Ready; Catalysis
Hydrogenation
Categories and Dichotomies:
Heterogeneous or Homogeneous
Heterolytic or Homolytic H2 Activation
Neutral or Cationic
Racemic or Enantioselective
Directed or Non-directed
Syn or Trans Addition
Ph3P
Homogeneous Hydrogenation
Ph3P
Advantages:
Mild conditions
Improved selectivity
Directed Hydrogenation
Enantioselective Hydrogenation
Mechanistically accessible
Ready; Catalysis
Rh
Cl
PPh3
Disadvantages:
Purification
$$$$
Often less reactive than heterogeneous
Hydrogenation
CH3
cond.
Ph3P
Ph3P
Rh
n-But
Cl
CH3
H3C
CH3
TOF
PPh3
Wilkinson's Catalyst
1st eg of homogeneous cat with
activity similar to heterogeneous
J. Chem. Soc. (A) 1966, 1711
PPh3
H3C
rt
Benz/EtOH
650
700
13
--
4000
10
--
--
6400
4500
+
[PF6]-
Rh
PPh3
rt
CH2Cl2
Schrock-Osborn Cat
Cationic version of Wilkinson's
JACS, 1976, 2134, 2143, 4450
+
0oC
PCy3
Ir
N
Crabtree's catalyst
Acc. Chem. Res. 1979, 331
[PF6]-
CH2Cl2
3800
4000
-cationic cat more active than neutral
-Ir only cat. for tri- and tetrasubstituted olefins
1
Ready; Catalysis
Hydrogenation
Mechanism of Hydrogenation with Wilkinson's Cat
k4 > k1 (by 104) likely b/c 14ek3 > k2 b/c trans effect of H
H
Ph3P
H2, k1
H
Rh
Ph3P
Note: cationic cat don't need to diss L
-L, k3
Cl
PPh3
H
Ph3P
Ph3P
Rh
PPh3
Ph3P
Cl
H
-L, k2
H
Ph3P
PPh3
Rh
PPh3
Rh
Cl
H2, k4
Cl
H
fast, stereospecific
Ph3P
Rh
H
PPh3
Cl
H
H
Ph3P
Ready; Catalysis
Rh
PPh3
rate limiting
olefin insertion
Cl
Hydrogenation
Reactions with Wilkinson's Catalyst
selectivity based on substitution:
O
Pd/C, H2
O
75%
O
O
O
H
O
O
1 mol% (PPh3)3RhCl, H2
O
95%
O
Pedro JOC, 1996, 3815
selectivity based on geometry:
O
O
CO2Me
CO2Me
Cat. (PPh3)3RhCl, H2
80%
HO
HO
AcO
AcO
Schneider JOC, 1973, 951
diastereoselectivity
O
Cat. (PPh3)3RhCl, H2
O
Semmelhack JACS, 1980,
5924
%Y? 'stereospecifically'
Acorenone B
2
Ready; Catalysis
Hydrogenation
Stereospecific: Stereochemical outcome dictated by mechanism
Stereoselective: Stereochemical outcome dictated by relative rates
really good stereoselectivity does not get promoted to stereospecificity
vs.
cis
stereospecific
H
H
H
M, H2
H
trans
M, H2
H
H
vs.
stereoselective
H
H
endo
Ready; Catalysis
exo
Hydrogenation
cod or nbd
Cationic Catalysts:
-very reactive
-can be directed
PR2
PCy3
+
Rh
[PF6]-
PR2
Schrock-Osborn cats
+
Ir
[PF6]-
N
chelating or not
Crabtree's Cat.
