Post on 27-Nov-2015
Metal Hydrides
Many different routes to metal hydrides:
LnM H(H)
LnM X M2 H+
transmetallation(M2 = Sn, B, Si)
LnM + H2
oxidative addition
protonationLnM + H+
β-elimination
MLnH
β-elimination
OLnM
H
OLnMH
O
HO–
LnM C O
(insertion)
Transition metal hydrides are important intermediates and show up in many different processes, such as hydrogenation, hydroformylation, and hydrometallation. Because of their facile generation (see below) they can often be a bit of a nuisance. Their reactivity can vary from hydride donors to strong protic acids.
Common Homogeneous Hydrogenation Catalysts
Two classes of hydrogenation catalysts–monohydride and dihydride. Each have different mechanisms and different selectivities.
Homogeneous hydrogenation are usually carried out with catalysts based on Rh, Ru, and Ir. These complexes are more sensitive than heterogeneous catalysts (Pd/C), but are more selective. Also the presence of ligands around the metal allows for asymmetric hydrogenation.
Rh(H)(PPh3)3(CO): monohydride catalyst, specific for terminal alkenes, double bond isomerization competes, little used
Rh PPh3
H
COPh3PPh3P H2R+ RH
HR+
does not react with catalyst
The monohydride pathway is also important with Ru(II) asymmetric hydrogenations
RhCl(PPh3)3–Wilkinson's catalyst: dihydride catalyst, predictable olefin selectivities, no isomerization with neutral conditions
Cl Rh PPh3
PPh3
PPh3
H2R+ RHH
R≈ >
RR>
R
R
>R
R
>R R
R
R
R
R
R
Rdo not react
Ir
Common Homogeneous Hydrogenation Catalysts
Ir(cod)(PCy3)(Pyr)PF6–Crabtree's catalyst: at least 100 times more active than Wilkinson's catalyst, typically used with nopolar, noncoordinating solvents (CH2Cl2), dihydride mechanism
PCy3
NPF6
d8, 16e–
H2
CH2Cl2" Ir(PCy3)(pyr)(CH2Cl2) " = L2Ir(I)
d8, 12e–
(very unsaturated)
In the presence of H2, the cod ligand suffers hydrogenation, while the solvent may be loosely associated with the metal, it can be replaced by just about any olefin, including tri- and tetrasubstituted.
Cationic Rh catalysts are used as well and have a similar mechanism
Crabtree's cat.
Wilkinson's cat.
6400
650
4500
700
4000
0turnover frequency (h-1)
Homogeneous Hydrogenation ExamplesMe
OBz
O
Me
H
MeMe
OBz
O
Me
H
MeH2
RhCl(PPh3)3
90% yield
Org. Lett. 2000, 2, 2125.
O
Br Br
O
Br Br
4 mol%Crabtree cat.
94% yield
Tetrahedron Lett. 1981, 22, 303.
O
OMe
MeOTr
O
OMe
MeOTr
Me
H
H2RhCl(PPh3)3
80% yieldCan. J. Chem. 1978, 56, 2700.
R1 R
R2
OH
0,1Me
R1 R
R2
OH
0,1
H2 (1-3 atm)RhCl(PPh3)3
90% yieldR1 = H, Me 76-96% yield
>95:5 selectivityJ. Am. Chem. Soc. 2004, 126, 4130.
Directed HydrogenationsLewis basic groups (typically alcohols) in the allylic or homoallylic position can be used to direct the delivery of the hydrogenation from the same side, oftern with high diastereoselectivity. Cationic catalysts are usually employed.
Typical catalysts: [Ir(COD)pyr(PCy3)]PF6 [Rh(nbd)(dppe)]BF4 [Ir(COD)(dppb)]BF4
OH
ML
L H2
solventM
s
L s
L ML
O
L
R
HR
RH
OH
RR
R
OH
RR
L2M(COD)BF4
H2
Utility is in setting new stereocenters diastereoselectively
ML
O
L
R
H
HR
vs.
H2
MLL
R
H
OHH
RH
ML
O
LMe
R
H
RH
H
Me
OH
RR
Me H
Other Lewis basic sites can direct as well.
