Hydrogenation versus Transfer Hydrogenation of Ketones: Two Established Ruthenium Systems Catalyze Both

Article abstract of DOI:10.1002/chem.200304884

The established standard ketone hydrogenation (abbreviated HY herein) precatalyst [Ru(Cl)₂((S)-tolbi-nap){(S,S)-dpen}] ((S),(S,S)-1) has turned out also to be a precatalyst for ketone transfer hydrogenation (abbreviated TRHY herein) as tested on the substrate acetophenone (3) in iPrOH under standard conditions (45°C, 45 bar H₂ or Ar at atmospheric pressure). HY works at a substrate catalyst ratio (s:c) of up to 10⁶ and TRHY at s:c<10⁴. Both produce (R)-1-phenylethan-1-ol ((R)-4), but the ee in HY are much higher (78-83%) than in TRHY (4-62%). In both modes, iPrOK is needed to generate the active catalysts, and the more there is (1-4500 equiv), the faster the catalytic reactions. The ee is about constant in HY and diminishes in TRHY as more iPrOK is added. The ketone TRHY precatalyst [Ru(Cl)₂((S,S)-cyP₂(NH)₂)] ((S,S)-2), established at s:c=200, has also turned out to be a ketone HY precatalyst at up to s:c=10⁶, again as tested on 3 in iPrOH under standard conditions. The enantioselectivity is opposite in the two modes and only high in TRHY: with (S,S)-2, one obtains (R)-4 in up to 98% ee in TRHY as reported and (S)-4 in 20-25% ee in HY. iPrOK is again required to generate the active catalysts in both modes, and again, the more there is, the faster the catalytic reactions. The ee in TRHY are only high when 0.5-1 equivalents iPrOK are used and diminish when more is added, while the (low) ee is again about constant in HY as more iPrOK is added (0-4500 equiv). The new [Ru(H)(Cl)((S,S)-cyP₂(NH) ₂)] isomers (S,S)-9A and (S,S)-9B (mixture, exact structures unknown) are also precatalysts for the TRHY and HY of 3 under the same conditions, and (R)-4 is again produced in TRHY and (S)-4 in HY, but the lower ee shows that in TRHY (S,S)-9A/(S,S)-9B do not lead to the same catalysts as (S,S)-2. In contrast, the ee are in accord with (S,S)-9A/(S,S)-9B leading to the same catalysts as (S,S)-2 in HY. The kinetic rate law for the HY of 3 in iPrOH and in benzene using (S,S)-9A/(S,S)-9B/iPrOK or (S,S)-9A/(S,S)-9B/tBuOK is consistent with a fast, reversible addition of 3 to a five-coordinate amidohydride (S,S)-11 to give an (S,S)-11-substrate complex, in competition with the rate-determining addition of H₂ to (S,S)-11 to give a dihydride [Ru(H)₂((S,S)-cyP₂(NH)₂)] (S,S)-10, which in turn reacts rapidly with 3 to generate (S)-4 and (S,S)-11. The established achiral ketone TRHY precatalyst [Ru(Cl)₂(ethP ₂(NH)₂)] (12) has turned out to be also a powerful precatalyst for the HY of 3 in iPrOH at s:c=10⁶ and of some other substrates. Response to the presence of iPrOK is as before, except that 12 already functions well without it at up to s:c=10⁶.

Full text of DOI:10.1002/chem.200304884

FULL PAPER
Hydrogenation versus Transfer Hydrogenation of Ketones: Two Established
Ruthenium Systems Catalyze Both
Valentin Rautenstrauch,*[a] Xua√n Hoang-Cong,[a] Raphae»l Churlaud,[b]
Kamaluddin Abdur-Rashid,[b] and Robert H. Morris*[b]
Abstract: The established standard ke-
tone hydrogenation (abbreviated HY
herein) precatalyst [Ru(Cl)2((S)-tolbi-
enantioselectivity is opposite in the two
modes and only high in TRHY: with
(S,S)-2, one obtains (R)-4 in up to 98%
ee in TRHYas reported and (S)-4 in 20
25% ee in HY. iPrOK is again required
to generate the active catalysts in both
modes, and again, the more there is, the
faster the catalytic reactions. The ee in
TRHY are only high when 0.5 1 equiv-
alents iPrOK are used and diminish
when more is added, while the (low) ee
is again about constant in HY as more
iPrOK is added (0 4500 equiv). The
new [Ru(H)(Cl)((S,S)-cyP2(NH)2)] iso-
mers (S,S)-9A and (S,S)-9B (mixture,
exact structures unknown) are also pre-
catalysts for the TRHY and HY of 3
under the same conditions, and (R)-4 is
again produced in TRHY and (S)-4 in
HY, but the lower ee shows that in
TRHY (S,S)-9A/(S,S)-9B do not lead to
the same catalysts as (S,S)-2. In contrast,
the ee are in accord with (S,S)-9A/(S,S)-
9B leading to the same catalysts as (S,S)-
2 in HY. The kinetic rate law for the HY
of 3 in iPrOH and in benzene using
(S,S)-9A/(S,S)-9B/iPrOK or (S,S)-9A/
(S,S)-9B/tBuOK is consistent with a fast,
reversible addition of 3 to a five-coor-
dinate amidohydride (S,S)-11 to give an
(S,S)-11-substrate complex, in competi-
tion with the rate-determining addition
of H2 to (S,S)-11 to give a dihydride
nap){(S,S)-dpen}]
((S),(S,S)-1)
has
turned out also to be a precatalyst for
ketone transfer hydrogenation (abbre-
viated TRHY herein) as tested on the
substrate acetophenone (3) in iPrOH
under standard conditions (458C, 45 bar
H2 or Ar at atmospheric pressure). HY
works at a substrate catalyst ratio (s:c)
of up to 106 and TRHYat s:c < 104. Both
produce (R)-1-phenylethan-1-ol ((R)-4),
but the ee in HY are much higher (78
83%) than in TRHY (4 62%). In both
modes, iPrOK is needed to generate the
active catalysts, and the more there is
(1 4500 equiv), the faster the catalytic
reactions. The ee is about constant in HY
and diminishes in TRHYas more iPrOK
is added. The ketone TRHY precatalyst
[Ru(Cl)2((S,S)-cyP2(NH)2)] ((S,S)-2), es-
tablished at s:c ˆ 200, has also turned
out to be a ketone HY precatalyst at up
to s:c ˆ 106, again as tested on 3 in
iPrOH under standard conditions. The
[Ru(H)2((S,S)-cyP2(NH)2)]
(S,S)-10,
which in turn reacts rapidly with 3 to
generate (S)-4 and (S,S)-11. The estab-
lished achiral ketone TRHY precatalyst
[Ru(Cl)2(ethP2(NH)2)] (12) has turned
out to be also a powerful precatalyst for
the HY of 3 in iPrOH at s:c ˆ 106 and of
some other substrates. Response to the
presence of iPrOK is as before, except
that 12 already functions well without it
at up to s:c ˆ 106.
Keywords: asymmetric catalysis
¥
homogenous catalysis ¥ ketone hy-
drogenation ¥ ruthenium ¥ transfer
hydrogenation
enantioselective reductions of ketones, in particular of
Introduction
ˆ
unsaturated ketones in which the C C double bonds are left
Among the most spectacular recent developments in asym-
metric catalysis are the RuII-catalyzed, highly chemo- and
entirely intact. There are two ways of doing this. One is an
enantioselective RuII-catalyzed version of the Meerwein
Ponndorf Verley reduction, thus the redox reaction between
the substrate and most typically excess iPrOH to give
8]
selectively one product alcohol enantiomer;[1 this is called
[a] Dr. V. Rautenstrauch, Dr. X. Hoang-Cong
Firmenich SA, Corporate R&D Division
1211 Geneva 8 (Switzerland)
transfer hydrogenation, abbreviated TRHY herein. Here
iPrOH is both the reducing agent and the solvent. The other
Fax : (‡41)22-780-33-34
way is enantioselective hydrogenation with molecular H2 as
E-mail: valentin.rautenstrauch@firmenich.com
valentin.rautenstrauch@wanadoo.fr
11, 22]
the reducing agent,[9
abbreviated HY herein, and here
[b] Prof. R. H. Morris, Dr. R. Churlaud, Dr. K. Abdur-Rashid
Department of Chemistry, University of Toronto
Ontario, M5S 3H6 (Canada)
iPrOH is usually also the solvent of choice.
The TRHY have been studied longer and by numerous
groups and a multitude of systems has been described. Among
the most advanced catalysts are the [Ru(amidoalkoxy)(ar-
Fax : (‡1)416-978-16-31
E-mail: rmorris@chem.utoronto.ca
4954
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/chem.200304884
Chem. Eur. J. 2003, 9, 4954 4967

4954 4967
ene)]/[Ru(H)(aminoalkoxy)(arene)][1] (A/B) and [Ru(bis-
amido)(arene)]/[Ru(H)(aminoamido)(arene)][2] (C/D) redox
pairs (Scheme 1). The method is mature and well understood,
but has several disadvantages: the substrate catalyst ratios
(s:c) are low–typically 102 103; one is obliged to work with
concentrations, typically around 2m in iPrOH. A certain
disadvantage is that they normally require autoclaves.
Academe has focussed almost exclusively on enantioselec-
tive TRHY and HY, but HY of ketones to give achiral or
racemic alcohols or to give mixtures of diastereoisomeric
alcohols and of all kinds of aldehydes just using very low
loadings of achiral or racemic precatalysts already have
considerable industrial potential, because such HY can re-
place reductions by means of the traditional hydride reagents
(NaBH4, LiAlH4, polymethylhydrosiloxane, etc.). Most of
these reagents are difficult to handle and require a heavy
workup, involving hydrolysis and a separation, plus the
disposal of the large amounts of inorganic hydroxides
produced. In HY, one normally uses H2 in large excess, but
it can be recycled and is one of the ideal reactants: lowest
possible molecular weight, total atom economy, very low cost,
effortless separation on degassing.
Until very recently, mechanistic investigations, both exper-
imental and theoretical, have concentrated on TRHY rather
than on HY, and on the TRHY that use the redox couples of
type A/B and C/D (Scheme 1) mentioned above. For both
types, representative catalysts are identified and the mecha-
nisms largely understood. Thus upon treatment of an amino
alcohol with a [{Ru(Cl)2(arene)}2] in iPrOH in the presence of
Scheme 1.
a base, the active catalysts are formed in four steps, ! F !
dilute solutions to shift the equilibrium concentration of the
product alcohol–typically around 0.1m in iPrOH; the ee is
subject to erosion at long reaction times because the
reversibility of the fast step that leads to the major enantiomer
eventually comes into play. There are also advantages, namely
the existence of catalysts that produce alcohols in high ee and
the simplicity of the operation. The method is therefore often
proposed as an operationally simpler alternative to HY that is
suitable for small and medium scale applications.
i,k,n,q, 8d]
G ! A ! B[1e,g
(Scheme 1). Compound F is the first
[Ru(Cl)2(aminoalcohol)(arene)] precatalyst to be formed.
Then follow two consecutive dehydrochlorinations. The first
gives the [Ru(Cl)(aminoalkoxy)(arene)] precatalyst G and
the second the [Ru(amidoalkoxy)(arene)] catalyst A. Catalyst
A is the dehydro form of the redox pair and is coupled with its
reduced form [Ru(H)(aminoalkoxy)(arene)] B by the redox
reaction with iPrOH; see below. Once formed, A and B
function alone; base is only required to generate A from Fand
G. When a diamine is used instead of an amino alcohol, the
redox pair C/D is formed via the analogous sequence ! H !
I ! C ! D.[1i,q, 2c,f, 8d] Most of the C/D pairs have one amido
function N-tosylated, but there are some specific exceptions in
which they bear just alkyl or aryl groups.[2b,g]
The HY are a more recent discovery. The Noyori group×s
HY precatalysts [Ru(Cl)2(bisphosphane)(diamine)] E essen-
tially constitute a single group, which performs outstanding-
ly.[9, 11]
A representative example is [Ru(Cl)2((S)-tolbi-
nap)((S,S)-dpen)] (S),(S,S)-1[9e,f, 12]. These precatalysts are
The reduced forms B and D both contain a near-planar syn-
H-Ru-N-H motif at the active site, and a common general
mechanism for the redox step has been proposed (Scheme 2).
transformed in situ into the active catalysts by treatment with
base in iPrOH under H2. The active catalysts are suspected to
be hydridoamido/dihydride redox pairs;[9m,q] we will discuss
this in detail further on in this section, as well as later in the
section on HY kinetics. From the industrial viewpoint, with a
view to application on a large scale, HY has a much greater
potential because very large s:c ratios can be reached–the
highest s:c on record is about 2 Â 106,[9f] more than 103 to 104
times higher than in TRHY. HY have two further important
advantages: no erosion of the enantioselectivity (see further
on in this section) and they can be run at much higher
Scheme 2.
In the sense of the reduction of the substrate ketone, the
hydridic H on Ru and the protic H on N in B and D are more
or less simultaneously transferred from the H-Ru-N-H site to
the carbonyl dipole (™metal ligand bifunctional catalysis∫,[1i]
Chem. Eur. J. 2003, 9, 4954 4967
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4955

