A soluble-polymer system for the asymmetric transfer hydrogenation of ketones

Article abstract of DOI:10.1021/jo049479u

The appropriate combination of methacrylate polymers permits the synthesis of a soluble polymer for use in ruthenium(II)-catalyzed asymmetric transfer hydrogenation reactions. Using a 7:3 copolymer of a poly(ethylene glycol) ester and a hydroxyethyl ester, a derived ruthenium(II)/norephedrine complex catalyses reduction of acetophenone in up to 95% yield and 81% ee.

Full text of DOI:10.1021/jo049479u

A Solu ble-P olym er System for th e Asym m etr ic Tr a n sfer
Hyd r ogen a tion of Keton es
Stephanie Bastin,† Richard J . Eaves,† Christopher W. Edwards,† Osamu Ichihara,‡
Mark Whittaker,‡ and Martin Wills*,†
Department of Chemistry, University of Warwick, Coventry CV4 7AL, U.K., and EvotecOAI,
151 Milton Park, Abingdon, Oxon OX14 4SD, U.K.
m.wills@warwick.ac.uk
Received March 31, 2004
The appropriate combination of methacrylate polymers permits the synthesis of a soluble polymer
for use in ruthenium(II)-catalyzed asymmetric transfer hydrogenation reactions. Using a 7:3
copolymer of a poly(ethylene glycol) ester and a hydroxyethyl ester, a derived ruthenium(II)/
norephedrine complex catalyses reduction of acetophenone in up to 95% yield and 81% ee.
In tr od u ction
i.e., small by comparison with resin beads but large by
comparison with the attached catalyst. Such catalysts
have the advantage of total solubility and unhindered
active sites and may be analyzed without difficulty with
routine spectroscopic techniques. The removal of these
supported catalysts from the reaction mixture may be
achieved using membrane-separation methods9 or by
selective precipitation under specific conditions. Den-
drimer and soluble-polymer modifications have been
Recent years have seen significant advances in the
development of supported homogeneous catalysts for use
in asymmetric catalysis.1 These provide a significant
potential advantage by providing a means for the separa-
tion of the catalyst from the mixture after the reaction
is complete; the purification of the reaction product is
greatly facilitated, and the recovered catalyst may be
reused. Some supported systems depend on the use of
insoluble resin beads which may be removed from the
reaction by a simple filtration. Applications2-5 include
asymmetric epoxidation, the asymmetric catalysis of the
reduction of ketones with borane,2 dialkylzinc additions
to aldehydes,3 and asymmetric Diels-Alder reactions.4
A drawback of this approach, however, is that under
certain circumstances, i.e., if the bead is not compatible
with the required solvent, many of the potential active
catalyst sites may be inaccessible to the solution-borne
reagents.1 In addition, it may be difficult to assess the
level of catalyst loading on the polymer bead with
accuracy.
(6) (a) Wentworth, P., J r.; J anda, K. D. Chem. Commun. 1999,
1971-1924. (b) Hearshaw, M. A.; Moss, J . R. Chem. Commun. 1999,
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To circumvent these limitations, attention has recently
turned to the development of small soluble-polymer and
dendrimer supports.6-9 This class of supported system
is based on the use of a polymer or dendrimer with a
molecular weight typically in the order of 5-10 000 Da,
† University of Warwick.
‡ EvotecOAI.
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1217-1239. (d) Hodge, P. Chem. Soc. Rev. 1997, 26, 417-424. (e)
Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. Rev. 2003, 103, 3401-3430.
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R.; Chan, A. S. C. J . Org. Chem. 2000, 65, 295-296.
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10.1021/jo049479u CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/10/2004
J . Org. Chem. 2004, 69, 5405-5412
5405

Bastin et al.
SCHEME 1 a
a
Reagents and conditions: (a) 0.25 mol % [Ru(p-cymene)Cl2]2,
1 mol % ligand 1, 2.5 mol % KOH, i-PrOH; (b) 0.25 mol % [Ru(p-
cymene)Cl2]2, 0.5 mol % ligand 2, HCO2H/Et3N.
