Polystyrene-supported (2S)-(-)-3-exo-piperazinoisoborneol: An efficient catalyst for the batch and continuous flow production of enantiopure alcohols

Article abstract of DOI:10.1021/ol300415f

A polystyrene-supported analog (PS-PIB) of 3-exo-morpholinoisoborneol (MIB), designed for increased chemical stability, has been synthesized and used as a ligand in the asymmetric alkylation of aldehydes with Et₂Zn. The supported ligand turned out to be highly active and enantioselective for a broad scope of substrates (92-99% ee), allowing repeated recycling. A single-pass, continuous flow process implemented with PS-PIB shows only a marginal decrease in conversion after 30 h of operation.

Full text of DOI:10.1021/ol300415f

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1816–1819
Polystyrene-Supported (2S)-(À)-
3-exo-Piperazinoisoborneol: An Efficient
Catalyst for the Batch and Continuous
Flow Production of Enantiopure Alcohols
†
Laura Osorio-Planes, Carles Rodrıguez-Escrich, and Miquel A. Pericas*
†
,†,‡
ꢀ
´
Institute of Chemical Research of Catalonia (ICIQ), Av. Paısos Catalans, 16, E-43007
´
¨
Tarragona, Spain, and Departament de Quımica Organica, Universitat de Barcelona,
UB, E-08028, Barcelona, Spain
ꢀ
mapericas@iciq.es
Received February 20, 2012
ABSTRACT
A polystyrene-supported analog (PS-PIB) of 3-exo-morpholinoisoborneol (MIB), designed for increased chemical stability, has been synthesized
and used as a ligand in the asymmetric alkylation of aldehydes with Et2Zn. The supported ligand turned out to be highly active and
enantioselective for a broad scope of substrates (92À99% ee), allowing repeated recycling. A single-pass, continuous flow process implemented
with PS-PIB shows only a marginal decrease in conversion after 30 h of operation.
The ligand-accelerated, catalytic enantioselective addi-
tion of diorganozinc reagents to aldehydes represents one
of the most powerful methods for the production of
enantiopure secondary alcohols with a highly predictable
configuration.1 Ligands for these reactions belonging to
very different structural types have been synthesized over
the past two decades; among them, β-amino alcohols have
gained the most widespread use and acceptance. In recent
times, as sustainability issues have gained importance in
the practice of organic synthesis, the interest in homoge-
neous ligands has progressively shifted toward catalytic
species immobilized on a variety of supports (polymers,
inorganic solids, hybrid materials, and nanoparticles),2
which present additional advantages of simple separation,
recovery and reuse of the catalyst, and the possibility of use
under continuous flow conditions.3
† Institute of Chemical Research of Catalonia.
‡ Universitat de Barcelona.
(1) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30,
49–69.
ꢁ
(2) For early reports, see: (a) Itsuno, S.; Frechet, J. M. J. J. Org.
Chem. 1987, 52, 4140. (b) Soai, K.; Niwa, S.; Watanabe, M. J. Org.
Chem. 1988, 53, 927. (c) Soai, K.; Niwa, S.; Watanabe, M. J. Chem. Soc.,
Perkin Trans. 1 1989, 109. (d) Ellman, J. A.; Liu, G. J. Org. Chem. 1995,
ꢀ
60, 7712. (e) Vidal-Ferran, A.; Bampos, N.; Moyano, A.; Pericas, M. A.;
Riera, A.; Sanders, J. K. M. J. Org. Chem. 1998, 63, 6309. (f) ten Holte,
P.; Wijgengangs, J. P.; Thies, L.; Zwanenburg, B. Org. Lett. 1999, 1,
1095. For some recent reviews and monographs, see:(g) Chiral Catalyst
Immobilization and Recycling; De Vos, D. E., Vankelecom, I. F. J., Jacobs,
P. A., Eds.; Wiley-VCH: Weinheim, 2000. (h) Handbook of Asymmetric
Heterogeneous Catalysis; Ding, K., Uozumi, Y., Eds.; Wiley-VCH:
Weinheim, 2008. (i) Gruttadauria, M.; Giacalone, F.; Noto, R. Chem. Soc.
Rev. 2008, 37, 1666. (j) Kristensen, T. E.; Hansen, T. Eur. J. Org. Chem.
2010, 3179. (k) Cozzi, F. Adv. Synth. Catal. 2006, 348, 1367. (l) Lu, J.;
Toy, P. H. Chem. Rev. 2009, 109, 815. (m) Recoverable and Recyclable
Catalysts; Benaglia, M., Ed.; Wiley: Chichester, 2009. (n) Heterogenized
Homogeneous Catalysts for Fine Chemicals Production; Barbaro, P.,
Liguori, F., Eds.; Springer: Dordrecht, 2010. (o) Enantioselective Homo-
geneous Supported Catalysis; Sebesta, R., Ed.; RSC Publishing: Cambridge,
2012.
One of the major drawbacks associated with the use of
polymer-supported catalysts is a decrease in catalytic
activity with respect to the homogeneous case. However,
ꢀ
ꢀ
(3) (a) Pericas, M. A.; Herrerı
´
as, C. I.; Sola, L. Adv. Synth. Catal.
guez-Escrich, C.;
2008, 350, 927. (b) Rolland, J.; Cambeiro, X. C.; Rodrı
Pericas, M. A. Beilstein J. Org. Chem. 2009, 5, 56.
´
ꢀ
r
10.1021/ol300415f
Published on Web 03/14/2012
2012 American Chemical Society