Directed Hydrogenation Examples
MeMe
MeO
MeMe
MeO
H2Crabtree's cat
99% yield
Me
HO i-Pr
Me
HO i-Pr
Me
HO i-Pr
CrabtreePd/C
>99.9%20%
<0.1%80%
O
CO2MeMe
H2Crabtree's cat
OMe
CO2MeMe
OH
Me
i-PrOH
Me
i-Pr
[Rh(nbd)(dppe)]BF4H2 (800 psi)
H70:1
NH
N
Me
O
O
NH
N
Me
O
OH2
Crabtree's cat
>99:1
Asymmetric HydrogenationsAsymmetric hydrogenation has matured into an incredibly imporant technique for bench chemists as well as industrial chemists. Very clean reactions, essentially no background reaction to introduce racemic material, often very low catalyst loading can be used with modern ligands.
PPh2
PPh2
RuCl2
OH
O
CO2H
Me
OH
O
CO2H
Mecat.H2 (X psi)
Et3N
MeOH (13.4L)
3.92 kg, 18.8 mol) 3.32 kg, 86% yield)97.3% ee
cat.76.4 g, 0.096 mol
0.005 mol%Org. Proc. Res. Dev. 2009, 13, 525–534.
Editorial: If a process chemist can make a chiral center by hydrogenation that will likely become the preferred route.
2001 Nobel Prize in Chemistry: 1/4 William S. Knowles, 1/4 Ryoji Noyori both for asymmetric hydrogenation technology
Where does current innovation take us? Many substrate types can be considered to be "solved problems", though others are still challenging. Many times this problem is "nothing more" than screening ligands.
Asymmetric Hydrogenations-Ligand SurveySome of the more commonly used phosphine ligands:
O
O
MeMe
PPh2
PPh2
(R,R)-DIOP
PPh2
PPh2
(R)-BINAP
PPh2
PPh2
(R)-H8-BINAP
PPh2
PPh2
(R)-SegPHOS
PPh2
PPh2
MeOMeO
(R)-MeO-BIPHEP
O
O
O
O
PP
Me
MeMe
Me
(R,R)-Me-DUPHOS
P P
Me
Me
Me
Me(R,R)-Me-BPE
Me
Me
PPh2
PPh2
(R,R)-CHIRAPHOS
PPh2
PPh2
(S)-PHANEPHOS
PPh2
PPh2
O
OO
O
(R)-SYNPHOS
PPt-But-Bu
H
H
(S,S,R,R)-TANGPHOS
Ph2PP(t-Bu)2
MeH
Fe
Josiphos-type
PPh2 N
O
t-Bu
(R)-t-BuPHOX
O
O
(R)-MonoPhos-type
P NR
R
Asymmetric Hydrogenations–The First Highly Selective ResultsThe first highly selective hydrogenation results:
CO2H
NHAc
MeO
AcO
CO2H
NH2
HO
HO
1) 0.05 mol% Rh(COD)(R,R-DIPAMP)BF4 3.5 atm H2, 88% i-PrOH, 50 ºC
2) HBr, H2OL-DOPAfirst step: 94% ee
R,R-DIPAMP:
P P PhPh
MeO
OMeKnowles (Monsanto): J. Am. Chem. Soc. 1975, 97, 2567 J. Am. Chem. Soc. 1977, 99, 5946
CO2H
NHAc
CO2H
NH2
cat. Rh(COD)(R,R-DIOP)ClH2, Et3N, benzene:EtOH (1:2)
95% yield, 72% optical purity
O
O
MeMe
PPh2
PPh2
R,R-DIOP: Kagan: J. Chem. Soc., Chem. Commun. 1971, 481
Asymmetric Hydrogenations–The First Highly Selective ResultsMechanism of acetamidopropenoates is best studied and illustrates the issues associated with selectivity. All other mechanisms we have discussed still hold. The chiral ligand means diastereomeric complexes can be formed, each with their own set of rate constants
NH
Ms
L s
L
ML
O
L
MeMeO2C
ML
O
L
OPh
+
Me Me
Ph Ph
NH
NH CO2MeMeO2C
diastereomers
H2
k1k-1 k'-1
k'1
k2 k'2H2(fast) (very slow)
minor (< 5%) major (> 95%)
ML
H
L
NH
MeO2CO
Me
PhH
ML
H
L
NH
CO2MeO
Me
PhH
MeO2C NHAc
Ph
CO2MeAcHN
Ph
(R) > 98% (S) < 2%
rapid equillibration of diastereomeric complexes
one diastereomerreacts much quicker with H2 than the other(Curtin-Hammett)
Asymmetric Hydrogenations-Some examples
NHAc
CO2Me
NHAc
CO2Me
Rh(cod)2BF4H2 (10 atm)
CH2Cl2100% conv.
