New efficient synthesis of Taniaphos ligands: Application in ruthenium- and rhodium-catalyzed enantioselective hydrogenations

Article abstract of DOI:10.1016/j.tetasy.2003.11.004

A third generation of Taniaphos 1,5-diphosphine ferrocene ligands with the new and interesting (S_Fc,3S)- and (R_Fc,3R)-configurations has been prepared. With these ligands, the ruthenium-catalyzed hydrogenation of C=O bonds proceeded with high diastereo- and enantioselectivity (up to >99% de and 97% ee). Good results were also obtained for the rhodium-catalyzed hydrogenation of C=C (up to 96% ee) and C=N bonds (up to 65% ee).

Full text of DOI:10.1016/j.tetasy.2003.11.004

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 91–102
New efficient synthesis of Taniaphos ligands: application in
ruthenium- and rhodium-catalyzed enantioselective hydrogenations
Katja Tappe and Paul Knochel*
Department of Chemistry, Ludwig-Maximilians-University, Butenandtstr. 5-13, 81377 M €u nchen, Germany
Received 28 August 2003; revised 23 October 2003; accepted 4 November 2003
Abstract—A third generation of Taniaphos 1,5-diphosphine ferrocene ligands with the new and interesting (SFc,3S)- and (RFc,3R)-
configurations has been prepared. With these ligands, the ruthenium-catalyzed hydrogenation of C@O bonds proceeded with high
diastereo- and enantioselectivity (up to >99% de and 97% ee). Good results were also obtained for the rhodium-catalyzed hydro-
genation of C@C (up to 96% ee) and C@Nbonds (up to 65% ee).
ꢀ
2003 Elsevier Ltd. All rights reserved.
1
. Introduction
In the original Taniaphos ligands 1, we had prepared
diastereomeric 1,5-diphosphines with the relative
(SFc,3R)- or (RFc,3S)-configurations. The control of the
stereochemistry at position 3 proved to be essential.
Thus, the second generation of catalysts of type 2
bearing a methoxy group in position 3 with a (3S)-
configuration instead of (3R) as in the diphosphines 1
Metal-catalyzed asymmetric hydrogenation is an
important method for preparing chiral molecules such
as a-amino acids, 1,3-diols or aldol products. The
choice of an appropriate chiral ligand for each class of
substrate is essential for achieving high enantioselectiv-
ities. Although many chiral diphosphines have been
reported, there is still a need for preparing readily
available diphosphines, which have a broad application
1
5
proved in many cases to be superior. To prepare
ligands of type 2 we have used a different synthetic
approach to that for the original Taniaphos ligands of
5
2
range in asymmetric reductions. Recently, we have
type 1. This new synthesis had the advantage of
allowing the preparation of 1,5-diphosphines with two
reported a new class of chiral 1,5-diphosphine ferrocene
ligands of type 1 (Taniaphos), which gave exceptionally
high enantioselectivities for various metal-catalyzed
1
2
different groups R and R , but it had also the disad-
vantage that a tedious separation of diastereomers 4 and
5 was required (Scheme 2).
3
asymmetric reactions (Scheme 1).
The 1,5-diphosphine unit present in all Taniaphos
ligands is essential for the high catalytic activity of these
ligands. Although forming an eight-membered chelate
ring with metallic salts, the presence of the ferrocenyl
and the aryl rings assures a moderate flexibility (only a
few degrees of freedom are possible) of this large ring
Herein, we report another synthetic approach related to
the original Taniaphos-ligand synthesis avoiding the
separation of diastereomers as well as the need to use the
chiral sulfoxide 6. We demonstrate also the utility of
these new ligands 3 in asymmetric catalysis.
6
4
system allowing excellent enantiodifferentiation. The
configuration of the substituent of position 3 (Scheme 1)
in the Taniaphos ligands of type 1 proves to be espe-
cially important for achieving high enantioselectivities.
Keywords: Enantioselective hydrogenation; Ferrocene ligands.
*
Corresponding author. Tel.: +49-0-89-2180-77681; fax: +49-0-89-
180-77680; e-mail: paul.knochel@cup.uni-muenchen.de
2
Scheme 1. Taniaphos 1 and the related ligands 2 and 3.
0
957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.11.004

92
K. Tappe, P. Knochel / Tetrahedron: Asymmetry 15 (2004) 91–102
Scheme 2. Preparation of the diastereomeric alcohols 4 and 5.
2
. Results and discussion
Substitution of the dimethylamino groups with
o-bromophenylzinc bromide 14 in the presence of acetyl
2
.1. Synthesis of the ligands of type 3
chloride and subsequent recrystallization from Et
to the diastereomeric pure ligand precursors 15a–c and
2
O led
12
The synthesis of the new Taniaphos ligands with a 3S
configuration starts by connecting the group R to the
16a,b in high yields. Double halogen–lithium exchange
followed by the reaction with ClPPh gave the corre-
sponding diphosphines 17a,b and 18a,b (Scheme 5).
2
ferrocene moiety via Friedel–Crafts acylation (Scheme
7
3
).
Then, the resulting ferrocenyl ketones 7a–c were con-
verted into the amines 8a–c and 9a,b in three steps. The
CBS-reduction was performed either with the (R)-CBS
2.2. Asymmetric catalysis
The efficiency and selectivity of the new 1,5-diphos-
phines 17a,b and 18a,b as well as the influence of the
group R were examined in ruthenium- and rhodium-
catalyzed hydrogenation reactions. The stereoselectivity
of the new ligands were compared with Taniaphos (19,
8
catalyst or the (S)-CBS catalyst. Thus, CBS-reduction
of the ketones 7a–c with the (R)-CBS catalyst afforded
the ferrocenyl alcohols 10a,b whereas with the (S)-CBS
catalyst the alcohols 11a,b were obtained with high
9
3
5
enantioselectivity. Acylation gave quantitatively the
first generation) and Taniaphos 20 (second generation)
(Scheme 6).
intermediate acetates, which were converted to the cor-
responding ferrocenylamines 12a,b and 13a,b with
retention of configuration by treatment with dimethyl-
10
amine. Diastereoselective lithiation afforded the planar
chiral amines 8a–c and 9a,b (Scheme 4).
1;13
2
.2.1. Enantioselective hydrogenation of C@O bonds.
11
Taniaphos-analogous ferrocenyl phosphines are highly
efficient for the ruthenium-catalyzed asymmetric
3
;5
hydrogenation of various 1,3-ketoesters (Scheme 7).
All ruthenium-catalyzed hydrogenation reactions were
performed with 0.5 mol % of the catalyst formed in situ
from [Ru(cod)(C
4
H
7
)
2
]/HBr (ÔRuÕ; cod ¼ 1,5-cyclooct-
14
adiene; 0.5 mol %) and the ligand (0.5 mol %). The
results obtained for the hydrogenation of various 1,3-
ketoesters 21 are summarized in Table 1.
In the case of the 1,3-ketoester 21a, the enantioselec-
tivity could be improved by maximizing the steric hin-
Scheme 3. Preparation of the ketones 7a–c.
Scheme 4. Synthesis of the amines 8a–c and 9a,b. Reagents and conditions: (i) (R)-CBS catalyst (0.3 equiv), BH
ii) Ac O, pyridine, rt, 12 h; (iii) HNMe , CH CNor MeOH, H O; (iv) t-BuLi (1.5 equiv), Et Cl
O, 0 ꢁC, 1 h; then C
catalyst (0.3 equiv), BH (1 equiv), THF, 0 ꢁC, 2 h.
ÁSMe
3
ÁSMe
2
(1 equiv), THF, 0 ꢁC, 2 h;
or I (2 equiv); (v) (S)-CBS
(
2
2
3
2
2
2
4
Br
2
2
3
2

K. Tappe, P. Knochel / Tetrahedron: Asymmetry 15 (2004) 91–102
93
Scheme 5. Synthesis of the diphosphines 17a,b and 18a,b.
dependency. By minimizing the steric hindrance of the
group R, the enantioselectivity could be raised from 87%
ee (S) (entry 11) for the phenyl-substituted ligand 17a to
96% ee (entry 16) for the methyl-substituted 18b. With
this result, 18b showed better selectivity for the hydro-
genation of the ketoester 21b than Taniaphos 19. In all
cases, the ligands 17a,b and 18a,b gave good conversion
and the enantioselectivities could be improved up to
3
Scheme 6. Taniaphos 19 (first generation) and Taniaphos 20 (second
4
generation).
1
5
1% (entries 6 and 7) by lowering the temperature from
0 to 30 ꢁC.
Hydrogenation was also successful for cyclic ketoesters
such as ethyl 2-oxocyclopentanecarboxylate (23, Scheme
8, Table 2).
Depending on the group R, excellent diastereoselectivi-
ties and good enantioselectivities were observed for the
hydrogenation of the ketoester 23 (Table 2, entry 4).
Scheme 7. Ruthenium-catalyzed asymmetric hydrogenation of the 1,3-
ketoesters 21a,b.
drance of the group R in position 3 from methyl [90% ee
(S), entry 9] to phenyl [92% ee (R), entry 5]. Hydro-
genation of the ketoester 21b showed the opposite
Hydrogenation of symmetrical 1,3-diketones such as
bis-benzoylmethane 25 led to the corresponding diol 26
in favor of the anti-product (Scheme 9, Table 3).
Table 1. Ruthenium-catalyzed asymmetric hydrogenation of the 1,3-ketoesters 21a,b
a
b
Entry
Substr.
Ligand
Temp. (ꢁC)
Time (h)
Conv. (%)
Ee (%)
3
1
2
3
21a
21b
21b
19
19
20
50
50
50
8
12
20
100
100
100
96 (R)
95 (S)
98 (R)
3
5
4
5
6
7
8
9
21a
21a
21a
21a
21a
21a
17a
17a
17b
17b
18b
18b
50
30
50
30
50
30
17
100
100
100
91
92 (R)
92 (R)
80 (R)
91 (R)
83 (S)
90 (S)
21.5
13
14.5
16.5
16.5
100
100
c
10
11
12
13
14
15
16
21b
21b
21b
21b
21b
21b
21b
17a
50
30
50
30
50
50
30
23
23
14
21
13
13
18
100
100
100
100
100
100
100
84 (S)
87 (S)
88 (S)
91 (S)
88 (R)
94 (R)
96 (R)
c
17a
17b
17b
18a ¼ ent-17b
18b
18b
a
b
c
1
Determined by H NMR spectroscopy.
Determined by HPLC analysis (Daicel Chiracel OD).
ÔRuÕ: 1 mol %, ligand: 1 mol %.