V. Rautenstrauch, R. H. Morris et al.
FULL PAPER
™concerted hydride and proton transfer∫[4d]) via a six-mem-
bered transition state. The resulting A and C, with an active
1) Within the constraints of the Meerwein Ponndorf Ver-
ley equilibria, an RuII catalyst redox pair that works in the
HYof ketones in iPrOH is likely to also work in the TRHY
with iPrOH as the reducing agent, owing to the principle of
microscopic reversibility, provided the pair is stable in the
absence of H2.
ˆ
Ru N site, then revert back to B and D by the same reaction
in reverse, with iPrOH to give acetone, through transfer of the
hydroxyl and a-C-bound hydrogen atom.
Numerous other RuII-based TRHY systems are known and
the corresponding precatalysts are almost always dichlorides
generated in situ; these are also treated with base to transform
them in situ into the active catalysts. Among these are systems
where one can imagine that a catalyst with an active H-Ru-N-
H site is involved although that is not established[5] and others
that seem to utilize a different mechanism,[6] but the latter
conclusion is not made in the literature, nor are there
suggestions as to what that latter mechanism may be.
2) Systems that work in TRHY should also work in HY if the
reduced form H-Ru-N-H of the TRHY redox pair can be
ˆ
regenerated by addition of H2 to the dehydro form Ru N
rather than by the backward reaction with iPrOH.[13]
For point 2 above, if the addition of H2 is efficient enough,
then it outpaces and replaces the slow, unfavorable backward
reaction with iPrOH, and this is then the essential advantage
in HY. The reduced form of the catalyst is then formed much
more rapidly; the step in which the substrate is reduced is,
therefore, also rapid, effectively irreversible, and thus not
subject to erosion of the enantioselectivity with time.
Strikingly, there are no systematic cross tests in the
literature. To the best of our knowledge, there are just a very
few papers that deal with advanced systems and in which the
activities in both modes are mentioned in passing or can be
inferred: these are listed in Table 1.
The Noyori group×s advanced [Ru(Cl)2(bisphosphane)(di-
amine)] HY precatalysts E are likewise transformed into the
active catalysts by treatment with base in situ in iPrOH, but
under H2. Nothing concrete was known about these active
catalysts until recently, but it was suspected that they probably
also have a syn-H-Ru-N-H motif at the active site and reduce
ketones as in the TRHY mechanism just discussed.[8e, 9e, 11b,c, 22]
This is depicted in Scheme 3 in terms of a dihydride of the
Reference [14] provides the
only positive cross test from
HY to TRHY that we know of
in the area; however, the
TRHY experiment was not run
in iPrOH but in (S)-1-deutero-
1-phenylethan-1-ol/THF, and it
seems that the mechanistic sig-
nificance was not recognized.
Further, it is established that
the structurally related Shvo
catalyst is active in both HY
and TRHY, but the experi-
ments in the two modes were
also carried out in different
solvents.[4] The rest of the re-
ported tests we know of con-
cern early systems with lower
activities and are again not true
Scheme 3.
cross tests, because the condi-
tions were also not the same.[15]
There is also a paper in which the differing performance of
(different) HY and TRHY systems on the same class of
substrates is compared.[1m]
We reiterate that there are striking similarities, but also
differences, in the literature recipes that are used to generate
type K; reduction of the ketone by K gives the dehydro form
L. The regeneration of the H-Ru-N-H catalyst K from the
ˆ
Ru N catalyst L then occurs by the reaction of L with H2, not
iPrOH as in TRHY. Some of us recently provided exper-
imental support for this sequence;[9m,p,q,s] we will discuss this
evidence in later sections.
We were struck by the following situation: although the
mechanism of the reduction step is viewed as being essentially
the same, TRHY and HY are otherwise treated completely
apart in the literature. Papers either deal with TRHY or with
HY, but never with both. In particular, (pre)catalysts are also
either used for TRHY or for HY, but never for both. The goal
of the present work is to discover new HY systems by
examining known TRHY systems, or in other words by
running cross tests. A two point rationale can be spelled out
for this:
Table 1. Known cross tests.
(Pre)catalyst type
TRHY
HY
[Ru(H)(aminoamido)(arene)]
[Ru(H)(Cp*)(diamine)]
[Ru(Cl)2(PPh3)3]/NH2-CH2-
CH2-NH2/iPrOH/KOH
[Ru(Cl)2(PPh3)2(NH2-CH2-
CH2-NH2)]/iPrOH/KOH
Shvo catalyst
active[10]
almost inactive[10]
almost inactive[9a]
almost inactive[10]
active[10]
very active[9a]
active[14]
active[4]
very active[9f]
active[4]
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Chem. Eur. J. 2003, 9, 4954 4967

