6-)
+
diene ligatedcatalyst precursor
solvated active catalyst
H2
cis-oxidativeaddition
cis-migratory insertion
cis-reductiveelimination
Crabtree Acc Chem Res 1979 (12) 331.
Ph3PRh(I)
Ph3P PPh3
Cl
Ir(I)
N
PCy3(PF6
-)
Rh(I)
PPh3
PPh3(PF6
-)
+
+
Turnover Frequency (TOF)
TOF = mol reduced substrate/mol catalyst/h
CH2Cl2, 25oC
CH2Cl2, 25oC
benzene/EtOH, 25oC
Schrock-Osborn catalyst
Crabtree's catalyst
Wilkinson's catalyst
650
4000
6400
700
10
4500
13
----
3800
----
----
4000
"Coordinatively" unsaturatedcationic hydrogenation catalystsare the most active homogeneous hydrogenation catalystsdeveloped thus far. Use ofweakly coordinating solventsprovides the olefin substratewith relatively free access to themetal's reactive site. Thesecationic catalysts are alsoremarkably selective....
M.C. White, Chem 253 Hydrogenation -147- Week of October 18, 2004
Cationic catalysts: substrate-directed hydrogenations
CH2Cl2, H2 (1 atm), rtMe
OHIr(I)
PCy3
N
(PF6-)
+
2.5 mol%
Me
OH
H
i-Pr
OH
Me
H
Ir(III)Cy3P Py
(PF6-)
H +
Me
OH
H
98% 64:1
Pd/C (EtOH), 1:5 (sterics)
Crabtree JOC 1986 (51) 2655.
The availability of a second "open" coordinationsite on the catalyst now makes it possible to bind aligating group on the substrate in addition to theolefin. This "two-point" binding has importantimplications on the selectivity of product formation. The ability of a late metal complex to effectivelybind hard functionality (hydroxyls, ketones, etc...)is attributed to the lewis acidic properties impartedon the complex by the overall positive charge.
Other functionalities with lewis basic sites also direct:
CO2Me
HMe
CO2Me
Me Me
MeO MeO
Me H
O
Me
MeO
Me
Me H
Esters:
56:1Pd/C 1.35:1
above
124:1Pd/C 1.26:1
above
Ketones:
97% >99%
999:1Pd/C 1:4
above
>99%
Ethers
NH
N
O
ONH
N
O
O
Me
above
>99:1Pd/C 1:9 (steric approach control)
HAmides:
5 mol%
(±) (±) (±)
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.
M.C. White/Q. Chen Chem 253 Hydrogenation -148- Week of October 18, 2004
High catalyst loadings: diminished yields and selectivities
Dimished yields are observed with higher catalyst loadings. This can berationalized on the basis that higher catalyst loadings promote the irreversibletrimerization of the coordinatively unsaturated catalysts to yield inactive triiridium hydride bridged complexes. Such complexes have been isolated by Crabtree fromreaction mixtures of more sterically hindered olefins that did not proceed tocompletion.
Crabtree Acc. Chem. Res. 1979 (12) 331.
CH2Cl2, H2 (1 atm), rtMe
OHIr(I)
PCy3
N
(PF6-)
+
2.5 mol%
Me
OH
H
Me
OH
H
99% 139:1
yieldselectivity (ratio A:B)
20 mol% 48%
A B
74:1
Stork JACS 1983 (105) 1072.Crabtree JOC 1986 (51) 2655.
A decrease in selectivity is observed at higher catalyst loadings. It is possible that higher catalyst loadingspromote the formation of dimeric (Crabtree suggestedM-H-M) species that no longer have the "open"coordination site necessary for providing effectivedirecting effects in olefin hydrogenation. Noexperimental data exists thus far to support thishypothesis.
