A one-step, enantioselective reduction of ethyl nicotinate to ethyl nipecotinate using a constrained, chiral, heterogeneous catalyst

Article abstract of DOI:10.1039/b005689h

A chiral catalyst derived from 1,1'-bis(diphenylphosphino)-ferrocene and anchored within MCM-41 displays remarkable increases in both enantioselectivity and activity, in the hydrogenation of ethyl nicotinate to ethyl nipecotinate, when compared to an analogous homogeneous model compound.

Full text of DOI:10.1039/b005689h

A one-step, enantioselective reduction of ethyl nicotinate to ethyl nipecotinate
using a constrained, chiral, heterogeneous catalyst†
Stuart A. Raynor,ab John Meurig Thomas,*a Robert Raja,ab Brian F. G. Johnson,*b Robert G. Bellb and
Mike D. Mantlec
a Davy-Faraday Research Laboratory, The Royal Institution of Great Britain, 21 Albemarle Street, London,
UK W1X 4BS. E-mail: jmt@ri.ac.uk
b University of Cambridge, Department of Chemistry, Lensfield Road, Cambridge, UK CB2 1EW
c
Department of Chemical Engineering, The University of Cambridge, New Museum Site, Cambridge, UK CB2 3QZ
Received (in Liverpool, UK) 12th July 2000, Accepted 29th August 2000
First published as an Advance Article on the web
A chiral catalyst derived from 1,1A-bis(diphenylphosphino)-
ferrocene and anchored within MCM-41 displays remark-
able increases in both enantioselectivity and activity, in the
hydrogenation of ethyl nicotinate to ethyl nipecotinate,
when compared to an analogous homogeneous model
compound.
It is acknowledged that, in view of their biological activity, the
enantioselective synthesis of chiral saturated ring systems
involving piperidine or cyclohexane is of considerable practical
interest. Previously, efforts to hydrogenate enantioselectively
an aromatic ring such as that in ethyl nicotinate (Scheme 1) have
resulted in values of enantiomeric excess (ee) that are less than
6%.1 However, very recently, a two-step process, involving
initial hydrogenation in high yield to the comparatively stable
1,4,5,6-tetrahydronicotinate, followed by subsequent hydro-
genation in the presence of a dihydrocinchonidine modified
noble metal catalyst, yielded a quite high ee of the nipecotinate.
Fig. 1 Schematic diagram of the chiral catalyst constrained within a
The best activity reported by Blazer et al. [using a Pd on carbon
(plus cinchonidine) catalyst for step (ii)] was 19% ee at 12%
conversion.2 Using the principle, first conceived five years
ago,3 of chirally constraining a designed active centre attached
to a chiral ligand and tethered to the inner walls of mesoporous
silica, as schematized in Fig. 1, we have produced an effective
enantioselective catalyst for the direct hydrogenation of ethyl
nicotinate to ethyl nipecotinate, with an ee of 17% and
conversions in excess of 50%.
We have previously demonstrated that in the allylic amina-
tion of cinnamyl acetate, the enantiomeric excess achieved by
the spatially confined (tethered) catalyst, which is derived from
1,1A-bis(diphenylphosphino)ferrocene (dppf), far exceeds that
attained with the same active site when it is unconfined.4
Mesoporous silica of the M41S type (used earlier as the support
for several high performance catalysts5) was used to confine the
designed catalyst, thereby creating the chiral space. The
confinement is a crucial feature of the enantioselectivity of our
catalyst. When an alkyl silsesquioxane with the same tethered,
designed catalyst is subjected to identical conditions, degrees of
conversion are appreciably lower and the catalyst exhibits no
enantiodiscrimination.
mesopore.
precursor which possessed a functionality capable of reacting
directly with a silica surface. This precursor could be charac-
terized in detail using solution spectroscopic techniques, and
then anchored to the surface of the mesoporous silica support in
a one-step reaction. The synthetic strategy involved the reaction
between
(S)-1-[(R)-1,2A-bis(diphenylphosphino)ferrocenyl]-
ethyl acetate6,7 and 3-(methylamino)propyltrimethoxysilane to
form a silane functionalised ferrocenyl ligand (1), the in-
corporation of palladium dichloride to which forms the target
ferrocenyl precursor (2) (Scheme 2). The ferrocenyl precursor 2
was then reacted with the mesoporous silane MCM-41, the
outer walls of which were previously deactivated via treatment
with [Ph2SiCl2], a method which we have already shown to be
applicable in this situation.8
The anchored catalyst was characterised using 13C and 31P
MAS NMR spectroscopy (ESI†). The 13C spectrum was fully
assignable when compared to that of (S)-1-[(R)-1,2A-bis(diphe-
nylphosphino)ferrocenyl]ethylallylamine palladium dichlor-
Our approach in the synthesis of the heterogeneous catalyst
was to design a homogeneous, metal-containing ferrocenyl
Scheme 1 The two-step hydrogenation of ethyl nicotinate to ethyl
nipecotinate via 1,4,5,6-tetrahydronicotinate.
† Electronic supplementary information (ESI) available: 1H, 13C and 31P
NMR spectroscopic data for the ferrocenyl precursor 2, the anchored
heterogeneous catalyst and the silsesquioxane-bound homogeneous cata-
lyst. See http://www.rsc.org/suppdata/cc/b0/b005689h/
Scheme 2 The synthesis of the ferrocenyl precursor 2 from a chiral
ferrocenyl acetate, via the silane functionalised ferrocenyl ligand 1.
DOI: 10.1039/b005689h
Chem. Commun., 2000, 1925–1926
This journal is © The Royal Society of Chemistry 2000
1925

