M.C. White/M.S.

Taylor Chem 153 Hydrogenation -161- Week of October 21, 2002

Substrate-directed hydrogenations with cationic complexes +

+
Ph 2
PCy3
P (BF4- ) Ir(I) (PF6 -)
(I)
CH3 OH Rh OH N CH3 OH
P ()n= 3
Ph 2
CO2Et CO2Et CO2Et
OTBDPS OTBDPS OTBDPS
60:40 anti:syn 65:35 syn:anti
Ph3P (I)
PPh3
Rh
P h3P Cl

It was observed experimentally (and may have been predicted) that In contrast, hydrogenation with the cationic iridium
hydrogenation of the enantiomerically enriched homoallylic alcohol complex Ir[(cod)(pyr)(PCy 3)]PF6 favored the formation
CH3 OH
with the neutral catalyst complex (Ph3P)3RhCl produced a 1:1 of the syn isomer.
mixture of diastereomeric products. Use of the cationic complex
CO2Et
Rh(cod)(dppb)BF 4 led to a preference, albeit small, for the
OTBDPS
formation of the anti hydrogenation product.
50:50 anti:syn Du Bois JACS 2002, ASAP, Oct., 2002.
+OTf +
OTf
Et
Et
P
Rh P
Rh P
P Et
CH3 OH OH CH3 OH
Et (5 mol%)
(5 mol%) CO2Et CO2Et
CO2Et
OTBDPS OTBDPS OTBDPS
>95:5 anti:syn 75:25 syn:anti
General conditions:
H2 (1000psi), CH2Cl 2, rt
Br Br
HN N HN N
The use of chiral bidentate phosphine ligands
O makes it possible to reinforce or partially O
N CO2H N CO2H
H CH3 override substrate bias. H CH3
O O
Manzacidin C Manzacidin A
M.W. Kanan/M.C. White Chem 153 Hydrogenation -162- Week of October 21, 2002

Asymmetric hydrogenation in the synthesis of

unnatural amino acids
OH
Cl
O O

NO2 + Cl
O SbF 6- NO2 HO
Ph2 P O O O
F (COD)Rh F H H H
S N N N NH2
N N
CMe3 O H H
O O
1 atm. H 2, THF, rt NH
OMe MeO HO
AcHN 94% ee, 96% yield NHAc
HO O
O O O
OH
OH
OH Teicoplanin aglycon
HO
reductive elimination
+
* L S +
Rh R
L S COOMe
+ * L H
O R Rh
* L L O NH
H2 Rh
L H Asymmetric hydrogenation is a very general and
+
NH reliable route to amino acids, which are key
MeOOC
building blocks for the synthesis of many natural
* L
Rh H2 insertion products. In this example, the hydrogenation is
L
carried out in the presence of a nitro group.
H +
oxidative addition R N

* L O COOMe
Rh
L H
H

Evans JACS 2001 (123) 12411

M.C. White, Chem 153 Hydrogenation -163- Week of October 21, 2002

Asymmetric hydrogenations of trisubstituted

“unfunctionalized” olefins

+
+
Recall that Crabtree's catalyst is able to effect the efficient
PCy3 - O (PF6 -) hydrogenation of both tri-and tetrasubstituted olefins.
Ir( I) (PF6 )
Replacement of the monophosphane and pyridine ligands
N Ar2P N
Ir with the bidentate phosphanodihydrooxazole ligand
R produces a catalyst that is highly effective in promoting the
asymmetric hydrogenation of trisubstituted,
unfunctionalized olefins.
Crabtree's catalyst Pfaltz hydrogenation catalyst

Counterion effects on conversion (and

selectivity) can be dramatic
counterion catalyst loading conversion
+
X-
PF6- hexafluorophosphate 4 mol% 57 %
O
_
o-Tol2P N F F
Ir
Me
Me B F tetrakis(pentafluorophenyl)- 84%
.1 mol%
borate
F F
* 4
H2, CH2Cl2, rt _
CF3
97 % e.e, >99 % conv. tetrakis[3,5-bis(trifluoromethyl)- .05 mol% >99%
B phenyl]borate (BARF)
CF3
4

Pfaltz ACIEE 1998 37 2897.

M.C. White, Chem 153 Hydrogenation -164- Week of October 21, 2002

Titanocene hydrogenation of “unfunctionalized” olefins

Original report of catalytic hydrogenation activity: First asymmetric example:

Me

i-Pr Me
Ti( IV)
Cl Cl Cl
Ti(IV)
Cl i-Pr
1 mol%
Ph
Ph
25 mol% "Red-Al" (Li(H2Al(OCH2CH2OCH3)2)] 6 mol%

LiAlH(OR)3 (7.5 eq), H2 (16 psi), H2 (1 atm), 20 oC (S)

o
heptane/THF, 40 C
quantitative conversion 15 % ee

Stern TL 1968 (60) 6313. Kagan ACIEE 1979 (18) 779.

First asymmetric example resulting in high ee Asymmetric hydrogenation of "unfunctionalized" trisubstituted olefins

Ph

Cl
Ti( IV)
Cl
Ph
Ph Ti( IV)
Cl Cl
E olefins are reduced more rapidly
and with higher ee's than Z olefins 5 mol%
1 mol% Ph
Ph Me Me 1. 10 mol%. n-BuLi, 0oC. Me
Ph
(S) H2 (1 atm) *
n-BuLi (1 mol%), H2 (1 atm), -75oC
2. 13 mol% PhSiH3 Ph
Ph
3. olefin, H 2 (136 atm)
95% optical purity all substrates reported are 79% yield
65oC 95% ee
alkenes α to an aromatic
ring.

Vollhardt JACS 1987 (109) 8105. Buchwald JACS 1993 (115) 12569.
 M.C. White, Chem 153 Hydrogenation -165- Week of October 21, 2002

Titanocene hydrogenation of “unfunctionalized” olefins

Synthesis of allyldicyclopentadienyltitanium (III) complexes from dicyclopentadienyltitanium (IV) dichloride:

H
2 equ. MgCl
Cl
Ti(IV) Ti(III) Ti(III) H Ti(III)
Cl

2 MgCl2

Martin and Jellinek JOMC 1966 (6) 293; JOMC 1968 (12) 149.
Buchwald argues that the silane does not serve as a
H source based on the following experiment: when
D2 was used in the hydrogenation of
(E)-1,2-diphenylpropene, 1,2-diphenyl propane
1. 10 mol%. n-BuLi, 0oC. resulted which was 98% D2 by GCMS. Buchwald
( IV) Cl goes on to note that the only purpose of the
Ti H2 (1 atm) Ti( III) H
Cl phenylsilane is to stabilize the catalyst during
2. 13 mol% PhSiH3 manipulations prior to starting the rxn.

Me
Me Me
5 mol% * postulated intermediate
based on Martin and
Ph
Jellinek papers Ph

σ-bond metathesis olefin insertion

Ti(III)
H H note:
* regioselectivity
Ph of insertion not
determined
Buchwald JACS 1993 (115) 12569
M.C. White, Chem 153 Hydrogenation -166- Week of October 21, 2002

Stereochemical model

Hydride transfer via a four-centered transition state. leads to ‡

the formation of a new stereogenic center at the
disubstituted carbon of the olefin. In this model, the olefin
approaches from the "front" of the complex with
Me
hydrometallation resulting in formation of the less sterically
hindered Ti alkyl bond. H Ti H (R)

Me
Me major product, >99% e.e.

transition state A
H Ti vs.