F IGURE 1. Copolymers of methacrylates.
made to catalysts for the addition of dialkylzinc reagents
to aldehydes7 and the Sharpless dihydroxylation.8
In previous work in our laboratories, we have inves-
tigated the ruthenium(II)- and rhodium(III)-catalyzed
asymmetric reduction of ketones to alcohols using trans-
fer hydrogenation.10-12 In our studies, we have focused
on the use of â-amino alcohols such as cis-aminoindanol
1 and monotosylated 1,2-diamines such as TsDPEN 2 as
ligands for this process (Scheme 1).10 Both of these ligand
systems were introduced by Noyori, who has also re-
ported extensively on the applications and mechanism
of the new catalysts.11 Amino alcohols afford the greatest
rate enhancements but are limited to the reduction of
CdO bonds, while the monotosylated diamines are more
versatile and may be used in the asymmetric reduction
of CdO and CdN bonds.
transfer catalyst CoBF 3.15 Since the reaction is highly
versatile, with a high degree of substrate-tolerance, it is
possible to employ it in copolymerization of two or more
monomers. In our work, we have examined the combina-
tion of two monomers to create such a copolymer, in
which one provides the required solubility properties and
the other provides a point of attachment for a catalyst
in the post-polymerization modification of the system.
The ratio of each monomer, and also the overall polymer
weight, may potentially be selectively modified for use
under any prescribed reaction solvent and conditions.
In our work on the asymmetric catalysis of diethylzinc
addition to aldehydes, for example, a soluble polymer 4
containing a combination of methacrylate and hydroxy-
ethyl methacrylate (7:3 ratio) provided the foundation for
a suitable support.13 This was elaborated to the ephe-
drine-functionalized derivative 5 using a Suzuki aryl-
aryl bond-forming reaction in a key step (Scheme 2).16-18
Since this work had been successful, we theorized that
the extension of this class of methacrylate copolymer to
asymmetric transfer hydrogenation reactions might pro-
vide a valuable tool for asymmetric catalysis. Previous
investigations into supported systems for this class of
reaction have led to the development of bead-based
systems containing TsDPEN-type ligands19 and several
classes of soluble polymer-supported variants.20 One of
these new systems was a polymer bead supported system
In a parallel research program, we have investigated
the potential of copolymers of methacrylates (Figure 1)
to operate as supporting systems for asymmetric
catalysis.9h,13,14 Such polymers are relatively simple to
prepare, in predictable molecular weights, using estab-
lished radical polymerization chemistry with the chain-
(12) (a) Nordin, S. J . M.; Roth, P.; Tarnai, T.; Alonso, D. A.; Brandt,
P.; Andersson, P. G. Chem. Eur. J . 2001, 7, 1431. (b) Everaere, K.;
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G.; Carpentier, J .-F. Eur. J . Org. Chem. 2001, 275. (c) Hennig, M.;
Puntener, K.; Scalone, M. Tetrahedron: Asymmetry 2000, 11, 1849.
(d) Blacker, A. J .; Mellor, B. J . (Avecia/Zeneca) WO 98/42643 A1, 1998.
(e) Mashima, K.; Abe, T.; Tani, K. Chem. Lett. 1998, 1199. (f) Mao, J .
M.; Baker, D. C. Org. Lett. 1999, 841. (g) Vedejs, E.; Trapencieris, P.;
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Nordin, S. J . M.; Andersson, P. G. J . Am. Chem. Soc. 1999, 121, 9580.
(13) Edwards, C. W.; Haddleton, D. M.; Morsley, D.; Shipton, M.
R.; Wills, M. Tetrahedron 2003, 59, 5823-5830.
(10) (a) Palmer, M. J .; Wills, M. Tetrahedron: Asymmetry 1999, 10,
2045. (b) Palmer, M.; Walsgrove, T.; Wills, M. J . Org. Chem. 1997, 62,
5226. (c) Wills, M.; Gamble, M.; Palmer, M.; Smith, A. R. C.; Studley,
J . R.; Kenny, J . A. J . Mol. Catal. A: Chem. 1999, 146, 139. (d) Kenny,
J . A.; Palmer, M. J .; Smith, A. R. C.; Walsgrove, T.; Wills, M. Synlett
1999, 1615. (e) Wills, M.; Palmer, M. J .; Smith, A. R. C.; Kenny, J . A.;
Walsgrove, T. Molecules 2000, 5, 1. (f) Kenny, J . A.; Versluis, K.; Heck,
A. J . R.; Walsgrove, T.; Wills, M. Chem. Commun. 2000, 99. (g)
Kawamoto, A. M.; Wills, M. Tetrahedron: Asymmetry 2000, 11, 3257.
