Screening of chiral ferrocenyl amino alcohols as ligands for ruthenium-catalysed transfer hydrogenation of ketones

Article abstract of DOI:10.1016/S0957-4166(02)00835-2

A variety of ferrocenyl amino alcohols possessing central chirality have been screened as ligands for ruthenium(II)-catalysed transfer hydrogenation of acetophenone using 2-propanol in the presence of KOH as the hydrogen source. Enantiomerically enriched

Full text of DOI:10.1016/S0957-4166(02)00835-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 597–602
Screening of chiral ferrocenyl amino alcohols as ligands for
ruthenium-catalysed transfer hydrogenation of ketones
Angela Patti* and Sonia Pedotti
Istituto di Chimica Biomolecolare del CNR, Sez. di Catania, Via del Santuario 110, I-95028 Valverde CT, Italy
Received 29 November 2002; accepted 9 December 2002
Abstract—A variety of ferrocenyl amino alcohols possessing central chirality have been screened as ligands for ruthenium(II)-
catalysed transfer hydrogenation of acetophenone using 2-propanol in the presence of KOH as the hydrogen source. Enantiomer-
ically enriched 1-phenylethanol was obtained in high yield and 70% e.e. using ligand 9. This ligand was employed in the
asymmetric reduction of different arylalkyl ketones and the corresponding alcohols were obtained in up to 80% e.e. A comparison
of the catalytic properties of ferrocenyl amino alcohols and their phenyl analogues is discussed briefly. © 2003 Elsevier Science
Ltd. All rights reserved.
1. Introduction
ferrocene derivatives whose properties as catalysts can
be easily modulated by the introduction of suitable
functional groups and, in some cases, enhanced by
cooperativity effects between central and planar
chirality.9
The asymmetric reduction of ketones is a pivotal reac-
tion for the preparation of chiral alcohols1 which form
an extremely important class of intermediates for fine
chemicals and pharmaceuticals.2 Ruthenium(II)-
catalysed asymmetric transfer hydrogenation has
recently received much attention due to its operational
simplicity and the use of non-hazardous hydrogen
donors such as 2-propanol or formic acid.3 Several
complexes of [(h6-arene)RuCl2]2 with structurally differ-
ent bidentate ligands have been tested and some
efficient catalyst systems are available for the reduction
of both simple4 and functionalised ketones.5 The reac-
tion mechanism and the origin of the enantioselectivity
have recently been proposed on the basis of theoretical
and experimental approaches for the case when b-
amino alcohol–Ru complexes are used and the presence
of an NH moiety in the ligand has been shown to be
crucial for efficient catalysis and asymmetric induction.6
Although some ferrocenyl diamines and phosphines
have been employed successfully as ligands in ruthenium-
(II)-promoted transfer hydrogenation of ketones,10
a
screening of catalytic activity of ferrocenyl amino alco-
hols in this reaction is not yet reported.
Herein, we describe the results obtained in the transfer
hydrogenation of ketones using ferrocenyl amino alco-
hols possessing central chirality as ligands and the
evidence of some structure–activity relationships.
2. Results and discussion
2.1. Simple ferrocenyl amino alcohols: comparison with
phenyl analogues
Enantiopure ferrocenyl derivatives have been reported
as active catalysts in several reactions7 and are very
attractive compounds for the design of new ligand–
metal complexes owing to their different chirality fea-
tures according to the substitution pattern on the
ferrocene backbone. Using stereoselective synthesis pro-
tocols,8 it is possible to access a large number of chiral
The recent availability of ferrocenyl amino alcohol
(S)-3,11 which can be considered the ‘three-dimensional’
analogue of phenylglycinol (R)-2, allowed us to test it
as a ligand for transfer hydrogenation of acetophenone
using [RuCl2(p-cymene)]2 as precatalyst and 2-propanol
in the presence of KOH as hydrogen source.
