Ferrocene-based aminophosphine ligands in the Ru(II)-catalysed asymmetric hydrogenation of ketones: assessment of the relative importance of planar versus carbon-centred chirality

Article abstract of DOI:10.1016/j.tetasy.2006.04.033

Several ferrocene-based aminophosphine ligands have been prepared and shown to be effective in the Ru(II)-catalysed asymmetric hydrogenation of ketones. The enantioselectivity is mainly determined by the carbon-centred chirality of the ligands but the planar chirality is also important such that (R_C,S_Fc)- or (S_C,R_Fc)- are the matched chiralities.

Full text of DOI:10.1016/j.tetasy.2006.04.033

Tetrahedron: Asymmetry 17 (2006) 1161–1164
Ferrocene-based aminophosphine ligands in the Ru(II)-catalysed
asymmetric hydrogenation of ketones: assessment of the relative
importance of planar versus carbon-centred chirality
*
Weiping Chen, William Mbafor, Stanley M. Roberts and John Whittall
StylaCats Ltd, Chemistry Department, University of Liverpool, Liverpool L69 7ZD, UK
Received 3 April 2006; accepted 27 April 2006
Abstract—Several ferrocene-based aminophosphine ligands have been prepared and shown to be effective in the Ru(II)-catalysed asym-
metric hydrogenation of ketones. The enantioselectivity is mainly determined by the carbon-centred chirality of the ligands but the pla-
nar chirality is also important such that (R
2006 Elsevier Ltd. All rights reserved.
C C
,SFc)- or (S ,RFc)- are the matched chiralities.
ꢀ
1. Introduction
trans-RuHCl(PPh -Q-NH ) and RuHCl(PPh -Q-NH )
2 2 2 2 2
(
BINAP) (where aminophosphine PPh -Q-NH is derived
2 2
The asymmetric hydrogenation of simple ketones catalysed
by ruthenium complexes formed from chiral diphosphine
and diamine ligands provides the most efficient process
for the production of optically active secondary alcohols,
which, in turn, are some of the most valuable intermediates
for the manufacturing of pharmaceuticals and advanced
from amino acids or norephedrine), which are active pre-
catalysts for the hydrogenation of ketones and imines to
alcohols and amines, respectively, in the presence of an alk-
1
0
oxide base.
As part of our studies on the design and synthesis of new
1
1
materials. Precatalysts of the type trans-RuXY(PAr -Q-
ferrocene-based chiral ligands for asymmetric catalysis,
2
1
,2
3
PAr )(NH -Q-NH ) (X = Y = Cl;
X = H, Y = BH4;
we have developed a very simple, highly stereoselective
and modular synthesis of ferrocene-based P-chiral phos-
phine ligands. Herein, we report the preliminary results
of ferrocene-based aminophosphine ligands for the con-
struction of Ru(II) complexes and their use as catalysts in
the asymmetric hydrogenation of ketones. The interplay
of carbon-centred and planar chirality was found to be
important in the catalytic reaction.
2
2
2
4
5
X = H, Y = Cl; X = H, Y = H ), in which ruthenium is
combined with a chiral diphosphine (PAr -Q-PAr ) and a
2
2
chiral diamine (NH -Q-NH ) ligand, to form an octahedral
2
2
complex, have been used successfully in such asymmetric
hydrogenations. The high degree of enantioselectivity was
considered to be the result of the synergistic effect of the
chiral diphosphane and diamine ligands. Alternatively,
Ru(II) complexes composed of racemic BINAP or chirally
flexible diphosphane ligands in the presence of enantiopure
6
diamine, or of Ru(II) complexes of enantiopure diphos-
2. Results and discussion
7
phane in combination with an inexpensive achiral amine,
have been used to good effect. Even Ru(II) complexes of
We anticipated that a ligand of type 1 could react easily
with [RuCl (benzene)] to form complex 2, which should
be an active precatalyst for the asymmetric hydrogenation
of ketones. Furthermore, as the ligands are sterically
demanding, the catalysts might accomplish higher stereo-
selectivity in asymmetric reactions.