M.C. White, Chem 253 Hydrogenation -149- Week of October 18, 2004
Synthetic applications of directed hydrogenations
O
O
O
OH
HHOSEM
MOMO
Me
O
O
O
OH
HOSEM
MOMO
MeMOMO MOMO
[Rh(NBD)(DIPHOS-4)]+BF4-
NaH, THFH2 (800 psi), rt
Paquette OL 2002 (4) 937.
HO
H
OHO
Me H2, CH2Cl2HO
H
OHO
Me
Me
Barriault OL 2001 (3) 1925.
HO
HO
O
Me
H
HO
HO
O
Me
HMe
H
Rh(I)
Ph2P
PPh2
(BF4-)
+
()n= 3
68%
[Ir(COD)(py)(PCy3)]+PF6-
99% Yield, d.r. 11:1 at C10
10
Ir(I)PCy3
N
(PF6-)
+
M.C. White, Chem 253 Hydrogenation -150- Week of October 18, 2004
Mechanism of hydrogenation:bidentate cationic complexes
Rh(I)PPh3
PPh3
(PF6-)
+
Schrock-Osborn catalyst
Rh(I)
Ph2P
PPh2
(PF6-)
+
()n= 3
nbd (norbornadiene) ring strain results in more facilehydrogenation
diphos
Schrock-Osborn type catalystmost commonly used:
[Rh(nbd)(diphos-4)]BF4
Halpern's mechanism for cationic Rh(I) catalysts with bidentatephosphine ligands:
Halpern Science 1982 (217) 401.
H2MeOH
Ph CO2Me
NHAc
H2 oxidative addition (OA)RDS
(rate determining step)
stereospecificcis-migratory
insertion
stereospecificreductive
elimination
observed by NMR
observed by NMRobserved by NMR
SRh(I)
SPh2P
PPh2
+
Rh(I)
Ph2P
PPh2
+
NH
PhH
O
Rh(I)
Ph2P
PPh2
+
R
NH
PhH
HRh(III)
Ph2P
PPh2
+
R
H
O
(R)
NHO
Rh(III)
Ph2P
PPh2
+
HPh
H
R
H
S
Ph CO2Me
NHAc
M.C. White, Chem 253 Hydrogenation -151- Week of October 18, 2004
Mechanism of monodentate cationic complexesHalpern notes that the hydrogenation mechanism for bidentate ligated cationic complexes where olefin substrate coordination precedes oxidative addition of H2 maynot 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.
Rh(I)PPh3
PPh3Ph3P
Rh(III)S PPh3
H
H
S
++
Rh(I)
Ph2P
PPh2
H2
SRh(I)
SPh2P
PPh2
+ +
In the absence of olefin substrate, no further uptake of H2 can bedetected. The only species observedby NMR is the cationic,4-coordinate solvated species.
Treatment of the monodentatecatalyst with H2 resulted in detection of the Rh(III)-dihydride complex.
Halpern JACS 1977 (99) 8055. Schrock & Osborn JACS 1976 (98) 2135.
Ph3PRh(I)
S PPh3
S
+
only speciesobserved by NMR
k1
k-1
HRh(I)S
Ph2P
PPh2
+
k1
k-1
H2
only species observed by NMR
H
S
To explain the difference in reactivities towards H2 of the catalysts, Halpern invokes the trans effect. The trans effect is defined as thelabilization of ligands trans to certain other ligands. The trans effect often arises when a ligand shares an orbital with another ligand of strongσ-bonding character. Because phosphine forms a strong σ bond with Rh, trans Rh-H bonds formed will be weak because the orbital is not asavailable 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 revertsback via reductive elimination to the solvated 4-coordinate species. In the case of the monodentate phosphine complex, a H2 adduct can formwhere neither H ligand is trans to a phosphine.