94
K. Tappe, P. Knochel / Tetrahedron: Asymmetry 15 (2004) 91–102
Scheme 8. Ruthenium-catalyzed hydrogenation of ethyl 2-oxocyclo-
pentanecarboxylate 23.
Scheme 9. Ruthenium-catalyzed hydrogenation of the symmetrical
1,3-diketone 25.
The new diphosphine ligands were also tested in the
rhodium-catalyzed hydrogenation of dimethyl itaconate
The results obtained for the hydrogenation of the
diketone 25 showed the strongest dependency on the
steric hindrance of the group R in the ligands 17a and
2
9 (Scheme 11). The hydrogenation reactions of 29 were
performed in MeOH or MeOH/toluene (1:1), at rt and
bar of hydrogen pressure. The results are summarized
1
1
8b. Unfortunately, using the phenyl-substituted ligand
7a afforded the diol 26 with moderate diastereoselec-
1
in Table 5.
tivity and practically no enantiodifferentiation [60% de,
% ee (R,R), entry 3]. Instead, the product trans-26
3
In comparison with Taniaphos 19 [91% ee (R), entry 1],
the enantioselectivity could be improved by using ligand
could be obtained with good selectivity using the
methyl-substituted ligand 18b [>99% de, 97% ee (R,R),
entry 4].
1
8b [96% ee (S), entry 5]. In all cases, after short reaction
times (less than 4.5 h) and mild reaction conditions,
complete conversion was observed.
2
.2.2. Enantioselective hydrogenation of C@C bonds. The
ligands 17a,b and 18a,b have been tested in the rhodium-
catalyzed asymmetric hydrogenation of a-(acyl-
amino)acrylic ester 27, since it is an important way to
produce the corresponding amino acid (Scheme 10).
All the rhodium-catalyzed hydrogenations were per-
formed with 1 mol % of the catalyst prepared in situ
2
.2.3. Enantioselective hydrogenation of C@N bonds. The
preparation of optically pure amines by catalytic
asymmetric hydrogenation of imines is still a very
challenging task. The new ligands 17a,b and 18a,b
were tested in the hydrogenation of the N-benzoyl
hydrazone 31 by using MeOH as solvent in the pres-
ence of 1 mol % of the catalyst prepared in situ from
15
16
17
from [Rh(cod)
(
2
]BF
1 mol %). The results are summarized in Table 4.
4
(ÔRhÕ; 1 mol %) and the ligand
In all cases using the ligands 17a,b and 18a,b, the con-
version and the enantioselectivity could be improved by
using a mixture of MeOH/CH Cl (1:10) instead of
2 2
MeOH/toluene (1:1). The best result could be obtained
with the methyl-substituted ligand 18b [94% ee (S), entry
Scheme 10. Rhodium-catalyzed hydrogenation of a-(acylamino)-
acrylic ester 27.
9
].
Table 2. Ruthenium-catalyzed hydrogenation of ethyl 2-oxocyclopentanecarboxylate 23
a
b;c
b
Entry
1
Ligand
Solvent
Time (h)
63
Conv. (%)
100
De (%)
Ee (%)
3
19
EtOH/CH
2
Cl
2
(1:10)
98
91 (R,R)
2
3
4
17a
17b
18b
EtOH
EtOH
EtOH
20.5
14
100
100
100
96
98
99
80 (R,R)
86 (R,R)
85 (S,S)
13
a
b
c
1
Determined by H NMR spectroscopy.
Determined by HPLC analysis (Daicel Chiracel OD).
The major diastereomer is the anti-product.
Table 3. Ruthenium-catalyzed hydrogenation of the symmetrical 1,3-diketone 25
a
b;c
b
Entry
Ligand
Temp. (ꢁC)
Time (h)
Conv. (%)
De (%)
Ee (%)
3
1
2
19
20
25
50
12
36
100
100
98
>99
98 (S,S)
>99 (R,R)
5
3
4
17a
18b
50
50
13.5
16.5
100
100
60
>99
3 (R,R)
97 (R,R)
a
b
c
1
Determined by H NMR spectroscopy.
Determined by HPLC analysis (Daicel Chiracel OD).
The major diastereomer is the anti-product.

K. Tappe, P. Knochel / Tetrahedron: Asymmetry 15 (2004) 91–102
Table 4. Rhodium-catalyzed hydrogenation of a-(acylamino)acrylic ester 27
95
a
b
Entry
Ligand
Solvent
Time (h)
Conv. (%)
Ee (%)
3
1
2
19
20
MeOH/toluene (1:1)
MeOH/toluene (1:1)
0.5
1.5
100
100
95 (R)
99 (S)
5
3
4
5
6
7
8
9
17a
17a
MeOH/toluene (1:1)
MeOH/CH
MeOH/toluene (1:1)
16.5
3.5
4
16
100
Traces
100
100
50
64 (R)
90 (R)
50 (R)
86 (R)
88 (S)
86 (S)
94 (S)
2 2
Cl (1:10)
17b
17b
MeOH/CH
MeOH/CH
2
2
Cl
Cl
2
2
(1:10)
(1:10)
3.5
6
18a ¼ ent-17b
18b
18b
MeOH/toluene (1:1)
MeOH/CH Cl (1:10)
4
2
2
4
100
a
1
Determined by H NMR spectroscopy.
Determined by GC analysis (Chirasil-L-Val).
b
The new 1,5-diphosphine ferrocene ligands 17a,b and
8b showed in all cases better reactivity and enantio-
1
selectivity than Taniaphos 19 by using milder reaction
conditions (entries 2–4). Interestingly, the best result
could be obtained using the phenyl-substituted ligand
Scheme 11. Rhodium-catalyzed hydrogenation of dimethyl itaconate
9.
17a [65% ee (S), entry 2].
2
Table 5. Rhodium-catalyzed hydrogenation of dimethyl itaconate 29
3. Conclusion
a
b
Entry
Ligand
Solvent
Time (h) Conv. (%) Ee (%)
3
1
2
19
20
MeOH
MeOH/
toluene
14
0.5
100
100
91 (R)
98 (S)
In summary, we have developed a stereoselective syn-
thesis of a third generation of Taniaphos-analogous 1,5-
diphosphine ferrocene ligands with the interesting
(SFc,3S)- and (RFc,3R)-configurations, which offers
many possibilities for variation. The new ligands could
successfully be applied to ruthenium- and rhodium-
catalyzed hydrogenations of C@O, C@C and C@N
bonds. Generally, we found that ligand 18b (R ¼ Me)
gave the best enantioselectivities. The increase of steric
hindrance at position 3 had a rather detrimental effect.
Further modifications of the R group are under inves-
tigation.
5
3
4
5
17a
17b
18b
MeOH
MeOH
MeOH
4.5
2.5
4
100
100
100
85 (R)
91 (R)
96 (S)
a
1
Determined by H NMR spectroscopy.
Determined by HPLC analysis (Daicel Chiracel OD).
b
4. Experimental
Scheme 12. Rhodium-catalyzed hydrogenation of the N-benzoyl
hydrazone 31.
All reactions were carried out under argon using stan-
1
dard Schlenk techniques. H and C NMR spectra were
13
31
recorded on a Bruker AMX 300 instrument. P N MR
spectra were recorded on a Varian Mercury 200 instru-
ment. Chemical shifts (d) are given as ppm relative to the
residual solvent peak. IR spectra were recorded on a
Perkin–Elmer 1420 IR spectrometer. Mass spectra were
recorded on a Finnigan MAT 95 Q spectrometer.
Optical rotations were measured on a Perkin–Elmer 241
polarimeter. Column chromatography was performed
on Merck silica gel 60 (230–400 mesh ASTM). Thin
layer chromatography was performed on Merck TLC-
plates silica gel 60 F-254. Enantiomeric excesses were
determined by HPLC analysis (Chiralcel OD-H, OD an
OJ, Daicel Chemical Industries, n-heptane/isopropanol
as mobile phase and detection by a diode array UV–vis
Table 6. Rhodium-catalyzed hydrogenation of the N-benzoyl hydra-
zone 31
b
Entry
1
Ligand
Pressure
bar)
Time (h) Conv.
a
(%)
Ee (%)
(
18
19
50
22–24
40
45 (S)
2
3
4
17a
17b
18b
30
30
30
22
22
22
100
100
100
65 (S)
59 (S)
59 (R)
a
1
Determined by H NMR spectroscopy.
Determined by HPLC analysis (Daicel Chiracel OJ).
b
detector) or GC analysis (Chirasil-L-Valin, Chrompak,
with hydrogen as carrier gas). Racemic compounds were
used for calibration in each case for the separations.
[
(
Rh(cod)
2
]BF
Scheme 12, Table 6).
4
(ÔRhÕ; 1 mol %) and the ligand (1 mol %)