Fig. 2 Depiction of the catalytically active centre attached to a soluble silsesquioxane moiety and bound in a constrained manner inside mesoporous
silica.
ide.9 The spectrum showed two broad peaks centred at d 135
and 75 which may be attributed to the phenyl and cyclopenta-
dienyl rings, respectively. There is a peak at d 12 which may be
assigned to the methyl group bound to the chiral carbon and the
carbon bound to the silicon. The central carbon in the propyl
tether may be assigned to the peak at d 22, whilst the final
carbon of the tether, that bound to the nitrogen, can be attributed
to the peak at d 52. The final peaks in the spectrum are at d 41
and 58 and may be assigned to the methyl group of the amine
and the chiral carbon, respectively. The 31P MAS NMR
spectrum revealed a broad, split signal centred around d 30,
which is comparable to that observed with the ferrocenyl
precursor 2.
The ferrocenyl precursor 2 was also reacted with an
incompletely condensed silsesquioxane cube,10 to form a
homogeneous model of the anchored heterogeneous catalyst.
Solution 1H NMR spectroscopy in C4D8O was used to
characterise the model compound (ESI†), and the absence of the
peaks for the hydroxy protons of the box at d 6.97 and the
methoxy protons of 2 at d 3.47, are diagnostic in this regard. The
MCM-41 bound catalyst and the silsesquioxane catalyst are
illustrated in Fig 2.
The two catalysts were tested in the one-step hydrogenation
of ethyl nicotinate to ethyl nipecotinate.‡ The catalysis was
performed under mild conditions (20 bar H2, 40 °C) and in both
cases proceeded with the formation of the desired nipecotinate.
However, analysis of the products revealed that the MCM-41
anchored species catalysed the reaction with a 17% ee whilst the
use of the homogeneous silsesquioxane complex resulted in a
racemic product. This remarkable change in stereoselectivity
demonstrates the profound importance of confinement in the
catalysis. The free catalyst shows no enantioselectivity whilst
chiral confinement results in a catalyst that shows greater
selectivity by almost a threefold margin than any other
reported.1 The confined catalyst also displayed a higher degree
of activity (TON = 291) compared to the homogeneous form
(TON = 98), after a reaction time of 72 h, and is remarkably
stable. The reaction mixture of the anchored catalyst contained
less than 3 ppb of metal (by ICP analysis), thereby ruling out the
possibility of any leaching.
We thank EPSRC for a rolling grant to J. M. T. and an award
to B. F. G. J. We also wish to thank ICI for a case studentship
to S. A. R. M.S.I. Inc. is gratefully acknowledged for the
molecular modelling software. We are also grateful for
assistance from Professor L. F. Gladden.
Notes and references