Classic example of the trans effect: synthesis of "cis-platinum" a chemotherapeutic agent
ClPt(II)
Cl Cl
Cl
2-NH3
ClPt(II)
Cl Cl
NH3
-
Cl has a stronger "trans influence" than NH3
NH3
ClPt(II)
Cl NH3
NH3
only the cis isomer is formed
H3NPt(II)
H3N NH3
NH3
2+
Cl
H3NPt(II)
H3N Cl
NH3
+
Cl has a stronger "trans influence" than NH3
ClPt(II)
H3N Cl
NH3
only the trans isomer is formed
Cl
The Trans Effect:
M.C. White, Chem 253 Hydrogenation -152- Week of October 18, 2004
Asymmetric Hydrogenation
A variety of bidentate chiral phosphines have since been synthesized and used to effect the hydrogenation of aromatic enamides (important substrates for the efficientgeneration of amino acids):
PPh2
PPh2
Chiraphos (99% ee)
PPh2
PPh2
SKEWPHOS (92% ee)
PPh2
PPh2
BINAP (100% ee)
P
P
R
RR
RDuPHOS (99% ee)
PPh2
PPh2
NORPHOS (95% ee)
HH
PPh2
PPh2
BICP (97% ee)
O
O
PPh2
PPh2
H
H
DIOP (85% ee)
Fe PPh2
NMe2
PPh2
BPPFA (93% ee)
Fe PPh2
PCy2
PPh2
JOSIPHOS (96% ee) E. N. Jacobsen. Chem 153 notes. Spring 2001.For review on DuPhos: Burk Acc. Chem. Res. 2000 (33) 363.
We'll see these ligands again effecting asymmetry ina wide assortment of mechanistically unrelated metal catalyzed reactions with prochiral substrates."Privileged ligand class": ligands that communicateasymmetry effectively with a transition statelocalized at the metal center, irrespective of thenature of the transition state.
E.N. Jacobsen;personal communication
Rh(I)PPh3
PPh3
(PF6-)
+
Schrock-Osborn catalyst
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 chiraltransition metal complex could effectively transfer chirality to a non-chiral substrate with selectivities that rivalthose observed in enzymes. Recall that this led to the 1st commericalized asymmetric process using a chiraltransition metal complex: Monsanto Process for the industrial production of L-DOPA (see Structure andBonding, pg. 4)
CO2H
NHAc
Rh(I)P
P
(PF6-)
+MeO
OMe
i-PrOH, H2 (1 atm), rt>99% yield
CO2H
NHAc
93% eeKnowles JACS 1975 (97) 2567.
DIPAMP (common name for this bidentate chiral phosphineligand)
M.C. White, Chem 253 Hydrogenation -153- Week of October 18, 2004
Origin of Asymmetric Induction
It was concluded from kinetic measurements thatthe minor diastereomer was 580 fold more reactivetowards H2 oxidative addition (recall the RDS at rt). This factor offsets its lower concentration insolution and results in a 60:1 product ratio in favorof the R enantiomer.
Halpern Science 1982 (217) 401.
CO2H
NHAc
H2 (1 atm), 25oC, MeOH
CO2Et
NHAc
N-acetyl-(R)-phenylalanine>95% ee
(R)
Rh(I)P
P
(ClO4-)
+
H3C
H3C
(S,S-CHIRAPHOS)
Rh(I)P
P O
NH
(ClO4-)
+
H3C
H3C
MeO2C
Ph
olefin bound to Rh via its
si-face
stereospecific H migratory insertion /stereospecific H/C reductive elimination
both to the olefin face bound to Rh
minor diastereomer formednone detected by NMR (must be less than 5% present in solution)
Rh(I)P
PO
HN
(ClO4-)
+
CH3
CH3
CO2Me
Ph
olefin boundto Rh via its
re-face
major diastereomer formedin solution (identified by NMR
and x-ray crystallography)
M.C. White/Q. Chen Chem 253 Hydrogenation -154- Week of October 18, 2004
Rh(I)P
PO
HN
(ClO4-)
+
CH3
CH3
CO2Me
Ph
olefin boundto Rh via its
re-face
major diastereomer formedin solution (identified by NMR
and x-ray crystallography)
Halpern Science 1982 (217) 401.