+
PCy3
Ir
[PF6]-
N
-c-oct
PCy3
S
OH
S
+
+
Ir
N
[PF6]-
cationic complexes:
-open coordination site for chelating group
-positive charge = lewis acidic
H
PCy3
H
Ir
Py
OH
OH
>50:1
Evans, TL, 1984, 4637
3
Ready; Catalysis
Hydrogenation
Directed Reductions: examples
Hoveyda, Fu, Evans Chem Rev. 1993, 1307
(the review on directed reactions)
OH
H
OH
H
H
OH
H
H
H
H
H
secondary
33:1
primary
6:1
Ir+
Pd/C
H
H
H
tertiary
>100:1
OMe
COMe
CO2Me
H
56:1
1.4:1
>100:1
1.3:1
>100:1
1:4
Stork, JACS 1983, 1072
in synthesis:
11:1
only isomer
MOMO
H
MOMO
O
Me
O
OSEM
Cond: NaH, [Rh(NBD)(DIPHOS-4)]BF4, 800 psi H2
Cond: [Ir(COD)(Py)(PCy3)]PF6
68%
99%
Paquette, OL, 2002, 937
Barriault, OL, 2001, 1925
Ready; Catalysis
Hydrogenation
The inventive process is not clearly understood, but
one factor that seems to be important is to have a
heavy infusion of naivety. That is why, so
frequently, it is not the experts that do the inventing,
but they are the ones who, once the lead is
established, come in and exploit the area
Knowles, Nobel Lecture (ACIEE, 2002, 1998)
Asymmetric Hydrogenation
an experiment that changed the world:
Cf. Wilkinson's
Pr
ClRh
Ph
O
O
OH
OH
OH
H
P
CO2H
Me
Ph
3
H2
Target Rxn:
MeO
CO2H
Ph
CO2H
15% ee
-Phosphines configurationally stable under rxn conditions
-can communicate asymmetry to substrate
-1st eg of asymmetric hydrogenation
HO
1. Hydrogenation
2. Steps
CO2H
L-DOPA
NHAc
AcO
NH2
HO
cHex
Pr
Test Substrate
P
CO2H
28% ee
NHAc
P
Me
Ph
O
PPh2
O
DIOP 83 %ee
-Invented by Kagan
-P not stereogenic
-Importance of C2 Symmetry
MeO
88% ee
Ph
OMe
P
PPh2
Me
P
PPh2
PPh2
P
MeO
P
Ph
DIPAMP
96 %ee
DuPHOS 99% ee
Burk
BINAP >99% ee
Noyori
4
Ready; Catalysis
Hydrogenation
chiraphos
Ph2
P
H3C
Rh(COD)[ClO4]
CO2Me
H3C
NHAc
CO2Me
H2
P
Ph2
NHAc
97% ee
E
P
Rh
P
NH
O
O
k1/k2 = 580
k1 H2
H
P
Rh
P
ee-determining: 1st irreversible step
that involves enantioselection
k2 H 2
ee determining
E
Rh
P
Ph
Observed by NMR, X-Ray
Ph
H
Curtin-Hammett:
Equilibrium between two reactive
intermediates on separate reactions
paths.
E
HN
Keq = ~10
E
HN
NH
O
O
P
H
P
P
Ph
Ph
H
Rh
CO2Me
CO2Me
NHAc
NHAc
60
:
1
Halpern Science, 1982 (217) 401
Ready; Catalysis
Hydrogenation
General Enantioselective Synthesis of Amino Acids
Background: ligand design
B
1.
R
2
HO
R
R
R
H
R
>90% ee for:
H
R
2. H2O2
-a "simple and asthetically pleasing" chiral borane
-synthesized in 7 steps (resolution)
-Masamune, Jacs, 1985, 4549
R
R
P
P
R
R
R
P
R
DuPHOS
CO2Me
R
P
R
BPE
-e rich
-steric tuning possible
-stereogenic centers close to Rh
-comercially available (strem)
-Burk, JACS, 1993, 10125
Like NMR experiments, comming up with a catchy
name seems to be as important as the actual utility
R
R
[Rh(DuPhos)]+
0.01 mol%
NHAc
E
NHAc
R = n, s-alk
CO2Me
H2 (1-2 atm)
R
Ar
E
NHAc
Ar = x-Ph (x = H, edg, ewg)
thiophenyl, Fc
NHAc
H
R
R
H
E
NHAc
R,R' = alkyl; ring;
Ph, alkyl;
vinyl,alkyl;
E, alkyl
One of the most general asymmetric cat rxns
5
Ready; Catalysis
Hydrogenation
Monohydride Mechanisms
P
P
RuCl2(PPh3)3
H
H
P
Ru
P
Cl
Cl
16e-
H2
σ-met.