Asymmetric Catalysis
4954 4967
the catalysts in TRHYand HYand that were discussed above.
As outlined, the precatalysts in TRHY and HY were always
different until the present study; nevertheless, they are usually
dichlorides in both cases. In both cases, the standard solvent
(iPrOH) is the same, but the substrate/product concentrations
are normally much lower in TRHY than in HY. In both cases,
standard HY precatalyst [Ru(Cl)2((S)-tolbinap)((S,S)-dpen)]
((S),(S,S)-1) for TRHY activity. Table 2 lists the published
record result for the HY of the standard substrate acetophe-
none (3) at s:c 2.4 Â 106 and a typical result from the same
paper for 1-acetonaphthone (5) at s:c 105 (to give compound
6) which is more convenient for rapid screening, and then our
tests with 3 from s:c 104 to 106 with and without H2 and in the
presence of varying amounts of iPrOK, mainly under standard
HY conditions, that is, at 2.1m substrate concentration. HY is
slow with one equivalent iPrOK and works well with 5
4500 equivalents at s:c 105 to 106. The HY rates increase as
the active catalyst is produced by dehydrochlorination
3, 5 9, 11]
reactions induced by addition of base.[1
In HY, the
catalysts are generated by this reaction in the presence H2.[13]
In both cases, the base is typically iPrOK, but much more is
usually used in HY than in TRHY: about 5000 times more in
two systems we deal with herein ((S,S)-2-based TRHY at s:c
200, 0.5 equiv iPrOK;[3a,b] (S),(S,S)-1-based HYat s:c 2.4 Â 106,
2.4 Â 104 equiv iPrOK[9f, 16]). iPrOK is most often generated
from commercially available tBuOK that is added to the
solvent iPrOH; MeONa, iPrONa, KOH, NaOH, and K2CO3
are also used. It seems that these dosages were developed
empirically, and only recently have explanations been ad-
vanced; see later. A consequence of the different amounts of
base that are used or required and of the presence of H2 in
HY[13] could be that, starting from the same precatalyst,
different catalysts are formed in TRHY and HY. A further
complication is that several isomers with different geometries
may be accessible for any given catalyst. The conclusions of
points 1 and 2 above would nevertheless apply to all of these
catalysts. Accordingly, we decided to carry out the first
systematic cross tests and to study the effect of varying the
amount of iPrOK in both modes.
more base is added, while the ee for the product (R)-1-
phenylethan-1-ol ((R)-4) are about constant throughout this
range.
In the absence of H2 under otherwise the same conditions,
slow TRHYoccurs at s:c 104 to 105, which also produces (R)-4,
but the ee are much lower than in HY, decrease as more base
is added, and also decrease with time; this last decrease being
probably due to equilibration. We also did one run under
typical TRHY conditions (cf. next section and Table 3), at s:c
200 (Table 2, TRHY4). It also works, but the ee is now in
Results and Discussion
Cross
tests
with
[Ru(Cl)2((S)-tolbinap)((S,S)-dpen)]
((S),(S,S)-1): For completeness, we began by testing the
Table 2. Conversions and ee for the precatalyst [Ru(Cl)2((S)-tolbinap)((S,S)-dpen)] ((S),(S,S)-1) in the hydrogenation (HY, ™H2∫) and transfer
hydrogenation (TRHY, ™no H2∫) of acetophenone (3), 1-acetonaphthone (5) and cyclohexyl methyl ketone (7).
Run
Conditions[a]
Substrate
Precatalyst/
iPrOK/Substrate
Conversion
1[b]
ee 1[c]
Conversion
2[b]
ee 2[c]
ref. [9f]
ref. [9f]
HY1
HY2
HY3
HY4
HY5
HY6
HY7[d]
TRHY1
TRHY2[d]
TRHY3[d]
TRHY4
HY8
45 bar H2, 308C, 2.4m
10 bar H2, 308C, 2.4m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
no H2, 608C, 2.1m
no H2, 608C, 2.1m
no H2, 608C, 2.1m
no H2, 458C, 0.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
3
5
3
3
3
3
3
3
3
3
3
3
3
7
7
1/2.4 Â 104/2.4 Â 106
1/455/105
1/90/106
100/48
100/40
32/3
100/3
0.4/24
95/1.5
100/1.5
100/1.5
100/3
2/3
11/3
25/1.5
11/3
0/24
97/3
80 (R)
98 (R)
78 (R)
79 (R)
n.d.
80 (R)
78 (R)
80 (R)
83 (R)
42 (R)
11 (R)
13 (R)
62 (R)
37/14
100/3
79 (R)
80 (R)
1/450/106
1/1/105
1/5/105
1/90/105
1/450/105
1/4500/105
1/450/105
1/4500/105
1/4500/104
1/0.5/200
1/90/105
4/24
23/20
87/20
15/24
26 (R)
4 (R)
9 (R)
52 (R)
HY9
1/450/104
20[e]
[a] The standard conditions throughout Tables 2 4, 7 are 45 bar H2 for HY, Ar at atmospheric pressure for TRHY, 608C, ca. 2.1m solution of the substrate in
iPrOH. Runs were typically carried out on a 20 mmol scale. Conditions that are different from these standard ones are indicated in bold face. Precatalyst/
base/substrate ˆ mol iPrOK (generated by adding tBuOK) and mol substrate per mol precatalyst. [b] Conversion 1 ˆ conversion in %, usually at the first
control (GC) after n h; conversion 2 ˆ conversion in % at the maximal reaction time (when the run was stopped) in h, thus 100/48 means 100% conversion
within ꢀ48 h. [c] ee 1 and 2: corresponding ee in % for the alcohols (R)- or (S)-1-phenylethan-1-ol (R)- or (S)-4, (R)- or (S)-1-(1-naphthalenyl)ethan-1-ol (R)-
or (S)-6, and (R)- or (S)-1-cyclohexylethan-1-ol (R)- or (S)-8. The selectivities for the product alcohols throughout were normally close to 100% and rarely, at
high base concentration, down to about 96%. [d] The actual experiment was done with (R),(R,R)-1. For clarity, the table lists these results mirrored to the
(S),(S,S)-1 series. [e] (R) or (S) was not assigned.
Chem. Eur. J. 2003, 9, 4954 4967
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V. Rautenstrauch, R. H. Morris et al.
FULL PAPER
Table 3. Results for [Ru(Cl)2((S,S)-cyP2(NH)2)] ((S,S)-2) with acetophenone (3) as the substrate.
Run
Conditions[a]
Precatalyst/
iPrOK/Substrate
Conversion
1[b]
ee 1[c]
Conversion
2[b]
ee 2[c]
ref. [3a]
ref. [3a]
TRHY1
TRHY2
TRHY3
TRHY4
TRHY5
TRHY6
TRHY7
TRHY8
TRHY9
TRHY10
HY1
no H2, 238C, 0.1m
no H2, 458C, 0.1m
no H2, 458C, 0.1m
no H2, 458C, 0.1m
no H2, 458C, 0.1m
no H2, 458C, 2.1m
no H2, 458C, 2.1m
no H2, 458C, 2.1m
no H2, 458C, 2.1m
no H2, 458C, 2.1m
no H2, 458C, 2.1m
no H2, 458C, 2.1m
45 bar H2 458C, 2.1m
45 bar H2 458C, 2.1m
45 bar H2 458C, 2.1m
45 bar H2 458C, 2.1m
45 bar H2 458C, 2.1m
45 bar H2 608C, 2.1m
45 bar H2 608C, 2.1m
45 bar H2 608C, 2.1m
45 bar H2 608C, 2.1m
45 bar H2 608C, 2.1m
45 bar H2 608C, 2.1m
45 bar H2 608C, 2.1m
45 bar H2 608C, 2.1m
45 bar H2 458C, 2.1m, benzene
45 bar H2 458C, 2.1m, benzene
1/0.5/200
1/0.5/200
1/0.5/200
1/1/104
91/25
93/7
32/1.5
5/6
12/5
4/6
97 (R)
97 (R)
94 (R)
98 (R)
96 (R)
96 (R)
92 (R)
82 (R)
53 (R)
8 (R)
88/9
90 (R)
98 (R)
92 (R)
92 (R)
90 (R)
64 (R)
46 (R)
6 (R)
14/46
43/40
8/47
30/47
43/47
44/47
86/100
1/450/104
1/1/104
1/90/104
1/450/104
1/900/104
1/4500/104
1/1/105
1/450/105
1/1/105
1/1/105
1/450/105
1/450/105
1/4500/105
1/0/105
1/90/105
1/90/105
1/450/105
1/450/105
1/4500/105
1/90/106
1/450/106
1/450/104
1/450/105
8/6
9/6
14/6
24/7
0.1/48
1.7/22
4/7
12/6
36/7
79/3.5
26/2
1/3
n.d.
92 (R)
26 (S)
24 (S)
24 (S)
24 (S)
24 (S)
16 (S)
19 (S)
n.d.
22 (S)
19 (S)
20 (S)
20 (S)
25 (S)
2/48
35/23
15/24
100/23
100/6.5
100/4
2/24
99/6
100/24
100/6
92 (R)
25 (S)
20 (S)
23 (S)
23 (S)
24 (S)
13 (S)
19 (S)
20 (S)
20 (S)
HY2
HY3
HY4
HY5
HY6
HY7
HY8[d]
HY9
HY10[d]
HY11[d]
HY12[d]
HY13[d]
HY14
12/3
3/3
62/3
100/3
100/3
19/3
23/3
0/24
0/24
100/22
100/24
20 (S)
18 (S)
HY15
[a] See footnote [a] in Table 2. [b] See footnote [b] in Table 2. [c] See footnote [c] in Table 2. [d] Actual run done with (R,R)-2 and mirrored.
between those seen in HY and under HY conditions in the
absence of H2; the reaction also does not go to completion.
Point 1 in the Introduction is thus further confirmed,[14] but
there is a surprise: in this first strict cross test from HY to
TRHY for an enantioselective system, the enantioselectivities
are different. The system has turned out to be optimal for HY
in that only HY gives high enantioselectivity.
Table 2 also lists results on the HY of cyclohexyl methyl
ketone (7) by means of (S),(S,S)-1. Ketone 7 is unaffected
from TRHY to HY, because it so much resembles a typical
HY precatalyst such as (S),(S,S)-1; recall that the best-
understood TRHY systems, the redox couples A/B and C/D
and their precursors (Scheme 1), contain some similar ele-
ments, but have otherwise quite different structures. The
tetradentate ligand cyP2(NH)2 in (S,S)-2 provides essentially
the same coordination environment as the combined biden-
tate TolBINAP and DPEN ligands in (S),(S,S)-1, except that
(S,S)-2 has NH sites and (S),(S,S)-1 NH2 sites.[12] It is known
that (S,S)-2[3a] has the P and NH sites arranged around the Ru
in the same way as in (S),(S,S)-1,[9f] that is, in a plane with the
Cl above and below and in the same order, P, NH, NH, P in
(S,S)-2 and P, NH2, NH2, P in (S),(S,S)-1. The flexibilities of
the environments, bidentate/bidentate and tetradentate, are
clearly different, and, therefore, different precatalyst geo-
metries and especially catalyst geometries could be accessible
in the two systems. These active catalysts have not yet been
identified. In view of all of this, it was truly intriguing that only
opposite and unique reactivities had been reported: only
TRHY in the case of the (S,S)-2[3d] and only HY in he case of
(S),(S,S)-1,[9e,f] without mention of the opposite mode.
after 24 h at s:c 105 in the presence of 90 equivalents of iPrOK,
while 3 is completely converted within 1.5 h under these
conditions, but 7 is readily hydrogenated (to give compound
8) at s:c 104 and by using 450 equivalents iPrOK. This is in line
with our general experience in this area: 3 and its derivatives
are always the most reactive substrates; see also section on
HY by means of precatalyst 12 (see later).
Cross tests with [Ru(Cl)2((S,S)-cyP2(NH)2)] ((S,S)-2): We
chose the Gao Noyori Ikariya TRHY precatalyst
[Ru(Cl)2((S,S)-cyP2(NH)2)] ((S,S)-2)[3, 12] for a first cross test
4958
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Chem. Eur. J. 2003, 9, 4954 4967

Asymmetric Catalysis
4954 4967
We were once more in for a surprise: again with acetophe-
none (3) as the substrate, (S,S)-2 works very efficiently in HY
as regards the rate, but the enantioselectivity is opposite to,
and unfortunately much lower than, that in TRHY. Table 3
shows the published TRHY results at s:c 200 at 238C and
458C, controls without H2 at s:c from 200 up to 105 with
varying amounts of base added, at 0.1m (standard for TRHY)
and 2.1m (standard for HY) at 458C, and then under 45 bar H2
at s:c 105 and up to 106, at 458C and 608C, again with varying
amounts of base added. Here TRHY has turned out to be the
better method in that it gives a high ee, but the HY activity is
otherwise very high, at about the same level as that of the very
good HY system based on (S),(S,S)-1. Thus only half of the
potential of the system was known, and the tantalizing
question is just why high enantioselectivity is only attained
in TRHY, at the cost of 104 times more catalyst. Intriguingly,
one can conclude outright that the active catalysts that are
both generated from (S,S)-2 must be different in TRHY and
HY, and yet the basic mechanisms for the reduction steps
similar as outlined.
needed to determine the optimal amount of base with regard
to ee and rate. The drop in ee when more base is added is
already seen at low conversion and is thus due mainly to
catalyst modification and not to racemization via equilibra-
tion. Note that Table 3 lists several HY runs in duplicate,
showing that reproducibility is not perfect (throughout this
paper), but that the above conclusions (rate versus amount of
base present) are on solid ground.
Work by some of us and new results that are discussed in the
next two sections cover HY of 3 in benzene as the solvent. In
the second of these sections, we show that HY, by what is
presumably the active catalyst pair that we also obtain from
(S,S)-2 upon treatment with base, is about 10 times faster in
iPrOH than in benzene at ambient temperature. To correlate
these results, we also tested the (S,S)-2-based HY under our
standard conditions in benzene rather than iPrOH as the
solvent, which confirm this large solvent effect. We saw no
conversion within 24 h at s:c 105 and 104 (450 equiv iPrOK,
Table 3, runs HY14 and HY15). We continued this calibration
with a more reactive system (complex 12; see later).
In detail, the data in Table 3 show that HYalready proceeds
slowly in the absence of base; this is not TRHY because the
enantioselectivity is opposite to that for TRHY. One equiv-
alent iPrOK already suffices to make the HY really go, but the
HY rate increases as more base is added up to 4500 equiv-
alents, while the enantioselectivity is about the same over that
entire range. In the parallel TRHY runs, thus without H2 but
otherwise using the HY conditions, the (opposite) enantiose-
lectivity decreases, while the rate increases as more and more
base is added (Figure 1). Some further tuning would be
Cross tests with the [Ru(H)(Cl)((S,S)-cyP2(NH)2)] isomers
(S,S)-9A and (S,S)-9B: Some of us recently prepared and
characterized hydridochlorides of the type [Ru(H)(Cl)(bis-
phosphane)(diamine)] (J) and dihydrides of the type
[Ru(H)2(bisphosphane)(diamine)] (K) (Scheme 4) along with
related complexes.[9m,p,q,s] Both types were potential HY
catalysts that could be formed from the dichloride precata-
lysts [Ru(Cl)2(bisphosphane)(diamine)] (E) under the HY
conditions. They were tested only in HY and in benzene
solution or starting with the neat substrate, and it was
concluded, that, in these media, the hydridochlorides J are
inactive and the dihydrides K active. It was further shown that
the hydridochlorides J are transformed into dihydrides K, the
hydrogenated form of the catalysts, by treatment with one
equivalent iPrOK in benzene under H2. This involves
dehydrochlorination of J to give the dehydro form L, which
then adds H2, thus J ! L ! K (Scheme 4). In the catalytic
cycle (Scheme 3), K then reacts with the substrate ketone to
give L and the product alcohol, and L then again adds H2.
This would seem to suggest the sequence E ! M ! J !
L ! K leading from the first dichloride precatalyst E to the
redox pair L/K (Scheme 4), but there is so far no evidence for
Figure 1. Effect of added iPrOK on TRHY activity using (S,S)-2.
Scheme 4.
Chem. Eur. J. 2003, 9, 4954 4967
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¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4959