8
9
achiral diphosphane or achiral triaryl phosphine in com-
bination with enantiopure amine, have been employed in
the asymmetric hydrogenation of ketones. Very recently,
Morris and co-workers reported complexes of the type
2
2
*
Corresponding author at present address: Solvias AG, WRO-
1
1
6
055.6.68B, 4002 Basel, Switzerland. Tel.: +41 61 68 66 433; fax: +41
1 68 66 311; e-mail: weiping.chen@solvias.com
In order to investigate the influence of R, R and Ar on
activity and enantioselectivity, we first synthesised a series
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.04.033

1162
W. Chen et al. / Tetrahedron: Asymmetry 17 (2006) 1161–1164
R
1,2-Disubstituted ferrocenyl ligands have both planar and
R
central chiralities. Hence, in other transformations, one
or both elements of chirality influenced the outcome of
the reaction. Kumada found that planar chirality is a deci-
sive factor for exerting control over the enantiomeric excess
and absolute configuration in a Ni-catalysed Grignard
NHR1
H
N
R1
1 H R
R
Cl
Fe
N
PAr2
Fe
Ru
Cl
P
Fe
P
Ar
2
Ar
2
1
4
cross-coupling reaction. Sammakia reported similar re-
sults in an asymmetric copper-catalysed conjugated addi-
tion of Grignard reagents to enones with chiral ferrocenyl
1
2
1
5
of type 1 ligands from the readily available (R)-amines (R)-
(Scheme 1). Highly diastereoselective ortho-lithiation of
amines (R)-3 followed by treatment with ClPAr gave com-
pounds 4, which have the (R ,S )-configuration. After
reaction of 4 with Ac O at 100 ꢁC, followed by treatment
with a large excess of ammonia or amine in a mixture of
water, methanol and THF at 60 ꢁC, the dimethylamino
group of 4 was substituted by either a primary or a second-
ary amino group to form ligand 1. In the literature,13 com-
pounds 4 were prepared by lithiation of amines 3 with
phosphine oxazoline ligands. In some other examples,
the effect of planar chirality is not as apparent. Dai found
that carbon-centred chirality played a decisive role in a
hydrogen transfer reaction with a phosphine-oxazoline
1
2
3
2
C
Fc
1
6
ferrocenyl ligand. Furthermore, Dai examined the role
of the planar chirality of S,N and Se,N bidentate ligands
2
1
7
in palladium catalysed allylic alkylation, and found that
the absolute configuration and enantiomeric excess were
governed mainly by the C-centred chirality, but that the
planar chirality was also important. Hence we were most
interested in assessing the role of planar and central chiral-
ities of ligands 1 in the Ru-catalysed asymmetric hydro-
genation of ketones.
n-BuLi followed by reaction with ClPAr . However, we
2
found that amines 3 could not be lithiated completely with
n-BuLi and hence the yields of compounds 4 were unsatis-
factory. Replacement of n-BuLi with sec-BuLi or tert-BuLi
led to compounds 4 in very high yield (normally >95%).
Similarly, the enantiomer of (R ,S )-1a, (S ,R )-1e was
Ligand 1 reacted with [Ru(benzene)Cl ] in DMF at 100 ꢁC
2 2
for 10 min followed by removal of DMF in vacuo to give
the precatalyst 2 as yellow crystals. In the presence of
t-BuOK in i-propanol, some of precatalysts 2 displayed
high reactivity and moderate to good enantioselectivity in
the hydrogenation of 1-acetonaphthone (Table 1). Thus,
the complete hydrogenation of 1-acetonaphthone to (R)-
1-naphthylethanol in 66.7% ee occurred in less than 3 h
C
Fc
C
Fc
prepared from (S)-Ugi’s amine (Scheme 1). The diastereo-
mer of both (R ,S )-1a and (S ,R )-1e, (S ,S )-1f was
C
Fc
C
Fc
C
Fc
prepared from easily available (S )-a-(diphenylphos-
Fc
1
8
phino)ferrocenecarboxaldehyde 5 (Scheme 2). Thus, the
reaction of (S )-5 with MeMgBr gave product in 95%
Fc
yield with a ratio of 9:1 for the (S ,S )/(R ,S ) diastereo-
C
Fc
C
Fc
1
1b,19
mers.