(h) Kawamoto, A. M.; Wills, M. J . Chem. Soc., Perkin Trans. 1 2001,
1916. (i) Hannedouche, J .; Kenny, J . A.; Walsgrove, T.; Wills, M. Synlett
2002, 263-266. (j) Kenny, J . A.; Palmer, M. J .; Walsgrove, T.;
Kawamoto, A. M.; Wills, M. J . Chem. Soc., Perkin Trans. 1 2002, 416.
(k) Cross, D. J .; Kenny, J . A.; Houston, I.; Campbell, L.; Walsgrove,
T.; Wills, M. Tetrahedron: Asymmetry 2001, 12, 1801. (i) Alcock, N.
W.; Mann, I.; Peach, P.; Wills, M. Tetrahedron: Asymmetry 2002, 13,
2485. (j) Hannedouche, J .; Clarkson, G. J .; Wills, M. J . Am. Chem.
Soc. 2004, 126, 986-987.
(11) (a) Takehara, J .; Hashiguchi, S.; Fujii, A.; Inuoe, S.-I.; Ikariya,
T.; Noyori, R. Chem. Commun. 1996, 233. (b) Fujii, A.; Hashiguchi,
S.; Uematsu, N.; Ikariya, T.; Noyori, R. J . Am. Chem. Soc. 1996, 118,
2521. (c) Hashiguchi, S.; Fujii, A.; Takehara, J .; Ikariya, T.; Noyori,
R. J . Am. Chem. Soc. 1995, 117, 7562. (d) Haack, K.-J .; Hashiguchi,
S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997,
36, 285. (e) Murata, K.; Ikariya, T.; Noyori, R. J . Org. Chem. 1999, 64,
2186. Mechanism: (f) Yamakawa, M.; Yamada, I.; Noyori, R. Angew.
Chem., Int. Ed. Engl. 2001, 40, 2818. (g) Uematsu, N.; Fujii, A.;
Hashiguchi, S.; Ikariya, T.; Noyori, R. J . Am. Chem. Soc. 1996, 118,
4916. (h) Yamakawa, M.; Ito, H.; Noyori, R. J . Am. Chem. Soc. 2000,
122, 1466.
(14) (a) Hodge, P.; Monvisade, P.; Morris, G. A.; Preece, I. Chem.
Commun. 2001, 239-240. (b) Bergbreiter, D. E.; Osburn, P. L.; Wilson,
A.; Sink, E. M. J . Am. Chem. Soc. 2000, 122, 9058-9064. (c) Bergbre-
iter, D. E. Chem. Rev. 2002, 102, 3345-3383. (d) Osburn, P. L.;
Bergbreiter, D. E. Prog. Polym. Sci. 2001, 26, 2015-2081. (e) Berg-
breiter, D. E.; Liu, Y.-S. Tetrahedron Lett. 1997, 38, 7843-7846. (f)
Bergbreiter, D. E.; Liu, Y.-S. Tetrahedron Lett. 1997, 38, 3703-3706.
(15) (a) Haddleton, D. M.; Morsley, D. R.; O’Donnell, J . P.; Richards,
S. N. J . Polym. Sci., Part A: Polym. Chem. 1999, 37, 3549-3557. (b)
Bon, S. A. F.; Morsley, D. R.; Waterson, J .; Haddleton, D. M.; Lees, M.
R.; Horne, T. Macromol. Symp. 2001, 165, 29-41.
(16) Hassan, J .; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359-1469.
(17) Badone, D.; Barone, M.; Cardamone, R.; Ielmini, A.; Guzzi, U.
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3841-3844.
(19) (a) Bayston, D. J .; Travers, C. B.; Polywka, M. E. C. Tetrahe-
dron: Asymmetry 1998, 9, 2015-2018. (b) Sandee, A. J .; Petra, D. G.
I.; Reek, J . N. H.; Kamer, P. C. J .; van Leeuwen, P. W. N. M. Chem.
Eur. J . 2001, 7, 1202-1208. (c) ter Halle, R.; Schulz, E.; Lemaire, M.
Synlett 1997, 1257-1258.