_
H
B
P
H
H
Ru
H
Cl
+[BH][Cl]
P
Ru
Cl
H
P
P
H
H
P
H
accepted
route
H
No ox. state change
H
Heterolytic cleavage
-HCl
P
Ru
Cl
P
Ru
Cl
P
P
P
RuCl2(PPh3)3
H2 (126 atm)
Base (1equiv)
benzene
conv.
base
NEt3
Aniline
Na2CO3
None
O
O
P
95
88
73
76
Tsuneda, Bull Chem Soc, Jpn, 1973 (46) 279
Ready; Catalysis
Hydrogenation
Heterolytic activation: Mechanistic Considerations
σHH->M > πM->HH
H
Mn
H
+ H+
no ox state change
M
H
H
πM->HH > σHH->M
M(n+2)
+2 ox. state change
H
-σ-coordination acidifies H
-common for high ox state metals
-heterolytic more favored for e- poor M
-effect of other ligands:
+
+
Keq
N
L
Ir
H
LH
H
NH2
N
L
L = PPh3; Keq>1
L = PBu3; Keq<1
Ir
L
H
NH3
H
crabtree, chem com. 1999, 297
6
Ready; Catalysis
Hydrogenation
(BINAP)Ru(II) complexes: Great catalysts for directed asymmetric reduction:
0.01 mol% (S-BINAP)Ru(OAc)2
H2 (30 atm), 5M in MeOH
OH
E olefin (geraniol)
OH
96% ee
0.2 mol% (S-tol-BINAP)Ru(OAc)2
H2 (30 atm), 5M in MeOH
Z olefin (nerol)
98% ee
OH
OH
Noyori, JACS, 1987, 1596
note much higher pressure than cationic Rh
MeO
MeO
N
MeO
O
N
MeO
O
(S-BINAP)Ru(OAc)2
OMe
OMe
H2
quant., >99% ee
Noyori, JACS, 1986, 7117
OMe
OMe
(S-BINAP)Ru(OAc)2
H2, 135 atm
CO2H
CO2H
97% ee
MeO
MeO
Ready; Catalysis
Hydrogenation
95% H
D2 (4atm) CH3OH
CO2H
D 84%
Deuterium: A great mechanistic tool
CO2H
~100% D
(BINAP)Ru(OAc)2
CO2H
H2 (4 atm) CH3OD
H 71%
40/60 H/D
H2 (100 amt) CH3OD
CO2H
H 68%
Noyori, TL, 1990, 7189
For alternate mech, see
Halpern, JACS, 1991, 589
O
L
L
O
Ru
O
O
H2
Hydrogenolysis
CO2H/D
H
H
H2
O
L
L
Ru
O
Protonation
RCO2H
S
O
O
can you guess?
JOC, 1987, 3175
Naproxen
L
heterolytic
H2 activation
L
Ru
O
H
O
S
L
ee determining
H-
umpolung
addn
L
S
Ru
O
O
H
S
L
L
CO2H
Ru
O
CO2H
H2
Hydrogenolysis
H
O
divergence after ee determining step
H
H
7
Ready; Catalysis
Hydrogenation
Substrate-Directed asymmetric Ketone Hydrogenations (aka 'Noyori hydrogenations')
Catalyst preparation
2 equiv. HX
(X = Cl, Br, I)
(BINAP)Ru(OAc)2
[(BINAP)RuX2]
mol wt and structure unknown
likely higher aggregates present
5-membered chelates:
O
OH
O
Ru
O
O
OH
NMe2
(BINAP)Ru(OAc)2
H2 (50 atm) EtOH
note OAc is OK with
strongly coordinating amine
O
OH
OH
OMe
quant.
92 %ee
O
L
6-membered chelates:
best substrates
L
[(BINAP)RuCl2]
H2 (93 atm)
Ru
O
[(BINAP)RuCl2]
H2 (100 atm)
O
O
OMe
quant., >99% ee
OH
O
[(BINAP)RuX2]
OH
NMe2
NMe2
O
72%
96% ee
NMe2
quant, >96% ee
OH
OH
OH
[(BINAP)RuCl2]
H2 (70 atm)
quant, 98 %ee
O
Br
OH
Br
[(BINAP)RuBr2]
H2 (100 atm)
Noyori, Jacs 1987, 5856 and 1988, 629
97%, 92% ee
Ready; Catalysis
Hydrogenation
Non-Directed Asymmetric Ketone Hydrogenations (aka 'Noyori hydrogenations')
challege: how to reduce carbonyl in presence of olefin?