96
K. Tappe, P. Knochel / Tetrahedron: Asymmetry 15 (2004) 91–102
þ
Hydrogenations were performed in 100 or 200 mL
stainless steel autoclaves or in a Schlenk tube with a
hydrogen-filled balloon for the reactions under 1 bar
pressure.
15), 228 (M , 100), 213 (11), 186 (11), 185 (61), 129 (12);
CHNcalcd for C 12
C, 63.15; H, 5.31.
H12FeO: C, 63.20; H, 5.30. Observed:
4
4
.2. Reduction of the ferrocenyl ketones 7a–c
.2.1. (S)-(3-Hydroxyphenylmethyl)ferrocene, 10a. A
4
4
.1. Acylation of ferrocene
.1.1. Benzoylferrocene, 7a. Aluminum(III) chloride
solution of borane dimethyl sulfide complex (4.3 mL,
45 mmol) in THF (45 mL) was prepared. The (R)-CBS
catalyst (methyl oxazaborolidine; 3.7 g, 13.5 mmol,
0.3 equiv) was dissolved in 20% of this solution. A
solution of benzoylferrocene 7a (13.1 g, 45 mmol) in
THF (45 mL) and the remaining borane dimethyl sulfide
complex solution were added simultaneously at 0 ꢁC
over 45 min. The disappearance of the red colored
ketone indicated the reaction progress. After complete
reduction, methanol (4 mL, CAUTION: gas evolution)
was added dropwise. The reaction mixture was quen-
(
16.4 g, 123 mmol) was added to a solution of benzoyl
chloride (14 mL, 123 mmol) in CH Cl
(110 mL) at 0 ꢁC.
This solution was added to a solution of ferrocene
2
2
(
3
1
20.8 g, 112 mmol) in CH Cl2 (110 mL) at 0 ꢁC over
2
0 min. The reaction mixture was stirred at rt and after
.5 h, the mixture was quenched by adding it to ice cold
water. The phases were separated and the aqueous phase
was extracted with CH Cl
(3 · 100 mL). The organic
layers were washed with saturated K CO solution,
2
2
2
3
water, and brine and dried over MgSO . The crude
4
material was purified by column chromatography
(
ched with saturated NH
Et O (150 mL). The organic layers were washed with
4
Cl solution and extracted with
n-pentane/Et
2
O 4:1). Benzoylferrocene 7a was obtained
2
as a red solid (22.9 g, 79 mmol, 71%); mp 106–107 ꢁC
water and brine and dried over MgSO . The crude
4
product was purified by column chromatography
(n-pentane/Et O 4:1). The alcohol 10a was isolated as a
2
7
(
(
lit. 108 ꢁC); IR (KBr): m 3436 (br, m), 3114 (w), 3092
w), 3066 (w), 1627 (vs), 1598 (m), 1578 (m), 1451 (m),
1
440 (m), 1376 (m), 1290 (s), 1167 (m), 1057 (m), 1026
1
yellow solid [12.1 g, 41 mmol, 92%, >98% ee (S)]. HPLC
analysis (OD-H, 92% n-heptane, 8% isopropanol,
0.6 mL/min): retention time (min) 23.3 (R), 37.2 (S); mp
(
m); H NMR (CDCl ): d 7.82–7.79 (m, 2H), 7.47–7.34
3
(
2
1
m, 3H), 4.81 (t, J ¼ 2:0 Hz, 2H), 4.48 (t, J ¼ 1:8 Hz,
13
H), 4.11 (s, 5H); C NMR (CDCl
3
): d 199.5, 140.2,
31.9, 128.6, 128.5, 78.6, 73.0, 71.9, 70.6; MS (EI, 70 eV)
88–89 ꢁC; ½aꢀ ¼ +132.2 (c 0.79, CHCl
3
); IR (KBr): m
3566 (m), 3401 (br, m), 3082 (m), 3028 (w), 2855 (w),
D
þ
þ
m=z (%): 291 (M +1, 29), 290 (M , 100), 288 (9), 197
6), 133 (6); HRMS calcd for C17 14FeO: 290.0394.
Observed: 290.0395.
1652 (br, w), 1494 (m), 1453 (m), 1410 (w), 1320 (w),
1
(
H
1182 (m), 1104 (m), 1048 (m), 1018 (m), 1000 (m); H
NMR (CDCl ):
d
7.31–7.13 (m, 5H), 5.35 (d,
3
J ¼ 2:7 Hz, 1H), 4.11 (s, 5H), 4.07 (s, 4H), 2.46 (d,
1
3
J ¼ 3:0 Hz, 1H); C NMR (CDCl
3
): d 142.3, 127.1,
126.4, 125.2, 93.1, 71.0, 67.5, 67.1, 67.0, 66.4, 65.0; MS
4
.1.2. Propionylferrocene, 7b. Prepared according to the
procedure described above from ferrocene (17.1 g,
2 mmol), aluminum(III) chloride (13.5 g, 10 mmol), and
þ
þ
(EI, 70 eV) m=z (%): 293 (M +1, 21), 292 (M , 98), 291
(M )1, 14), 290 (62), 277 (16), 276 (81), 275 (73), 274
þ
9
propionyl chloride (8.8 mL, 101 mmol) with a reaction
time of 1.5 h and isolated as a red oil (19.7 g, 81.5 mmol,
(27), 273 (10), 227 (51), 209 (13), 186 (12), 154 (52), 153
(100), 152 (56), 151 (10), 138 (25), 121 (40), 56 (17);
19
89%); (mp lit. 67–68 ꢁC); IR (KBr): m 3930 (br, w),
3097 (m), 2975 (m), 2936 (m), 1669 (vs), 1454 (s), 1413
CHNcalcd for C 17
C, 69.95; H, 5.54.
H16FeO: C, 69.89; H, 5.52. Observed:
(
1
m), 1378 (m), 1248 (s), 1106 (m), 1098 (m), 1050 (m),
1
3
026 (m), 1002 (m); H NMR (CDCl ): d 4.71 (s, 2H),
4
.40 (s, 2H), 4.11 (s, 5H), 2.66 (q, J ¼ 7:2 Hz, 2H), 1.13
13
(
7
t, J ¼ 7:4 Hz, 3H); C NMR (CDCl ): d 205.3, 79.3,
4.2.2. (S)-(3-Hydroxypropyl)ferrocene, 10b. Prepared
according to the procedure described above from pro-
pionylferrocene 7b (19.2 g, 79 mmol) with borane
dimethyl sulfide complex (7.5 mL, 79 mmol) and the
(R)-CBS catalyst (6.6 g, 24 mmol, 0.3 equiv). 10b was
isolated as an orange oil [18.9 g, 78 mmol, 98%, >98% ee
3
2.4, 70.1, 69.6, 33.1, 8.9; MS (EI, 70 eV) m=z (%): 243
þ
þ
(
M +1, 25), 242 (M , 100), 240 (10), 213 (60), 186 (19),
85 (87), 129 (59), 128 (16), 121 (32), 56 (14); CHNcalcd
for C H FeO: C, 64.50; H, 5.83. Observed: C, 64.29;
1
13
14
H, 5.80.
(S)]. HPLC analysis (OD, 92% n-heptane, 8% isopro-
panol, 0.6 mL/min): retention time (min) 12.6 (R), 13.2
4
.1.3. Acetylferrocene, 7c. Prepared according to the
procedure described above from ferrocene (10.6 g,
7 mmol), aluminum(III) chloride (8.4 g, 63 mmol), and
acetyl chloride (4.5 mL, 63 mmol) with a reaction time of
h and isolated as a red solid (11.6 g, 51 mmol, 89%);
(S); ½aꢀ ¼ +56.9 (c 1.55, CHCl
3
); IR (KBr): m 3927 (br,
w), 3434 (br, m), 3094 (m), 2963 (s), 2932 (m), 2875 (m),
D
5
2376 (w), 1643 (br, m), 1463 (m), 1455 (m), 1411 (m),
1
1385 (m), 1105 (vs), 1090 (m), 1035 (s), 1001 (s); H
NMR (CDCl ): d 4.16–4.08 (m, 9H), 1.91 (d,
3
1
20
mp 85–86 ꢁC (lit. 84–86 ꢁC); IR (KBr): m 3436 (br, w),
096 (w), 1662 (vs), 1457 (m), 1376 (m), 1281 (m), 1115
J ¼ 3:3 Hz, 1H), 1.63–1.55 (m, 2H), 0.88 (t, J ¼ 7:5 Hz,
13
3
3H); C NMR (CDCl
3
): d 94.6, 71.5, 68.6, 68.2, 68.1,
1
þ
(
w), 1102 (w), 1005 (w); H NMR (CDCl
3
): d 4.70 (t,
67.7, 65.6, 31.4, 10.8; MS (EI, 70 eV) m=z (%): 244 (M ,
41), 227 (18), 226 (100), 225 (20), 224 (13), 186 (12), 161
(21), 138 (37), 134 (19), 121 (29), 56 (15); HRMS calcd
J ¼ 2:0 Hz, 2H), 4.43 (t, J ¼ 2:0 Hz, 2H), 4.13 (s, 5H),
13
2
7
.32 (s, 3H); C NMR (CDCl ): d 202.5, 79.7, 72.7,
3
þ
0.3, 70.0, 27.8; MS (EI, 70 eV) m/z (%): 229 (M +1,
for C13H16FeO: 244.0551. Observed: 244.0560.