The olefin arrangement shown in transition state A Me

minimizes the steric interactions between the large
substituents on the olefin and the cyclohexyl portion of the Me H Ti
(S)
tetrahydroindenyl ligand.The rate of reduction for Z olefins
is slower than the rate of reduction for E olefins. Can this H
result be rationalized based on this model for the transition
state?
transition state B
M.C. White, Chem 153 Hydrogenation -167- Week of October 21, 2002

Asymmetric hydrogenation of cyclic imines

Ti H Ti H
MeO MeO

N H2 NH N
MeO MeO N H2 H
H
Me Me 81 % yield, 98 % e.e.
82 % yield, 98 % e.e.

RHN R'

R' * R'' RN R''

H
*
L Ti

e.g.
‡

R''
‡ ‡
Kinetic studies suggest that the
hydrogenolysis of the Ti-N bond R' * R H R'
may be the rate-determining step in L*Ti R
N * Ti
this catalytic cycle N R'' N H
L*Ti H R
H

the ethylene bridge is

omitted for clarity
R H
N R'
Buchwald JACS 1994 (116) 8952 H2 L*Ti *
R''
M.C. White, Chem 153 Hydrogenation -168- Week of October 21, 2002

Asymmetric hydrogenation of acyclic imines

Acyclic imines exist as mixtures of anti and Ti H

syn isomers. This property proves relevant Me Me
in the asymmetric hydrogenation of these
substrates. N Ph N Ph
H2

anti/syn : 11/1 93 % yield, 76 % e.e.

Me Me
Ph
Ti c-hex N Ph Ti c-hex N Ph
N H N H
(R)
Ph
Me Me Me
Me
favored disfavored
N Ph N

anti Ph
syn
Ph Me Me
Ti Me Ti Me
H N Ph H N Ph
N N
Ph (S)
c-hex c-hex
disfavored favored

the ethylene bridge is omitted for clarity

Buchwald JACS 1994 (116) 8952
M.C. White, Chem 153 Hydrogenation -169- Week of October 21, 2002

Substrate-Directed Ketone Hydrogenations

binap O Ru hydride must have black box chemistry
Ph2 some hydridic character.
P O
Ru(II)
P O
Ph2 O
O O O OH O Ph 2
P O
(R)-1(0.1 mol%) Ru(II)
OEt (S) OEt
MeOH, H2 (100 atm), 23oC, 48h P O
41% yield Ph 2
4% ee O
O OH
(R)-1(0.1 mol%)
N N 2 equ. HX (X= Cl, Br, I)
EtOH, H 2 (50 atm), 23 oC, 12h (R)
72% yield
96% ee RuX2[(R)-binap]
Ru(II)-BINAP dicarboxylate catalysts were found to be ineffective for ketone hydrogenations molecular weight unknown
mediated via α or β-oxygenated functionality. These hydrogenations could be effected in high
yields and ee's with poorly defined halogen-containing Ru complexes. The dicarboxylate catalysts
were effective for ketone hydrogenations mediated via highly basic α (or β) amino functionality.
May pre-coordinate to
the Ru center via a Note: opposite sense of stereoinduction
5-membered ring chelate
O OH OH OH Br OH OH
RuX2[(R)-binap] 0.1 mol%
X X OH Br
R EtOH, H 2 (50-100 atm), rt R (R) (R)

Lewis basic quantitative yield 97% yield <1% yield <1% yield
functionality 92% ee 92% ee 74% ee 30% ee
Hydrogenation of ketones performed
under forcing conditions (recall that RuX2[(S)-binap] gives
May pre-coordinate to olefin hydrogenations were performed the (S) enantiomer
the Ru center via a at 4 atm with this catalyst).
6-membered ring chelate
O X OH X OH OH O OH O
RuX2[(R)-binap] 0.1 mol%
EtOH, H 2 (50-100 atm), rt OH OEt N(Me)2
R R (R)
Noyori JACS 1987 (109) 5856 quantitative yield quantitative yield
98% ee quantitative yield
Noyori JACS 1988 (110) 629. >99% ee (best substrates) >96% ee
M.C. White, Chem 153 Hydrogenation -170- Week of October 21, 2002

Noyori substrate-directed ketone hydrogenation: mechanism

O X OH X
RuX2[(R)-binap] 0.1 mol% May pre-coordinate to
the Ru center via a
R EtOH, H 2 (50-100 atm), rt R (R) 6-membered ring chelate

O
Ph 2
P O
Ru (II)
P O
Ph 2
O

2 eq HX (X= Cl, Br, I)

RuX2[(R)-binap]
molecular weight unknown
H2

OH X HCl

R (R) RuHX[(R)-binap]

Ru(II) monohydride
H2

X R X R
* P * P
P Ru O O P Ru O O
O O
H
H

X R
* P
P Ru O O
O
H
M.W. Kanan/M.C. White, Chem 153 Hydrogenation -171- Week of October 21, 2002

Dynamic Kinetic Resolution of 2-substituted-ß-keto esters

O O OH O
RuBr2[(R)-BINAP]
99:1 syn:anti, 98% ee,
OMe H2 (100 atm) OMe 100% conversion
NHAc CH2Cl2 15°C, 50h
NHAc
Noyori JACS1989 (111), 9134

Scenario 1: There are at least two possibilities for the mechanism of stereoselectivity. One is Scenario 2: Both starting enantiomers are converted to a single
that the β-keto-ester enantiomers can interconvert under the reaction conditions and the intermediate species (a prochiral enol formed via deprotonation
catalyst reacts with one isomer much more rapidly than the other and with high of the α-proton) and the catalyst reacts stereoselectively with
stereoselectivity to produce a single product. this species to produce a single stereoisomer.

O O OH O OH O
RuBr2[(R)-BINAP], H2 O O OH O
+
OMe k1 OMe OMe
OMe OMe
NHAc NHAc NHAc
NHAc NHAc
major product
RuBr 2[(R)-BINAP], H2
OH O OH O
O O OH O
+
OMe
OMe k2 OMe
OMe
NHAc major
NHAc NHAc product
k1>k2 NHAc

The following observations support the interconversion mechanism:

O O OH
[RuCl(C6H6)((R)-BINAP)]Cl O
O O 1:99 syn: anti, 93% ee
reacts to give β-hydroxy ester in OMe H2 (100 atm)
88-96% ee depending on the solvent OMe
OMe CH2Cl2 50°C, 70h

Question: why does the result with the cyclic

substrate support the interconversion mechanism?
M.C. White/M.W. Kanan Chem 153 Hydrogenation -172- Week of October 21, 2002

Diastereoselectivity in the Noyori dynamic kinetic resolution

O O OH O OH O
RuBr2[(R)-BINAP] (R) + (R) syn:anti 99:1 in CH2Cl2
Me OMe H2, CH2Cl2 Me (S) OMe Me (R) OMe syn:anti 71:29 in MeOH