answer: Additive change reactivity (generally true in catalysis; very hard to predict! Review: ACIEE, 1999, 1570)
+
O
CH2
0.2% RuCl2(PPh3)2
+
OH
H2, i-PrOH
relative rate
additive
aldehyde
olefin
none
1
250
KOH (1%), H2N(CH2)2NH2 (0.5%)
1500
1
Enantioselective version:
Noyori, Jacs 1995, 10417
OH
RuCl2(phosphine) 0.2 mol%
Diamine (0.5 mol%), KOH (1 mol%)
H2 (4atm)
O
Phosphine
S-Binap
Diamine
Ph
H2N
"
"
PPh3
Ph
% ee
Ph
Ph
H2N
NH2
H2N
NH2
Ph
H2N
97
NH2
Ph
NH2
14
57
75
Noyori, JACS, 1995, 2675
8
Ready; Catalysis
Hydrogenation
OMe
Optimized systems for non-directed hydrogenation:
Transfer Hydrogenation conditions with 2
0.5-0.1 mol% Ru, 2M 5:2 HCO2H:Et3N
or
0.5-0.1 mol% Ru, 2.5-0.5 mol% KOH, 0.1M IPA
2
Cl H
N
P
OMe
Ru
N
Cl H
P
2
H2
N
Ph
Hydrogenation conditions with 1
0.05-0.01 mol% Ru
~1.5M in IPA, cat K2CO3, 8-10 atm H2
N
Ts
2
Ph
-10 steps total (4 for P, 4 for N) to make cat
1
1
Substrate
99
X=H
O
3-Cl
X-Ph
99
4-Cl
Me
3-OMe
99
4-OMe
% ee (% y)*
2-IPA
2-HCO2H
97
98
98
97
93
95
96
98
72(53)
97
R
n=1
91 (45)
99
n=2
97 (65)
99
R
Ready; Catalysis
NH
Cl
97-99
Noyori, JACS
1996, 2521
1997, 8738
1998, 13529
2005, 8288
90-97
tert-alkyl
alkyl/vinyl/aryl
Hydrogenation
R
N
Base
Stereochemical model: CH -> π donatation
R
N
Ln
H
iPrOH or HCO2H
H2
HO
R
O
H
R
R
N
R
Ln
Ln
Ru
H
N
Ln
Ru
H
NH
N
H
R
N
H
Ru
Ru
H
H
99
Ln
Ru
H
n = 1-3
R'
R = Ph, n-Bu TMS
R' = Me, Et, iPr, tBu, cHex
Mechanism of Ru(diamine) hydrogenations
Ru
97
O
* all %y >90 unless noted
N
H
86
R = pent
R' = Me
n
95
R
N
R' R = Ph
R' = iPr
O
O
R
N
96
O
4-Br,I,NO2,NH2
n
R = Ph
R' = Me
O
Cl
% ee (% y)*
2-IPA
2-HCO2H
1
Substrate
99
O
R
Ru
outer sphere
H
R
NH
H
H
O
R
H
O
note H transfer from IPA is reverse of
transfer to ketone. Ketone reduction can be
reversible. High dilution, short rxn time
needed for good ee.
O
R
R
N
R
Ln
Ru
NH
Noyori JACS, 2000, 1466
computational: ACIEE 2001, 2818
H
H
9
Ready; Catalysis
Hydrogenation
Immine Hydrogenation: Same story, less effective
H
N
Ph
R
Ru
NR
Ar
N
Ph
BzHN
Cl
NHR
SO2Ar
R
Ar
HCO2H/Et3N
MeO
*
R
N
N
MeO
N
H
R
84-95% ee
Ar
N
1. Rh(Et-DuPhos)+
R
NHR
H2
Ar
2. SmI2
NH2
*
R
NH2
R
E
73-97% ee
88-95 %ee
NBn
91% ee
NBn
Burk, JACS, 1992, 6266
Tet, 1994, 4399
89% ee
77% ee
Noyori, JACS, 1996, 4916
Asymmetric hydrogenation of imines (enamines).