V. Rautenstrauch, R. H. Morris et al.
FULL PAPER
the postulated first elimination of HCl and the first addition of
H2, E ! M ! J (Scheme 4, ™boxed in∫). Further, things are
unfortunately more complicated in the standard solvent
iPrOH (the hydrides of type J and K were observed by
1H NMR spectroscopy in [D6]benzene and the HY then
monitored in the same solvent) and less is still known about
the active catalyst(s) in this medium. Thus it is not yet known
whether the hydridochlorides J are involved at all in iPrOH,
either as precatalysts or as catalysts. On the other hand, it is
very likely that the amidohydride/dihydride redox pairs L/K
are also the active catalyst pairs in the HY in iPrOH.
However, the situation is complicated by the fact that K and
iPrOH are in equilibrium with complexes of the type
[Ru(H)(iPrO)(bisphosphane)(diamine)]
(N)
and
H2
(Scheme 4).[9s] The more base and the more H2 is present,
the more this equilibrium favors the dihydrides K;[9s] the
dihydrides K and the amidohydrides L may be too basic to
survive in iPrOH alone and would thus be stabilized in the
presence of base as proposed for related systems.[9s] H2 gas is
probably also required to stabilize K. The complexes N are
also potential precatalysts and/or active catalysts, but nothing
concrete is yet known about their role, except that partial b-
hydride elimination N ! K plus acetone has been also
observed in the absence of H2, as another possible mode of
generation of K.[9s]
ably this reaction proceeds by means of deprotonation to give
an amido intermediate that is then protonated on the opposite
side. Scheme 5 depicts this isomerization in terms of tentative
structures for A and B.
Therefore, in the hope of learning more about the active
catalysts in TRHYand HY based on the use of [Ru(Cl)2((S,S)-
cyP2(NH)2)] ((S,S)-2), we tried to synthesize the complexes
[Ru(H)(Cl)((S,S)-cyP2(NH)2)] ((S,S)-9), corresponding to J in
Scheme 4) and [Ru(H)2((S,S)-cyP2(NH)2)] ((S,S)-10), corre-
sponding to K in Scheme 4, in order to test them in both
TRHY and HY and, thus, to verify whether and if so how they
are involved in the (S,S)-2-based processes.
Scheme 5.
Table 4 lists the tests with 3 as the substrate using a 60:40
mixture of the [Ru(H)(Cl)((S,S)-cyP2(NH)2)] isomers (S,S)-
9A and (S,S)-9B, and (S,S)-9B alone. TRHY activity was
tested in the absence of base or with very little base added,
0.5 equivalents iPrOK, because of the procedure given in
reference [3a], see Table 3. TRHY is very slow in the absence
of base, and works in its presence. We obtain the same product
enantiomer (R)-1-phenylethan-1-ol ((R)-4) as in the case of
(S,S)-2, but the ee are much lower. The mixture {A‡B}and B
alone are thus not the active catalysts in the (S,S)-2-based
Refluxing an equimolar mixture of [Ru(H)(Cl)(PPh3)3] and
the tetradentate ligand (S,S)-cyP2(NH)2 in THF as described
previously[9m,p,q,s] resulted in the near-quantitative formation
of a mixture of two new diastereoisomeric hydridochloro
complexes (S,S)-9A and (S,S)-9B. Two sets of dd (doublet of
doublets) and two AB patterns with similar chemical shifts
1
and coupling constants were observed in the H and 31P{1H}
NMR spectra, respectively. Further, we found that isomer A
can be isomerized to isomer B in THF in the presence of a
catalytic amount of DBU or tBuOK, but not Et3N. Presum-
Table 4. Results for the [Ru(H)(Cl)((S,S)-cyP2(NH)2)] isomers ((S,S)-9A and (S,S)-9B) with acetophenone (3) as the substrate.[a]
Run
Isomer
Ratio
Conditions[a]
Precatayst/
iPrOK/Substrate
Conversion
1[b]
ee 1[c]
Conversion
2[b]
ee 2[c]
TRHY1[d]
TRHY2[d]
TRHY3[d]
HY1[d]
HY2[d]
HY3[d]
HY4
A/B ˆ 60:40
A/B ˆ 60:40
B alone
A/B ˆ 60:40
A/B ˆ 60:40
A/B ˆ 60:40
B alone
no H2, 458C, 0.1m
no H2, 458C, 0.1m
no H2, 458C, 0.1m
45 bar H2, 458C, 2.1m
45 bar H2, 458C, 2.1m
45 bar H2, 458C, 2.1m
45 bar H2, 458C, 2.1m
45 bar H2, 458C, 2.1m
45 bar H2, 458C, 2.1m
1/0/200
4/3
54/3
72/1.5
5/3
1/1
18/3
100/3
100/3
100/3
44 (R)
20 (R)
13 (R)
31 (S)
35 (S)
27 (S)
27 (S)
26 (S)
26 (S)
7/24
89/24
95/24
7/20
6/24
40/24
37 (R)
7 (R)
5 (R)
34 (S)
22 (S)
24 (S)
1/0.5/200
1/0.5/200
1/1/106
1/90/106
1/450/106
1/90/106
1/90/105
1/90/104
HY5
HY6
B alone
B alone
[a] See footnote [a] in Table 2. [b] See footnote [b] in Table 2. [c] See footnote [c] in Table 2. [d] Actual run done with [Ru(H)(Cl)((R,R)-cyP2(NH)2)] (R,R)-9
and mirrored.
4960
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Chem. Eur. J. 2003, 9, 4954 4967

Asymmetric Catalysis
4954 4967
TRHY and are not transformed into them under the reaction
conditions.
The conditions for the kinetic runs were different from the
standard conditions listed in Tables 2 4, and 7 (see later) in
order to put the rates of reaction into a conveniently and
reliably measurable range at 293 K (estimated error for the
rate constants about 10%), 6 11 bar H2, 0.167 0.555m 3,
substrate/precatalyst ratios 4175 25000 [with respect to the
total of the isomers (S,S)-9A plus (S,S)-9B)].
Alkoxide base (iPrOK generated from tBuOK added to
excess iPrOH) served to generate the catalyst as usual, but at
the resulting, purposely high catalyst concentrations, the
alkoxide concentration does not significantly affect the HY
rate as in the runs under the preparative standard conditions,
where the catalyst concentrations are much lower. The rate of
1-phenylethan-1-ol (4) production as monitored by GC and
NMR spectroscopy increased approximately linearly with
total Ru concentration and H2 pressure ([H2] has a linear
relationship with pressure). The ee for the (S)-4 produced by
HY at 293 K by use of the mixture (S,S)-9A plus (S,S)-9B
range between 23 to 26%. This range is similar to the range of
values 22 to 35% reported in Tables 2 4 for temperatures of
318 and 333 K.
HY with the mixture {A‡B}and B alone also works, and we
obtain the same enantiomer (S)-4 with about the same ee as in
the case of (S,S)-2. Addition of 1 to 450 equivalents iPrOK
speeds up the HY in the case of the mixture {A‡B}. The use of
B alone was only tested in the presence of 90 equivalents
iPrOK, but at an s:c of 105 to 106. In terms of rate, B performs
much better than the mixture {A‡B}although we do not
understand why this is so. Compound B also performs much
better than (S,S)-2, probably because the active catalysts are
more directly generated starting from the hydridochloride B
than from the dichloride (S,S)-2. The fact that the ee are
similar suggests that the active catalyst(s) in these HYand the
(S,S)-2-based HY could be the same.
HY kinetics using (S,S)-9A and (S,S)-9B as the precatalysts:
Since (S,S)-9A and (S,S)-9B are the catalyst precursors we
have in hand at present that are probably the closest (in terms
of reaction steps) to the active HY catalysts, we used them
(rather than the dichloride precatalyst (S,S)-2) to investigate
the kinetics of the HY. The resulting rate law is also valid for
the HY based on (S,S)-2 if our assumption that (S,S)-2 and
(S,S)-9 are both transformed into the same active redox pair
(S,S)-11/(S,S)-10 under the HY conditions is correct. Table 5
The results given in Table 5 lead to the rate law of
Equation (1) (derivation, see the Experimental Section, for
iPrOH, k3 ˆ 1.23  103 mÀ1 sÀ1, K2 ˆ 1.20mÀ1), in which [Rutot] is
the total Ru concentration and [H2] is the concentration of
dissolved H2. The rates that are calculated on the basis of
Equation (1) are also listed in Table 5.
rate ˆ k3[Rutot][H2]/(1 ‡ K2[acetophenone])
(1)
This rate law is consistent with a fast, reversible addition of
acetophenone (3) to a five-coordinate Ru amidohydride
ˆ
species (S,S)-11 with a Ru N double bond to give an
amidohydride acetophenone complex [Eq. (2)] and proba-
ˆ
bly also an enolate complex [Ru(H)(O-C(Ph) CH2)((S,S)-
cyP2(NH)2)]. This acts in competition with the rate-determin-
ing addition of H2 to (S,S)-11 to give a dihydride complex
[Ru(H)2((S,S)-cyP2(NH)2)] ((S,S)-10) [Eq. (3)]. Compound
(S,S)-10 corresponds to K and (S,S)-11 to L in Scheme 3, but
(S,S)-10 may have the hydride ligands trans (as depicted) or
cis to each other. It must react very rapidly with the substrate
3 to generate the alcohol (S)-4 and regenerate the amidohy-
dride complex (S,S)-11 [Eq. (4)]. The ketone complexes must
be much less active HY catalysts than the amidohydride
complex (S,S)-11. The ketone and/or the enolate complexes
have not been directly observed. However, related complexes
Table 5. Observed and calculated initial rates of production of (S)-1-
phenylethan-1-ol ((S)-4; 23 26% ee)[a] by the HY of acetophenone 3 in
iPrOH/iPrOK at 293 K using a 1:1 precatalyst mixture (S,S)-9A plus (S,S)-
9B.
Run [Rutot
]
[H2]
[iPrOK] [3]
Rate
[Â104 m sÀ1
Rate
[Â104 m sÀ1
[c]
[Â105 m] [Â102 m][b] [Â102 m] [m]
]
]
1
2
3
4
5
6
7
4.0
4.0
4.0
6.0
4.0
4.0
4.0
1.91
1.91
1.91
1.91
1.91
1.91
3.29
1.79
3.57
5.36
3.57
1.79
1.79
1.79
0.167 7.8
7.8
6.7
5.8
10.0
6.7
5.8
0.333 6.6
0.500 5.3
0.333 10.7
0.333 6.6
0.500 6.5
0.500 10.1
ˆ
[Ru(H)((R)-binap)(HNCMe2CMe2NH2)(O C(Ph)Me)] and
ˆ
10.1
[Ru(H)((R)-binap)(H2NCMe2CMe2NH2)(O-C(Ph) CH2)]
have been characterized.[9]
[a] Actually (R,R)-9A and (R,R)-9B were used so that (R)-4 was
produced; however for consistency the results have been mirrored.
[b] Obtained from ref. [20]; 0.0191m and 0.0329m correspond to 6 and
12 bar H2. [c] Calculated by means of Equation (1).
A cross test with TRHY conditions identical to those of the
HY in the kinetic runs (as in run 5 in Table 5, 895 equiv
iPrOK), but without H2, produced the alcohol (R)-4 in 72%
ee; however, the conversion was only 3% after two days.
The effect of a change in solvent from iPrOH to benzene,
which was used previously[9m,p,q,s] (and to tBuOK as the base),
was also investigated. Since tBuOK is only moderately soluble
in benzene,[17] there is an induction period until the generation
of the catalyst from the precatalyst, tBuOK, and H2 gas is
complete. In the absence of base, the precatalyst (S,S)-9 is
lists the results of a study of the effect of variation of the
concentrations of the reactants on the rates of the HY of 3 in
iPrOH at room temperature catalyzed by a 1:1 mixture of the
isomers (S,S)-9A and (S,S)-9B.
Chem. Eur. J. 2003, 9, 4954 4967
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¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4961