high catalytic activities and enantioselectivities can be
achieved if the homogeneous catalyst is supported in such
a way that the catalytic site is not perturbed by the polymer
backbone.2dÀf,4 In the application of this principle, we
reported some years ago an immobilized analog of (R)-2-
piperidino-1,1,2-triphenylethanol 1a5 (resin 1b), which, to
the best of our knowledge, had no precedents in terms of
activity and enantioselectivity as an heterogeneous catalyst
for the addition of diethylzinc toaldehydes (2 mol %, 4 h at
0 °C, 100% conversion and 95% ee).3,4b Despite the
impressive results obtained with this immobilized ligand,
we realized that it had a limited lifetime that hampered its
application in continuous flow devices operating for long
periods of time.3 Gel phase NMR analysis of altered resins
showed the presence of 4-benzylpiperazinyl moieties sup-
ported on the polymer. These resins (2b, X = NÀCH2ÀPS)
proved catalytically active, albeit through a nonenantiose-
lective pathway.6
Scheme 2. MIB Structural Modification To Allow Anchoring
on a Solid Support through a Remote Position
The piperazine ring was built on (2S)-(À)-3-exo-
aminoisoborneol9 with bis(2-chloroethyl)amine10 (6).
After hydrogenolysis of the benzyl group, 4 was obtained
in almost quantitative yield (Scheme 3).
Scheme 3. Synthesis of the Ready-to-Anchor Ligand 4
According to previous observations with related amino
alcohols4a,7 and to control experiments with resin 1b, the
amino-substituted resin originates from a base-catalyzed
fragmentation of the CÀC bond in the β-amino alcohol
moiety. This largely overlooked fragmentation process
(Scheme 1) must be favored by substituents stabilizing
the R-amino carbanion primary product, and we reasoned
that amino alcohols lacking such substituents in their
structures should present greatly enhanced stability in
front of bases.
Immobilization of PIB to Merrifield resins with different
levels of functionalization was carried out in a straightfor-
ward manner by shaking a mixture of 4, the Merrifield
resin, and cesium carbonate in DMF2e (Table 1).
Scheme 1. Base-Catalyzed Fragmentation of 1
Table 1. Anchoring of Ligand 4 to Merrifield Resins
3-exo-Morpholinoisoborneol (MIB, 3), an efficient
mediator in diorganylzinc additions to aldehydes,8 fulfills
this requirement, and we accordingly postulated that a
supported version of MIB would exhibit an extended
lifespan. To allow immobilization without perturbation
of the catalytic site, we decided to synthesize the closely
related 3-exo-piperidinoisoborneol (PIB, 4) featuring a
suitably placed nitrogen atom for anchoring (Scheme 2).
time
(h)
yield11
(%)
a
c
f0
f b
fmax
5a
5b
1.3
24
96
0.85
0.38
1.03
0.48
83
79
0.53
a f0 = mmol of Cl/g of resin (initial substitution level). b f = mmol of
ligand/g of resin (calculated by elemental analysis of nitrogen). c fmax
=
maximum ligand substitution level (mmol of ligand/g of resin).11
ꢀ
ꢀ
´
guez, I.; Riera, A.; Sola,
(4) (a) Pericas, M. A.; Castellnou, D.; Rodrı
The functionalresins 5werethentestedinthe addition of
Et2Zn to benzaldehyde. Amino alcohol 7, a homogeneous
analog, was also tested for comparison purposes (Table 2,
entry 1) and exactly replicated the performance of MIB.8
Interestingly, enantioselectivity was unaffected when
ꢀ
L. Adv. Synth. Catal. 2003, 345, 1305. (b) Castellnou, D.; Sola, L.;
Jimeno, C.; Fraile, J. M.; Mayoral, J. A.; Riera, A.; Pericas, M. A.
J. Org. Chem. 2005, 70, 433. (c) Bastero, A.; Font, D.; Pericas, M. A.
J. Org. Chem. 2007, 72, 2460.
(5) (a) Sola, L.; Reddy, K. S.; Vidal-Ferran, A.; Moyano, A.; Pericas,
M. A.; Riera, A.; Alvarez-Larena, A.; Piniella, J. F. J. Org. Chem. 1998,
ꢀ
63, 7078. (b) Fontes, M.; Verdaguer, X.; Sola, L.; Pericas, M. A.; Riera,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
A. J. Org. Chem. 2004, 69, 2532.
(6) Font, D. Ph. D. Thesis, University of Barcelona, 2008.
(9) Chen, K.; Jeon, S. J.; Walsh, P. J.; Nugent, W. A. Org. Synth.
2005, 82, 87.
(10) Chang, C. S.; Lin, Y.; Shih, S.; Lee, C.; Lee, Y.; Tai, C.; Tseng,
ꢀ
(7) Reddy, K. S.; Sola, L.; Moyano, A.; Pericas, M. A.; Riera, A.
ꢀ
Synthesis 2000, 165.
(8) Nugent, W. A. Chem. Commun. 1999, 1369.
S.; Chern, J. J. Med. Chem. 2005, 48, 3522.
Org. Lett., Vol. 14, No. 7, 2012
1817