K. Tappe, P. Knochel / Tetrahedron: Asymmetry 15 (2004) 91–102
97
4
.2.3. (R)-(3-Hydroxypropyl)ferrocene, 11a. Prepared
from (S)-(3-hydroxypropyl)ferrocene 10b (110 mg,
0.5 mmol) with pyridine (0.6 mL) and acetic acid anhy-
dride (0.4 mL), the resulting acetate was reacted with
acetonitrile (2 mL) and dimethylamine (2 mL, 40%
solution in water) in a sealed tube at 60 ꢁC for 20 h.
After purification by acid–base workup, the amine 12b
was obtained as a yellow solid (106 mg, 0.4 mmol, 87%);
according to the procedure described above from pro-
pionylferrocene 7b (10.8 g, 45 mmol) with borane
dimethyl sulfide complex (4.2 mL, 45 mmol) and the
(S)-CBS catalyst (4.3 g, 16 mmol, 0.3 equiv). 10b was
isolated as an orange oil [10.6 g, 43.6 mmol, 98%, >98%
ee (R)]; ½aꢀ ¼ )83.6 (c 0.45, CHCl
3
).
D
mp 66–67 ꢁC; ½aꢀ ¼ +54.8 (c 1.39, CHCl
3
); IR (KBr): m
464 (br, w), 3102 (m), 3088 (m), 2960 (s), 2931 (vs),
D
3
4
.2.4. (R)-(3-Hydroxyethyl)ferrocene, 11b. Prepared
2884 (m), 2870 (m), 2851 (m), 2818 (m), 2776 (m), 1768
(w), 1738 (w), 1636 (w), 1472 (m), 1446 (m), 1264 (m),
according to the procedure described above from acet-
ylferrocene 7c (17.5 g, 77 mmol) with borane dimethyl
sulfide complex (7.3 mL, 77 mmol) and the (S)-CBS
catalyst (6.4 g, 23 mmol, 0.3 equiv). 10b was isolated as a
yellow solid [14.9 g, 65 mmol, 85%, >98% ee (R)]. HPLC
analysis (OD-H, 99% n-heptane, 1% isopropanol,
1
1255 (m), 1228 (m), 1105 (s), 1024 (m), 1002 (m); H
NMR (CDCl ): d 4.06–3.99 (m, 8H), 3.94–3.93 (m, 1H),
3
3.18 (dd, J ¼ 11:0, 3.5 Hz, 1H), 2.03–1.93 (m, 7H), 1.73–
13
1.57 (m, 1H), 1.03 (t, J ¼ 1:4 Hz, 3H); C N MR
(CDCl ): d 86.1, 69.7, 68.9, 67.8, 67.5, 67.2, 65.3, 40.9,
3
þ
0
7
.6 mL/min): retention time (min) 40.6 (S), 42.6 (R); mp
); IR
24.8, 12.7; MS (EI, 70 eV) m=z (%): 271 (M , 23), 243
(15), 242 (100), 227 (18), 226 (18); CHNcalcd for
10
7 ꢁC (lit. 72–73 ꢁC); [aꢀ ¼ )41.2 (c 0.26, CHCl
3
D
(
(
(
KBr): m 3922 (w), 3393 (br, s), 3086 (m), 2972 (m), 2959
m), 2922 (m), 1642 (br, w), 1456 (m), 1433 (m), 1410
C H FeN: C, 66.44; H, 7.81; N, 5.17. Observed: C,
21
15
66.23; H, 7.70; N, 5.09.
m), 1364 (m), 1309 (m), 1234 (m), 1105 (s), 1093 (vs),
1
1
NMR (CDCl
071 (m), 1036 (m), 1024 (m), 1011 (m), 1002 (m); H
): d 4.51–4.44 (m, 1H), 4.15–4.08 (m, 9H),
3
4.3.3. (R)-[3-(N,N-Dimethylamino)ethyl]ferrocene, 13a.
½aꢀ ¼ )57.1 (c 0.50, CHCl
13
1
.86 (d, J ¼ 4:8 Hz, 1H), 1.37 (d, J ¼ 6:3 Hz, 3H);
C
3
).
D
NMR (CDCl ): d 95.1, 68.7, 68.3, 68.2, 66.5, 66.0, 24.1;
3
þ
MS (EI, 70 eV) m=z (%): 213 (M )OH, 16), 212 (100),
121 (20); CHNcalcd for C 12
Observed: C, 62.88; H, 6.18.
21
H
14FeO: C, 62.64; H, 6.13.
4.3.4. (R)-[3-(N,N-Dimethylamino)ethyl]ferrocene, 13b. .
Prepared according to the procedure described above
from
4 mmol) with pyridine (100 mL) and acetic anhydride
(44 mL), the resulting acetate was reacted with MeOH
220 mL) and dimethylamine (44 mL, 40% solution in
water). The crude product was purified by column
chromatography (n-pentane/Et O 1:1 + 0.5% NEt ) and
afforded the amine 13b as an orange oil (5.5 g,
(R)-(3-hydroxyethyl)ferrocene
11b
(14.7 g,
6
4
4
.3. Synthesis of the amines 12a,b and 13a,b
.3.1. (S)-[3-(N,N-Dimethylamino)phenylmethyl]ferro-
(
cene, 12a. (S)-(3-Hydroxyphenylmethyl)ferrocene 10a
11.8 g, 40 mmol) was dissolved in pyridine (40 mL) and
2
3
(
acetic anhydride (36 mL) and stirred 12 h at rt. Solvents
were removed under vacuum and the resulting acetate
was dissolved in acetonitrile (200 mL) without further
purification. Dimethylamine (45 mL, 40% solution in
water) was added and the reaction mixture again stirred
for 12 h at rt. Solvents were removed under reduced
21.4 mmol, 34%); ½aꢀ ¼ +8.3 (c 2.65, CHCl
3
); IR (KBr):
D
m 3928 (w), 3094 (m), 2972 (s), 2935 (s), 2897 (m), 2856
(m), 2819 (s), 2777 (s), 1642 (br, w), 1472 (m), 1455 (s),
1367 (m), 1299 (m), 1261 (m), 1230 (m), 1215 (m), 1181
(m), 1156 (m), 1106 (s), 1083 (m), 1071 (m), 1040 (s),
1
1001 (m); H NMR (CDCl
3
): d 4.08–4.03 (m, 9H), 3.54
pressure and the crude product dissolved in Et O
2
(q, J ¼ 6:9 Hz, 1H), 2.02 (s, 6H), 1.38 (d, J ¼ 7:2 Hz,
13
(
150 mL). The organic phase was washed with saturated
NH Cl solution, water and brine and dried over MgSO
The crude product was purified by column chromato-
graphy (n-pentane/Et O 1:1 + 0.5% NEt ) and afforded
3H); C NMR (CDCl
3
): d 87.5, 69.8, 69.0, 67.8, 67.6,
4
4
.
67.3, 59.1, 41.0, 16.5; MS (EI, 70 eV) m=z (%): 258
þ
þ
(M +1, 13), 257 (M , 95), 243 (13), 242 (100), 227 (10),
214 (22), 213 (100), 212 (40), 186 (38), 121 (41), 72 (12),
2
3
the amine 12a as an orange solid (10.8 g, 34 mmol, 85%);
mp 63–64 ꢁC; ½aꢀ ¼ )135.2 (c 0.84, CHCl ); IR (KBr): m
56 (11); HRMS calcd for C14
Observed: 257.0845.
H19FeN: 257.0867.
D
3
3
2
436 (br, w), 3088 (w), 2985 (m), 2962 (m), 2942 (m),
858 (m), 2812 (m), 2762 (m), 1492 (m), 1465 (m), 1453
(
1
2
m), 1430 (m), 1294 (m), 1202 (m), 1147 (m), 1106 (m),
4.4. Diastereoselective lithiation of the amines 12a,b and
13a,b
1
038 (m), 1006 (m); H NMR (CDCl ): d 7.43–7.39 (m,
3
H), 7.34–7.28 (m, 2H), 7.25–7.18 (m, 1H), 4.12–4.09
(
1
m, 2H), 4.07–4.05 (m, 1H), 4.02–4.00 (m, 1H), 3.70 (s,
H), 3.66–3.63 (m, 4H), 2.00 (s, 6H); C NMR (CDCl ):
3
4.4.1. (RFc)-1-Bromo-2-[3-(S)-(N,N-dimethylamino)phen-
ylmethyl]ferrocene, 8a. A solution of (S)-[3-(N,N-di-
13
d 143.9, 128.9, 128.4, 127.5, 90.8, 72.8, 70.9, 69.1, 68.9,
methylamino)phenylmethyl]ferrocene
20 mmol) in Et
(16.8 mL, 29 mmol, 1.74 M solution in pentane,
1.5 equiv) was added, the mixture stirred for 1 h at 0 ꢁC
and a solution of dibromotetrachloroethane (12.7 g,
12a
(6.2 g,
þ
6
2
7.7, 66.8, 44.9; MS (EI, 70 eV) m=z (%): 319 (M , 29),
76 (28), 275 (100), 153 (10), 121 (15); HRMS calcd for
2
O (138 mL) was cooled to 0 ꢁC. t-BuLi
19
C H21FeN: 319.1023. Observed: 319.1035.
39 mmol, 2 equiv) in Et O (50 mL) added. After warm-
2
4.3.2. (S)-[3-(N,N-Dimethylamino)propyl]ferrocene, 12b.
Prepared according to the procedure described above
ing up to rt, a saturated solution of Na S O was added.
2 2 5
The organic phase was washed with water and brine and