NHAc NHAc NHAc

Excellent enantioselectivity and syn diastereoselectivity is seen in the dynamic kinetic resolution of Recall that in this system hydrogenation is thought to
racemic α-acetamido-ß-keto-esters when the reaction is carried out in CH2Cl2. The observed syn proceed through a Ru-monohydride species, capable of
selectivity with these substrates can be rationalized by considering the Felkin-Anh model for the coordinating the adjacent ester moiety. The transition state
transition state of hydride addition in which the small substituent (H) is adjacent to the Burgi- with the acetamido group anti to the incoming hydride may
Dunitz trajectory of the incoming hydride and the best acceptor (acetamido group) is additionally be stabilized via hydrogen bonding between the
preferentially oriented anti to the incoming hydride. NH of the acetamido group and the OR of the ester.
(H-) ‡ Interruption of this hydrogen bonding interaction via
competetive binding to solvent may account for the
H CO2Me H CO2Me H H OH O diminished syn selectivity seen in MeOH.
CO2Me
Me O Me O = (S)
Me OH Me OMe
NHAc NHAc X R X R
NHAc NHAc
* P O * P O
P Ru O H P Ru O
O vs. O
interconversion Note that ester position is fixed b/c
under reaction H N H H
of chelate formation w/the catalyst (S) Me (R)
conditions NHAc
H
(H-) favored O
‡
AcHN CO2Me AcHN CO2Me H
AcHN CO2Me OH O
Me O Me O = (R)
Me OH Me OMe
syn anti
H H NHAc
H
 M.W. Kanan/M.C.White Chem 153 Hydrogenation -173- Week of October 21, 2002

Stereoselective synthesis of iso-dolaproine: the power and

limitations of DKR with α-substituted-β-keto esters
As part of an effort to develop a stereocontrolled synthesis of dolaproine, Genet and coworkers carried out the Noyori DKR shown
Me below. Based on the literature precedents for DKR with α-methyl-substituted ß-keto esters. the authors were expecting a syn
relationship between C2 and C3. Instead that observed very good diastereoselectivity in the formation of the undesired anti
3R OH
2R isomer. This example highlights a lilmitation of the Noyori methodology. In DKR of α-substituted-β-keto esters, the ligand on
N 4S
H Ru controls the stereochemistry of the ketone being reduced, but the diastereoselectivity is controlled by the substrate. This means
OMe O that only one of the syn or anti relationships between the two stereocenters can be accessed reliably and, in this case, prevents
Dolaproine access to the desired product. This particular substrate has a γ-stereocenter which may be exerting an influence on the selectivity.

Me Me Me
10 bar H2, EtOH, 50°C
OEt OEt 3R OH
3R 2S
N 1 mol% Ru[(S)-MeO-BIPHEP]Br2 N 4S 2S N 4S

HCl; H O O OH O Boc OMe O

HCl; H
Boc-(2S)-iso-dolaproine
MeO PPh2 quant. yield
MeO PPh2 (2S,3R):(2R,3S) 92.5:7.5

(S)-MeO-BIPHEP

Me Me
Ru[(S)-MeO-BIPHEP]Br2, H2 3S OEt
OEt 2R
N 4S
N kslow
HCl; H O O HCl; H OH O

Me
Me
Ru[(S)-MeO-BIPHEP]Br2, H2 3R OEt
OEt 4S 2S
N
N
kfast
HCl; H OH O
Genet Org. Lett. 2001, (3) 1909. HCl; H O O
M.C. White, Chem 153 Hydrogenation -174- Week of October 21, 2002

Non-directed carbonyl hydrogenations:

The Original Report:
a reversal in chemoselectivity
RuCl2(PPh3) 3 0.5 mol%
O OH
H2 (10 atm), benzene, 70oC
83% yield under these conditions, ketones are
not hydrogenated.

Suzuki Chem. Lett. 1977 1085.

RuCl2(PPh3) 3 0.5 mol%

H2 (29 atm), ethanol/benzene, rt strong preference for
93% yield hydrogenation of
O O
sterically unhindered
olefins. Suzuki Chem. Lett. 1977 1083.

Hydrogenation conditions B:
O Hydrogenation conditions A: RuCl2(PPh3)2 ,0.2 mol%
O
+ 250 x RuCl2(PPh3)2 ,0.2 mol% 1500 x NH2(CH2)2NH2 (0.5 mol%),
faster +
H2 (4 atm), 2-propanol/toluene, rt faster KOH (1.0 mol%)
H2 (4 atm), 2-propanol/toluene, rt
Bases have been used in conjunction with Ru(II) catalysts to effect
olefin hydrogenations. Recall that base is thought to promote Noyori JACS 1995 (117) 10417.
heterolytic cleavage of H 2 to form the catalytically active Ru
monohydride species. Therefore, the observed reversal in
chemoselectivity must be primarily due to the added 1,2 diamine.
Selective hydrogenation of carbonyl vs. olefinic functionality using hydrogenation conditions B:
OH
OH

n-C8H17 OH
95% isolated yield 88% isolated yield 97% isolated yield
98.6:1.4 (unsat. alcohol: sat. alcohol) 100:0 (unsat. alcohol: sat. alcohol) 98.2:1.8 (unsat. alcohol: sat. alcohol)
OH
OH
OH

90% isolated yield quantitative isolated yield

99.6:0.4 (unsat. 70:30 (unsat. alcohol: sat.
98% isolated yield alcohol: sat. alcohol) alcohol)
100:0 (unsat. alcohol: sat. alcohol)
M.C. White, Chem 153 Hydrogenation -175- Week of October 21, 2002

Non-directed carbonyl hydrogenations

Ru-H formed acts as a "bulky hydride" 1,2-Diamine is a ligand for the Ru
Reactive Ru-H species generated acts as a bulky source of hydride Both the chiralityof the diphosphine(binap) and the 1,2-diamineaffect the stereochemical
displaying similar diastereoselectivities observed with other stoichoimetric outcome of the carbonyl hydrogenation. Therefore, the diamine ligand is attached to the Ru
large hydride reagents such as KBH(s-Bu) 3. center during the catalytic cycle.
b. torsionally favored axial trajectory
generally observed for non-bulky hydride
sources (recall: avoids formation of
eclipsing interactions in TS) O OH
M-H RuCl2[(S)-binap](dmf)n ,0.2 mol%
H b
O Diamine0.5 mol%, KOH 1.0 mol%
H a. sterically favored equatorial
trajectory generally observed H2 (4 atm), 28oC, 6h
t-Bu for bulky hydride reagents
a (recall: avoids unfavorable
steric interactions with diaxial
H
M-H H's during approach).

a b Phosphine Diamine % ee
Ph Ph
97%
OH H PPh2
H 2N NH2
(S,S)-Diamine
PPh2
t-Bu H t-Bu OH
Ph Ph
14%
H H (S)-Binap
cis trans H 2N NH2
(R,R)-Diamine
57%
Hydride source ratio (cis: trans)
H 2N NH2
Li in NH3 (non-bulky) 1:99
KBH(s-Bu) 3 (bulky) 97:3 Ph Ph
RuCl2(PPh3) 3/ 98.4:1.6 PPh3 (in RuCl2(PPh3)3) 75%
NH2(CH2)2NH 2/KOH H 2N NH2
(S,S)-Diamine