V. Rautenstrauch, R. H. Morris et al.
FULL PAPER
H2. In addition the acetophenone adduct is more stable
ˆ 16mÀ1) in benzene than in iPrOH (K2
ˆ
(benzene)
(iPrOH)
(K2
1.20mÀ1).
Calibrations with HY using the dichloride precatalysts
(S,S)-2 and 12 (see below) under our standard conditions in
benzene are provided in other sections. Under these standard
conditions, the HY in benzene are also much slower.
Attempts to generate dihydrides of type (R,R)-10 and to
observe the active TRHY catalyst that is generated from the
dichloride (S,S)-2: Preparatively, it should be simpler to
generate the dihydrides (R,R)-10 by treating the hydrido-
chloride(s) (R,R)-9 with HBsBu3K rather than by dehydro-
chlorination and addition of H2.[9m,p,q,s] When a mixture (R,R)-
9A plus (R,R)-9B was treated with HBsBu3K in THF at room
temperature under N2, a mixture of isomeric dihydrides of
type (R,R)-10 [Eqs. (3) and (4)] was indeed generated. This
was ascertained by analysis by NMR spectroscopy (in C6D6,
see the Experimental Section); this demonstrated the pres-
ence of a trans-dihydride (R,R)-10 (t at À5.5 ppm for RuH)
and a cis-dihydride (R,R)-10 (ddd at À4.5 and dt at
À15.5 ppm for RuH) along with a third isomer. However,
when this reaction was repeated (this time with (S,S)-9A plus
(S,S)-9B and under Ar), the resulting THF solution manip-
ulated and dosed under Ar at ambient temperature, and then
tested under TRHY and HY conditions, practically no
reaction occurred; this suggests that this mixture of hydrides
is too unstable to handle under these conditions.
inactive under these conditions. Therefore, these runs were
done by activating the precatalyst with tBuOK under H2 for
45 min before adding 3. The results are listed in Table 6.
Attempts to observe the active catalyst in TRHY as it is
formed from the dichloride precatalyst (S,S)-2 upon treatment
with iPrOK in iPrOH at ambient temperature and up to 608C
(see above, Table 3) by NMR spectroscopy failed. The reason
for this is probably the low solubility of (S,S)-2 in iPrOH. We
actually use mostly finely dispersed ™stock suspensions∫
rather than true stock solutions of (S,S)-2 in iPrOH in our
TRHY and HY experiments. The reaction mixtures in TRHY
and HY at the beginning of the reaction (containing the total
of the substrate 3) appear to be homogenous (see the
Experimental Section), but even the concentrations used in
TRHY are too low to permit the detection of the catalyst by
NMR.
Table 6. Observed and calculated initial rates of production of (S)-1-
phenylethan-1-ol ((S)-4; ee 17 24%)[a] by the HY of acetophenone 3 in
benzene/tBuOK mixtures at 293 K using a 1:1 precatalyst mixture (S,S)-9A
plus (S,S)-9B.
run [Rutot
]
[H2]
[3]
[tBuOK] Rate
[Â102 m] [Â104 m sÀ1
Rate
[Â104 m sÀ1
[c]
[Â104 m] [Â102 m][b] [m]
]
]
1
2
3
4
5
6
7
8
9
2.0
2.0
2.0
2.0
2.0
1.0
4.0
2.0
2.0
1.59
1.59
1.59
1.59
1.59
1.59
1.59
3.18
2.52
0.167 5.4
1.2
1.8
1.1
0.7
1.1
0.4
2.2
2.0
1.9
1.1
1.8
1.1
0.7
1.1
0.6
2.2
2.2
1.8
0.084 1.8
0.167 1.8
0.333 1.8
0.167 1.8
0.167 0.9
0.167 1.8
0.167 1.8
0.167 1.8
HY with [Ru(Cl)2(ethP2(NH)2)] (12): Since we also wanted
achiral HY catalysts, we tested the ethano-bridged precatalyst
[Ru(Cl)2(ethP2(NH)2)] (12),[12, 18a] which is a simple achiral
analogue of (S,S)-2 that was again (like (S,S)-2) already
known to be a TRHY precatalyst;[18b] see Table 7.
[a] See footnote [a] in Table 5. [b] See footnote [b] in Table 5. [c] Calcu-
lated by means of Equation (1).
The rate law appears to be the same as that for iPrOH,
[Eq. (1)] above, with k3 ˆ 1.3  102 mÀ1 sÀ1, K2 ˆ 16mÀ1 in the
case of benzene.
The rates of alcohol production that are calculated on the
basis of Equation (1) (Table 6) are in excellent agreement
with the observed values. Therefore, there is substrate
inhibition and the chemistry is again described by reactions
given in Equations (2) (4). The activation of H2 by the amido
complex (S,S)-11 is again the rate-limiting step, but it is
(benzene)
approximately ten times slower in benzene (k3
ˆ 1.3 Â
HY with 12 work beautifully and are much more rapid than
those with 2. Complex 12 already performs quite well at s:c 106
without base, and already gives record rates at s:c 106 with
(iPrOH)
102 mÀ1 sÀ1) than in iPrOH (k3
ˆ 1.23  103 mÀ1 sÀ1). The
more polar alcohol solvent favors the heterolytic splitting of
4962
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2003, 9, 4954 4967

Asymmetric Catalysis
4954 4967
Table 7. HYof acetophenone (3) and three further substrates by using the precatalyst [Ru(Cl)2(ethP2(NH)2)] 12.
the role of base by using DBU
(which generates iPrOÀ and
Run Conditions[a]
Substrate Precatalyst/
iPrOK/substrate
Conversion Conversion
1[b] 2[b]
‡
DBUH ), and found that only
when both are added is the
effect of adding tBuOK repro-
duced (508C, 5 bar H2). In the
hope of accelerating our HY
yet further and to see whether
both explanations (refs. [9s]
and [19]) are valid, we repeated
their tests in the case of 12 at
the extreme s:c 106 level; see
Table 7. These tests were nega-
tive: the combined presence of
500 equivalents KBAF and
1
2
3
4
5
6
7
8
45 bar H2, 608C, 2.1m
3
3
3
3
3
3
3
3
3
3
3
7
7
7
7
7
1/0/105
85/3 98/6
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m, benzene
45 bar H2, 608C, 2.1m, benzene
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 3.1m
45 bar H2, 608C, 3.1m
45 bar H2, 608C, 3.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 2.1m
45 bar H2, 608C, 3.1m
45 bar H2, 608C, 2.1m
1/5/105
100/1.5
100/1.5
24/3
1/450/105
1/0/106
100/30
99/30
1/0/106
8/3
1/90/106
100/3
2.6/3
3/3
1/6.2 Â 104 DBU/106[c]
32/24
6/24
1/500 KBAF/106[c]
9
1/500 KBAF/6.2 Â 104 DBU/106[c] 25/3
100/24
99/24
10
11
12
13
14
15
16
17
18
19
20
21
1/450/104
1/450/105
1/5/105
0/6
23/24
0/72
0/72
0/28
0/28
99/3
0/23
100/1
100/1
100/1
2/3
1/450/105
1/5/104
1/450/104
1/4500/104
1/90/106
1/90/105
1/450/105
1/450/105
1/450/105
6.2 Â 104 equivalents
DBU,
about
which
generates
14
14
14
14
16[d]
500 equivalents iPrOÀ, and
should thus have about the
same effect as 500 equivalents
iPrOK, gives about the same
performance as 12 alone, while
KBAF and DBU each alone
actually slow down the reac-
tion. Note in passing, that, from
a practical viewpoint, it is much
96/24
[a] See footnote [a] in Table 2. [b] See footnote [b] in Table 2. [c] KBAF and/or DBU in plac of iPrOK.
[d] Compound 16 is (E)-2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)buten-2-al.
90 equivalents iPrOK. In terms of rate, (S,S)-2 performs about
the same as (S),(S,S)-1. For the latter, the published record
overall TOF (TOF ˆ turnover frequency) is 5  104 hÀ1 at
308C (complete conversion within 48 h, 45 bar) at a TON
(TON ˆ turnover numberˆ s:c) of 2.4  106 and in the
presence of 2.4 Â 104 equivalents iPrOK.[16] In the case of 12,
we reach an overall TOF ꢁ 3.3 Â 105 hÀ1 at 608C (3 h, 45 bar)
at a TON of 106 in the presence of 90 equivalents iPrOK.
We used 12 to further calibrate the difference in the rate of
the HY of 3 in iPrOH versus benzene, which we had begun
with (S,S)-2, see earlier sections. Runs HY10 and HY11 in
Table 7 at s:c 105 and 104 demonstrate again that the reaction
is very much slower in benzene, but we at least now achieve
near-complete conversion at s:c 104 within 24 h.
simpler and much less costly to add iPrOK.
We tested this very active achiral system on some further
representative substrates: again cyclohexyl methyl ketone 7 as
a saturated analogue of acetophenone (3), b-ionone (14), to
give compound 15, as an a,b-unsaturated analogue of 3, and
also the a,b-unsaturated aldehyde (E)-2-methyl-4-(2,6,6-tri-
methylcyclohex-1-en-1-yl)buten-2-al (16) to give compound
17. All three are hydrogenated much more slowly than 3, and 7
HY with 12 works well in iPrOH in the absence of iPrOK at
the s:c 106 level and still responds strongly to its presence, and
we see similar responses in the case of (S),(S,S)-1 and (S,S)-2.
We already discussed the explanation for this that was
provided by some of us:[9s] the less acidic the iPrOH medium
is, and the higher the H2 pressure, the more the corresponding
dihydrides are favored, see above. An earlier explanation is
‡
Chen and Hartmann×s conclusion that K ion is a cocatalyst in
the HY.[19] From experiments using [Ru(Cl)2((S)-binap)((S,S)-
dpen)] ((S),(S,S)-13)[12] in iPrOH at s:c ꢂ2000 and using 3 as
is the least reactive. To obtain conversions that are compa-
rable to those for 3, one needs 100 times more precatalyst 12
in the case of 7 and 16, and ten times more in the case of 14,
and in the case of 7 more base as well. As already noted at the
beginning of the Results and Discussion, these HY systems
are best at dealing with acetophenones. The reasons for this
are presently not clearly understood. For steric and electronic
reasons, 7 is more difficult to hydrogenate than 3. For 16,
catalyst deactivation by CO abstraction from the aldehyde
could be a problem. Changes in the polarity of the medium
could also be a factor. We chose substrates 14 and 16 also to
‡
the substrate, they deduced that both a base and K ions are
needed: according to them, the base (iPrOÀ) serves to
generate the dehydro form of the catalyst by dehydrochlori-
‡
nation (cf. Scheme 4, J ! L in the catalytic cycle), and K can
then intervene in, and accelerate the addition and cleavage of
H2 (cf. Scheme 3, L ! K) and the subsequent reduction step
(cf. Scheme 3, K ‡ substrate ! L ‡ product alcohol). They
‡
‡
tested for the effect of K by using K tetrakis(3,5-bis(tri-
‡
fluoromethyl)phenyl)borate (KBAF) as the K source and
Chem. Eur. J. 2003, 9, 4954 4967
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4963