5406 J . Org. Chem., Vol. 69, No. 16, 2004

Asymmetric Transfer Hydrogenation of Ketones
SCHEME 2 a
SCHEME 3 a
a
Reagents and conditions: (a) TBDMSCl, imidazole, THF,
reflux, o/n, 79%; (b) p-BrC6H4CH2Br, Et3N, THF, 63%; (c) 7,
Pd(dppf)Cl2‚DCM, THF, 3 equiv of KOAc, 1.1 equiv of bis (pina-
colato)diboron, 80 °C, 2 h; then 6, Na2CO3, Pd(dppf)Cl2, THF, 80
°C, o/n; (d) TBAF, THF, 4 h, rt.
a
Reagents and conditions: (a) cat. AIBN, sodium bis (2-
ethylhexyl)sulfosuccinate, 0.06 mol % CoBF, 4 h, rt.
developed at EvotecOAI.19a Other supported systems
feature a silica support for use in continuous reactions19b
and the direct incorporation of TsDPEN into a polysty-
rene polymer during the polymerization step.19c The
reported soluble polymers include a methacrylate/ethyl-
ene copolymer bearing a chiral amino acid,20a poly(acrylic
acid) supports,20b polyamide-linked DPEN derivatives,20c
and dendrimer-supported TsDPEN ligands.20e,f Many of
these have given excellent results in the ketone reduction
in terms of both conversion and enantioselectivity.
SCHEME 4 a
a
Reagents and conditions: (a) [Ru(p-cymene)Cl2]2 (0.4 equiv
with respect to amino alcohol), mol % catalyst indicated in Table
1, KOH (2.5 equiv with respect to Ru(II), i-PrOH.
TABLE 1. Asym m etr ic Red u ction of Acetop h en on e
Usin g (1S,2R)-Nor ep h ed r in e Liga n d on Solu ble P olym er
Su p p or ts
Resu lts a n d Discu ssion
entry
1
ligand
mol % time (h) cosolvent yield/% ee/%
Our starting point for this investigation was the
polymer that had been employed in our dialkylzinc
addition work, i.e., 4, which was derived from a 7:3
copolymer of methyl methacrylate and hydroxyethyl
methacrylate. Polymer 4 is soluble in a range of organic
solvents and may be conveniently analyzed using 1H
NMR spectrometry in order to verify both its molecular
weight and composition. Polymer 4 was first converted
via a tosylate derivative to the p-bromophenol derivative
6 following a procedure already reported by this group.13
Polymer 6 was then coupled to the TBDMS-protected
N-(p-bromobenzyl) derivative 7 of (1S,2R)-norephedrine
8 using an aryl-aryl coupling reaction17 which we had
previously developed in the group (Scheme 3). Treatment
of the resulting polymer 9 with TBAF resulted in depro-
tection to give 10 in 60% yield.
Norephedrine was selected as an appropriate amino
alcohol for this application because its secondary amine
derivatives have been demonstrated to be excellent
ligands for asymmetric transfer hydrogenation of ketones
when used in complexes with Ru(II).11,12 The modified
Suzuki reaction was based on a previously reported
procedure17 in which a boronic acid is first generated in
(1S,2R)-nor-
ephedrine
1
o/n
DCM
82
73
2
3
4
5
6
7
8
9
10
12
10
10
10
10
10
10
15
19
1
4
none
none
DCM
none
none
CHCl3
MeCN
DCM
none
70
9
20
13
11
7
14
44
52
82
77
77
51
73
71
8
0.71
0.44
0.44
1.42
1.42
0.88
0.56
2.62
o/n
o/n
o/n
o/n
o/n
o/n
o/n
o/n
81
81
situ and then coupled directly to an aryl bromide through
the use of essentially identical conditions but a stronger
base. To provide a nonpolymer-bound ligand for com-
parison, this reaction was also used for the coupling of 7
with 4-bromoanisole, resulting in successful formation of
11 in 76% yield, which was subsequently deprotected
with TBAF to give amino alcohol 12 in 54% yield.
(20) (a) Rolland, A.; Herault, F.; Touchard, F.; Saluzzu, C.; Duval,
R.; Lemaire, M. Tetrahedron: Asymmetry 2001, 12, 811-815. Saluzzo,
C.; Lamouille, T.; Herault, D.; Lemaire, M. Biorg. Med. Chem. Lett.
2002, 12, 1841-1844. (b) Gao, J .-X.; Yi, X. D.; Tang, C.-L.; Xu, P.-P.;
Wan, H.-L. Polym. Adv. Technol. 2001, 12, 716-719. (c) Gamez, P.;
Dunjic, B.; Fache, F.; Lemaire, M. Chem. Commun. 1994, 1417-1418.