In a standard protocol, 1% mol of ligand and 0.25%
mol of [RuCl2(p-cymene)]2 were dissolved in 2-
propanol to give a red complex that was used in situ to
* Corresponding author. E-mail: patti@issn.ct.cnr.it
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(02)00835-2

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A. Patti, S. Pedotti / Tetrahedron: Asymmetry 14 (2003) 597–602
reduce acetophenone (0.1 M) in the presence of 2.5%
mol KOH at room temperature.
a-position to the b-position with respect to the
cyclopentadienyl ring has a positive effect on the selec-
tivity of the hydrogen transfer, possibly a result of
release of steric hindrance in the Ru–ferrocene complex.
However, the same change in the position of the stereo-
genic centre is detrimental in the analogous phenyl
ligand.
Compound (S)-3 showed comparable activity with
respect to phenylglycinol, (R)-2, but lower efficiency in
the asymmetric induction (Table 1, entries 1 and 2) so
that (S)-1-phenylethanol, (S)-1, was recovered with
only 10% e.e. (Fig. 1). Increasing the catalyst loading
influenced only the reaction rate without affecting the
enantioselectivity (Table 1, entry 3).
The isomeric b-ferrocenyl amino alcohol (R)-612 gave
higher asymmetric induction, affording (R)-1 with 46%
e.e. (Table 1, entry 6) in agreement with data from
other catalyst screenings, indicating that steregenicity of
the carbon bearing the hydroxyl group is required for
better selectivity.5b,5c
Using ligand (R)-4,12 where the stereogenic carbon is in
the b-position with respect to the cyclopentadienyl ring,
we observed the same reaction course and stereoprefer-
ence as phenylglycinol (R)-213 (Table 1, compare entries
4 and 1). This finding could be rationalised on the basis
of better spatial similarity of ligand 4 (cf. 3) with
phenylglycinol, as shown by molecular mechanics mod-
els (Fig. 2) and previously reported experimental data
on enzymatic recognition of 1-aryl-1,2-ethandiols and
1,2-dihydroxy-3-ferrocenylpropane.14
2.2. Optimisation of ligand structure
Taking amino alcohol (R)-6 as a reference (Fig. 3), we
tried to vary the ligand structure by N-alkylation.
Derivatives 7–11 were, therefore, prepared by nucleo-
philic opening of the known b-ferrocenyl epoxide12 with
the appropriate primary amines and tested under the
standard conditions described above.
For comparison, the phenyl derivative (R)-5 was also
tested and a marked decrease in the reaction rate
together with a lower selectivity was observed with
respect to both (R)-2 and (R)-4 (Table 1, entry 5). So,
it is evident that moving the stereogenic centre from the
The presence of an N-methyl group in ligand (R)-7
provided an improvement in the reaction rate and the
level of stereoinduction so that (R)-1 was obtained in
Table 1. Asymmetric transfer hydrogenation of acetophenone in the presence of ligands 2–6a
Entry
Ligand
Time (h)
Conversion (%)b
E.e. (%)c
Config.d of 1
1
2
3
4
5
6
2
2
2
0.5
2
24
3
94
84
96
97
48
75
26
10
10
27
20
46
R
S
S
R
R
R
3
3e
4
5
6
a The reaction was carried out at rt using acetophenone (5 mmol) in a 0.1 M solution in 2-propanol solution with [acetophenone]/[KOH]/[ligand]/
[Ru]=200:5:2:1.
b Determined by GC analysis.
c Determined by chiral GC analysis.
d Assigned by comparison of the specific rotation with literature values.
e 2% ligand was used and [acetophenone]/[KOH]/[ligand]/[Ru]=100:5:2:1.
Figure 1. Phenyl- and ferrocenyl-amino alcohols for use in Ru(II)-catalysed transfer hydrogenation of acetophenone.

A. Patti, S. Pedotti / Tetrahedron: Asymmetry 14 (2003) 597–602
599
Figure 2. Superimposition of minimised (MM2) structures of (R)-2 and ferrocenyl amino alcohol (S)-3 (left) or (R)-4 (right).
Figure 3. N-Alkyl ferrocenyl amino alcohols as ligand for Ru(II)-transfer hydrogenation of acetophenone.