V. Rautenstrauch, R. H. Morris et al.
FULL PAPER
ˆ
reconfirm the chemoselectivities, and the C C double bonds
are indeed not affected.
that have been proposed, including those where the enantio-
selectivity is unsatisfactory.
Experimental Section
Conclusion
Ligands and precatalysts: All ligands and their RuII complexes were
prepared by combining glove box and standard Schlenk techniques using
Ar or N2. The ligands, (S,S)-cyP2(NH)2,[21e,f] its enantiomer, and ethP2-
(NH)2,[21a,c] and the derived complexes, [Ru(Cl)2((S,S)-cyP2(NH)2)] ((S,S)-
2),[3a,b, 21d] its enantiomer, and [Ru(Cl)2(ethP2(NH)2)] (12),[18a, 21b] are known
compounds and were prepared according to the literature.
Our results provide 1) positive cross tests from TRHY to HY
and vice versa, and 2) establish at the same time that,
nevertheless, for a given system (i.e., starting out with the
same precatalyst), different catalysts (or different mixtures of
catalysts) operate in the two modes. Further, we find (under
our standard conditions) that the response to base is different
in the two modes: while added iPrOK speeds up both HY and
TRHY, the enantioselectivity is not affected in HY and is
lowered in TRHY.
The active catalysts in the HY in the standard solvent
iPrOH are almost certainly amidohydride/dihydride redox
couples of the type L/K (Scheme 3), such as (S,S)-11/(S,S)-10
[Eqs. (2) (4)], and the dihydrides K are only accessible or
much more accessible under H2 and in the presence of iPrOK.
Accordingly, higher concentrations of 3 actually reduce the
activity of the system for HY by competing for the five-
Preparation of [Ru(H)(Cl)((S,S)-cyP2(NH)2)] as a mixture of two isomers
(S,S)-9A and (S,S)-9B: THF (2 mL) was added to
a mixture of
[Ru(H)(Cl)(PPh3)3] (300 mg, 0.34 mmol) and (S,S)-cyP2(NH)2 (225 mg,
0.34 mmol), and the resulting solution refluxed for 1 h. After cooling to
ambient temperature, the solution was filtered and hexanes (10 mL) were
added to the filtrate, precipitating a pale yellow solid. Yield: 254 mg (94%).
The NMR spectra indicate the presence of a mixture of two isomers.
1H NMR (360 MHz, C6D6, 258C), isomer A: d ˆ À17.1 ppm (br); isomer B:
2
À17.8 ppm (brt); 31P{1H}NMR, isomer A: d ˆ 69.9 (d, JPP ˆ 32.4 Hz),
63.2 ppm (d, 2JPP ˆ 32.4 Hz); isomer B: 65.4 (d, 2JPP ˆ 31.5 Hz), 61.1 ppm (d,
2JPP ˆ 31.5 Hz); elemental analysis calcd (%) for C44H45ClN2P2Ru (800.3):
C 66.0, H 5.7, N 3.5; found C 67.5, H 6.1, N 3.3 (the presence of hexane of
crystallisation would explain the discrepancies).
Preparation of (S,S)-9B on the NMR scale: Upon treatment with base
(10 equiv) of a mixture of [Ru(H)(Cl)((S,S)-cyP2(NH)2)] (S,S)-9A ‡ (S,S)-
9B (ca. 1:1, 40 to 80 mg) in [D8]THF or C6D6 (0.7 mL) at ambient
temperature, isomer A was transformed into isomer B (rapidly with
tBuOK, more slowly with DBU, no reaction with NEt3). In the case of
DBU, the hydride peaks in the 1H NMR spectrum sharpen to clear dd
ˆ
coordinate amidohydride complex (S,S)-11 with a Ru N
double bond [Eq. (2)]; the addition of H2 to (S,S)-11 to give a
dihydride species (S,S)-10 [Eq. (3)] is the turnover-limiting
step, while the reaction of (S,S)-10 with 3 to give (S)-1-
phenylethan-1-ol ((S)-4) [Eq. (3)] is very fast; the heterolytic
splitting of H2 at the complex (S,S)-11 is much faster in iPrOH
than in benzene, because the higher dielectric constant of
iPrOH and its ability to form hydrogen bonds to stabilise the
polar transition state.
2
2
patterns [isomer A: À17.1 (dd, JHP ˆ 33 Hz, JHP ˆ 28.8 Hz; isomer B:
2
2
À17.8 (dd, JHP ˆ 32.4 Hz, JHP ˆ 32.1 Hz)] in the course of the rearrange-
ment. Isolation after isomerization with DBU in C6D6: precipitation with
pentanes, stirring (2 h), filtration, and rinse with pentanes produces a
yellow solid.
Generation of isomeric dihydrides [Ru(H2)((R,R)-cyP2(NH)2)] ((R,R)-
10): Under N2, HBsBu3K in THF (100 mg of a 1.0m solution in THF,
0.12 mmol) was diluted with THF (1.0 mL), and the resulting solution was
added to the mixture of 9A and 9B (100 mg, 0.12 mmol) and the mixture
stirred for 4 h. The suspension was then filtered and the filtrate exaporated
What the active catalysts in the parallel TRHY are is still
something of a mystery. This is surprising because the
[Ru(Cl)2((S,S)-cyP2(NH)2)] (S,S)-2-based TRHY were dis-
covered at about the same time as the Ru(H)(aminoalkoxy)-
(arene)]/[Ru(H)(amidoalkoxy)(arene)][1] and [Ru(H)(ami-
1
to dryness. The solids were extracted with C6D6 (1 mL total). The H and
31P NMR spectra for this C6D6 solution show the presence of three hydride
species. The two major isomers are assigned as a trans-dihydride (37%) and
an unsymmetrical cis-dihydride (45%). trans-(R,R)-10: 1H NMR
(360 MHz, 258C): d ˆ À5.55 ppm (t, JHP ˆ 16.7 Hz); 31P{1H}NMR: d ˆ
78.7 ppm (s). Note that a symmetrical cis-dihydride structure would give
similar spectra, but the position of the hydride resonance at À5.5 ppm is
typical of other trans-dihydrides we have observed previously.[9q] cis-(R,R)-
10: 1H NMR: d ˆ À4.49 (ddd, JHPtrans ˆ 96.0, JHPcis ˆ 29.1, JHH ˆ 6.0 Hz),
À15.48 ppm (dt, JHH ˆ 6.0, JHP ˆ 19.2 Hz); 31P{1H}NMR: d ˆ 71.33 (d,
JPP ˆ 38.6 Hz), 70.27 ppm (d). Unknown hydride: 1H NMR: d ˆ À7.12 ppm
(dd, JHP ˆ 29, 22 Hz); 31P{1H}NMR: d ˆ 78.2 ppm (br).
noamido)(arene)]/[Ru(H)(bisamido)(arene)][2]
systems
(Scheme 1). We have at least excluded that the hydridochlor-
ides [Ru(H)(Cl)((S,S)-cyP2(NH)2] 9A and 9B are the active
catalysts in the (S,S)-2-based TRHY and shown that they are
not transformed into them under the reaction conditions. We
note that the stereochemical outcomes in our experiments
suggest the following. In TRHY, for a given system, different
catalysts (different entities or isomers with different geo-
metries, perhaps different mixtures) are formed from differ-
ent precatalysts (e.g., from the dichloride (S,S)-2 versus the
hydridochloride (S,S)-9). The geometries of the TRHY
catalyst (whose identity is still unknown) and of the dihydride
HY catalyst, which are formed from the same precatalyst
(e.g., from (S,S)-2), must also different. Different mixtures
may of course also be involved here.
Further unraveling of these complex mechanisms is thus
still a rather daunting challenge, but meeting it will be
worthwhile, because only then will we fully understand the
exceptionally potent systems that already exist, will the
discovery of new and perhaps even better HY catalysts
become less arduous. It is clearly also worthwhile to run
further cross tests, especially for the numerous TRHY systems
Standard HY and TRHY runs: The HYand TRHY runs listed in Tables 2
4, 7 were carried out in cylindrical open glass inserts placed inside a 70 mL
stainless steel autoclave (manufactured at Firmenich) fitted with two
valves, one for pressurizing/degassing and the other for taking samples by
septum/syringe. The autoclave was charged and sealed in a glove box
operated with Ar. H2 gas (99.99990%) was used as received. All substrates
and solvents were distilled from appropriate drying agents under Ar.
General procedure for catalytic HY–representative example for a stand-
ard run (run HY12 in Table 3): Use of (R,R)-2 for the HY of acetophenone
(3), precatalyst/base/substrate ratio 1:90:106, 2.1m in iPrOH; actual mmolar
ratios (2 Â 10À5):(1.8 Â 10À3):20. Volumetry: automatic pipettes with a
disposable plastic heads were used.
A 0.02m milky yellow/white suspension/solution of (R,R)-2 (low solubility)
was prepared by dissolving/suspending (R,R)-2 (9.9 mg, 0.01 mmol) in
iPrOH (500 mL) with magnetic stirring (5 min). A 0.002m yellow/white
suspension/solution of (R,R)-2 was then prepared by diluting 100 mL
4964
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Chem. Eur. J. 2003, 9, 4954 4967