Recrystallisation from hexane gave the pure dia-
stereomer (S ,S )-6 in 73% yield. Esterification of 6 with
Ac O in the presence of pyridine, followed by treatment
with a large excess of aqueous ammonia solution in a
at room temperature under an H
the presence of precatalyst 2a (0.1 mol %), generated from
(R ,SFc)-1a (entry 1). Similarly, precatalyst 2e, the enantio-
mer of 2a, prepared from (S ,RFc)-1e, gave (S)-1-naphthyl-
2
pressure of 20 bar in
C
Fc
2
C
C
mixture of methanol and THF at 60 ꢁC gave (S ,S )-1f.
ethanol in 66.5% ee (entry 5). Replacement of the methyl
C
Fc
R
R
1
2
) t-BuLi or s-BuLi
1) Ac2O
NMe2
NMe2
) Ar PCl
2) R'NH2 H2O-MeOH-THF
2
Fe
Fe
PAr2
(R)-3
(RC
,
SFc)-4
>95%
R
NHR'
(
(
(
(
RC
,
,
,
,
SFc)-1a: Ar = Ph, R = Me, R' = H, 86%
SFc)-1b: Ar = Ph, R = Ph, R' = H, 71%
PAr2
RC
RC
RC
Fe
SFc)-1c: Ar = 3,5-Me -C H , R = Me, R' = H, 84%
2
6 3
SFc)-1d: Ar = Ph, R = Me, R' = Bn, 96%
PPh2
NH2
NMe2
Fe
Fe
(S)-Ugi's amine
(SC,RFc)-1e
Scheme 1.

W. Chen et al. / Tetrahedron: Asymmetry 17 (2006) 1161–1164
1163
CHO
OH 1) Ac2O
pyridine
NH2
PPh2
MeMgBr
PPh2
PPh2
Fe
Fe
Fe
2
) NH H O
3. 2
THF, MeOH
(SFc)-5
(
SC
,SFc)-6
(SC
,
SFc)-1f
90%
8
3%
Scheme 2.
1
,2
Table 1. Asymmetric hydrogenation of 1-acetonaphthone catalysed by
various Ru-complexes
(NH -Q-NH ). Thus, precatalyst 2, generated in situ by
2 2
a
stirring a mixture of ligand 1 and [Ru(benzene)Cl ] in
2
2
i-PrOH for 15 min at room temperature, gave the same
results as using the prepared precatalyst 2 (entry 7 and
entry 8 vs entry 1 and entry 3). The easy formation of pre-
catalyst 2 indicates a possibility of finding a better catalyst
in a combinatorial manner, using two different aminophos-
phine ligands. The concept of using two different chiral
monodentate phosphine ligands for asymmetric catalysis,
H (20 bar)
2
HO
O
RuCl -L (0.1 mol%)
2
2
t
-BuOK (1 mol%)
i-PrOH, rt
b
Entry Ligand
Precatalyst Time (h) Conv. (%) ee (%)
1
2
3
4
5
6
7
8
(R
(R
(R
(R
C
C
C
C
,SFc)-1a 2a
,SFc)-1b 2b
,SFc)-1c 2c
,SFc)-1d 2d
,RFc)-1e 2e
,SFc)-1f 2f
3
3
3
4
3
3
3
3
100
88
100
3.7
100
56
66.7 (R)
44.3 (R)
78.7 (R)
20.5 (R)
66.5 (S)
16.4 (S)
66.5 (R)
78.9 (R)
20
which was first proposed by us, has been confirmed suc-
21
cessfully by other groups.
(S
(S
C
C
3. Conclusion
c
c
(R
(R
C
,SFc)-1a
,SFc)-1c
100
100
C
In conclusion, ferrocene-based aminophosphine ligands
have been shown to be effective in the Ru(II)-catalysed
asymmetric hydrogenation of ketones. The enantioselectiv-
ity is mainly determined by the C-centred chirality of the
ligands but the planar chirality is also important, and
a
b
c
Reaction conditions: 5 mmol of substrate, 0.005 mmol of 2, 0.05 mmol of
t-BuOK, 3 mL of i-PrOH, room temperature and H pressure of 20 bar.
Determined by GC using Chrompack Chirasil-Dex CB (25 m ·
.25 mm).
