Mechanistic studies on ruthenium-catalyzed hydrogen transfer reactions

Article abstract of DOI:10.1039/b000530o

Ruthenium-catalyzed hydrogen transfer from (S)-α-deuterio-α- phenylethanol [(S)-1] to acetophenone with catalyst 3 occurs with retention of deuterium at the α-carbon of the alcohol product whereas H/D scrambling occurs with catalyst 2.

Full text of DOI:10.1039/b000530o

Mechanistic studies on ruthenium-catalyzed hydrogen transfer reactions
Y. R. Santosh Laxmi and Jan-E. Bäckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden.
E-mail: jeb@organ.su.se
Received (in Cambridge, UK) 19th January 2000, Accepted 1st March 2000
Ruthenium-catalyzed hydrogen transfer from (S)-a-deu-
terio-a-phenylethanol [(S)-1] to acetophenone with catalyst
3 occurs with retention of deuterium at the a-carbon of the
alcohol product whereas H/D scrambling occurs with
catalyst 2.
the hydrogen transfer catalyzed by the achiral catalyst should
lead to racemization. The alcohol (S)-1 is readily obtained from
the enzymatic resolution of the corresponding racemic alco-
hol.11 The latter was in turn obtained from LiAlD4 reduction of
acetophenone.
Ruthenium-catalyzed reaction of (S)-1 with acetophenone
resulted in moderate to slow racemization of the alcohol. Two
different catalysts 2 and 3 were used in the present study. The
Hydrogen transfer reactions in which hydrogen is transferred
from one organic molecule to another is of great importance in
organic synthesis since one can avoid the use of molecular
hydrogen.1,2 In particular the reaction in which one equivalent
of hydrogen is transferred from an alcohol to a ketone [eqn. (1)]
has become useful. This transformation has been known since
19253,4 and in the original version an aluminium alkoxide was
employed as promotor [Meerwein–Ponndorf–Verley (MPV)
reduction and Oppenauer oxidation].1 In these reactions a direct
transfer of a hydride is supposed to take place (Fig. 1, A).5
important question is to what extent deuterium is retained in the
racemized alcohol. The racemization of (S)-1 with both
catalysts was carried out in aprotic as well as in protic solvents
(Table 1). The reaction of (S)-1 with 2 as the catalyst in THF in
the presence of base and 0.5% of water resulted in complete
1
racemization within 4 h (Table 1, entry 1). H NMR and MS
analyses showed that a significant loss of the deuterium had
occurred and the deuterium content in the a-position was only
37%. In contrast, when 3 was employed as catalyst in the
racemization of (S)-1, which took 24 h, essentially all of the
deuterium was maintained in the a-position of the alcohol
(entry 2). When the racemization experiment was carried out in
a protic solvent (ButOH) catalyst 2 gave a dramatic drop in the
deuterium content to 15% (entry 3), whereas with catalyst 3 a
high a-deuterium content was still maintained (91% D, entry 4).
Interestingly, when catalyst 3 was employed in toluene, (S)-1
gave a racemized product with 82% deuterium in the a-position.
This suggests that slow aromatic activation of toluene by the
active catalyst takes place leading to some H/D exchange.
The results from the racemization of (S)-1† suggest that
catalysts 2 and 3 operate by two different mechanisms. With
catalyst 2 it is evident that the hydride on the metal arises both
from the a-position and the OH group of the alcohol (path II,
Scheme 1), whereas with catalyst 3 the hydride arises only from
the a-position (path I, Scheme 1). The former mechanism (path
Fig. 1
More recently, transition metal-catalyzed versions of these
reactions have been developed.6,7 The latter reactions are
supposed to involve metal hydride intermediates7,8 (Fig. 1, B)
and recently hydride intermediates were isolated from ruthe-
nium–catalyzed hydrogen transfer reactions.9,10 An interesting
question is whether the metal hydride arises purely from the a-
hydrogen of the secondary alcohol (path I, Scheme 1) or if
hydride on the metal also originates from the OH group (path II,
Scheme 1).
Table 1 Racemization of (S)-1 via Ru-catalyzed hydrogen transfera
Scheme 1
To answer this question and to gain further insight into the
mechanism of hydrogen transfer reactions we have studied the
ruthenium-catalyzed hydrogen transfer from (S)-a-deuterated
a-phenylethanol [(S)-1)] to acetophenone [eqn. (2)].
Water
(%)
Entry
Catalyst Base
Solvent
t/h
Resultb
1
2
3
4
5
a
2
3
3
2
3
NaOH
—
—
NaOH
—
THF
THF
ButOH
ButOH
Toluene
0.5
—
0.5
0.5
—
4
24
72
4
37% D
95% D
91% D
15% D
82% D
24
2 mol% of the catalyst was employed together with 1 equiv. of
acetophenone at 70 °C. b The deuterium content was determined by 1H
NMR and also by mass spectrometry and refers to the amount in the a-
position.
The use of enantiomerically pure a-deuterated alcohol (S)-1
makes it possible to monitor the progress of the reaction since
DOI: 10.1039/b000530o
Chem. Commun., 2000, 611–612
This journal is © The Royal Society of Chemistry 2000
611