99% eesubst:cat:L(100:1:2)
J. Am. Chem. Soc. 2002, 124, 14552.
O
OP N
Bn
Me
CN
CO2– tBuNH3+
Rh(cod)(ligand)BF4H2 (50 psi)
MeOH, rt, 40 h
CN
CO2– tBuNH3+
(S/C: 27000:1)
PPMe
(S)-trichickenfootphosJ. Am. Chem. Soc. 2004, 126, 5966.
Too many examples to make a representative list - best to search for similar system. Many cases need functional group to bind to metal
Asymmetric Hydrogenations-Some examplesIridium is becoming important for isolated olefins
N
O
(COD)IrN
N
i-Pr
i-PrPhPh
Me
PhPh
Me
cat. I
0.6 mol% cat. IH2 (50 atm)
25 ºC, CH2Cl2
J. Am. Chem. Soc. 2003, 125, 113.98% ee
MeO
MeMe
MeO
MeMe
*
1 mol% [IrL1(cod)]BArF50 bar H2
CH2Cl2, 23 ºC
MeMe
MeMe
*
1 mol% [IrL2(cod)]BArF50 bar H2
CH2Cl2, 23 ºC92% ee
93% ee
NO
(o-Tol)2P
Ph
N
O(t-Bu)2P
PhL1 L2Science 2006, 311, 642.
Ru-Catalyzed Asymmetric HydrogenationsRuthenium catalysts are also quite useful, but proceed through a different mechanism. Useful for unsatruated acids, but other coordinating groups work as well. Thought to proceed through a "monohydride mechanism"
R2
R1
CO2H
R3
R2
R1
CO2H
R3
* *
Ru(OAc)2(binap)H2
MeOH
Ru
O
OO
OP
P
R
Ru
H
OO
SP
P
R3
R1
R2 R3 R2
R1
+ H2+ S
– RCO2HRu
S
O
SP
P R2
O
R3
H
R1
A
+ RCO2HA
Mechanism of olefin hydrogenation by LnRu(OAc)2
+ S
Insertion
Ruthenium remains in +2 oxidation state throughout the mechanism.
Noyori Asymmetric HydrogenationMost hydrogenation catalysts are selective for olefins over other potentially reduceable functional groups (ketones, aldehydes, esters, etc.). But halogen- or methallyl-containing Ru(+2) catalysts can reduce ketones, as long as there is a heteroatom in the α-, β-, or γ-position.
R
O
CnX
n = 1–3X = OH, OMe, NMe2, Br, COSMe, CONMe2, PO(OMe)2, SArCn = sp2, sp3
Ru(II)-BINAPH2
R
OH
CnX
*
reduction of β-ketoesters is illustrative of overall mechanism
+ H2
– HClA
(BINAP)RuCl2S2 (BINAP)RuHClS2R OR
O O
R
OR
O
ORuBINAPCl
Hinsertion+ H+
R
OR
O
ORuBINAPCl
HH
+ Sn
R OR
OH O
(BINAP)RuClSn
+ H2– H+
Noyori Asymmetric HydrogenationThe stereoselectivity can be rationalized by a "quadrant" model. This is a fairly general model that can be used in many metal-catalyzed reactions.
P Ru P
simplified X-raystructure of catalyst
Ru(OAc)2[(S)-BINAP] =
equitorial forward
axial back
only two quatrants are available for the ligand (substrate)
to occupy
PRu
P
O O
Cl
ORR
H
(R)-BINAP
R OR
OH O
PRu
P
OO
Cl
RO R
H
(S)-BINAP
R OR
OH O
(R)-β-hydroxy ester (S)-β-hydroxy ester
R-group in open quadrant
R-group in open quadrant
Noyori Asymmetric Hydrogenation-Examples
(R)-BINAP (S)-BINAPO
OEt
OBnO
H2 (4 atm)7.0 g [RuCl2(C6H6)]2
18.0 g (R)-BINAP
DMF/EtOH100 ºC, 12 hrs10.0 kg (42.3 mol)
OH
OEt
OBnO
9.7 kg96% yield, 97.1% ee
Synthesis 1995, 1014
in situ catalyst preparation
C5H11
O
OMe
OH2 (1 atm)
2 mol% Ru(methallyl)2(cod)2 mol% (S)-MeO-BIPHEP
acetone/aq. HBr then MeOH50 ºC, 5 hrs
C5H11
OH
OEt
O
100% yield97% ee
Tetrahedron Lett. 1995, 36, 4801
methallyl precursor allows for use of 1 atm H2
other binding groups possible as well. In this case a kinetic resolution.