98
K. Tappe, P. Knochel / Tetrahedron: Asymmetry 15 (2004) 91–102
dried over MgSO
column chromatography (CH
NEt ) and afforded the amine 8a as an orange solid
4
. The crude product was purified by
68.5, 66.4, 63.2, 45.7, 41.5, 26.4, 12.8; MS (EI, 70 eV)
þ
2
Cl /Et 1:1 + 0.5%
2
2
O
m=z (%): 397 (M , 42), 369 (22), 368 (100), 353 (20), 312
(12), 226 (20), 184 (11), 121 (16), 86 (27), 56 (10); HRMS
calcd for C15H20FeIN: 396.9990. Observed: 397.0005.
3
(
960 mg, 2.4 mmol, 12%, dr 89:11); mp 94–97 ꢁC;
); IR (KBr): m 3437 (br, m),
067 (w), 3033 (w), 2978 (m), 2952 (m), 2858 (m), 2813
½
aꢀ ¼ )74.3 (c 0.90, CHCl
3
D
3
(
(
1
7
4
m), 2767 (vs), 1641 (br, w), 1489 (m), 1465 (m), 1452
m), 1374 (w), 1288 (m), 1242 (m), 1188 (m), 1106 (m),
4.4.4. (SFc)-1-Iodo-2-[3-(R)-(N,N-dimethylamino)propyl]-
ferrocene, 9a. Prepared according to the procedure
described above from (R)-[3-(N,N-dimethylamino)pro-
pyl]ferrocene 13a (1.3 g, 4.8 mmol) with t-BuLi (3.5 mL,
5.3 mmol, 1.5 M solution in pentane, 1.1 equiv) and
1
008 (m); H NMR (CDCl ): d 7.54–7.50 (m, 2H), 7.38–
3
.33 (m, 2H), 7.28–7.22 (m, 1H), 4.36–4.34 (m, 1H),
.24–4.23 (m, 1H), 4.10–4.08 (m, 1H), 3.91 (s, 1H), 3.57
13
(
s, 1H), 2.02 (s, 6H); C NMR (CDCl ): d 144.9, 128.7,
iodine (1.4 g, 5.5 mmol, 1.15 equiv) in Et O (100 mL).
2
3
1
4
28.6, 127.7, 89.9, 81.5, 71.6, 71.3, 69.7, 69.1, 67.2, 66.0,
þ
þ
The crude product was purified by column chromato-
graphy (n-pentane/Et O 1:1 + 0.5% NEt ) and afforded
2 3
4.9; MS (EI, 70 eV) m=z (%): 399 (M +1, 14), 397
(
(
(
(
5
5
M )1, 16), 356 (13), 355 (54), 354 (12), 353 (62), 309
14), 275 (21), 274 (22), 273 (100), 217 (29), 216 (14), 215
41), 203 (11), 202 (33), 154 (46), 153 (73), 134 (75), 121
29), 56 (19), 43 (41); CHNcalcd for C 19H
7.32; H, 5.06; N, 3.52; Br, 20.07. Observed: C, 57.59; H,
the amine 9a as an orange solid (1.4 g, 3.4 mmol, 72%, dr
95:5); mp 101–102 ꢁC; ½aꢀ ¼ )29.7 (c 0.89, CHCl ); IR
D
3
(KBr): m 3436 (br, m), 3090 (m), 2978 (m), 2063 (s), 2928
(s), 2882 (m), 2817 (m), 2778 (m), 1637 (br, w), 1470 (m),
20BrFeN: C,
1449 (m), 1366 (m), 1354 (m), 1259 (m), 1230 (m), 1198
1
.14; N, 3.44; Br, 19.44.
(m), 1154 (m), 1106 (s); H NMR (CDCl
3
): d 4.40–4.38
(
m, 1H), 4.17 (t, J ¼ 2:4 Hz, 1H), 4.05 (s, 5H), 3.97–3.96
(
m, 1H), 3.30 (dd, J ¼ 10:5, 3.6 Hz, 1H), 2.12–2.00 (m,
13
4
.4.2. (RFc)-1-Iodo-2-[3-(S)-(N,N-dimethylamino)phenyl-
7H), 1.87–1.70 (m, 1H), 1.08 (t, J ¼ 7:4 Hz, 3H);
C
methyl]ferrocene, 8b. Prepared according to the proce-
dure described above from (S)-[3-(N,N-
dimethylamino)phenylmethyl]ferrocene 12a (614 mg,
.92 mmol) with t-BuLi (3.6 mL, 2.9 mmol, 0.8 M solu-
tion in pentane, 1.5 equiv) and iodine (976 mg, 3.9 mmol,
equiv) in Et O (14 mL). The crude product was puri-
3
NMR (CDCl ): d 89.1, 74.5, 72.1, 68.5, 66.4, 63.2, 45.7,
þ
41.5, 26.4, 12.8; MS (EI, 70 eV) m=z (%): 397 (M , 41),
369 (14), 368 (100), 353 (24), 352 (17), 226 (32), 184 (18),
184 (10), 169 (11), 154 (10), 153 (13), 141 (13), 121 (35),
86 (53), 77 (15), 56 (20), 42 (18); CHNcalcd for
1
2
C H FeIN: C, 45.37; H, 5.08; N, 3.53; I, 31.96.
15 20
2
fied by column chromatography (n-pentane/Et
1
2
O
:1 + 0.5% NEt ) and afforded the amine 8b as an orange
Observed: C, 45.30; H, 5.00; N, 3.44; I, 31.93.
3
solid (716 mg, 1.6 mmol, 84%, dr 83:17); mp 94–96 ꢁC;
½
aꢀ ¼ )72.9 (c 0.77, CHCl
3
); IR (KBr): m 3436 (br, vs),
935 (m), 2856 (m), 2810 (m), 1636 (br, m), 1450 (m),
4.4.5. (SFc)-1-Iodo-2-[3-(R)-(N,N-dimethylamino)ethyl]-
ferrocene, 9b. Prepared according to the procedure
D
2
1
1
366 (w), 1186 (m), 1106 (m), 1006 (m); H N MR
): d 7.54–7.50 (m, 2H), 7.39–7.33 (m, 2H), 7.27–
described
above
from
(R)-[3-(N,N-dimethyl-
(
CDCl
3
amino)ethyl]ferrocene 13b (1.69 g, 6.6 mmol) with
t-BuLi (4.8 mL, 7.2 mmol, 1.5 M solution in pentane,
1.1 equiv) and iodine (2.0 g, 7.9 mmol, 1.2 equiv) in Et O
7
4
.21 (m, 1H), 4.37–4.35 (m, 1H), 4.29–4.27 (m, 1H),
.21–4.19 (m, 1H), 3.81 (s, 1H), 3.52–3.50 (m, 5H), 2.02
2
13
(
s, 6H); C NMR (CDCl ): d 145.2, 128.7, 128.6, 127.7,
(50 mL). The crude product was purified by column
3
9
2.3, 73.6, 72.1, 71.4, 69.8, 66.5, 45.0; MS (EI, 70 eV)
þ
2 2 2 3
chromatography (CH Cl /Et O 1:1 + 0.5% NEt ) and
m=z (%): 445 (M , 34), 402 (24), 401 (100), 275 (14), 274
afforded the amine 9b as an orange oil (2.0 g, 5.2 mmol,
79%, dr 94:6); ½aꢀ ¼ )0.33 (c 0.61, CHCl ); IR (KBr): m
(
(
17), 273 (60), 217 (16), 215 (16), 202 (15), 153 (20), 152
29), 134 (32), 121 (15); HRMS calcd for C19H20FeIN:
D
3094 (m), 2971 (s), 2935 (vs), 2856 (m), 2817 (s), 2773 (s),
3
4
44.9990. Observed: 444.9971.
1642 (br, w), 1451 (s), 1373 (m), 1262 (m), 1194 (m),
1
1
NMR (CDCl
156 (m), 1106 (m), 1089 (m), 1057 (m), 1002 (m); H
): d 4.40–4.38 (m, 1H), 4.18–4.16 (m, 1H),
3
4
.4.3. (RFc)-1-Iodo-2-[3-(S)-(N,N-dimethylamino)propyl]-
4.09–4.07 (m, 1H), 4.05 (s, 5H), 3.55 (q, J ¼ 6:8 Hz, 1H),
13
ferrocene, 8c. Prepared according to the procedure
described above from (S)-[3-(N,N-dimethylamino)pro-
pyl]ferrocene 12b (4.1 g, 15 mmol) with t-BuLi (14.1 mL,
23 mmol, 1.6 M solution in pentane, 1.5 equiv) and
iodine (5.7 g, 23 mmol, 1.5 equiv) in Et O (100 mL). The
crude product was purified by column chromatography
2.08 (s, 6H), 1.43 (d, J ¼ 6:6 Hz, 3H); C N MR
(CDCl ): d 90.6, 74.7, 72.1, 68.6, 66.0, 58.0, 45.9, 41.6,
3
þ
þ
16.3; MS (EI, 70 eV) m=z (%): 384 (M +1, 19), 383 (M ,
100), 369 (14), 368 (79), 340 (18), 339 (97), 338 (72), 337
(12), 336 (10), 312 (41), 213 (16), 212 (18), 211 (12), 208
(10), 184 (13), 155 (20), 154 (13), 153 (30), 152 (12), 128
(11), 121 (28), 72 (21), 56 (16); HRMS calcd for
C H FeIN: 382.9833. Observed: 382.9846.
2
(n-pentane/Et
amine 8c as an orange solid (3.7 g, 9.3 mmol, 62%, dr
2 3
O 1:1 + 0.5% NEt ) and afforded the
14
18
9
3:7); mp 95–97 ꢁC; ½aꢀ ¼ +26.2 (c 1.14, CHCl
3
); IR
D
(KBr): m 3436 (br, w), 3090 (w), 2963 (s), 2929 (s), 2818
(m), 2778 (m), 1644 (w), 1470 (m), 1449 (m), 1366 (m),
4.5. Substitution of the amino function
1
259 (m), 1230 (m), 1198 (m), 1154 (m), 1106 (s), 1043
1
(
(
2
m); H NMR (CDCl
s, 5H), 3.97 (s, 1H), 3.3 (dd, J ¼ 10:5, 3.3 Hz, 1H),
.09–2.01 (m, 7H), 1.85–1.70 (m, 1H), 1.08 (t,
3
): d 4.39 (s, 1H), 4.17 (s, 1H), 4.05
4.5.1. (RFc)-1-Bromo-2-[3-(S)-(o-bromophenyl)phenyl-
methyl]ferrocene, 15a. o-Bromoiodobenzene (0.16 mL,
1.26 mmol, 1.5 equiv) was dissolved in THF (4 mL) and
cooled to )30 ꢁC. i-PrMgCl (0.67 mL, 1.3 mmol, 1.95 M
13
J ¼ 1:7 Hz, 3H); C NMR (CDCl
3
): d 89.1, 74.5, 72.1,