‡ The catalytic testing was performed in a high-pressure stainless steel
reactor (Cambridge Reactor Design) lined with PEEK (polyether ether
ketone). The catalyst (250 mg MCM-anchored, 100 mg box) was added to
5 g of ethyl nicotinate in 100 ml solvent (90 ml THF, 10 ml methanol). The
vessel was pressurised to 20 bar with hydrogen and heated to 40 °C, whilst
stirring was maintained at 400 rpm. During the reaction small aliquots were
removed, using a mini-robot autosampler, to enable the kinetics to be
studied. The products of the reaction were analysed by gas chromatograpy
(GC, Varian, Model 3400 CX) employing a BPX5 capillary column (25 m
3 0.32 mm) and flame ionisation detector. The ee was determined on the
same machine via the conversion of the nipecotinate to a diastereomeric
amide using (R)-(2)-Mosher’s acid chloride.2
1 (a) R. M. Laine, G. Hum, B. J. Wood and M. Dawson, Stud. Surf. Sci.
Catal., 1981, 7, 1478; (b) K. Nasar, F. Fache, M. Lemaire, J.-C. Beziat,
M. Besson and P. Gallezot, J. Mol. Catal., 1994, 87, 107; (c) C. Exl, E.
Ferstl, H. Honig and R. Rogi-Kohlenprath, Chirality, 1995, 7, 211.
2 H.-U. Blazer, H. Honig, M. Studer and C. Wedemeyer-Exl, J. Mol.
Catal. A: Chem., 1999, 139, 253.
3 (a) T. Maschmeyer, Unpublished Presentation at the Annual Progress
Meeting of the Davy-Faraday Research Laboratories, 17 March 1995;
(b) J. M. Thomas, Philos. Trans. R. Soc. London, Ser. A, 1990, 333, 173;
(c) J. M. Thomas, T. Maschmeyer, B. F. G. Johnson and D. S. Shephard,
J. Mol. Catal., 1999, 141, 139.
4 B. F. G. Johnson, S. A. Raynor, D. S. Shephard, T. Mashmeyer, J. M.
Thomas, G. Sankar, S. Bromley, R. Oldroyd, L. Gladden and M. D.
Mantle, Chem. Commun., 1999, 1167.
5 (a) T. Maschmeyer, F. Rey, G. Sankar and J. M. Thomas, Nature, 1995,
378, 159; (b) R. D. Oldroyd, J. M. Thomas and G. Sankar, Chem.
Commun., 1997, 2025.
6 G. W. Gokel and I. K. Ugi, J. Chem. Educ., 1972, 49, 294.
7 T. Hayashi, T. Mise, M. Fukushima, M. Kagotani, N. Nagashima, Y.
Hamada, A. Matsumoto, S. Kawakami, M. Konishi, K. Yamamoto and
M. Kumada, Bull. Chem. Soc. Jpn., 1980, 53, 1138.
8 D. S. Shephard, W. Z. Zhou, T. Mashmeyer, J. M. Matters, C. L. Roper,
S. Parsons, B. F. G. Johnson and M. Duer, Angew. Chem., Int. Ed., 1998,
37, 2719.
9 S. A. Raynor, R. Raja, J. M. Thomas, B. F. G. Johnson and M. D.
Mantle, manuscript in preparation.
10 F. J. Feher, D. A. Newman and J. F. Walzer, J. Am. Chem. Soc., 1989,
111, 1741.
These results show the considerable potential that this type of
catalyst offers, and how, by careful design of an active centre, a
heterogeneous catalyst may be engineered, the performance of
which is far superior than its free, homogeneous analogue.
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Chem. Commun., 2000, 1925–1926