Noyori JOC 1996 (61) 4874. Noyori JACS 1995 (117) 2675.
D.A. Evans. Chem 206 Notes. October 2000
M.C. White Chem 153 Hydrogenation -176- Week of October 21, 2002

Asymmetric, non-directed ketone hydrogenations

In situ method using binap MeO

O OH
RuCl2[(S)-binap](dmf)n ,0.5 mol% MeO NH 2
(S)-Diamine, 0.5 mol%, KOH 1.0 mol%
NH 2
H2 (8 atm), 28 oC, 3h
(S)-Diamine
>99 % yield
>99 % chemoselectivity DAIPEN = 1,1-dianisyl-2 -isopropyl-
Noyori JACS 1995 (117) 10417. 70 % ee 1,2-ethylenediamine
Preformed catalyst using xylbinap
α,β
β -unsaturated ketones: OMe
O OH
(S,S)-1 (0.001 mol%)
Ph K2CO3 (0.04 mol%) Ph (R) Cl OMe
2-propanol, H 2 (80 atm), Ar2 H2
>99% yield P N
rt, 43 h >99% chemoselectivity
97% ee Ru(II)
base-sensitive P N
Ar2 H2
Cl
O OH
(S,S)-1 (0.2 mol%) (S,S)-1
n-C5H11 K2CO3 (0.04 mol%) n-C5H11 (R)
2-propanol, H2 (8 atm), Ar =
98% yield
rt, 43 h >99% chemoselectivity
97% ee

aryl ketones: heteroaromatic ketones

O for: R = p-OMe OH O OH
(S,S)-1 (0.002 mol%) (S,S)-1 (0.2 mol%)
KOt-Bu (0.08 mol%) KOt-Bu (0.08 mol%)
2-propanol, H2 (8 atm), N 2-propanol, H 2 (50 atm), N
R rt, 16 h R rt, 24 h
99.9% yield also effective for furyl and 99.9% yield
R = F, Cl, Br, I, CF 3, C(O)OR,
99% ee thiazolyl ketones 96% ee
NO2, NH 2 in m, p, o positions
Noyori JACS 1998 (120) 13529. Noyori OL 2000 (2) 1749.
M.C. White, Chem 153 Hydrogenation -177- Week of October 21, 2002

Catalyst Synthesis
Catalyst is O2 sensitive: does not store well
OMe Workup done under strictly anhydrous
conditions under an Ar atomosphere
· Remove DMF (pump)
1. DMF (degassed), · Dissolve in Et2O (degassed, dried)
[RuCl2(benzene)]2 Cl OMe · Filter through Si pad
Ar 2 H2
+ Ar, 100 oC,10 min P N · Concentrate
(S)-XylBINAP Ru(II) · Add hexanes (degassed, dried)
2. (S)-DAIPEN, 25oC Ar =
P N · Cannula filtration
6h Ar 2 Cl H2 · Concentrate and store under Ar
(S,S)-1 Noyori, JACS, 1998, 120, 13529

Chiral elements are not commercially available

XylBINAP Prep:

optical resolution using

chiral organic acid
Br 1. Mg P(O)Ar2 1.dibenzoy-L- tartaric acid PAr2
Br 2. Ar 2POCl P(O)Ar2 2. HSiCl 3, NEt3, 92% PAr2
~ 89%

Ar = (±) (S)-XylBINAP

Takaya, JOC, 1994, 59, 3064

DAIPEN Prep:
OMe OMe OMe

p-MeOC 6H 5MgBr 1. CbzCl, 60% H2 (50 psi)

CO2Me OH N3 NH2
2. NaN3, 95% 10% Pd/C
ClH3N 67% H 2N BzCN H 2N
H 85%

L-alanine methyl ester

hydrochloride OMe OMe OMe
(S)-DAIPEN
Burrows, TL, 1993, 34, 1905
M.C. White, Chem 153 Hydrogenation -178- Week of October 21, 2002

Non-Classical Bifunctional Catalyst

Cl
Ph2 H2
P N
Ru(II)
P N
Ph 2 H2
H

H 2, KOH

KCl, H2O

H trans effect results in weakening

Ph2 H2 of the Ru-H bond and may
P N increase it's hydridic behavor
Ru(II) towards ketones.
P N O
Ph 2 H2
H

1
note: 1 is generated from the
RuH(Cl)(R-binap)(tmen) precursor
1
rather than the dichloro precursor
typically used in ketone O
hydrogenations
H δ+
Ph 2 H H Ph 2 H δ-
P N P N
Ru(II) H Ru(II) H
P N P N
Ph2 H H2 Ph2 H H2

hydridoamido intermediate:observed
by NMR when dihydride is treated
with ketone in the absence of H2. The proposed mechanism for ketone hydrogenation involves a
When the hydridoamido complex is concerted transfer of the hydridic Ru-H and protic N-H to the
placed under H2, the dihydride is ketone via a 6-membered pericyclic TS. The ketone substrate
regenerated. cannot interact directly with the 18 e-, coordinatively saturated
O Ru-H catalyst without disrupting one of it's chelate rings or
H displacing a hydride, both energetically unfavorable processes.
H This may account for the observation that 1,2-diamines are
effective at shutting down the olefin hydrogenation pathway,
Morris JACS 2001 (123) 7473. known to proceed through olefin coordination to the metal
followed by hydride migratory insertion.
M.C. White, Chem 153 Hydrogenation -179- Week of October 21, 2002

Transfer hydrogenations: organic hydride donors

The catalysts:
Ts Ts
Cl Cl NTsH N N
Ru RuII Rn RuII
Ru
Cl Cl NH2 N Cl N
+ H2 H Rn

[RuCl2(mesitylene)]2 (S,S)-TsDPEN (S,S)-1 (S,S)-2

(S,S)-2 is the active transfer hydrogenation catalyst and can be formed in situ from pre-catalyst
(S,S)-1 in the presence of KOH or from [RuCl 2(aryl)] 2/ligand/KOH. For base sensitive substrates,
(S,S)-2 can be prepared and isolated separately.
Aryl ketones α,β-Acetylenic ketones

O OH
(S) O OH
[RuCl2(mesitylene)]2 0.5 mol%
(S,S)-TsDPEN 1 mol%, KOH 2.5 mol% (S,S)-1 0.5 mol%
CH3 CH3
i-PrOH (0.1M in ketone) KOH 0.6 mol%
C 4H9 i-PrOH (0.1M) C H
R R 4 9
70% yield
R=H Both aryl and alkylethynyl ketones 98% ee
R = H: 95% yield, 97% ee
Cl Cl: 95% yield, 93% ee serve a good substrates.
OMe OMe: 53% yield, 72% ee

Noyori JACS 1995 (117) 7562. Noyori JACS 1997 (119) 8738.