Catalyst 2 was prepared in situ by reaction of ligand 1 with [Ru(benz-
ene)Cl in i-PrOH at room temperature for 15 min.
2
0
(
R ,S )- or (S ,R )- is the matched combination of chi-
C Fc C Fc
2 2
]
ralities. Studies are currently under way in order to obtain
highly enantioselective ligands by modification of Ar on
phosphorus and R on carbon.
group in 1a with phenyl group, (R ,S )-1b, lowered both
C
Fc
the reactivity and enantioselectivity (entry 2). In contrast,
and mimicking Noyori’s precatalysts of the type trans-
1
–5
RuXY(PAr -Q-PAr )(NH -Q-NH ),
the introduction
2
2
2
2
References
of 3,5-dimethyl groups to P-phenyl rings, (R ,S )-1c, sig-
C
Fc
nificantly increased the enantioselectivity to 78.7% ee (entry
). Substitution of one hydrogen atom of the amino group
in 1a with a benzyl group, (R ,S )-1d, dramatically low-
1. For reviews see: (a) Noyori, R.; Koizumi, M.; Ishii, D.;
Ohkuma, T. Pure Appl. Chem. 2001, 73, 227–232; (b) Noyori,
R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40–73; (c)
Noyori, R. Adv. Synth. Catal. 2003, 345, 15–32; (d) Blaser,
H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer,
M. Adv. Synth. Catal. 2003, 345, 103–151.
3
C
Fc
ered both reactivity and enantioselectivity (entry 4).
Carbon-centred chirality plays the decisive role in the
Ru(II)-catalysed asymmetric hydrogenation of ketones a
ligand 1. Thus, in the presence of precatalyst 2f, generated
2
. (a) Ralph, C. K.; Akotsi, O. M.; Bergens, S. H. Organomet-
allics 2004, 23, 1484–1486; (b) Hartmann, R.; Chen, P. Adv.
Synth. Catal. 2003, 345, 1353–1359; (c) Wu, J.; Ji, J. X.; Guo,
R. W.; Yeung, C. H.; Chan, A. S. C. Chem. Eur. J. 2003, 9,
from ligand (S ,S )-1f, hydrogenation of 1-acetonaph-
C
Fc
thone gave (S)-1-naphthylethanol in only 16.4% ee and
6% conversion under the standard reaction conditions
entry 6 vs entry 1 and entry 5). While the atom-centred
2
963–2968; (d) Henschke, J. P.; Zanotti-Gerosa, A.; Moran,
5
(
P.; Harrison, P.; Mullen, B.; Casy, G.; Lennon, I. C.
Tetrahedron Lett. 2003, 44, 4379–4383; (e) Deng, G. J.;
Fan, Q. H.; Chen, X. M.; Liu, G. H. J. Mol. Catal. A: Chem.
chirality is the main governing factor, the planar chirality
2
003, 193, 21–25; (f) Xie, J.-H.; Wang, L.-X.; Fu, Y.; Zhu,
is also important, and (R ,S )- or (S ,R )-1 is the ligand
C
Fc
C
Fc
S.-F.; Fan, B.-M.; Duan, H.-F.; Zhou, Q.-L. J. Am. Chem.
Soc. 2003, 125, 4404–4405.
. Sandoval, C. A.; Ohkuma, T.; Muniz, K.; Noyori, R. J. Am.
Chem. Soc. 2003, 125, 13490–13503.
. Abdur-Rashid, K.; Lough, A. J.; Morris, R. H. Organomet-
allics 2001, 20, 1047–1049.
. Abdur-Rashid, K.; Clapham, S. E.; Hadzovic, A.; Harvey,
J. N.; Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2002,
124, 15104–15118.
with matched C-centred and planar chiralities. The match-
ing of planar and central chiralities is essential for obtain-
ing high asymmetric induction and also demonstrates the
importance of planar chirality.
3
4
5
Finally, precatalyst 2 is very easy to form and, in this
respect, is quite different from the formation of Noyori’s
precatalysts of the type trans-RuCl (PAr -Q-PAr )-
2
2
2

1164
W. Chen et al. / Tetrahedron: Asymmetry 17 (2006) 1161–1164
6
. (a) Ohkuma, T.; Doucet, H.; Pham, T.; Mikami, K.;
Korenaga, T.; Terada, M.; Noyori, R. J. Am. Chem. Soc.