K. Tappe, P. Knochel / Tetrahedron: Asymmetry 15 (2004) 91–102
99
solution in THF, 1.55 equiv) was added and the reaction
mixture stirred for 30 min. ZnBr solution (0.92 mL,
.6 mmol, 1.7 M solution in THF, 1.8 equiv) was added
o-bromoiodobenzene (1.01 mL, 7.8 mmol, 1.5 equiv),
i-PrMgCl (4.15 mL, 8.1 mmol, 1.95 M solution in THF,
1.55 equiv), ZnBr (5.53 mL, 9.4 mmol, 1.7 M solution in
2
1
2
and after stirring for 30 min at )30 ꢁC the reaction
mixture was cooled to )78 ꢁC. A solution of (RFc)-1-
bromo-2-[3-(S)-(N,N-dimethylamino)phenylmethyl]ferro-
cene 8a (334 mg, 0.8 mmol) in THF (4 mL) was added
THF, 1.8 equiv), and acetyl chloride (0.56 mL, 6.3 mmol,
1.2 equiv) in THF (40 mL). The crude product was
purified by column chromatography (n-pentane/CH Cl2
2
2
20:1), recrystallized from Et O and afforded 15c as an
and the resulting solution stirred at rt overnight. Et
(
water and brine and dried over MgSO
2
O
5 mL) was added and the organic phase washed with
orange solid (1.82 g, 3.6 mmol, 69%, dr >99:<1); mp 95–
96 ꢁC; ½aꢀ ¼ +95.2 (c 2.51, CHCl ); IR (KBr): m 3436
D
(br, m), 3092 (w), 3054 (w), 2963 (m), 2926 (m), 1641 (br,
3
4
. The crude
product was purified by column chromatography
n-pentane/CH Cl 20:1) and afforded 15a as an orange
w), 1466 (s), 1428 (m), 1370 (m), 1106 (m), 1019 (m),
1
(
1001 (m); H NMR (CDCl ): d 7.43 (d, J ¼ 8:1 Hz, 1H),
2
2
3
solid (423 mg, 0.8 mmol, 99%, dr 92:8); mp 116–117 ꢁC;
7.02 (t, J ¼ 7:5 Hz, 1H), 6.89 (t, J ¼ 7:5 Hz, 1H), 6.74
(d, J ¼ 7:8 Hz, 1H), 4.33 (s, 1H), 4.29 (s, 1H), 4.23 (dd,
13
½
aꢀ ¼ )79.6 (c 0.73, CHCl
3
); IR (KBr): m 3431 (br, m),
056 (w), 3027 (w), 1638 (br, w), 1563 (w), 1492 (w),
D
3
1
J ¼ 9:9, 4.2 Hz, 1H), 4.15–4.11 (m, 5H), 2.35–2.22 (m,
1
462 (m), 1106 (m), 1022 (m), 1001 (m); H N MR
): d 7.40–7.37 (m, 1H), 7.32–7.25 (m, 4H), 7.22–
1H), 1.81–1.66 (m, 1H), 0.96 (t, J ¼ 7:4 Hz, 3H);
C
(
CDCl
3
NMR (CDCl
3
): d 144.3, 132.7, 129.6, 127.8, 127.7,
126.2, 94.9, 75.3, 72.2, 68.2, 66.7, 45.5, 44.8, 30.1, 12.4;
7
6
.17 (m, 1H), 7.11–7.06 (m, 1H), 6.96–6.91 (m, 1H),
.86–6.83 (m, 1H), 5.58 (s, 1H), 4.42 (s, 1H), 4.05–4.03
þ
þ
MS (EI, 70 eV) m=z (%): 510 (M +1, 15), 509 (M , 3),
13
þ
(
m, 6H), 3.75 (s, 1H); C NMR (CDCl
3
): d 141.9, 139.2,
31.8, 129.1, 128.5, 127.0, 126.8, 126.1, 125.6, 123.9,
9.9, 78.2, 70.3, 70.0, 69.6, 66.7, 64.7, 49.2; MS (EI,
508 (M )1, 100), 217 (4), 215 (4), 152 (5); CHNcalcd
for C19H18BrFeI: C, 44.83; H, 3.56; Br, 15.70; I, 24.93.
Observed: C, 45.01; H, 3.38; Br, 16.39; I, 25.08.
1
8
7
þ
þ
0 eV) m=z (%): 512 (M +2, 12), 511 (M +1, 48), 510
þ
þ
(
M , 25), 509 (M )1, 100), 508 (14), 507 (55), 465 (10),
3
2
50 (12), 230 (14), 229 (79), 228 (87), 227 (32), 226 (52),
15 (19), 203 (10), 202 (32), 165 (10), 152 (23), 120 (15);
4.5.4. (S )-1-Iodo-2-[3-(S)-(o-bromophenyl)propyl]ferro-
Fc
cene, 16a. Prepared according to the procedure
described above from (SFc)-1-iodo-2-[3-(R)-(N,N-di-
methylamino)propyl]ferrocene 9a (217 mg, 0.6mmol) with
o-bromoiodobenzene (0.10 mL, 0.8 mmol, 1.4 equiv),
i-PrMgCl (0.43 mL, 0.8 mmol, 1.95 M solution in THF,
2
HRMS calcd for C23H18Br Fe: 507.9125. Observed:
5
07.9127.
4
.5.2.
(RFc)-1-Iodo-2-[3-(R)-(o-bromophenyl)phenyl-
2
1.5 equiv), ZnBr (0.57 mL, 1.0 mmol, 1.72 M solution in
methyl]ferrocene, 15b. Prepared according to the proce-
dure described above from (RFc)-1-iodo-2-[3-(S)-(N,N-
dimethylamino)phenylmethyl]ferrocene 8b (570 mg,
THF, 1.8 equiv), and acetyl chloride (0.05 mL, 0.7 mmol,
1.3 equiv) in THF (8 mL). The crude product was puri-
fied by column chromatography (n-pentane/CH Cl
2 2
1
1
1
2
.3 mmol)
.9 mmol, 1.5 equiv), i-PrMgCl (1.02 mL, 2.0 mmol,
.95 M solution in THF, 1.55 equiv), ZnBr (1.28 mL,
.31 mmol, 1.7 M solution in THF, 1.8 equiv), and acetyl
with
o-bromoiodobenzene
(0.25 mL,
20:1), recrystallized from Et O and afforded 16a as an
2
orange solid (196 mg, 0.4 mmol, 71%, dr >99:<1); mp
101.5–102 ꢁC; ½aꢀ ¼ )118.4 (c 0.44, CHCl
2
D
3
); IR (KBr): m
3436 (br, vs), 3092 (w), 2957 (m), 2927 (m), 1636 (br, m),
1
chloride (0.13 mL, 1.5 mmol, 1.2 equiv) in THF (12 mL).
The crude product was purified by column chromatog-
raphy (n-pentane/Et O 9:1), recrystallized from Et
and afforded 15b as an orange solid (699 mg, 1.3 mmol,
1564 (w), 1467 (m), 1106 (m), 1022 (m); H N MR
(CDCl
3
): d 7.43 (dd, J ¼ 8:1, 1.2 Hz, 1H), 7.02 (td,
2
2
O
J ¼ 7:6, 1.3 Hz, 1H), 6.92–6.86 (m, 1H), 6.74 (dd,
J ¼ 7:7, 1.7 Hz, 1H), 4.33 (dd, J ¼ 1:2, 2.4 Hz, 1H),
4.30–4.29 (m, 1H), 4.23 (dd, J ¼ 10:1, 4.4 Hz, 1H), 4.15–
4.13 (m, 1H), 4.13–4.10 (m, 5H), 2.35–2.22 (m, 1H),
9
8%, dr >99:<1); mp 121–122 ꢁC; ½aꢀ ¼ )92.1 (c 2.55,
D
CHCl ); IR (KBr): m 3436 (br, vs), 3084 (w), 3058 (w),
3
13
3
1
028 (w), 1629 (br, w), 1493 (w), 1463 (m), 1107 (m),
1
1.81–1.66 (m, 1H), 0.96 (t, J ¼ 7:5 Hz, 3H); C N MR
(CDCl ): d 144.3, 132.7, 129.6, 127.9, 127.7, 126.2, 94.9,
75.3, 72.2, 68.2, 66.7, 45.5, 44.8, 30.1, 12.4; MS (EI,
024 (m), 1002 (m); H NMR (CDCl
3
): d 7.39 (d,
3
J ¼ 8:1 Hz, 1H), 7.30–7.25 (m, 4H), 7.21–7.16 (m, 1H),
.10–7.05 (m, 1H), 6.96–6.91 (m, 1H), 6.80 (d,
J ¼ 7:8 Hz, 1H), 5.47 (s, 1H), 4.42 (d, J ¼ 1:5 Hz, 1H),
þ
þ
7
70 eV) m=z (%): 511 (M +2, 20), 510 (M +1, 90), 509
(M , 22), 508 (100), 481 (10), 479 (11), 273 (11), 217
þ
13
4
.13–4.12 (m, 1H), 4.00 (s, 5H), 3.80 (s, 1H); C N MR
(48), 216 (21), 215 (37), 202 (46), 180 (10), 179 (14), 178
(12), 166 (17), 165 (40), 153 (14), 152 (61), 151 (14), 121
(16); CHNcalcd for C 19H BrFeI: C, 44.83; H, 3.56; Br,
(
CDCl ): d 143.4, 140.6, 133.2, 130.6, 130.2, 128.4,
3
1
5
28.2, 127.5, 127.0, 125.6, 93.9, 75.5, 72.2, 68.9, 68.5,
þ
18
2.3, 45.0; MS (EI, 70 eV) m=z (%): 559 (M +2, 24), 558
15.70; I, 24.93. Observed: C, 44.79; H, 3.32; Br, 15.48; I,
24.91.
þ
þ
(
M +1, 96), 557 (M , 26), 556 (100), 229 (55), 228 (65),
27 (24), 226 (35), 215 (15), 202 (22), 152 (14), 121 (10);
HRMS calcd for C23 18BrFeI: 555.8986. Observed:
2
H
5
55.9005.
4.5.5. (SFc)-1-Iodo-2-[3-(S)-(o-bromophenyl)ethyl]ferro-
cene, 16b. Prepared according to the procedure
described above from (SFc)-1-iodo-2-[3-(R)-(N,N-di-
methylamino)ethyl]ferrocene 9b (1.87 g, 4.9 mmol) with
o-bromoiodobenzene (0.92 mL, 7.3 mmol, 1.5 equiv),
i-PrMgCl (3.9 mL, 7.6 mmol, 1.95 M solution in THF,
4
cene, 15c. Prepared according to the procedure
described above from (R )-1-iodo-2-[3-(S)-(N,N-di-
Fc
.5.3. (RFc)-1-Iodo-2-[3-(R)-(o-bromophenyl)propyl]ferro-
methylamino)propyl]ferrocene 8c (2.07 g, 5.2 mmol) with
2
1.55 equiv), ZnBr (5.1 mL, 8.8 mmol, 1.72 M solution in