resins 5aÀb were used under the same experimental con-
ditions (entries 2, 4, and 6). The catalytic activity of resin 5a
was only marginally lower than that of 7, and full conver-
sion could be achieved with the resin in an even shorter
reaction time (4 h) by increasing the amount of resin
(entries 1, 2, and 4). For comparison, an immobilized
version of DAIB supported on PS through the amino
group required 73 h (5 mol % loading) for 91%
conversion.2a In the present instance, reactions could be
conveniently performed at room temperature with only a
minor erosion in ee (entries 3 and 5), and for higher
productivity, more densely loaded 5a worked as well as
5b (entries 2 and 6).
Table 3. Scope of Resin 5a
Table 2. Optimization of Reaction Conditions with Resins 5aÀb
Et2Zn
catalyst
t
conv
ee
entry catalyst [equiv] loading temp [h] [%]a [%]a
1
2
3
4
5
6
7
1.5
2
4%
0 °C
0 °C
rt
4.5
4
4b
4c
5.5
6
98
98
98
97
98
96
98
5a
5a
5a
5a
5b
10%
10%
5%
>99
>99
86
2
2
0 °C
rt
2
5%
98
2
10%
0 °C
98
a By GC on a β-DEX 120 column. b After 2.5 h, conversion was 90%.
c After 1 h, conversion was 55%.
The optimized conditions for the enantioselective addi-
tion of diethylzinc to benzaldehyde were next applied to a
representative family of aldehydes (Table 3).
We were pleased to observe that both conversion and
enantioselectivity were excellent with aromatic aldehydes
bearing both electron-donating and -withdrawing groups
(Table 3, entries 1À7) and irrespectively of congestion near
the carbonyl group (entries 1, 4, and 6). For R-unsubsti-
tuted aliphatic aldehydes (entries 8À9) as well as for R,β-
unsaturated aldehydes (entries 10À11) excellent results
were equally recorded. It is important to remark that, to
the best of our knowledge, 5 is the most enantioselective
polystyrene-supported ligand for the ethylation of alde-
hydes reported so far.2,4
Once the efficiency and applicability of 5 were demon-
strated, the possibility of recovery and reuse of the resin
was evaluated (Table 4). For practical reasons, intercycle
hydrolytic steps are best omitted, but contact of the
charged catalytic resin with air needs to be completely
avoided12 due to the high sensitivity to oxygen of the
nitrogen-chelated ethylzinc alkoxide.13 Under these
a By GC on a β-DEX 120 column.
conditions, we managed to run up to five cycles without
any decrease in either enantioselectivity or conversion.
With this key aspect affecting the stability of 5 ZnEt
3
properly clarified, we undertook its implementation in a
single-pass, continuous flow process for enantioselective
aldehyde ethylation. This ought to be possible in light of
the very high catalytic activity exhibited by PIB resins 5.
The employed experimental setup was prepared as in
previously described similar processes.3 To our delight,
direct translation of the reaction conditions used in batch
mode ([PhCHO]: 0.44 M in toluene; [ZnEt2]: 0.88 M in dry
toluene; reaction at 0 °C) with a loading of 0.5 g of 5a (f =
(11) Yield calculated as 100f/fmax. Details are given in refs 2e and 4c.
(12) See Supporting Information for practical details.
(13) Oxygen could give rise to the gradual decrease of catalytic
activity, probably by generation of an inactive zinc peroxide species.
See: Sosnovsky, G.; Brown, J. H. Chem. Rev. 1966, 66, 529.
0.78 mmol gÀ1) resulted in very high conversion at a
3
convenient (0.24 mL minÀ1) combined flow rate and
3
1818
Org. Lett., Vol. 14, No. 7, 2012