Table 2. Asymmetric transfer hydrogenation of acetophenone in the presence of ligands 7–12a
Entry
Ligand
Time (h)
Conversion (%)b
E.e. (%)c
Config.d of 1
1
2
3
4
5
6
7
8
9
6
7
7
8
3
1
5
24
3
48
24
24
24
1
47
68
68
–
94
24
78
18
14
86
46
65
61
–
70
72
65
33
61
68
R
R
R
–
R
R
R
R
R
R
9
9e
10a
10b
11
12
10
a The reaction was carried out at rt using acetophenone (5 mmol) in a 0.1 M solution in 2-propanol solution with [acetophenone]/[KOH]/[ligand]/
[Ru]=200:5:2:1.
b Determined by GC analysis.
c Determined by chiral GC analysis.
d Assigned by comparison of the specific rotation with literature values.
e The reaction was carried out at −15°C.

600
A. Patti, S. Pedotti / Tetrahedron: Asymmetry 14 (2003) 597–602
65% e.e.; however, a little erosion of the enantiomeric
purity of the formed alcohol was detected during the
reaction time,15 as a consequence of the known
reversibility of the hydrogen transfer when 2-propanol
is used as hydride donor (Table 2, entries 2 and 3).
asymmetric induction was roughly the same and (R)-1
was produced with 68% e.e. (Table 2, entry 10). This
result could be explained as a consequence of the
possible coordination of each b-amino alcohol moiety
with a ruthenium atom, so that a single molecule of
ligand 12 affords two reaction centres. The alternative
coordination of the two amine groups of 12 with ruthe-
nium should also be taken into account and at this
stage cannot be ruled out.
Amino alcohol (R)-8, containing the more sterically
demanding N-tert-butyl substituent, was completely
inactive (Table 2, entry 4), whereas good improvement
in the catalytic activity was obtained with N-benzyl
derivative (R)-9 that catalysed fast formation of (R)-1
with 70% e.e. (Table 2, entry 5). This improvement in
enantioselectivity with N-methylation or N-benzylation
is in agreement with reported data for the use of
phenylethanolamine and norephedrine derivatives in
Ru(II)-catalysed transfer hydrogenation.5a,16 Instead, in
the case of 1,1-bis-ferrocenyldiamines, complete inactiv-
ity had been reported for the N-benzyl derivative.10b
2.3. Variation of the substrate
In order to check the application range of the Ru(II)-
catalysed transfer hydrogenation, arylalkylketones
other than acetophenone were subjected to asymmetric
reduction using the conditions described above and
amino alcohol (R)-9 as ligand.
Substitution of the phenyl ring of the acetophenone
substrate led to a marked decrease in the enantioselec-
tivity: 4-bromo- and 2-bromoacetophenone were con-
verted with quite different reaction rates into the
corresponding alcohols possessing the same enan-
tiomeric purity, whereas the lowest reactivity was
observed in the reduction of 4-methoxyacetophenone
(Table 3, entries 1–3),
Diastereoisomeric amino alcohols 10a and 10b, con-
taining an additional stereogenic centre, led to different
enantioselectivities and reaction rates, the (R,R)-deriva-
tive possessing the matched configuration (Table 2,
entries 7 and 8); in both cases alcohol (R)-1 was
produced allowing us to deduce the low influence of
remote chirality on the sense of asymmetric induction.
The exchange of the phenyl group of 10a for a cyclo-
hexyl group in ligand 11 resulted in a considerable loss
of catalytic activity while the stereoselectivity was
affected to a lesser degree (Table 2, entry 9).
1-Acetylnaphtalene gave comparable results with
respect to acetophenone and the best result in terms of
enantioselectivity was observed with a-tetralone, which
was reduced in moderate yield and 80% e.e. (Table 3,
entry 5).
As the Ru(II)-9 catalytic system gave the best result so
far, we tried further optimisation of the stereoselection
by lowering the reaction temperature to −15°C, but
only the expected decrease in the reaction rate was
observed without a significant effect on the enan-
tiomeric excess of the formed (R)-1 (Table 2, entry 6).
3. Conclusion
In summary, we have shown that ferrocenyl amino
alcohols bearing a stereogenic carbon at the b-position
with respect to the cyclopentadienyl ring represent a
promising class of ligands for ruthenium(II)-catalysed
transfer hydrogenation of ketones with 2-PrOH/KOH
as hydrogen source. We have also evidenced the paral-
lels in the catalytic activity and the effects influencing
the activity between b-ferrocenyl amino alcohols and
a-phenylethanolamine derivatives.