Overriding substrate bias: OH

(S)
(S) 98% ee
97% yield
NHCBz
O (R,R)-2 1 mol%
i-PrOH, rt
(S) OH

(S)
NHCBz (S)
>99% ee
(S,S)-2 2 mol% NHCBz >97% yield
98% ee
i-PrOH, rt
M.C. White, Chem 153 Hydrogenation -180- Week of October 21, 2002

Proposed mechanism of Noyori transfer hydrogenations

RuII
Cl
TsN
Both the hydroamido ("true catalyst") and dihydride
HN
("loaded catalyst") Ru complexes have been isolated * H
and characterized by x-ray crystallography. Both *
compounds are capable of effecting transfer pre-catalyst
hydrogenations to aryl ketones at comparable rates to
the pre-catalyst without the presence of base. base

HCl· base

The presence of NH or NH2 on the

The reversability of the hydrogenation step may chelating ligand is critical for catalytic
lead to an erosion in ee's and incomplete activity. The dialkylamino analogues are
conversions for substrates with low oxidation ineffective.
Ph R RuII
potentials. To minimize interaction of the product
with the catalyst, the reactions are often run at X NH
2-propanol
substrate concentrations of 0.1M. OH
OH
* *
true catalyst hydrogen transfer

X = NTs, O
±
±
Ph R
H H3C CH3
Ru
H
X Ru
HN O X
* H HN O
* * H
*

RuII
X H
HN Noyori Acc. Chem. Res. 1997 (30) 97.
Ph R
* H Noyori JACS 2000 (122) 1466
* O Noyori JOC 2001 (66) 7931.
O loaded catalyst
M.C. White, Chem 153 Hydrogenation -181- Week of October 21, 2002

Origin of asymmetric induction: C-H/π attraction

DFT calculations indicate that the
sterically more congested Si-TS for the
hydrogenation of benzaldehyde is 8.6 The partial positive charge on the C(sp 2)H of the benzene
(S)
Ru is enhanced by binding to the metal (recall: benzene is a
kcal/mol more stable than its relatively H
uncrowded diastereomeric Re-TS. The O good π-donor) resulting in its increased ability to act as a
rationale given is that Si-TS is stabilized HN CH donor to the electron rich π-system of the aryl group
by the C-H/π attractive interaction Ph H
on the substrate.
between a C(sp2)H substituent on the
benzene ligand of the Ru complex and the Ph
π system of the aryl group on the
"loaded catalytic intermediate"
substrate.
O

Ar R

± ±
H H
Ph R R Ph
H H
Ru Ru
O O
HN O HN O
H H
Ph Ph

Ph Ph

Si-TS Re-TS

OH OH
(R) (S)
Ar R Ar R

major enantiomer observed in aryl

ketone and benzaldehyde-1-d
Noyori ACIEE 2001 (40) 2818.
transfer hydrogenations
M.C. White/M.S. Taylor Chem 153 Hydrogenation -182- Week of October 21, 2002

Synthetic application of Noyori transfer hydrogenation

Ts
N
RuII
N
H
PMBO O i-Pr PMBO OH
Fostriecin
O O i-PrOH O O
Me OTES TMS Me OTES TMS
93% yield
>95:5 d.r.

O OH
R R
TMS TMS
It was possible to control the relative
stereochemistry of the 1,3 diol unit by selection
of the appropriate enantiomer of Noyori's
transfer hydrogenation catalyst.

Ts Ts
N N
RuII RuII
N H N
H2 i-Pr
H
i-Pr
Ru(II) Ru(II)
d6, 18e - d6, 16e -

O OH

Jacobsen ACIEE 2001 (113) 3779.

M.C. White, Chem 153 Hydrosilyation -183- Week of October 21, 2002

Wilkinson’s catalyst: not just for hydrogenations

Generally, the rate of olefin isomerization for terminal olefins is much slower Internal olefins are not hydrosilylated. However the catalyst isomerizes them to
than the rate of isomerization. However, the yields are seldom quantitative terminal olefins which then undergo hydrosilylation:
because of this side reaction.

RhCl(PPh3) 3 SiMe2Ph RhCl(PPh 3) 3 SiMe2Ph

PhMe2Si-H PhMe2Si-H
80% + trans-2-pentene cis-2-pentene 75%
Chalk JOMC 1970 (21) 207.
Ph3P PPh3
Reductive elimination from the branched
metal alkyl is not observed. Once formed, Rh(I)
this intermediate can undergo β-hydride Ph3P Cl
elimination to form an internal olefin or a
terminal olefin. The terminal olefin will PPh3
Ph3P
re-enters the catalytic cycle at a faster rate
than the internal olefin (recall high sensitivity R Rh(I) Cl
Ph3P oxidative
to sterics of the Wilkinson catalyst towards SiR 3 R3Si-H addition
alkene hydrogenations.
reductive
elimination
SiR 3 SiR3
SiR 3
PPh3 PPh3
PPh3
Rh(III) + Rh(III)
R PPh3 H Rh(III)
H PPh3
PPh3
Cl R Cl
Cl
branched linear
metal alkyl metal alkyl SiR 3

H PPh3
β-hydride cis-migratory
insertion Rh(III)
elimination
(hydrometallation) PPh3 R

Cl
R

olefin isomerization Jardine Prog. Inorg. Chem. 1981 (28) 63.

biproduct
M.C. White, Chem 153 Hydrosilylation -184- Week of October 21, 2002

Hydrosilylation of alkynes
C 4H 9 C 4H9 SiEt3
RhCl(PPh3)3 0.001 mol%
+
Et3Si-H, rt 1h
SiEt3
trans product cis product
65% 20%

Parish JOMC 1978 (161) 91

Stereospecific cis hydrometallation of the coordinated alkyne followed stereospecific reductive elimination of the alkenyl
silane should result exclusively in trans product. The experimental observation that cis product formed was accounted for
by envoking addition of a second round of hydrometallation on the alkene followed by β-hydride elimination. This
hypothesis is supported by the observation that pure trans product partially isomerizes to the cis upon treatment with the
catalyst and silane (note: no isomeriztion occurs in the absence of silane)

SiR 3 SiR 3

Ph3P C 4H 9 SiEt3 PPh3

C 4H9
C 4H9 Rh (I)
Cl Rh(III)
SiR 3 Ph3P R3Si-H PPh3
H
stereospecific reductive Cl
β -hydride
elimination
elimination
SiR 3
SiR 3
PPh3 PPh3
(III)
Rh H Rh(III)
R PPh3 PPh3
H Cl Cl
SiR 3
SiR 3
H PPh3 H PPh3
cis-migratory Rh (III) C4H9 C 4H 9 Rh(III)
insertion SiR 3 C4H9 PPh3
(hydrometallation) PPh3
R R3Si
Cl
Cl
M.C. White/Q. Chen Chem 153 Hydrosilylation -185- Week of October 21, 2002

Application of trans hydrosilylation to the synthesis of Brefeldin A

HO OH
CO2Et 1) [Cp*Ru(CH 3CN)3][PF6] 1 mol%
(EtO)3SiH, CH2Cl2 CO2Et
TBSO TBSO (+)-Brefeldin A
N N
OMe 2) CsF, EtOH
OMe
O O

Trost JACS 2002 (124) 9328

+ + +
Cp* Cp* Cp* +L
R3SiH R CO2Et
Ru Ru Ru cis migratory
L L R3Si H
-L R3Si H insertion
-L
L L R CO2Et
oxidative addition L L
L = CH3CN

L
Cp*
Ru
SiR 3
? Cp*
+ H
CsF, EtOH R
H

R
Ru + CO2Et CO2Et
L R L L
H SiR 3 H
L
CO2Et

Note that this substrate contains a free hydroxyl and an epimerizable stereogenic center α to the Weinreb amide;
both of these functionalities are well tolerated in this reaction which proceeds with very high trans selectivity.