100
K. Tappe, P. Knochel / Tetrahedron: Asymmetry 15 (2004) 91–102
THF, 1.8 equiv), and acetyl chloride (0.51 mL,
.86 mmol, 1.2 equiv) in THF (60 mL). The crude
product was purified by column chromatography (n-
pentane/CH Cl 20:1), recrystallized from Et O and
1.6 M solution in pentane, 4.2 equiv) and chlorodiphe-
nylphosphine (0.16 mL, 0.9 mmol, 2.3 equiv) in THF
(5 mL). The crude product was purified by column
5
2
2
2
chromatography (n-pentane/Et
from Et O and afforded the diphenylphosphine 17b as
an orange solid (91 mg, 0.1 mmol, 36%, dr >99:<1); mp
2
O 20:1), recrystallized
afforded 16b as an orange solid (2.41 g, 4.9 mmol, 99%,
dr >99:<1); mp 103–104 ꢁC; ½aꢀ ¼ )52.1 (c 1.65,
2
D
CHCl
w), 1468 (m), 1458 (m), 1373 (w), 1251 (w), 1240 (w),
3
); IR (KBr): m 3436 (br, m), 2967 (m), 1628 (br,
150–151 ꢁC; ½aꢀ ¼ +313.1 (c 0.19, CHCl
3
); IR (KBr): m
3436 (br, vs), 2927 (w), 1629 (br, m), 1479 (w), 1434 (w);
D
1
1
1
106 (m), 1022 (s); H NMR (CDCl ): d 7.43 (dd,
H NMR (CDCl ): d 7.54–7.48 (m, 2H), 7.27–7.20 (m,
3
3
J ¼ 8:0, 1.4 Hz, 1H), 7.00 (td, J ¼ 7:6, 3.9 Hz, 1H), 6.90
8H), 7.09–6.95 (m, 7H), 6.88–6.70 (m, 5H), 6.51–6.45
(m, 2H), 6.26 (br s, 1H), 4.48 (br s, 1H), 4.23 (s, 1H),
(
td, J ¼ 7:6, 1.7 Hz, 1H), 6.65 (dd, J ¼ 7:7, 1.7 Hz, 1H),
4
1
1
6
.39–4.32 (m, 3H), 4.19 (t, J ¼ 2:4 Hz, 1H), 4.12 (s, 5H),
3.90 (s, 5H), 3.78 (br s, 1H), 2.32–2.34 (m, 1H), 1.79–
13
13
.51 (d, J ¼ 6:9 Hz, 3H); C NMR (CDCl ): d 144.5,
1.76 (m, 1H), 0.53–0.49 (m, 3H); C NMR (CDCl ): d
3
3
31.4, 127.3, 126.5, 126.4, 123.0, 92.7, 74.0, 70.7, 66.8,
5.3, 43.9, 38.8, 19.6; MS (EI, 70 eV) m=z (%): 497
150.3 (d, J ¼ 27.6 Hz), 139.2 (d, J ¼ 8:3 Hz), 138.3 (d,
J ¼ 12:3 Hz), 138.0–137.8 (m), 136.9 (d, J ¼ 41:7 Hz),
134.7 (d, J ¼ 30:0 Hz), 134.0, 133.1 (d, J ¼ 19:9 Hz),
132.2 (d, J ¼ 17:5 Hz), 127.9, 127.2 (d, J ¼ 3:7 Hz),
127.1, 126.8 (d, J ¼ 7:1 Hz), 126.5, 126.1 (d, J ¼ 5:3 Hz),
125.5, 124.5, 100.3 (d, J ¼ 30:0 Hz), 73.7 (d,
J ¼ 12:4 Hz), 70.3 (d, J ¼ 4:3 Hz), 69.0 (d, J ¼ 3:2 Hz),
þ þ þ
(
M +2, 20), 496 (M +1, 88), 495 (M , 21), 494 (100),
2
1
1
88 (15), 273 (12), 217 (36), 216 (17), 215 (29), 202 (28),
67 (53), 166 (56), 165 (83), 153 (13), 152 (69), 151 (13),
21 (25), 115 (11), 58 (13), 56 (12), 43 (37); HRMS calcd
for C18H16 BrFeI: 493.8829. Observed: 493.8860.
31
6
3
8.7, 67.9, 41.2–40.8 (m), 29.5, 11.7; P NMR (CDCl ):
d )19.2 (d, J ¼ 37:0 Hz), )21.7 (d, J ¼ 36:6 Hz); MS
þ
4
4
.6. Synthesis of the diphosphines 17a,b and 18a,b
.6.1. (RFc)-1-Diphenylphosphino-2-[3-(R)-(o-diphenyl-
(EI, 70 eV) m=z (%): 672 (M , 20), 488 (38), 487 (100),
4
10 (16), 337 (18), 183 (19); HRMS calcd for
: 672.1798. Observed: 672.1788.
43 2
C H38FeP
phosphino)phenylmethyl]ferrocene, 17a. (R )-1-Bromo-
Fc
2
(
-[3-(R)-(o-bromophenyl)phenylmethyl]ferrocene
254 mg, 0.5 mmol) was dissolved in THF (4 mL) and
15a
4.6.3. (SFc)-1-Diphenylphosphino-2-[3-(S)-(o-diphenyl-
phosphinophenyl)propyl]ferrocene, 18a, ent-17a. Pre-
pared according to the procedure described above from
(SFc)-1-iodo-2-[3-(S)-(o-bromophenyl)propyl]ferrocene
16a (169 mg, 0.3 mmol) with t-BuLi (0.93 mL, 1.4 mmol,
1.5 M solution in pentane, 4.2 equiv) and chlorodiphen-
ylphosphine (0.14 mL, 0.8 mmol, 2.3 equiv) in THF
(3 mL). The crude product was purified by column
cooled to )78 ꢁC. n-BuLi (0.73 mL, 1.1 mmol, 1.5 M
solution in hexane, 2.2 equiv) was added and the
resulting solution stirred 15 min at )78 ꢁC. Chlorodi-
phenylphosphine (0.21 mL, 1.2 mmol, 2.4 equiv) was
added and the reaction mixture stirred overnight and
warmed up to rt. Water was added and the organic
phase washed with water and brine and dried over
MgSO . The crude product was purified by column
4
chromatography (n-pentane/Et O 20:1), recrystallized
2
chromatography (n-pentane/Et
from Et O and afforded the diphenylphosphine 17a as
an orange solid (155 mg, 0.2 mmol, 44%, dr >99:<1); mp
2
O 20:1), recrystallized
2
from Et O and afforded the diphenylphosphine 18a as
2
an orange solid (89 mg, 0.1 mmol, 40%, dr >99:<1); mp
93–94 ꢁC; ½aꢀ ¼ )314.7 (c 0.27, CHCl ); IR (KBr): m
D
3436 (br, m), 3051 (m), 2962 (m), 2929 (w), 2872 (w),
3
1
(
(
70 ꢁC; ½aꢀ ¼ +26.4 (c 0.58, CHCl
3
); IR (KBr): m 3436
br, vs), 3054 (w), 1630 (br, m), 1480 (w), 1436 (m), 1159
D
1629 (br, w), 1586 (w), 1479 (m), 1465 (m), 1434 (m),
1
1
w), 1108 (w); H NMR (CDCl ): d 7.55–7.54 (m, 2H),
1164 (m), 1107 (m); H NMR (CDCl ): d 7.54–7.49 (m,
3
3
7
3
.29–7.12 (m, 10H), 6.99–6.77 (m, 13H), 6.69–6.61 (m,
H), 6.51–6.47 (m, 1H), 4.28 (s, 2H), 3.88 (s, 1H), 3.77
2H), 7.29–7.11 (m, 8H), 7.11–6.95 (m, 7H), 6.87–6.72
(m, 5H), 6.51–6.46 (m, 2H), 5.27 (br s, 1H), 4.49 (br s,
1H), 4.25 (s, 1H), 3.91 (s, 5H), 3.79 (br s, 1H), 2.30–2.24
13
(
s, 5H); C NMR (CDCl ): d 150.0 (d, J ¼ 26:0 Hz),
3
13
1
1
1
42.4, 139.6 (d, J ¼ 10:0 Hz), 139.1 (d, J ¼ 11:2 Hz),
38.7 (d, J ¼ 9:1 Hz), 136.4–135.2 (m), 133.9–133.4 (m),
32.6 (d, J ¼ 18:4 Hz), 130.7, 129.3–126.0 (m), 99.9–99.6
(m, 1H), 1.77 (br s, 1H), 0.51 (t, J ¼ 6:5 Hz, 3H);
C
NMR (CDCl
3
): d 139.3 (d, J ¼ 10:9 Hz), 138.4 (d, J ¼
12:6 Hz), 137.9 (d, J ¼ 10:6 Hz), 136.9 (d, J ¼ 10:2 Hz),
134.8 (d, J ¼ 22:0 Hz), 134.0 (d, J ¼ 2:6 Hz), 133.2
(d, J ¼ 20:4 Hz), 132.3 (d, J ¼ 17:3 Hz), 130.6 (d,
J ¼ 16:8 Hz), 127.9–127.1 (m), 126.8 (d, J ¼ 7:6 Hz),
126.5–125.4 (m), 124.5, 100.5–100.1 (m), 73.8 (d,
J ¼ 12:7 Hz), 70.3 (d, J ¼ 4:7 Hz), 69.0–68.7 (m), 67.9,
(
m), 75.3 (d, J ¼ 9:7 Hz), 72.1 (d, J ¼ 4:9 Hz), 71.7 (d,
31
J ¼ 2:9 Hz), 70.1, 69.5; P NMR (CDCl
3
): d )17.1 (d,
J ¼ 18:7 Hz), )23.1 (d, J ¼ 19:0 Hz); MS (EI, 70 eV)
þ
þ
m=z (%): 721 (M +1, 10), 720 (M , 19), 655 (26), 654
(
(
(
44), 653 (13), 537 (10), 536 (46), 535 (100), 469 (12), 468
10), 458 (16), 414 (13), 413 (27), 337 (24), 259 (16), 257
15), 183 (24), 120 (11); HRMS calcd for C H FeP :
31
3
41.1–40.8 (m), 29.6–29.5 (m), 11.7; P NMR (CDCl ): d
19.2 (d, J ¼ 37:0 Hz), )21.7 (d, J ¼ 36:7 Hz); MS (EI,
47
38
2
þ
7
20.1798. Observed: 720.1781.
70 eV) m=z (%): 673 (M , 11), 489 (43), 488 (100), 458
(10), 421 (11), 337 (21), 183 (17); HRMS calcd for
C H FeP : 673.1876 (M +H). Observed: 673.1887
þ
4
3
þ
38
2
4.6.2. (RFc)-1-Diphenylphosphino-2-[3-(R)-(o-diphenyl-
phosphinophenyl)propyl]ferrocene, 17b. Prepared accor-
ding to the procedure described above from (R )-1-
Fc
(M +H).
iodo-2-[3-(R)-(o-bromophenyl)propyl]ferrocene 15c
(198 mg, 0.4 mmol) with t-BuLi (1.0 mL, 1.6 mmol,
4.6.4. (SFc)-1-Diphenylphosphino-2-[3-(S)-(o-diphenyl-
phosphinophenyl)ethyl]ferrocene, 18b. Prepared accord-