Since C2-symmetrical ligands often give high levels of
enantioselectivity in asymmetric reactions,17 we decided
to prepare the 1,1%-disubstituted derivative (R,R)-12, as
a C2-symmetrical analogue of (R)-9 starting from
(R,R)-1,1%-bis[(2,3-epoxy)propyl]ferrocene.18
Using
(R,R)-12 at 1 mol% loading, the reaction rate was
nearly doubled with respect to ligand (R)-9, but the
Table 3. Asymmetric transfer hydrogenation of arylalkylketones in the presence of ligand 9a
Entry
Ar
R
Time (h)
Conversion (%)b
E.e.c (%)
Config.d
1
2
3
4
5
(p-Br)Ph
(o-Br)Ph
(p-OMe)Ph
1-Naphtyl
a-Tetralone
Me
Me
Me
Me
2
24
24
3
91
40
30
72
35
54
54
61
68e
80
R
R
R
R
R
a-Tetralone
24
a The reaction was carried out at rt using acetophenone (5 mmol) in a 0.1 M solution in 2-propanol solution with [ketone]/[KOH]/[ligand]/[Ru]=
200:5:2:1.
b Determined by GC analysis.
c Determined by chiral GC analysis.
d Assigned by comparison of the specific rotation with literature values.
e Determined by chiral HPLC analysis.

A. Patti, S. Pedotti / Tetrahedron: Asymmetry 14 (2003) 597–602
601
Ligand 9 afforded satisfactory levels of asymmetric
4.3. General procedure for synthesis of amino alcohols
7–11
induction in the Ru(II)-catalysed transfer hydrogena-
tion of ketones, considering that high enantioselectivity
in this reaction has been achieved only with ligands
possessing more than one stereogenic centre and/or a
cyclic structure.3 Fine-tuning of the induction proper-
ties of 9 by functionalisation of its N-benzyl group or
by introduction of additional planar chirality (a charac-
teristic peculiar to ferrocene stereochemistry) is cur-
rently in progress.
(R)-1,2-Epoxy-3-ferrocenylpropane (100 mg, 0.4 mmol)
was dissolved in a MeOH:H2O 1:1 mixture (10 ml) and
treated with an excess (2–4 equiv.) of the appropriate
amine. The solution was maintained at 45°C until TLC
analysis showed the complete conversion of the sub-
strate. After addition of water the reaction mixture was
partitioned with AcOEt and the organic phase
extracted with 10% solution of citric acid. The acidic
aqueous phase was then alkalinised with 1N NaOH and
extracted with AcOEt. The final organic phase was
dried over Na2SO4 and taken to dryness to afford a
residue that was purified by Silica gel column chro-
matography using AcOEt–Et3N 2–5% mixtures as
eluant.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded in CDCl3 on a
Bruker Avance™ 400 spectrometer at 400.13 and
100.62 MHz, respectively. Chemical shifts (l) are given
as ppm relative to the residual solvent peak and cou-
pling constants (J) are in Hz. Melting points are uncor-
rected. Optical rotations were measured on a DIP 135
JASCO instrument at 25°C. Propan-2-ol (HPLC grade)
was distilled over CaH2. [RuCl2(p-cymene)]2 was pur-
chased from Aldrich and used as given. Reactions were
carried out under argon using standard Schlenk tech-
niques. Column chromatography was performed on
silica gel 60 (70–230 mesh) using the specified eluants.
4.3.1.
(R)-1-N-Methylamino-2-hydroxy-3-ferrocenyl-
propane, 7. 68% yield, mp 96°C (dec.), [h]D=−11.5 (c
1
0.37, C6H6); H NMR: l 2.27 (3H, s), 2.33 (1H, dd,
J=9.1 and 12.0), 2.34 (1H, dd, J=5.4 and 14.2), 2.42
(1H, dd, J=7.1 and 14.2), 2.49 (1H, dd, 3.2 and 12.0),
3.55 (1H, m), 3.95 (2H, m), 3.96 (5H, s), 3.98 (2H, m);
13C NMR: l 35.80, 35.85, 56.60, 67.70, 68.60, 68.96,
69.11, 70.00, 84.12. Anal. calcd for C14H19FeNO: C,
61.55; H, 7.01; N, 5.13. Found: C, 61.80; H, 7.14; N,
5.20%.