Group on N: a variable and a burden
H
H
P
P
H
H
P
tBu t
Bu
P
tBu t
Bu
TangPhos
DuanPhos
Zhang, ACIE, 2009, 6052
Zhang, ACIE, 2009, 800
10
O
P
O
N
PipPhos
compare to:
Ph
O
P
O
*
N
Ph
*
PipPhos
Minnard, Feringa, de Vries, JACS, 2009, 8358
Ready; Catalysis
Hydrogenation
Dynamic Kinetic Resolution
O
OH
O
(+/-)- R
RuX2(R-BINAP), H2
OMe
O
O
R
OMe
O
R
NHAc
(syn)
NHAc
(also others)
Ru
OMe
NHAc
Noyori, JACS, 1989, 9134; 1993, 144;
1995, 2931
O
(+/-)-
OH
O
R
OMe
RuX2(R-BINAP), H2
R = alkyl
(+/-)-
Ar
O
OMe
O
OMe
NH3Cl
CO2Me
Hamada, ACIEE, 2004, 882
MeO-BIPHEP =
1. [IrCl(cod)2] 2, MeO-BIPHEP
100 atm H2, NaI (6 mol%)
NaOAc (1 equiv) in AcOH
2. BzCl
Ru
NH
NH3Cl
(anti)
NH3Cl
O
O
R
OH
O
Ar
OMe
NHBz
dr >99:1
MeO
PPh2
MeO
PPh2
Hamada, JACS, 2005, 5784
'...suggests that the Ir-catalyzed hydrogenation may proceed with a different mechanism from that of the Ru-catalyzed
hydrogenation.'
11
Ready; Catalysis
Hydrogenation
Simple olefins: Largely unsolved substrate class
catalyst
Ir
substrate
Ir
P(Cy)3
(Tol)2
P
N
Py
crabtree
R R = Ar or CH2OR
Ar
O
Me
91-97% ee
only a few examples
Pfaltz
ACIEE, 1998, 2897
catalyst
Me
R
Ar
R
substrates
Ti
H
Buchwald
JACS, 1993, 12569
96% ee
MeO
MeO
93% ee
MeO
OMe
94% ee
90% ee
R'
R'
H
Ar
Ti
R
Ar
H
R
ethylene bridge omitted for clarity
Ar
H
Ti
H
Ar
R
R'
H
Ti
H
R'
H
!-bond metathesis
Rate limiting
R
4-centered ts.
bulky groups in
empty quadrants
Ar
Ti
H
R
H
R'
12
Ready; Catalysis
Hydrogenation
R
R
0.5 mol% [Ir(cod)(PN*)]BArf
H2
Ar
Ar
open
semi-blocked
OPAr2
N
O
Ph
O
O
H
Ir
N
CH3
P
H
=
H
L
PN*
blocked
open
Substrates
CH3
Ph
>99% ee
Ph
CH3
p-MeO-C6H4
CH3
CH2
CH3
p-MeO-C6H4
96% ee
CH3
97%
CH3
CH3
Ph
OAc
CO2Et
Ph
CH3
>99% ee
>99% ee
Ph
>99% ee
33% ee
CO2Et
Andersson, JACS, 2004, 14308
Ready; Catalysis
Hydrogenation
Asymmetric hydrogenation of truly unfunctionalized olefins: Pfaltz, Science, 311, 2006, 644
phosphinites
[Ir(A)(cod)]BArF
1 mol%
MeO
MeO
93% ee
O
(oTol)2P
[Ir(A)(cod)]BArF
1 mol%
MeO
A
MeO
Ph
-98% ee
[Ir(B)(cod)]BArF
1 mol%
O
t
Bu2P
92% ee
AcO
N
N
B Ph
O
[Ir(A)(cod)]BArF
1 mol%
AcO
O
>98% RRR
γ-tocopherol acetate
(vitamin E)
13
Ready; Catalysis
Hydrogenation
Some recent industrial applications of asymmetric hydrogenation:
F
F
F
NH2
O
N
N
F
N
N
rxn via !-imine
CF3
F
Josiphos
[(cod)RhCl]2
0.3 mol% Rh
H2
160 Kg
95% conv
94% ee
NH2
O
N
N
F
N
N
Januvia
Sitagliptin (diabetes, Merck) CF3
Merck, JACS, 2004, 9918
F
P(tBu)2
PPh2
Fe
HO2C
HO
S
O
(JOSIPHOS)
usually P(cHex)2
O
Josiphos/Rh(I)
H2
H3C
CO2-
H
N
N
H
P
CH3
S
O O
Antrax LF inhibitor
OL, 2005, 3405
97% ee
O
CN
F
O
H
N
O
P
CO2-
(TCFP)
Rh(cod)2BF4 (0.004mol%)
H2
TCFP = trichickenfootphos
NH2
CN
100g scale
>98% conv
98% ee
CO2pregabalin (Lyrica)
Anxiety, epilepsy and pain
Pfizer, JACS, 2004, 5966
Recent examples of asymmetric hydrogenation
14