Trost JACS 2002 (124) 9328

M.C. White, Chem 153 Hydrosilylation -186- Week of October 21, 2002

Platinum
"Speier's Catalyst" /H2PtCl6·H 2O/ chloroplatinic acid is an extremely active The widely accepted mechanism of this reaction, advanced by Chalk and
catalyst for olefin hydrosilylations. It demonstrates the same regioselectivity Harrod, involves reduction of H 2PtCl6 to a Pt(II) species that shuttles between
observed with Wilkinson's catalyst in the hydrosilylation of terminal olefins. It (II) and (IV) oxidation states to effect hydrosilylation in a manner analogous to
also effects isomerization of internal olefins to terminal olefins prior to that proposed for Wilkinson's catalyst. In support of this is the observation of
hydrosilylation. However unlike Wilkinson's catalyst, chloroplatinic acid is an induction period before hydrosilylations begins and that certain Pt(II)
able to hydrosilylate cyclic internal olefins such as cyclohexene in excellent complexes can effect hydrosilylation, although the exact reactivity (substrate
yields. scope, yields, etc...) has never been reproduced. It has also been suggested that
the active catalyst is colloidal platinum metal. Colloidal metals are suspensions
of fine particles (~10-1000 Å radius) of metal in a liquid. Often the solutions
terminal olefins
appear homogeneous and are able to pass though micropore filters and
surviving centrifugation unaffected.
H2PtCl6·H2O
0.005 mol% “On the basis of known chemistry of d8 metal complexes, a mechanism is
SiMe2Ph suggested…” Chalk and Harrod JACS 1965 (87) 16.
MeCl2Si-H
oxidative
100oC 93% R addition
SiR 3
internal olefins
R3Si-H
L H L
(II)
H2PtCl6·H2O Pt Pt(IV)
0.5 mol% SiMe2Ph L L L
MeCl2Si-H L
2-pentene 100oC 89% R

SiR 3 reductive migratory

cyclic internal olefins R elimination SiR 3 insertion

H2PtCl6·H2O SiMe2Ph R L
0.5 mol% Pt(IV)
MeCl2Si-H L L
100oC R
L
quantitative

For a lead reference on methods for testing for colloidal metal catalysis see:
Speier JACS 1957 (79) 974. Crabtree OM 1983 (2) 855.
M.C. White/Q. Chen Chem 153 Hydrosilylation -187- Week of October 21, 2002
Application of an intramolecular hydrosilylation
in the synthesis of Jatrophatrione
Me Me
O
O Si OSiMe2H Me
Me Me
10 mol% HMDS 1) LiAlH4
Me Me
Me +2 mol% H2PtCl6·6H2O Me Et2 O
BnO MeMe
BnO Me Me BnO Me 2) Me 2SiHCl
+Cl- Me
-(Me3Si)2NH 2 Et3 N
-(Me3Si)4N2 Me
Me Me
(PtCl2)
Nature of active catalyst unclear as
platinum colloids have also been
implicated as viable catalysts.

Me Me Cl Cl
Cl
Si Si Pt H
Pt Cl O Trisubstituted olefin and benzylic ether not
O
Me Me affected. Directed silyl transfer from convex face
of substrate. Alternative iodolactonization from
Me Me Me the corresponding carbonate was ineffective.
BnO Me BnO Me Me
Me

Me Me

Me Cl
Me Si Cl
O Pt H
Me
Me
Me
BnO Me Me

Me

Paquette JACS 2002 (124) 6542.

M.C. White, Chem 153 Hydrosilylation -188- Week of October 21, 2002

First report on palladium catalyzed hydrosilylations:

Palladium
Terminal olefins hydrosilylated with anti-Markovnikoff selectivities 1,3-dienes afford 2-silylated-3-ene products (π-allyl intermedaite?)

SiCl3
Pd(PPh3)4 0.1 mol% SiCl3 Pd(PPh3)4 0.1 mol%
Cl3Si-H, 110oC
90% Cl3Si-H, 110oC
80%

Internal olefins hydrosilylated at slower rates and lower yields than terminal olefins.
Unlike platinum catalyzed hydrosilylations, simple palladium salts are
Cl3Si inactive. It was found that a variety of Pd(II) sources can be activated
Pd(PPh3)4 0.1 mol% towards effecting hydrosilylation in the presence of phosphine ligands.
Cl3Si-H, 110oC Phosphines are thought to reduce Pd(II) to catalytically active Pd(0)
(avoids high energy Pd(IV) intermediates) and to act as ligands to the
Pd(0) preventing its plating out of solution. In support of this, Pd(PPh3) 4
30% can be used directly to effect hydrosilylation. The rate of hydrosilylation
is affected by the nature of the phosphine used indicating that
Pd-phosphine species are present in the catalytic cycle. This observation
No terminally hydrosilylated products from internal olefins were observed. suggests that the selectivity of the reaction may be tuned via the phosphine
ligand. Triphenylphosphine was found to afford a palladium catalyst with
the highest activity.
SiCl3
Pd(PPh3)4 cat.
Cl3Si-H PPh3 > PEt3 > PBu3 > PCy3 > P(OCH3)3
major product

Aryl-substituted olefins underwent Pd catalyzed hydrosilylation with high Proposed intermediate in Pd catalyzed hydrosilylation:
regioselectivity for the Markovnikoff products.

SiCl3 R

Pd(PPh3)4 0.1 mol% H

Cl3Si-H, 110 Co PdII
Cl3Si PPh3
95%

Tsuji Tetrahedron 1974 (30) 2143.

M.C. White, Chem 153 Hydrosilylation -189- Week of October 21, 2002
Preparation of optically active 2oalcohols from terminal olefins via
asymmetric hydrosilylation/Tamao oxidation sequence
Cl
Pd Pd
Cl SiCl3 Si(OEt)3 OH
0.1 mol% SiCl3 + EtOH H2O2
R R R * Me Et3N R * Me
HSiCl3 (1.2 eq) Stereospecific R * Me
minor product major product Tamao Oxidation
OMe
PPh2 The regioselectivities range from ~15:1 (major:minor), and the isolated yields of secondary
alcohols ranged from 45-75%. The ee's for this process are generally excellent and range from
"MOP" 0.002 mol% 94-97%.

Palladium complexes coordinated with a chelating bis(phosphine) (e.g. dppb, chiraphos, or

BINAP) did not catalyse the hydrosilation, even at 80 oC. Alternatively, the reaction PPh2
PPh2 BINAP
proceeded in good to excellent yields at 40 oC with monodentate phosphine ligands. Why?
Note: Only unfunctionalized, aliphatic terminal olefins were reported.

Cl OH Cl OH
Pd Pd Pd Pd
Cl 1. Cl
1.
+ MOP + MOP

HSiCl 3 (1.2 eq) regioselectivity (87:13) HSiCl 3 (1.2 eq)

2. EtOH, Et 3N 70% yield 94% ee 2. EtOH, Et 3N
regioselectivity (66:34)
3. H 2O2 3. H 2O 2
45% yield, 96% ee

Hayashi JACS 1991 113 9887-9888.