Crystal structure of major diastereomer
CO2Et
NHAc
N-acetyl-(R)-phenylalanine>95% ee
(R)
Major enantiomer observed upon exposing crystal to H2:
CO2Et
NHAc
Minor enantiomer observed uponexposing crystal to H2.
(S)
M.C. White/Q. Chen Chem 253 Hydrogenation -155- Week of October 18, 2004
Monohydride catalysts: RuClH(PPh3)3
O
O
cat.
H2 (126 atm), base (1 eq)
benzene, 40oC, 6h
RuCl2(PPh3)2
O
O
Base % Conversion
NEt3Et2NHBuNH2anilineCa2CO3Na2CO3none
95.495.486.588.195.273.076.0
Effect of base on conversion
fully satuturatedproducts
+
Tsuneda Bull. Chem. Soc. Jpn. 1973 (46) 279.
RuCl(H)(PPh3)3, highly distortedtrigonal bipyramidal. Skapski Chem.
Comm. 1968 1230.
Wilkinson's original report:
cat.
H2 (1 atm), benzene:ethanol, rtquantitative
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 anequivalent of NEt3 is added. One mole of H2 is absorbed with respect to Ru and aminehydrochloride is quantitatively formed. Wilkinson J. Chem. Soc. (A) 1968 3143.
Ph3P Ru(II)
PPh3
PPh3
H
Cl
RuCl2(PPh3)2
"In contrast to the rhodium system, ethanol plays an intimate part in the hydrogenation mechanism; in theabsence of such a co-solvent, hydrogenation is exceedingly slow." Wilkinson Nature 1965 (208) 1203.
RuCl2(PPh3)3H2 (1 eq)
NEt3 (1 eq), benzene+ -Cl +HNEt3
M.C. White, Chem 253 Hydrogenation -156- Week of October 18, 2004
Mechanism of H2 Activation
σ-bond metathesis: the base is effectively one of the ligands on the metal
RuCl2(PPh3)3H2
RuCl(PPh3)3
Cl
H
H
δ−
δ+ RuHCl(PPh3)3
HCl
σ-bond metathesis
external amine base may still drive the rxn forward by forming insoluble amine hydrochloride salts
Crabtree The Organometallic Chemistry of the Transition Metals: 3rd Edition; Wiley: New York; 2001.
Base promoted heterolytic cleavage:
H
H
Mn
σ-donation>>π-backbonding
heterolytic cleavage
σ-complex
Mn H BH++
note: there is no oxidation statechange at themetal
generally observed for electrophilicmetals that are in their highest stableoxidation state within the context of their ligand framework.
Example:
N NH2
Ir(III)
L
H
L H
H
+
(BF4)-
N NH3+
Ir(III)
L
H
H
L
+(BF4)
-
Complexation of dihydrogen to the electrophilic, cationicIr(III) center is predominantly σ-donating in nature.Donation of electron density from the H-H σ-bond to anempty Ir orbital leaves the H-H with a partial positivecharge. The pendent NH2 group is thought to act as aninternal base effecting heterolytic cleavage of the acidifieddihydrogen 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 H2complex 1 being observed exclusively by NMR. It washypothesized that moving to a more basic phosphineincreases the electron density at the metal center. Thismakes the metal a less effective σ-acceptor and attenuatesits ability to effectively acidify the dihydrogen complex.
1 2
Crabtree Chem. Commun. 1999 297.