remarkably, there was no deterioration in enantioselectiv-
ity at all in the whole process.
Table 4. Recycling Experiments with Resin 5a
In one single continuous flow operation 13.0 g of
enantiopure alcohol were isolated, which represents a
TON of 251 (referred to the product) and a productivity
of 6.4 mmol hÀ1 gresinÀ1. The recorded TON represents a
3
3
10-fold increase with respect to the recycling tests and a 30-
fold increase compared to batch conditions. Noteworthy,
this new supported ligand not only extends the lifetime of
its predecessor 1a by 1 order of magnitude under contin-
uous flow conditions but also has a TON that is 8 times
higher. The residence time under these flow conditions was
6 min, in sharp contrast with the required time for full
conversion at the same temperature under batch condi-
tions (6 h).
run
conv (%)
yield (%)
ee (%)
1
2
3
4
5
>99
>99
>99
>99
98
88
92
92
90
91
98
98
98
98
98
In conclusion, a very robust polystyrene-supported ami-
no alcohol ligand for the highly enantioselective alkylation
of aldehydes with diethylzinc has been developed. A con-
tinuous flow alkylation reaction relying on this ligand has
been operated for over 30 h at consistently high conversion
and enantioselectivity. Understanding the nature of che-
mical processes leading to catalyst decomposition and
deactivation has allowed the implementation of corrective
actions and paves the way for the development of catalytic
systems susceptible to industrial application. In particular,
the preservation of enantioselectivity with time during flow
operation strongly indicates that the fragmentation of the
amino alcohol moiety has been efficiently suppressed.
Scheme 4. Continuous Flow Ethylation of Benzaldehyde
Acknowledgment. This work was funded by the MI-
CINN (Grant CTQ2008-00947/BQU), DIUE (Grant
2009SGR623), Consolider Ingenio 2010 (Grant CSD2006-
0003), and ICIQ Foundation. L.O.-P. thanks the MECD
for an FPU fellowship. The authors gratefully acknowledge
Xacobe C. Cambeiro (ICIQ) for advice and for help with
the setup of the continuous flow device.
Supporting Information Available. Detailed experimen-
1
tal procedures, characterization data, and copies of H
and 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
showed an excellent robustness of the resin, as illustrated in
Scheme 4. The system could be submitted to continuous
flow operationfor 30h, and itwas not untilafter 20h that a
small drop in conversion was observed. Even more
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
1819