Cl SiCl3
Pd Pd
Cl 0.5 mol% This reaction proceeds in good to excellent
Me yields (74-94%) and with very high ee
R HSiCl 3 (1.2 eq) R (95-99%) for a variety of styrene derivatives:
O Me R = 3-NO2, 2 or 3-Cl, 2 or 3-CF3, 2-CH3.
P N Stereospecific Tamao oxidation yields nearly
O
Me optically pure benzylic alcohols.
2 mol%
Johannsen JACS 2002 124 4558-4559.
M.C. White, Chem 153 Hydrosilylation -190- Week of October 21, 2002

Preparation of optically active axially chiral allenylsilanes via

hydrosilylation of 4-substituted 1-buten-3-ynes
Cl
Pd Pd
Cl H H
1 mol% R MeMgBr R
R
Cl3Si Me3Si
Me Fe Me Me

R = t-Bu 59% yield, 85% ee

MeO HSiCl3 (2.2 eq)
PPh R = 2,4,6-Me 3C 6H2 90% yield, 77% ee
R = SiMe 2t-Bu 40% yield, 68% ee
Fe
OMe

2.2 mol% Me

H *L Pd
R HSiCl3
Cl3Si
Me

reductive oxidative
A bulky R group required to get selectivity in elimination addition
the formation of allenylsilane. The authors
speculate that this sterically bulky group is
important in retarding the competing R H Cl3Si Pd H
hydropalladtion of the alkyne moiety. R
L*
Me Cl3Si Pd
Pd Me
Cl3Si L* L*
proposed π-propargyl(silyl)-
palladium intermediate
migratory
insertion
R
R
Cl3Si Pd H

Hayashi JACS 2001 123 12915 -12916. L*

M.C. White, Chem 153 Hydroformylation -191- Week of October 21, 2002

The Oxo Process

Oxo Process: 1938 Otto Roelen. Co2(CO)8 is still the principle catalyst for hydroformaylation of terminal alkenes
industrially. More than 4 million tons of aldehydes are made annually this way. Linear aldehydes are more
desirable than branched aldehydes because they can be converted to linear alcohols used as chemical feedstocks and
detergents.
O
O
Co2(CO)8 cat.
+
H2:CO (1:1, 200-300 atm), R
R R H
120-170oC linear (n) branched (iso)

R = Me (70-80% yield)

Anti-Markovnikov addition
of water to a terminal olefin
OH
catalyst ??
R hydroformalation: n = 1
H2O R n hydration: n = 0
Proposed mechanism:
O

C
(OC)4Co Co(CO)4 H2 (OC)4Co Co(CO)4
(OC)3Co Co(CO)3
C H H
σ-bond metathesis
O
O
R
R H
2 H Co(CO)4
R
catalytically
σ-bond metathesis ?
H2 active species CO R
O

OC Co(CO)3 H Co(CO)3

Heck and Breslow JACS 1961 (83) 4023.

Sommer JACS 1969 (91) 7051. CO
OC Co(CO)3 CO
M.C. White, Chem 153 Hydroformylation -192- Week of October 21, 2002
H

PPh3
Wilkinson: hydroformylation
Ph3P Rh(I) Aliphatic terminal olefins O
PPh3 RhH(CO)(PPh3 )3 3mol% H ~ 4% hydrogenation
C5H11 benzene, H 2:CO (1:1, 1 atm), rt C5H11 H + C5H11 + and isomerization
CO products
RhH(CO)(PPh3)3 O
linear: branched (6.4:1)
Strem (2001-2003)
1g = $75 note: when excess PPh 3 is added (3 eq w/respect to catalyst) the ratio of linear: branched product increases from 6.4 to 9. The
Rates of hydroformylation of amount of hydrogenated/isomerization product also decreases (<4%). This increase in selectivity is at the expense of reaction rate.
terminal vs. internal olefins. Wilkinson notes that one way to increase the regioselectivity to favor linear product is to use a bulky phosphine.
Measured as rate of uptake of
H2+CO (1:1) Aromatic terminal olefins
O H
O
rate
RhH(CO)(PPh3 )3 1.5 mol%
C5H11 3.5 ml/min benzene, H 2:CO (1:1, 1 atm), rt
H
+

C 2H5 0.15 ml/min

linear:branched (0:11)

H H
O PPh3 PPh3
H PPh3 -PPh3 CO
OC Rh(I) Ph3P Rh (I)
Rh(I)
PPh3 PPh3
R H OC CO
CO CO
O H reductive H
elimination R O H
R PPh3 PPh3
Rh(III) Rh(I)
H CO CO R
PPh3 CO branched product
All steps up to H2 oxidative migratory
addition (RDS) insertion
OA are reversible H2
O
R R
R PPh 3 PPh3
Rh (I)
Rh(I) R
Ph3P CO OC CO PPh3
PPh3 Rh(I)
PPh3 desired intermediate
OC Rh(I)
Wilkinson J. Chem. Soc. A 1968 3133. CO migratory OC CO
Wilkinson J.Chem. Soc.A 1970 2753. insertion CO
Morokuma OM 1997 (16) 1065. PPh3
 M.C. White Chem 153 Hydroformylation -193- Week of October 21, 2002

Regioselectivity: bulky phosphine ligand

O CO
Rh(I)
O CO
0.54 mol%
O O O
Ligand, 2 mol%
H
H2/CO (5 atm), 60oC, THF
18h n (linear) iso (branched)
O H
O
Ligand n:iso
Buchwald proposes active hydroformylation catalyst
PPh3 2.4:1
OMe OMe
P(OPh)3 3:1

OMe OMe t-Bu t-Bu

O O O
20:1 (iso was P P O
t-Bu t-Bu
not observed by O RhI O
O P O O
P O NMR
O O OC H

This system was reported in the patent literature to give

high n:iso ratios under mild conditions: Billig US Patent
4,769,498 (1988). Buchwald screens substrate scope.

Substrate scope:

ketones, acids, esters, amides alcohols, halides, nitiles

O O Rh(CO)2(acac) 0.54 mol%

Rh(CO)2(acac) 0.54 mol% R R CHO
CHO 1 2 mol%, H2/CO (5 atm) n
1 2 mol%, H2/CO (5 atm) n
R n R n 60oC, THF
60oC, THF
18h
18h R = CH3, n= 1, 86% R = OH, n= 10, 53%
OH, n= 8, 68% note: the alkyl Br, n= 2, 71%
OMe, n= 8, 91% halides do not I, n= 2, 64%
Buchwald JACS 1993 (115) 2066. undergo OA CN, n= 2, 84%
N(Et)2, n= 2, 93%
M.C. White Chem 153 Hydroformylation -194- Week of October 21, 2002

Asymmetric hydroformylation
Ph 2
P CH 3
Rh O
O CH 3
O
P O
O

CHO
*
(0.5 mol%, 2:1 L*:Rh)
H2/CO (100 atm), 60oC, benzene
R 36 h R
note: chiral phosphinephosphonate ligand R = H, >99% conv.; iso:n (88:12), 94% ee
BINAPHOS and Rh(I)(CO)2(acac) were OMe, >99% conv.; iso:n (87:13), 88% ee
mixed in 2:1 ratio in situ. Cl, >99% conv.; iso:n (87:13), 93% ee

A few other substrates were reported:

CHO CHO CHO

O
* * *
AcO N C 4H9
99% conv. 98% conv. 90% conv.
iso:n (86:14) O iso:n (89:11) iso:n (24:76)
92% ee 85% ee 75% ee

H
Ph2 OC
P CH3
Rh O
O
H2/CO (1 atm) Rh CO Observed by NMR. The rhodium
O CH3 Ph2P monohydride complex displays the same
P O P
O
hydroformylation reactivity and
O
O selectivity as observed above, suggesting
O that it is a valid catalytically active
species.