Me
OOH
PhMe
OHOH
PhMe
OOH
Ph
H2 (100 atm)RuCl2[(R)-BINAP]
EtOH+
50.5%92% ee
49.5%92% ee
Noyori Dynamic Kinetic Asymmetric Hydrogenation
Racemic β-ketoesters – If the initial stereocenter present in the starting material can undergo rapid epimerization under the reaction conditions, a single diastereomer will be formed and with high ee.
Me
O
NHAc
O
OMe
H2 (100 atm)0.4 mol% RuBr2(R)-BINAP
CH2Cl2, 15 ºC, 50 hMe
OH
NHAc
O
OMe
99%, 98% eekS,R
kinv kinv
Me
O
NHAc
O
OMe
H2 (100 atm)0.4 mol% RuBr2(R)-BINAP
CH2Cl2, 15 ºC, 50 hMe
OH
NHAc
O
OMe
1%, >90% eekR,R
The stereoisomer of the alcohol is dependent on the ligand, but the configuration of the α-position is substrate dependent.
kinv > kS,R and kR,R
Noyori Dynamic Kinetic Asymmetric Hydrogenation
Me
O
Me
O
OEt
H2 (100 atm)RuBr2(R)-BINAP
Me
OH
Me
O
OEt Me
OH
Me
O
OEt
kinv < kS,R and kR,R
+
1 : 1
H2 (100 atm)RuCl2(R)-BINAP•C6H6
CH2Cl2, 50 ºCOMe
OO
OMe
OOH
OMe
OOH
H Hanti syn99:1
93% ee (R,R)
H2 (100 atm)RuCl2(R)-BINAP•C6H6
CH2Cl2, 50 ºCOMe
O O
OMe
OH O
OMe
OH O
syn anti99:1
J. Am. Chem. Soc. 1989, 111, 9134.J. Am. Chem. Soc. 1993, 115, 144.
Hydrogenation of "Unfunctionalized" KetonesBy combining a chiral diamine ligand with a chiral phosphine, the asymmetric hydrogenation of "unfunctionalized" (ketones without a second binding group) ketones can be acheived.
R1 R2
ORuCl2(S)-BINAP / dpen or daipen
H2, KOH or KOt-Bu, i-PrOH
R1 R2
OH Ph
NH2
NH2
Ph
(R,R)-dpenH2N
H2N
(R)-daipen
OMe
OMe
RuCl
Cl
NN
PP
H2–HCl
H H
H H
RuH
Cl
NN
PP
H H
H H
R1 R2
O
RuH
Cl
NN
PP
H H
H H
OR2
R1
activates C=O
Ru(II), 18 e–
RuCl
NN
PP
H
H H
Ru(II), 16 e–
H2RuCl
NN
PP
H
H H
HH
basic
nucleophilic
electrophilic
J. Am. Chem. Soc. 1998, 120, 13529.
J. Am. Chem. Soc. 2003, 125, 13490.
Hydrogenation of "Unfunctionalized" Ketones
O RuCl2[(S)-xyl-BINAP][(S)-daipen]H2 (8 atm), K2CO3, i-PrOH, 96%
OH
95% ee
O trans-RuH(η1-BH4)[(S)-xyl-BINAP][(S,S)-dpen]H2 (8 atm), i-PrOH, no base
OH
95%, 99% eeJ. Am. Chem. Soc. 2002, 124, 6508.
RuCl2[(R)-BINAP][(S,S)-dpen]H2 (8 atm), KOH, i-PrOH
97%, 90% ee
OMe
Me Me
OHMe
Me Me
cyclopropanesurvives
C=C survives
RuCl2[(S)-BINAP][(R,R)-dpen]H2 (4 atm), KOH, i-PrOH
syn:anti 99.8:0.2, 93% ee
O OH
Asymmetric Transfer HydrogenationIn all previous examples, H2 served as the terminal reductant. The elements of H2 can come from other sources as well (isopropanol and formic acid).Meerwein-Ponndorf-Verley Reduction
R1 R2
O Al(Oi-Pr)3
i-PrOHO
H
OAl
i-PrO Oi-Pr
MeMe
R1R2
R1 R2
OH
Me Me
O+
Metal-catalyzed transfer hyrdogenation – Two mechanisms are possible
M(n)
RCH2O M(n)RCH2OH
HX
RCHO
H M(n)
O M(n)
HR
R
RCH2O M(n+2)
H
H M(n+2)
H
RCHO
O M(n+2)
HR
RH
H+
R
O
RR
O
R
B.E.
insertion
O.A.
X M(n)
RCH2OH
B.E.
insertion R.E.