Asymmetric Catalysis
4954 4967
(0.002 mmol) of the 0.02m solution with iPrOH (900 mL) and stirring
(5 min). A 0.18m solution of iPrOK was prepared by dissolving tBuOK
(202 mg, 1.8 mmol) in iPrOH (10 mL). The glass insert of the autoclave was
successively charged, 1) with iPrOH (7.2 mL), 2) with the 0.18m solution of
iPrOK (10 mL, 1.8 Â 10À3 mmol), 3) acetophenone (3, 2.4 g, 20 mmol), and
4) with the 0.002m solution of (R,R)-2 (10 mL, 2 Â 10À5 mmol). The
resulting mixture was colorless and homogenous upon inspection with
the eye. The charged insert was placed inside the autoclave, the autoclave
was sealed and pressurized with 45 bar of H2, and its contents magnetically
stirred and heated to 608C with an oil bath. Samples for analysis by GC
were withdrawn with septum and syringe under a flow of H2 after taking the
autoclave out of the heating bath and degassing. The autoclave was then
repressurized with H2 and the HY continued.
f) K. Evereaere, J.-F. Carpentier, A. Mortreux, M. Bulliard, Tetrahe-
dron: Asymmetry 1999, 10, 4663 4666; g) D. A. Alonzo, P. Brandt,
S. J. M. Nordin, P. G. Andersson, J. Am. Chem. Soc. 1999, 121, 9580
9588; h) J. A. Kenny, K. Versluis, A. J. R. Heck, T. Walsgrove, M.
Wills, Chem. Commun. 2000, 99 100; i) M. Yamakawa, H. Ito, R.
Noyori, J. Am. Chem. Soc. 2000, 122, 1466 1478; j) C. G. Frost, P.
MendonÁa, Tetrahedron: Asymmetry 2000, 11, 1845 1848; k) M.
Henning, K. P¸ntener, M. Scalone, Tetrahedron: Asymmetry 2000, 11,
1849 1858; l) D. A. Alonso, S. J. M. Nordin, P. Roth, T. Tarnai, P. G.
Anderson, M. Thommen, U. Pittelkow, J. Org. Chem. 2000, 65, 3116
3122; m) I. Yamada, R. Noyori, Org. Lett. 2000, 2, 3425 3427; n) K.
Everaere, A. Mortreux, M. Bulliard, J. Brussee, A. van der Gen, G.
Nowogrocki, J.-F. Carpentier, Eur. J. Org. Chem. 2001, 275 291;
o) A. J. Sandee, D. G. I. Petra, J. N. H. Reek, P. C. J. Kamer,
P. W. N. M. van Leeuwen, Chem. Eur. J. 2001, 7, 1202 1208;
p) S. J. M. Nordin, P. Roth, T. Tarnai, D. A. Alonso, P. Brandt, P. G.
Andersson, Chem. Eur. J. 2001, 7, 1431 1436; q) M. Yamakawa, I.
Yamada, R. Noyori, Angew. Chem. 2001, 113, 2900 2903; Angew.
Chem. Int. Ed. 2001, 40, 2818 2821; r) J. W. Faller, A. R. Lavoie, Org.
Lett. 2001, 3, 3703 3706; s) J. W. Faller, A. R. Lavoie, Organometal-
lics 2002, 21, 2010 2012; t) J. W. Faller, A. R. Lavoie, Organometallics
Kinetics: HY reactions were run at 293 K at constant H2 pressures except
during the brief sampling periods that lasted 5 to 2 s by using a 50 mL Parr
reactor. The reactor was flushed several times with Ar and H2 at the pre-set
pressure prior to charging. Aliquots of the reaction mixture were quickly
withdrawn with a syringe under a flow of H2 at regular intervals (the
minimum interval was 120 s) by venting the reactor. Concentrations of
acetophenone (3) and 1-phenylethan-1-ol (4) were determined by 1H NMR
spectroscopy (in C6D6) or GC (in iPrOH and C6D6). The temperature was
maintained at 293 K by use of a constant temperature water bath. Initial
rates were taken from the first linear portion of the plot of alcohol
concentration versus time. This linear portion continued to at least 60%
conversion before a slowing of the reaction was observed. In some cases an
induction period was observed before this rate was established.
¬
¡
2002, 21, 3493 3495; u) M. Pasto, A. Riera, M. A. Pericas, Eur. J. Org.
Chem. 2002, 2337 2341.
[2] Pairs [Ru(bisamido)(arene)]/[Ru(H)(aminoamido)(arene)] C/D:
a) S. Hachiguchi, A. Fujii, J. Takehara, T. Ikariya, R. Noyori, J. Am.
Chem. Soc. 1995, 117, 7562 7563; b) K. P¸ntener, L. Schwink, P.
Knochel, Tetrahedron Lett. 1996, 37, 8165 8168; c) K.-J. Haack, S.
Hashiguchi, A. Fujii, T. Ikariya, R. Noyori, Angew. Chem. 1997, 109,
297 300; Angew. Chem. Int. Ed. Engl. 1997, 36, 285 288; d) S.
Hashiguchi, A. Fujii, K.-J. Haack, K. Matsumara, T. Ikariya, R.
Noyori, Angew. Chem. 1997, 109, 300 303; Angew. Chem. Int. Ed.
Engl. 1997, 36, 288 303; e) K. Matsumara, S. Hashiguchi, T. Ikariya,
R. Noyori, J. Am. Chem. Soc. 1997, 119, 8738 8739; f) L. Cai, Y. Han,
H. Mahmoud, B. M. Segal, J. Organometal. Chem. 1998, 568, 77 86;
g) L. Schwink, T. Ireland, K. P¸ntener, P. Knochel, Tetrahedron:
Asymmetry 1998, 9, 1143 1163; h) C. Bubert, J. Blacker, S. M. Brown,
J. Crosby, S. Fitzjohn, J. P. Muxworthy, T. Thorpe, J. M. J. Williams,
Tetrahedron Lett. 2001, 42, 4037 4039; see also refs. [1i, k, m, q].
[3] Systems based on the use of tetradentate ligands P-NH-NH-P: a) J.-X.
Gao, T. Ikariya, R. Noyori, Organometallics 1996, 15, 1087 1089;
b) J.-X. Gao, H. Zhang, X.-D. Yi, P.-P. Xu, C.-L. Tang, H.-L. Wan, K.-
R. Tsai, T. Ikariya, Chirality 2000, 12, 383 388; c) S. Laue, L. Greiner,
J. Wˆltinger, A. Liese, Adv. Synth. Catal. 2001, 343, 711 720; d) a
patent (N. Hirayama, K. Shibayama (Toray Co.), JP 2001294594
[Chem. Abstr. 2001, 135, 331550v]) was recently published that
describes the HY of 3 by using (R,R)-2 as the precatalyst (37 mol
KOH and 500 mol 3 per mol (R,R)-2 (s:c 500)) in EtOH/KOH to give
(S)-4 with 5% ee.
In C6D6 as the solvent: A stock solution of (R,R)-9A ‡ (R,R)-9B (1.00 Â
10À3 m) was prepared by dissolving the mixture of isomers (20 mg,
0.025 mmol) in C6D6 (25 mL). A catalyst base mixture was prepared by
pipetting the required amount of the stock solution of (R,R)-9A ‡ (R,R)-
9B onto a weighed amount of tBuOK and then adding C6D6 to give a final
volume of 3 mL. This mixture was introduced into the autoclave and
allowed to react under H2 for 45 min. A solution of 3 in C6D6 (2 mL) was
then added to start the reaction. Samples were taken at intervals of
between 2 and 10 min for analysis by NMR spectroscopy and GC. The
pressure was released for about 5 s while the sample was withdrawn against
a flow of H2.
In iPrOH as the solvent: Stock solutions of (R,R)-9A ‡ (R,R)-9B (2.00 Â
10À3 m) and tBuOK (0.089m) were prepared by dissolving the required
amount of (R,R)-9A ‡ (R,R)-9B (40 mg, 0.05 mmol) in toluene (25 mL)
and of tBuOK (250 mg, 2.23 mmol) in iPrOH (25 mL). The required
amount of (R,R)-9A ‡ (R,R)-9B solution (50 to 200 mL) and toluene were
then mixed to make up a total volume of 200 mL. To this was added the
solution of tBuOK in iPrOH (1 3 mL), then the desired amount of 3, and
finally the required amount of iPrOH to give a final volume of 5 mL. The
resulting solution was then introduced into the autoclave and placed under
H2 to start the reaction.
[4] Related Shvo catalyst with a H-Ru ¥¥¥ OH motif: a) Y. Blum, D.
Czarkie, Y. Rahamim, Y. Shvo, Organometallics 1985, 4, 1459 1461;
b) Y. Shvo, D. Czarkie, Y. Rahamim, J. Am. Chem. Soc. 1986, 108,
7400 7402; c) A. L. E. Larsson, B. A. Persson, J.-E. B‰ckvall, Angew.
Chem. 1997, 109, 1256 1258; Angew. Chem. Int. Ed. Engl. 1997, 36,
1211 1212; d) C. P. Casey, S. W. Singer, D. R. Powell, R. K. Hayashi,
M. Kavana, J. Am. Chem. Soc. 2001, 123, 1090 1100; derived catalyst
with a H-Ru ¥¥¥ NH motif: e) J. H. Choy, Y. H. Kim, S. H. Nam, S. T.
Shin, M.-J. Kim, J. Park, Angew. Chem. 2002, 114, 2479 2482; Angew.
Chem. Int. Ed. 2002, 41, 2373 2376.
Rate law derivation for Equation (1):
[Rutot] ˆ [11] ‡ [ketone adduct]
K2 ˆ [ketone adduct]/([11][ketone])
therefore:
[11] ˆ [Rutot]/(1 ‡ K2[ketone])
rate ˆ k3[H2][11]
therefore:
rate ˆ d[alcohol]/dt ˆ k3[H2][Rutot]/(1 ‡ K2[ketone])
[5] Some systems in which the generation of a H-Ru-N-H motif seems
feasible: a) Y. Jiang, Q. Jiang, G. Zhu, X. Zhang, Tetrahedron Lett.
1997, 37, 6565 6568; b) Y. Jiang, Q. Jiang, X. Zhang, J. Am. Chem.
Soc. 1998, 120, 3817 3818; c) E. Mizushima, H. Ohi, M. Yamaguchi,
T. Yamagishi, J. Mol. Catal. A 1999, 149, 43 49; d) C. M. Marson, I.
Schwarz, Tetrahedron Lett. 2000, 41, 8999 9003; e) P. Crochet, J.
Gimeno, S. Santiago-Granda, J. Borge, Organometallics 2001, 20,
4369 4377; f) J. W. Faller, A. R. Lavoie, Organometallics 2001, 20,
5245 5247; g) H. Brunner, F. Henning, M. Weber, Tetrahedron:
Asymmetry 2002, 13, 37 72; h) Y.-B. Zhou, F.-Y. Tang, H.-D. Xu, X.-
Y. Wu, J.-A. Ma, Q.-L. Zhou, Tetrahedron: Asymmetry 2002, 13, 469
473.
GC analyses: Chrompack Chirasil-Dex CB 25 m  0.25 mm capillary
column, H2 as carrier gas.
[1] Pairs Ru(amidoalkoxy)(arene)]/[Ru(H)(aminoalkoxy)(arene)] A/B:
a) J. Takehara, S. Hashiguchi, A. Fujii, S.-I. Inoue, T. Ikariya, R.
Noyori, Chem. Commun. 1996, 233 234; b) M. Palmer, T. Walsgrove,
M. Wills, J. Org. Chem. 1997, 62, 5226 5228; c) D. A. Alonso, D.
Guijarro, P. Pinho, O. Temme, P. G. Anderson, J. Org. Chem. 1998, 63,
2749 2751; d) M. Wills, M. Gamble, M. Palmer, A. Smith, J. Studley,
J. Kenny, J. Mol. Catal. A 1999, 146, 139 148; e) D. G. I. Petra, P. C. J.
Kamer, P. W. N. M. van Leeuwen, K. Goubitz, A. M. van Loon, J. G.
de Vries, H. E. Schoemaker, Eur. J. Inorg. Chem. 1999, 2335 2341;
[6] Some systems in which it is not clear how a H-Ru-N-H motif could be
generated: a) H. Yang, M. Alvarez, N. Lugan, R. Mathieu, J. Chem.
Chem. Eur. J. 2003, 9, 4954 4967
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4965