δ+
M.C. White, Chem 253 Hydrogenation -157- Week of October 18, 2004
BINAP-Ru complexes: Noyori increases the substrate scopefor asymmetric hydrogenations
The first report: asymmetric hydrogenation of (Z)-enamides
NCOCH3
H3CO
AcO
OAc
OCH3
PPh2
Ru(II)
Ph2P O
O
O
O
(0.5-1 mol%)
EtOH:CH2Cl2 (5:1), H2 (4 atm), 23oC
NCOCH3
H3CO
AcO
OAc
OCH3
NCH3
HO
HO
O
H
morphine92% yield95% ee
Interestingly, E-enamides are completely unreactive towards these hydrogenation conditions. Norationale for this has been presented.
Noyori JACS 1986 (108) 7117.Noyori ACIEE 2002 (41) 2008.
(R)-1
air-sensitive
Asymmetric hydrogenation of allylic and homoallylic alcohols:
PTol2
Ru(II)
Tol2P O
O
O
O
0.01 mol%
MeOH, H2, 18-20oC
(S)-1OH
OH
geraniol
nerol
0.2 mol%
MeOH, H2, 18-20oC
(S)-1
OH
OH
(R)-citronellol
97 to >99% yields
(S)-citronellol
96% ee
98% ee
allylic olefin geometry may dictate the stereochemical outcome of thehydrogenation. Practical consequence:to obtain high ee's must start withstereochemically pure olefins.
E-olefin
Z-olefin
regioselectivity: allylic and homoallylic alcohols are hydrogenated whereas bis homoallylic and higheranalogues are left untouched.
Noyori JACS 1987 (109) 1596.
M.C. White, Chem 253 Hydrogenation -158- Week of October 18, 2004
BINAP-Ru complexes: Noyori increases the substrate scopefor 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
The degree of asymmetric induction is significantlyaffected by the H2 pressure in a substrate specificmanner. The implication of this is that a range of H2pressures must be screened to achieve optimalasymmetric induction on a substrate by substrate basis. No trend was observed and no rationale for theemperical observation was given.
H3C CH3
CO2H
PPh2
Ru(II)
Ph2P O
O
O
O
(0.5-1 mol%)
MeOH, H2, 15-30oC
(S)-1
H3C CH3
CO2H
(S)
H2 (4 atm): 91% eeH2 (101 atm): 50% ee
CO2H
Ph
CO2H
(S)
H2 (4 atm): 48% eeH2 (112 atm): 92% ee
Asymmetric Synthesis of (S)-Naproxen:
H3CO
CO2H (0.5 mol%)
MeOH, H2 (135 atm), 15-30oC
(S)-1
H3CO
CO2H
(S)-Naproxen92% yield97% ee 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
Reactions in MeOD
H3C CH3
CO2H
H CO2HCH3H3C
D H
(S)-1H2, MeOD
Experiment indicates that the hydrogen α to the acid comes from H2 whereas the β-hydrogencomes from MeOH. Regio- and stereospecific deuterium incorporation indicates that cis-migratoryinsertion 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 andsolvent is slow.
Halpern JACS 1991 (113) 589.
PPh2
Ru(II)
Ph2P O
O
O
O
CO2H
PPh2
Ru(II)
Ph2P O
O
O
O
AcOH
PPh2
Ru(II)
Ph2P O
O
O
H
O
H2
H+
PPh2
Ru(II)
Ph2P O
O
O
O
H
PPh2
Ru(II)
Ph2P O
O
O
O
H+
CO2H
CO2H
Heterolytic cleavage of H2RDS
note: no oxidationstate change to themetal
note: mechanism is valid for both enantiomers of BINAP. No rationalization for the enantiofacialselectivity is given.
protonolysis
1
cis-migratory insertion
M.C. White, Chem 253 Hydrogenation -160- Week of October 18, 2004
Question of the Week
PPh2
Ru(II)
Ph2P O
O
O
ONH
O
CH3
O
MeO
Ph
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.
H
NH
O
CH3
O
OMe
Ph
H HH
NH
O
CH3
O
OMe
Ph
H DH
NH
O
CH3
O
OMe
Ph
H HD
(S)-1
H2 (1 atm), MeOD
79:14:2