Me
i-Pr
Asymmetric Transfer HydrogenationNoyori CATHy catalysts – Catalytic Asymmetric Transfer Hydrogenation
N
N
Ph
Ph
Ts
RuCl
Me
i-Pr
H Hcatalyst precursor
N
NH
Ph
Ph
Ts
Ru
amido complex(active catalyst)
KOH
CH2Cl2H2O
both complexes easy to prepare and are reasonably stable
HNH2N
PhPh
Ts(S,S)-TsDPEN ($$)
[RuCl2(η6-p-cymene)]2($$)
+
Et3N
i-PrOH80 ºC
Me
i-Pr
N
NH
Ph
Ph
Ts
Rui-PrOH
15 min
N
N
Ph
Ph
Ts
RuH
Me
i-Pr
H H
isolable, one diastereomer consistently forms, X-ray
active reducing agent for ketones
Angew. Chem. Int. Ed. 1997, 36, 285
Asymmetric Transfer Hydrogenation
N
N
Ph
Ph
Ts
RuH
Me
i-Pr
H H
NTsRu
N
Ph
Ph
i-Pr
Me
H
H
H
C
ORS
Ar RS
O
Ar RS
OHH
possible CH/π interaction
Chem. Asian J. 2006, 1-2, 102.
Ar R
O 0.5 mol% RuCl complex
5:2 HCO2H–Et3N
0.5 mol% [RuCl2(mesitylene)]21 mol% (S,S)-TsDPEN
2.5 mol% KOH, i-PrOHAr R
OH
72-98% eeJ. Am. Chem. Soc. 1995, 117, 7562.
Ar R
OH
90-99% eeJ. Am. Chem. Soc. 1996, 118, 2521.
Ar
OH
R
0. 2 mol% amido complex
acetoneracemic
Ar
OH
R Ar
O
R+
43-51% recovery93-98% ee
Angew. Chem. Int. Ed. 1997, 36, 288
Asymmetric Transfer Hydrogenationsome other reductions
OH
RR
90-99% eeJ. Am. Chem. Soc. 1997, 119, 8738.
NHR
R77-95% ee
J. Am. Chem. Soc. 1996, 118, 4916.
(from imine)
O
Ph
Me
NHCbz98% ee
(R,R)-catalystOH
Ph
Me
NHCbz>99% ee
(S,S)-catalystOH
Ph
Me
NHCbz>99% ee
J. Am. Chem. Soc. 1997, 119, 8738.
Ar OEt
O O
NHBocracemic
[RuCl2(benzene)]2(S,S)-BnDPAE
HCO2H:Et3N (5:2) Ar OEt
OH O
NHBoc
69-95% yield32-98% ee
1 diastereomerPh
PhOH
NHBn(S,S)-BnDPAE
Org. Lett. 2010, 12, 5274.
Enone Reductions With Copper HydridesMuch like the selective reaction of alkyl cuprates with enones, copper hydrides with reduce enones through a 1,4-addition pathway.
Stryker's reagent – [(Ph3P)CuH]6: reduces double bond of conjugated ketones, aldehydes, esters, nitriles, and nitro compounds. stoichiometric reagent. E-enones reduced faster than Z-enones.
J. Am. Chem. Soc. 1988, 110, 291.
H
MeH
H
MOMO
O
H
MeH
H
MOMO
O
0.32 equiv[(Ph3P)CuH]6
C6H6, H2O
O
MeO 0.16 equiv
[(Ph3P)CuH]6
C6H6O
MeO
H
82% yield
85% yield16:1 dr
0.32 equiv[(Ph3P)CuH]6
TMSClC6H6
95% yield18:1 dr
Ph Me
TMSO
Ph Me
O
Enone Reductions With Copper HydridesCatalytic methods have also been developed to address the atom economy of the process and to introduce asymmetry.
cat. [(Ph3P)CuH]6Bu3SnH or PhSiH3
PhCH3 (H2O), rt
O O
Tetrahedron Lett. 1998, 39, 4627.
5 mol% CuCl10 mol% (S)-p-tol-BINAP
5 mol% NaOt-Bu
4 equiv PMHS
Me
OEt
O
Me Me
Me
OEt
O
Me Me90% yield, 85% ee
Si O SiH
O Si
n
PMHS = polymethylhydrosiloxane
J. Am. Chem. Soc. 1999, 121, 9473.
0.1 mol% Ligand1 mol% Cu(OAc)2•H2O
PMHS, t-BuOH
PhCH3, rt
Org. Lett. 2008, 10, 289
EWG
R
EWG
RPPh2
PPh2Ligand
has been extened to other substrates