V. Rautenstrauch, R. H. Morris et al.
FULL PAPER
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Harvey, A. J. Lough, R. H. Morris, J. Am. Chem. Soc. 2002, 124,
15104 15118.
[10] [Ru(Cp*)(X)(diamine)] system: M. Ito, M. Hirakawa, K. Murata, T.
Ikariya, Organometallics 2001, 20, 379 381.
[11] Reviews: ref. [8c, e]; a) R. Noyori, T. Ohkuma, Pure Appl. Chem.
1999, 71, 1493 1501; b) R. Noyori, T. Ohkuma, Angew. Chem. 2001,
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Koizumi, D. Ishii, T. Ohkuma, Pure. Appl. Chem. 2001, 73, 227 232.
[12] BINAP ˆ 2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; TolBINAP ˆ
the di-p-tolyl analogue of BINAP; DPEN ˆ 1,2-diphenylethylenedi-
amine; cyP2(NH)2) ˆ N,N'-bis[o-(diphenylphosphino)benzyl]cyclo-
hexane-1,2-diamine; ethP2(NH2) ˆ N,N'-bis[o-(diphenylphosphino)-
benzyl]ethylenediamine.
[13] One can go full circle. If the addition of H2 is feasible, then it may be
reversible. In that case, TRHY/iPrOH systems would generate H2.
This is thermodynamically uphill, so only very low partial H2 pressures
would be available, but the H2 could escape from an open reactor, and
the TRHYand HY systems would merge into one. (See: a) D. Morton,
D. J. Cole-Hamilton, J. Chem. Soc. Chem. Commun. 1988, 1154 1156;
b) D. Morton, D. J. Cole-Hamilton, I. Utuk, M. Paneque-Sosa, M.
Lopez-Poveda, J. Chem. Soc. Dalton Trans. 1989, 489 495.) If so,
TRHY presumably still dominates when no H2 is introduced, and HY
takes over when it is and as the pressure is increased. It seems that
nobody has checked whether H2 is generated in the advanced RuII/
iPrOH TRHY systems. We also did not make any such checks in the
present work because our central interest is in bona fide HY.
¡
[14] O. Pamies, J.-E. B‰ckvall, Chem. Eur. J. 2001, 7, 5052 5058.
[15] [Ru(H)2(H2)(PPh3)3] is the classic RuII catalyst for the HY of
cyclohexanone. In the proposed catalytic cycle, it reduces cyclo-
hexanone, and the resulting [Ru(H)2(PPh3)3] then reacts with H2 to
give back [Ru(H)2(H2)(PPh3)3]: a) D. E. Linn, J. Halpern, J. Am.
Chem. Soc. 1987, 109, 2969 2974. [Ru(H)2(PPh3)3] {normally gener-
ated from [Ru(Cl)2(PPh3)3] by treatment with base in iPrOH), but see:
b) Y. Lin, Y. Zhou, J. Organomet. Chem. 1990, 381, 135 138}is
apparently the active catalyst in the related TRHY of ketones: c) E.
Mizushima, M. Yamaguchi, T. Yamagishi, Chem. Lett. 1997, 237 238;
E. Mizushima, M. Yamaguchi, T. Yamagishi, J. Mol. Catal. A 1999,
148, 69 75; d) A. Aranyos, G. Csjernyik, K. L. Szabo, J.-E. B‰ckvall,
Chem. Commun. 1999, 351 352, 2131. [RuH(Tp*)(H2)2] catalyzes the
HY of ketones in heptanes in the absence of base and their TRHY in
iPrOH/NaOH: e) C. Vicente, G. B. Shulpin, B. Moreno, S. Sabo-
[8] Reviews: a) R. Noyori, S. Hashiguchi, Acc. Chem. Res. 1997, 30, 97
102; b) M. J. Palmer, M. Wills, Tetrahedron: Asymmetry 1999, 10,
2045 2061; c) T. Ohkuma, R. Noyori in Comprehensive Asymmetric
Catalysis, Vol. 1 (Eds.: E. N. Jacobs, A. Pfaltz, H. Yamamoto),
Springer, Berlin, 1999, Chapter 6.1; d) R. Noyori, M. Yamakawa, S.
Hashiguchi, J. Org. Chem. 2001, 66, 7931 7944; e) R. Noyori, Angew.
Chem. 2002, 114, 2108 2123; Angew. Chem. Int. Ed. 2002, 41, 2008
2022.
Etienne, B. Chaudret, J. Mol. Catal.
A 1995, 98, L5 L8. The
[9] [Ru(Cl)2(diamine)(bisphosphane)] precatalysts and related systems:
a) T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am.
Chem. Soc. 1995, 117, 2675 2676; b) T. Ohkuma, H. Ooka, T. Ikariya,
R. Noyori, J. Am. Chem. Soc. 1995, 117, 10417 10418; c) T. Ohkuma,
J. Ooka, M. Yamakawa, T. Ikariya, R. Noyori, J. Org. Chem. 1996, 61,
4872 4873; d) T. Ohkuma, H. Ikehira, T. Ikariya, R. Noyori, Synlett
1997, 467 468; e) T. Ohkuma, H. Doucet, T. Pham, K. Mikami, T.
Korenaga, M. Terada, R. Noyori, J. Am. Chem. Soc. 1998, 120, 1086
1087; f) H. Doucet, T. Ohkuma, K. Murata, T. Yokozawa, M. Kozawa,
E. Katayama, A. F. England, T. Ikariya, R. Noyori, Angew. Chem.
1998, 110, 1792 1796; Angew. Chem. Int. Ed. 1998, 37, 1703 1707;
g) T. Ohkuma, M. Koizumi, H. Doucet, T. Pham, M. Kozawa, K.
Murata, E. Katayama, T. Yokosawa, T. Ikariya, R. Noyori, J. Am.
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Terada, T. Ohkuma, T. Pham, R. Noyori, Angew. Chem. 1999, 111,
517 519; Angew. Chem. Int. Ed. 1999, 38, 495 497; i) P. Cao, X.
Zhang, J. Org. Chem. 1999, 64, 2127 2129; j) T. Ohkuma, M.
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Lett. 2000, 2, 1749 1751; l) T. Ohkuma, D. Ishii, H. Takeno, R.
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Honda, R. Noyori, Adv. Synth. Catal. 2001, 343, 369 375; p) K.
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J. Am. Chem. Soc. 2001, 123, 7473 7474; r) T. Ohkuma, M. Koizumi,
[Ru(H)(Cl)(bis(1-pyrazolyl)methane)(1,3-cod)]/NaOH/MeOH sys-
tem catalyzes, inter alia, the HY of cyclohexanone and, in iPrOH
instead of MeOH, its TRHY: f) F. A. Jalon, A. Otero, A. Rodriguez,
M. Perez-Manrique, J. Organomet. Chem. 1996, 508, 69 74.
[Ru(Cl)2((R2(phosphino))-(2'-pyridyl)methane)2]/iPrOH/NaOH sys-
tems have TRHY activity, and HY activity with NH2-CH2-CH2-NH2
added: ref. [6k].
[16] The catalyst base ratio (c:b) ˆ 2.4  104 at s:c 2.4  106 corresponds to
a substrate/base ratio (s:b) ˆ 100.
[17] About 0.18m at ambient temperature: W. von E. Doering, R. S.
Urban, J. Am. Chem. Soc. 1956, 78, 5938 5942.
[18] a) J.-X. Gao, H.-L. Wan, W.-K. Wong, M.-C. Tse, W.-T. Wong,
Polyhedron 1996, 15, 1241 1251; b) P. P. Xu, R. H. Zheng, J. X. Gao,
P. Q. Huang, H. L. Wan, Chin. Chem. Lett. 1997, 8, 255 258.
[19] R. Hartmann, P. Chen, Angew. Chem. 2001, 113, 3693 3697; Angew.
Chem. Int. Ed. 2001, 40, 3581 3585. These workers added up to
‡
1000 equiv DBU and up to 400 equiv [18]crown-6 (to sequester K ),
but it is not established that these additives left the [Ru(X)2((S)-
binap)((S,S)-dpen)] catalyst intact. The corresponding ee for the
product 1-phenylethan-1-ol (4) would permit a control, but are not
reported.
[20] Solubility Data Series, Hydrogen and Deuterium, Vols. 5 & 6 (Ed.:
C. L. Young), Pergamon, New York, 1981.
[21] a) W.-K. Wong, K.-K. Lai, M.-S. Tse, M.-C. Tse, J.-X. Gao, W.-T.
Wong, S. Chan, Polyhedron 1994, 13, 2751 2762; b) J.-X. Gao, Z.
Chen, H. Wan, H. Yan, X. Yan, W. Huang, Y. Chen, Tianranqi
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H.-L. Wan, Y. Wang, W. K. Wong, Xiamen Daxue Xuebao, Ziran
Kexueban 1995, 34, 221 225 [Chem. Abstr. 1995, 123, 231905y]; d) W.-
K. Wong, T.-W. Chik, X. Feng, T. C. W. Mak, Polyhedron 1996, 15,
ƒ
K. Muniz, G. Hilt, C. Kabuto, R. Noyori, J. Am. Chem. Soc. 2002, 124,
6508 6509; s) K. Abdur-Rashid, S. E. Clapham, A. Hadzovic, J. N.
4966
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Asymmetric Catalysis
4954 4967
3905 3907; e) W.-K. Wong, T.-W. Chik, K.-N. Hui, I. Williams, X.
Feng, T. C. W. Mak, C.-M. Che, Polyhedron 1996, 15, 4447 4460; f) J.-
X. Gao, X.-D. Yi, P.-P. Xu, C.-L. Tang, H.-L. Wan, T. Ikariya, J.
Organomet. Chem. 1999, 592, 290 295.
RuII-catalyzed HY: C. Walling, L. Bollyky, J. Am. Chem. Soc. 1961, 83,
2968 2969; J. Am. Chem. Soc. 1964, 86, 3750 3752; A. Berkessel,
T. J. S. Schubert, T. N. M¸ller, J. Am. Chem. Soc. 2002, 124, 8693
8698.
[22] Added after termination of the manuscript: we and everybody else
have overlooked the following: it seems likely that, under harsh
conditions, a purely base-catalyzed HY may be competing with the
Received: February 25, 2003 [F4884]
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¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4967