K. Tappe, P. Knochel / Tetrahedron: Asymmetry 15 (2004) 91–102
101
ing to the procedure described above from (SFc)-1-iodo-
-[3-(S)-(o-bromophenyl)ethyl]ferrocene 16b with
t-BuLi (1.4 mL, 2.3 mmol, 1.61 M solution in pentane,
prepared catalyst solution is added to the substrate via a
syringe under an argon flow. Volatile substrates are
added directly to the catalyst solution before introduc-
tion in the autoclave under argon. The autoclave is then
purged three times with hydrogen, heated to the desired
temperature and placed under the indicated hydrogen
pressure.
2
4
1
.2 equiv) and chlorodiphenylphosphine (0.22 mL,
.3 mmol, 2.3 equiv) in THF (5 mL). The crude product
was purified by column chromatography (n-pentane/
Et O 20:1), recrystallized from Et O and afforded the
diphenylphosphine 18b as an orange solid (145 mg,
2
2
0
.2 mmol, 41%, dr >99:<1); mp 194–195 ꢁC;
D
½
aꢀ ¼ )209.4 (c 0.57, CHCl
3
); IR (KBr): m 3436 (br, m),
052 (w), 2962 (w), 2928 (w), 1635 (br, w), 1586 (w),
4.8. Hydrogenation products. Enantiomeric excess
determination
3
1
1
479 (m), 1434 (m), 1240 (w), 1164 (w), 1107 (w); H
NMR (CDCl ): d 7.50–7.44 (m, 2H), 7.28–7.24 (m, 8H),
The substrates used in hydrogenation are commercially
available or were prepared according to literature pro-
cedures. Most of the hydrogenation products have been
previously described.
3
7
1
3
3
.17–7.07 (m, 3H), 6.96–6.53 (m, 11H), 5.46–5.35 (m,
H), 4.57–4.56 (m, 1H), 4.27 (t, J ¼ 2:4 Hz, 1H), 3.97–
.96 (m, 5H), 3.73–3.72 (m, 1H), 1.26 (d, J ¼ 6:9 Hz,
13
H); C NMR (CDCl
3
): d 151.3 (d, J ¼ 26:2 Hz), 138.6
(
d, J ¼ 10:6 Hz), 137.6–137.3 (m), 136.5 (d,
J ¼ 11:4 Hz), 134.6 (d, J ¼ 21:4 Hz), 133.3–133.0 (m),
23
4
.8.1. Ethyl 3-hydroxybutanoate 22a. HPLC (OD,
1
32.3 (d, J ¼ 18:5 Hz), 130.8 (d, J ¼ 17:6 Hz), 127.9 (d,
2
0 ꢁC, 95% n-heptane, 5% isopropanol, 0.9 mL/min):
J ¼ 3:8 Hz), 127.5–127.3 (m), 127.0–126.7 (m), 126.3 (d,
retention time (min) 7.3 (R), 10.2 (S).
J ¼ 4:9 Hz), 126.1 (d, J ¼ 5:7 Hz), 125.5, 124.7, 99.5
(
dd, J ¼ 27:1, 1.8 Hz), 74.1 (d, J ¼ 11:1 Hz), 70.6 (d,
J ¼ 4:8 Hz), 68.7–68.6 (m), 67.7, 34.9 (dd, J ¼ 28:2,
23
4
(
.8.2. Ethyl 3-hydroxy-3-phenyl-propanoate 22b. HPLC
OD, 30 ꢁC, 95% n-heptane, 5% isopropanol, 0.9 mL/
min): retention time (min) 11.3 (S), 15.9 (R).
31
8
.3 Hz), 22.1;
3
P NMR (CDCl ): d )18.6 (d,
J ¼ 33:2 Hz), )21.9 (d, J ¼ 33:5 Hz); MS (EI, 70 eV)
þ
þ
þ
m=z (%): 674 (M +O, 25), 660 (M +1, 17), 659 (M ,
9), 658 (49), 657 (21), 609 (12), 93 (13), 581 (23), 475
12), 474 (44), 473 (100), 443 (12), 409 (14), 351 (26), 337
17), 331 (19); HRMS calcd for C42 : 659.1720
6
(
(
(
23
4
.8.3. Ethyl 2-hydroxycyclopentane carboxylate 24.
HPLC (OD, 40 ꢁC, 98% n-heptane, 2% isopropanol,
.32 mL/min): retention time (min) 19.7 (1R,2S), 25.7
1S,2R), 27.4 (1R,2R), 31.1 (1S,2S).
H
36FeP
2
þ
þ
M +H). Observed: 659.1736 (M +H).
0
(
4
4
.7. Asymmetric hydrogenation reactions
.7.1. In situ rhodium catalyst preparation. The rhodium
2
3
4.8.4. 1,3-Diphenyl-1,3-propanediol 26. HPLC (OD,
30 ꢁC, 90% n-heptane, 10% isopropanol, 0.6 mL/min):
retention time (min) 16.5 (S,S), 19.2 (R,R), 23.3 (S,R).
complex (0.01 mmol) and the ligand (1.05–1.1 equiv) are
placed in a dried Schlenk tube under an argon atmo-
sphere and the indicated solvent (4 mL) is added. The
mixture is then stirred for 10–20 min at rt (see Tables 4–
2d
6
).
4.8.5. N-Acetylphenylalanine methyl ester 28. GC
Chiralsil-
(
L
-Val) 140 ꢁC isotherm: retention time (min)
10.1 (R), 11.7 (S).
22
4
.7.2. In situ ruthenium catalyst preparation. . [Ru-
(
cod)(2-metallyl) ] (0.01 mmol) and the ligand (1.05–
2
1
.1 equiv) are placed in a dried Schlenk tube under an
2e
4
2
.8.6. Dimethyl 2-methylsuccinate 30. HPLC (OJ,
argon atmosphere and acetone (2 mL) is added. To this
solution is added dropwise a HBr solution (0.1 mL,
0
0 ꢁC, 95% n-heptane, 5% isopropanol, 0.6 mL/min):
retention time (min) 9.9 (R), 15.2 (S).
.3 M solution in MeOH). After 10–20 min of stirring,
the solvent is removed under vacuo before adding the
indicated solvent (4 mL) (see Tables 1–3).
17b
4.8.7.
1-Phenyl-1-(2-benzoylhydrazino)ethane
32.
HPLC (OJ, 30 ꢁC, 90% n-heptane, 10% isopropanol,
0,6 mL/min): retention time (min) 14.3 (R), 19.9 (S).
4
.7.3. Hydrogenation in Schlenk tubes. The in situ
formed catalyst solution is added to the substrate under
an argon atmosphere. The Schlenk tube is then shortly
connected to vacuo and purged with hydrogen from a
balloon.
Acknowledgements
We thank the Fonds der Chemischen Industrie for
financial support. K. T. thanks the Degussa AG (Pro-
jekthaus Katalyse) for a fellowship and Dr. A. Monsees
for his valuable support. We thank also Chemetall
4
.7.4. Hydrogenation in autoclaves. The substrate is
placed in a glass tube equipped with a stirring bar in the
autoclave. After three cycles of vacuo-argon, the in situ

102
K. Tappe, P. Knochel / Tetrahedron: Asymmetry 15 (2004) 91–102
(Frankfurt) and the BASF AG (Ludwigshafen) for the
generous gift of chemicals.
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1