Takaya JACS 1993 (115) 7033.

M.C. White/M.S. Taylor Chem 153 Hydroformylation -195- Week of October 21, 2002

First application of Takaya asymmetric

hydroformylation to TOS

CH3 CO / H2 (1:1, 20 atm) CH3

CH3 OHC CH3

O O
Ph 2
P Rh O CH3 CH3 91:9 iso:n
O CH3 96:4 d.r.
O
P O
O

(0.5 mol%, 2:1 L*:Rh)

This is the first application of the OH

Takaya catalytic asymmetric OH CH3
hydroformylation to target-oriented
synthesis. Other approaches to such CH3
stereocenters have relied upon chirality HO O O
transfer strategies, requiring several CH3 CH3
steps. CH3
(+) - Ambruticin

Total synthesis of (+) - Ambruticin

Liu, P.; Jacobsen, E.; JACS 2001, 123, 10772-10773.
M.C. White/M.W. Kanan Chem 153 Hydroformylation -196- Week of October 21, 2002

Substrate conformational bias leads to

diastereoselective hydroformylation
Ph Ph

O O 0.7 mol% [Rh(CO) 2acac/4P(OPh) 3] O O OPiv ODEIPS

toluene, 70°C, 20 bar (H2/CO, 1:1)

36 h. 80% I

O
dr ≥ 99:1 intermediate in Toshima's
bafilomycin A1 synthesis

Catalytic cycle:
CH3
O
Ph O CH3 reductive H PPh3 CH3 prefered olefin conformation
elimination Rh(I) O
H Ph to avoid syn-pentane-like
H O OC CO O CH3 interaction; this dictates
diastereoselectivity
H H H
Rh (III) H Rh (I) CO
(PhO)3P P(OPh)3
CO OC P(OPh)3
Stereoselectivity depends on which face of the olefin is
available for coordination to the Rh(I)H species. The stereospecific
H2 strongly preferred conformation of the substrate hydride insertion
CH3
O effectively blocks one face from coordination and
Ph CH3 allows the hydroformylation to proceed with excellent CH3
O diastereomeric excess. O
Ph O CH3
H O
H
CH3 H
O H
OC Rh(I) P(OPh)3 Ph CH3 OC Rh(I) CO
O

P(OPh)3 H P(OPh)3
H P(OPh)3
CO insertion OC Rh(I)
CO
Breit TL 1998, (39) 1901.
P(OPh)3
M.C. White, Chem 153 Q&A -197- Week of October 21, 2002
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.

O
Ph 2
CH3 P O CH3 CH3 CH3
Ru (II)
O P O O O O
Ph 2 O
Ph NH Ph NH Ph NH Ph NH
(S)-1
H O H2 (1 atm), MeOD H O H O H D H O
H H H D
MeO OMe OMe OMe
A B C
79:14:2
One mechanistic possibility that accounts for these observations is the following: Noyori JACS 2002 (124) 6649.
CH 3
O
O
Ph NH It's interesting to note that the
P O mechanism of a reaction may vary
H H O * Ru (II) H Ph depending on substrate.
CH 3 H
OMe P H2 Heterolytic cleavage of H2
O
Ph NH O R
NH H+
H O R = CO 2Me CH 3
MeO the amide carbonyl (more lewis
basic than ester carbonyl) H Ph H Ph
O Ph preferentially binds to Ru H D
P O H P P
* * MeOD
Ru (II) H Ru (II) R NH * Ru (II) R NH
P O NH P O P O
H OAc OAc
CH 3 CH 3

H2/σ-bond O
CH 3
CH 3 methathesis P O
* Ru (II) cis-migratory insertion O
O
P O regioselectively forms the Ph NH
Ph NH protonolysis
5 membered ring chelate
D+ H H D
N CH 3 H O
H H D O H OMe
OMe Ph
Q. Chen/M.C. White, Chem 153 Q&A -198- Week of October 21, 2002

Question 1
Mild hydrogenation of benzene can be achieved with the cobalt complex below. The rate of
cyclohexadiene reduction is similar to the rate of benzene hydrogenation while cyclohexene is
reduced at three to four times slower than benzene. Propose 2 mechanisms for the arene
hydrogenation.

H
H P(OMe)3
Co
cat. P(OMe)3
P(OMe)3
< 1 atm H2, 25 °C, rt.
M.S. Taylor/M.C. White, Chem 153 Q&A -199- Week of October 21, 2002

Question 2
Halpern's seminal mechanistic studies on the Rh + - DIPAMP system for asymmetric dehydroamino acid hydrogenation
permitted improvement of the reaction conditions to increase enantiomeric excess. Provide a rationalization for the following
observations, in light of Halpern's results.

i) Decreasing the H2 pressure of the reaction increases the enantiomeric excess.

ii) Increasing the reaction temperature increases the enantiomeric excess.

M.C. White, Chem 153 Q&A -200- Week of October 21, 2002

Question 3
Hydroformylation proceeds with RhCl(PPh3)3, however there is an induction period. It was shown that in the
presence of a base the induction period is removed. What is the role of the base? Indicate the active catalyst for this
process and specify how it is formed under the reaction conditions.

Ph3P PPh3
(I)
Rh O
Ph3P Cl
cat. + H
C 3H7 C 3H 7 H C 3H7
H2:CO (1:1, 100 atm), 70oC
O
16 h, >99% conversion
linear: branched (2.7:1)
M.S. Taylor/M.C. White Chem 153 Q&A -201- Week of October 21, 2002

Question 4
Provide a mechanism to account for the following transformation

CO O H
OH OH C6H13
NaOAc / AcOH
C6H13 H
PdCl 2, CuCl 2 O
O
H
M.C. White, Chem 153 Q&A -202- Week of October 21, 2002

Question 5
A rhodium hydroformylation catalyst was reported that hydroformylates internal alkenes to produce linear aldehydes
preferentially. Provide a detailed mechanism for this transformation. Rationalize the effect of the bulky phosphine ligand in the
observed regioselectivity.

R
O CO
Rh(I)
O CO
0.1 mol% O
R
C5H11 Ligand, 1 mol% C5H11 + mixture of
H branched aldehydes
H2/CO (20 atm), 80oC, toluene
18h n iso

t-Bu t-Bu Ligand n:iso % 1-nonanal

PPh3 0.9 46%
O
1 9.2 90%
P P

O O

1
Q.Chen/M.C. White, Chem 153 Q&A -203- Week of October 21, 2002

Question 6
The rhodium complex below catalyzes the isomerization of vinyl silanes to
silyl enol ethers. Propose a mechanism for the transformation.

Rh
(PrOi)3Si Si(OiPr)3 2% O
Si
Si(OiPr)3 OiPr
OiPr