in contrast to catalyst 3 for which there will be no such H/D
exchange since the hydride on the metal only arises from the a-
position of the alcohol.
In conclusion, the results presented here show that quite
different mechanisms may operate in ruthenium-catalyzed
hydrogen transfer. Evidence is provided that catalyst 2 does not
distinguish between the a-hydrogen and the OH hydrogen in
hydrogen transfer from an alcohol to a ketone. In contrast,
catalyst 3 selectively transfers the a-hydrogen to the carbonyl
group and the OH hydrogen to the keto oxygen in the
corresponding hydrogen transfer.
Fig. 2
II) is expected to give a H/D ratio of 50/50 in the a-position of
the racemized alcohol from (S)-1. With path I (Scheme 1), (S)-1
would give only ruthenium deuteride and as a result the a-
position would be 100% deuterated in the racemized product.
The mechanism for catalyst 3, which follows path 1, probably
involves an intermediate in which the hydrogen transferred to
the carbonyl carbon comes from the metal and the hydrogen
transferred to the ketone oxygen arises from the OH group of the
catalyst (Fig. 2). This may involve insertion of the ketone into
a Ru–D bond followed by protonation of the ruthenium
alkoxide by the OH group. In the reversed reaction a b-
elimination from the alkoxide gives the ruthenium deuteride.
This is in line with the mechanism proposed in our previous
studies on ruthenium-catalyzed hydrogen transfer reactions
with catalyst 3.12
In the hydrogen transfer reaction with catalyst 2 it is known
that the chlorides are eliminated under the formation of a
ruthenium dihydride species.9 With substrate (S)-1 a di-
deuterated complex 4 would be formed, which can react with
the ketone to give a ruthenium(0) complex RuL3 5 after
reductive elimination (Scheme 2). The latter complex should be
in equilibrium with 4.
Financial support from the Swedish Natural Science Re-
search Council and the Swedish Foundation for Strategic
Research is gratefully acknowledged.
Notes and references
† Typical procedure for racemization of (S)-1: the ruthenium catalyst (2
mol%) and the base (10 mol%) were placed in a Schlenk tube, which was
evacuated and filled with argon. Argon was bubbled through a solution of
(S)-1 (123 mg, 1 mmol) and acetophenone (120 mg, 1 mmol) in 1.25 ml of
the appropriate solvent and transferred via a canula to the Schlenk tube
containing the catalyst. The reaction mixture was heated to 70 °C (when
THF was used as the solvent, the Schlenk tube was sealed with the help of
a stopcock). The reaction was followed by chiral GC, worked up by
filtration through a bed of Celite and purified by column chromatography.
The racemized alcohol obtained was analyzed by 1H NMR and MS for the
deuterium content in the a-position.
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Scheme 2 Hydrogen transfer with catalyst 2.
11 (a) To a-deuterated a-phenylethanol (0.625 g, 5 mmol) in toluene was
added p-chlorophenyl acetate (0.844 g, 10 mmol) and enzyme N-435
(0.4 g) and the mixture stirred at 70 °C for 48 h.11b Workup followed by
chromatography gave (S)-1 (0.257 g, > 99% ee) and (R)-O-acetyl-a-
deuterated a-phenylethanol (0.249 g, > 99% ee). (b) B. A. Persson,
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In the catalytic cycle (Scheme 2) oxidative addition of (S)-1
to 5 would give a ruthenium alkoxide, which on b-elimination
produces acetophenone and DRuHL3 4A. The mixed hydride-
deuteride species 4A can now add to acetophenone, and after
reductive elimination, the alcohol obtained would have deute-
rium scrambled between the a- and oxygen-positions. Any
exchange with protons in the medium (e.g. a protic solvent) at
this stage will lower the deuterium content of 1 by exchange of
deuterium in the oxygen-position (cf. entry 4, Table 1). This is
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