4.3.2. (R)-1-N-tert-Butylamino-2-hydroxy-3-ferrocenyl-
propane, 8. 65% yield, mp 100°C, [h]D=−21.8 (c 1.30,
C6H6); H NMR: l 1.11 (9H, s), 2.47 (2H, m), 2.60
(1H, dd, J=6.9 and 14.1), 2.71 (1H, dd, J=2.8 and
11.7), 3.65 (1H, m), 4.06 (2H, bs), 4.10 (6H, bs), 4.13
(1H, m); 13C NMR: l 24.75, 35.98, 47.20, 51.82, 67.58,
67.66, 68.57, 68.92, 69.22, 70.18, 84.19. Anal. calcd for
C17H25FeNO: C, 64.77; H, 7.99; N, 4.44. Found: C,
64.49; H, 8.09; N, 4.52%.
Chiral HPLC analyses were carried out on Chiracel®
OD column (Daicel Chemical Industries) using n-hex-
ane/iso-propanol mixtures as a mobile phase and detec-
tion by UV–vis detector at 225 nm. Chiral GC analyses
were carried out on a MEGA® diacetyl-tert-butylsilyl-
b-CDX (coated on OV 1701) column.
1
4.2. General procedure for ruthenium-catalysed transfer
hydrogenation of ketones
4.3.3.
(R)-1-N-Benzylamino-2-hydroxy-3-ferrocenyl-
propane, 9. 74% yield, mp 69–70°C, [h]D=−7.9 (c 0.66,
C6H6); 1H NMR: l 2.50 (1H, dd, J=2.9 and 12.0), 2.51
(1H, dd, J=5.3 and 14.0), 2.57 (1H, dd, J=6.7 and
14.0), 2.75 (1H, dd, J=3.2 and 12.0), 3.69 (1H, m), 3.76
(1H, d, J=13.2), 3.82 (1H, d, J=13.2), 4.10 (2H, m),
4.12 (6H, bs), 4.14 (1H, m), 7.28–7.35 (5H, m); 13C
NMR: l 35.17, 53.72, 54.22, 67.67, 67.71, 68.60, 68.97,
69.11, 70.65, 84.28, 127.04, 128.09, 128.43, 140.08.
Anal. calcd for C20H23FeNO: C, 68.78; H, 6.64; N,
4.01. Found: C, 68.95 H, 6.59; N, 3.96%.
A solution of [RuCl2(p-cymene)]2 (7.7 mg, 0.0125
mmol) and ligand (0.05 mmol) in dry 2-propanol (4 ml)
was heated at 80°C for 20 min under argon. The light
brown solution was then cooled to rt and diluted with
45 ml of 2-propanol. Ketone (5 mmol) and KOH (1.25
ml of a 0.1 M in 2-propanol solution, 0.125 mmol) were
sequentially added and the solution turned dark red.
Aliquots were taken at different times, filtered through
a little pad of silica gel (with CH2Cl2 washings) and
analysed by GC or HPLC.
4.3.4. 1-N-[(R)-1-Phenylethyl]amino-2-(R)-hydroxy-3-
ferrocenylpropane, 10a. 75% yield, [h]D=+39.8 (c 0.6,
CHCl3), lit.13 [h]D=−40.0 (c 0.32, CHCl3) for (S,S)-
enantiomer.
4.2.1. Chiral chromatography. 1-Phenylethanol: GC
(80–150°C, 2°C/min), tR/min: 20.2 (R), 20.7 (S); 1-(p-
OMe)phenylethanol: GC (80–180°C, 2°C/min), tR/min:
35.6 (R), 36.2 (S); 1-(p-Br)phenylethanol: GC (80–
180°C, 2°C/min), tR/min: 41.8 (R), 42.1 (S); 1-(o-
Br)phenylethanol: GC (80–150°C, 2°C/min), tR/min:
30.3 (R), 30.8 (S); 1-(1-naphtyl)ethanol: HPLC (hex-
ane:2-PrOH 95:5, flow 0.7 ml/min), tR/min: 23.5 (S),
34.5 (R); 1-tetralol: GC (80–150°C at 2°C/min rate then
150–180°C at 1°C/min), tR/min: 33.6 (S), 34.6 (R).