998, 120, 1086–1087; (b) Mikami, K.; Korenaga, T.; Terada,
M.; Ohkuma, T.; Pham, T.; Noyori, R. Angew. Chem., Int.
Ed. 1999, 38, 495–497; (c) Mikami, K.; Korenaga, T.;
Ohkuma, T.; Noyori, R. Angew. Chem., Int. Ed. 2000, 39,
13. Hayashi, T.; Mise, T.; Fukushima, M.; Kagotani, M.;
Nagashima, N.; Hamada, Y.; Matsumoto, A.; Kawakani,
S.; Konishi, M.; Yamamoto, K.; Kumada, M. Bull. Chem.
Soc. Jpn. 1980, 53, 1138–1148.
1
14. Hayashi, T.; Konishi, M.; Fukushima, M.; Mise, T.; Kago-
tani, M.; Tajika, M.; Kumada, M. J. Am. Chem. Soc. 1982,
104, 180–186.
3
707–3709; (d) Mikami, K.; Korenaga, T.; Yusa, Y.; Yama-
naka, M. Adv. Synth. Catal. 2003, 345, 246–254.
. Genov, D. G.; Ager, D. J. Angew. Chem., Int. Ed. 2004, 43,
15. Stangeland, E. L.; Sammakia, T. Tetrahedron 1997, 53,
16503–16510.
7
8
2
816–2819.
16. Du, X.-D.; Dai, L.-X.; Hou, X.-L.; Xia, L.-J.; Tang, M.-H.
Chin. J. Chem. 1998, 16, 90–93.
. (a) Subongkoj, S.; Lange, S.; Chen, W.; Xiao, J. J. Mol.
Catal. A: Chem. 2003, 196, 125–129; (b) Xia, Y.; Tang, Y.;
Liang, Z.; Yu, C.; Zhou, X.; Li, R.; Li, X. J. Mol. Catal. A:
Chem. 2005, 240, 132–138.
17. (a) You, S.-L.; Zhou, Y.-G.; Hou, X.-L.; Dai, L.-X. Chem.
Commun. 1998, 24, 2765–2766; (b) You, S.-L.; Hou, X.-L.;
Dai, L.-X. Tetrahedron: Asymmetry 2000, 11, 1495–1500; (c)
You, S.-L.; Hou, X.-L.; Dai, L.-X.; Yu, Y.-H.; Xia, W. J.
Org. Chem. 2002, 67, 4684–4695.
9
. Jing, Q.; Zhang, X.; Sun, J.; Ding, K. Adv. Synth. Catal.
2
005, 347, 1193–1197.
1
0. (a) Guo, R.; Lough, A. J.; Morris, R. H.; Song, D.
Organometallics 2004, 23, 5524–5529; (b) Abdur-Rashid, K.;
Guo, R.; Lough, A. J.; Morris, R. H.; Song, D. Adv. Synth.
Catal. 2005, 347, 571–579.
18. Riant, O.; Samuel, O.; Flessner, T.; Taudien, S.; Kagan, H. B.
J. Org. Chem. 1997, 62, 6733–6745.
19. Taylor, C. J.; Roca, F. X.; Richards, C. J. Synlett 2005, 2159–
2161.
1
1
1. (a) Chen, W.; Mbafor, W.; Roberts, S. M.; Whittall, J. J. Am.
Chem. Soc. 2006, 128, 3922–3923; (b) Chen, W.; Roberts, S.
M.; Whittall, J. Chem. Commun., in press.
2. Marquarding, D.; Klunsacek, H.; Gokel, G.; Hoffmann, P.;
Ugi, I. J. Am. Chem. Soc. 1970, 92, 5389–5393.
20. Chen, W.; Xiao, J. Tetrahedron Lett. 2001, 42, 8737–8740.
21. (a) Reetz, M. T.; Sell, T.; Meiswinkel, A.; Mehler, G. Angew.
Chem., Int. Ed. 2003, 42, 790–793; (b) Pena, D.; Minnaard, A.
J.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G.;
Feringa, B. L. Org. Biomol. Chem. 2003, 1, 1087–1089.