4.3.5.
1-N-[(S)-1-Phenylethyl]amino-2-(R)-hydroxy-3-
ferrocenylpropane, 10b. 72% yield, [h]D=−30.5 (c 0.4,
CHCl3), lit.13 [h]D=+30.3 (c 0.32, CHCl3) for (R,S)-
enantiomer.
4.3.6. 1-N-[(R)-1-Cyclohexylethyl]amino-2-(R)-hydroxy-
3-ferrocenylpropane, 11. 62% yield, mp 65°C, [h]D=

602
A. Patti, S. Pedotti / Tetrahedron: Asymmetry 14 (2003) 597–602
−13.0 (c 0.55, CHCl3); 1H NMR: l 0.98 (3H, d, J=6.5),
1.17–1.28 (5H, m), 1.66–1.77 (6H, m), 2.39 (1H, m),
2.45 (1H, dd, J=8.8 and 12.1), 2.48 (1H, dd, J=5.7
and 14.2), 2.58 (1H, dd, J=6.8 and 14.2), 2.68 (1H, dd,
J=3.4 and 12.1), 3.59 (1H, m), 4.09 (2H, m), 4.12 (6H,
bs), 4.15 (1H, m); 13C NMR: l 16.93, 26.45, 26.55,
26.70, 28.23, 29.63, 35.68, 43.20, 51.84, 57.30, 67.60,
68.57, 69.02, 69.09, 70.26, 84.45. Anal. calcd for
C21H31FeNO: C, 68.29; H, 8.46; N, 3.79. Found: C,
68.46; H, 8.56; N, 3.84%.
Brunner, H.; Henning, F.; Weber, M. Tetrahedron:
Asymmetry 2002, 13, 37–42.
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Asymmetry 2000, 11, 1849–1858; (c) Everaere, K.;
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Nowogrocki, G.; Carpentier, J.-F. Eur. J. Org. Chem.
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Andersson, P. G. J. Am. Chem. Soc. 1999, 121, 9580–
9588; (b) Yamakawa, M.; Ito, H.; Noyori, R. J. Am.
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Reek, J. N. H.; Handgraaf, J.-W.; Meijer, E. J.; Dierkes,
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(d) Yamakawa, M.; Yamada, I.; Noyori, R. Angew.
Chem., Int. Ed. 2001, 40, 2818–2821; (e) Zhou, Y.-B.;
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4.4. Synthesis of (R,R)-1,1%-bis[(3-N-benzylamino-2-
hydroxy)propyl]ferrocene, 12
According to the procedure described above for amino
alcohols
7–11,
(R,R)-1,1%-bis[(2,3-epoxy)propyl]-
ferrocene was treated with benzylamine to afford
1
(R,R)-12 in 58% yield; [h]D=−22.9 (c 1.15, C6H6); H
NMR: l 2.42 (2H, dd, J=5.5 and 14.1), 2.45 (2H, dd,
J=8.9 and 12.0), 2.49 (2H, dd, J=7.0 and 14.1), 2.69
(2H, dd, J=3.2 and 12.0), 3.62 (2H, m), 3.70 (2H, d,
J=13.2), 3.76 (2H, d, J=13.2), 4.00 (8H, m), 7.22–7.30
(10H, m); 13C NMR: l 35.40, 53.60, 54.06, 68.43, 69.63,
69.79, 70.54, 84.30, 127.09, 128.12, 128.43, 129.01,
139.75. Anal. calcd for C30H36FeN2O2: C, 70.31; H,
7.08; N, 5.47. Found: C, 70.45; H, 7.15; N, 5.32%.
Acknowledgements
8. Richards, C. J.; Locke, A. J. Tetrahedron: Asymmetry
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Thanks are due to MURST (Roma) for financial sup-
port within the Project ‘Materiali Innovativi–Metodolo-
gie e diagnostiche per materiali e ambiente’.
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