(d) Breysse, E.; Pinel, C.; Lemaire, M. Tetrahedron: Asymmetry 1998,
9, 897-900. (e) Chen, Y.-C.; Wu, T.-F.; Deng, J .-G.; Liu, H.; J iang, Y.-
Z.; Choi, M. C. K.; Chan, A. S. C. Chem. Commun. 2001, 1488-1489.
Chen, Y.-C.; Wu, T.-F.; Deng, J .-G.; Liu, K.; Cui, H.; Zhu, J .; J iang,
Y.-Z.; Choi, M. C. K.; Chan, A. S. C. J . Org. Chem. 2002, 67, 5301-
5306.
With ligands 10 and 12 in hand, some asymmetric
transfer hydrogenations were investigated (Scheme 4,
Table 1) use acetophenone as the test substrate. Both
(1S,2R)-norephedrine and 12 gave good results (entries
1 and 2); however, the performance of polymer-bound
ligand 10 was restricted by the very poor solubility which
it exhibited in the reaction solvent, 2-propanol (Table 1,
entries 3-8). In the first reaction the yield of product,
J . Org. Chem, Vol. 69, No. 16, 2004 5407

Bastin et al.
SCHEME 5 a
TABLE 2. Use of Liga n d 19 in Tr a n sfer Hyd r ogen a tion
of Acetop h en on e
entry
catalyst (mol %)
time (h)
Yield/%
ee (%) (R/S)b
1
2
3
4
5
6
7
8
0.5a
0.5
1
2
2
2
2
2
o/n
o/n
o/n
1
2
4
16
30
46
26
50
66
75
85
80 (S)
77 (S)
79 (S)
79 (S)
79 (S)
81 (S)
81 (S)
81 (S)
6
20
a
1.7 equiv of ligand/Ru atom; ratio is 2.7 equiv of ligand/Ru
b
atom in other cases. ee’s were determined by chiral HPLC.
TABLE 3. Rep ea ted Red u ction of Acetop h en on e
Ca ta lyzed by 19/Ru (II)
a
Reagents and conditions: (a) cat. AIBN, 10 ppm CoBF, 48 h,
60 °C; (b) TsCl, Et3N, DCM, rt, 2 d, 45%; (c) TBDMS-(1S,2R)-
norephedrine, K2CO3, MeCN, reflux, 2 d, 62%; (d) TBAF, THF,
o/n, rt, 65%.
catalyst (mol %)
time (h)
conversion (%)
4
4
4
1
2
4
55
82
95
despite an extended reaction time, was only 9%, although
the ee was encouraging at 77% and in the direction
expected for this ligand (S). The use of a cosolvent and/
or sonication had no significant beneficial effect.
substrate reloadeda
4
4
4
1
2
4
58
74
85
substrate reloadeda
14
In view of this result, we sought alternative copolymers
which would exhibit improved solubility, yet retain the
catalytic properties of the ephedrine component. A poly-
(ethylene glycol) (PEG) chain seemed an attractive choice
because such groups have been employed in soluble
polymers for a number of asymmetric reactions.8 To
determine whether the PEG group would be compatible
with our solvent system, a reaction between tosylated
PEG5000 13 and TBDMS-protected (1S,2R)-norephe-
drine was completed in order to furnish 14, which was
then deprotected with TBAF to give 15. This compound
proved to be quite effective in ketone reduction (Scheme
4, Table 1, entry 9), and afforded a product of 81% e.e.
in 44% yield without the need for a cosolvent.
4
77
a
A quantity of substrate equal to that initially employed was
added at this point.
of supported catalyst. This was gratifying as we had been
anxious that the shorter separation of the ligand from
the backbone relative to earlier generations might reduce
its capacity to bind to the ruthenium. More encourag-
ingly, no cosolvent was required to maintain solubility,
suggesting that the short PEG chains provided the
required solubility for maximum reactivity. Further
studies revealed that the minimal catalyst loading for
the reaction was ca. 2 mol %, above; lower catalyst
loadings gave significantly lower conversions. A short
study of the extent of reaction with time was completed
(Table 2). This revealed that the reaction was some 75%
complete after 6 h when 2 mol % catalyst was used.
However, an overnight reaction period only raised this
to 85%, suggesting that a significant leveling-off of
conversion was taking place.
With the use of 4 mol % of ligand 19, the conversion
was raised sharply to 95% after 4 h. More interestingly,
the catalyst was still active; addition of a further quantity
of acetophenone (equal to the initial loading) revealed
that the catalyst continued to reduce the ketone (Table
3). This result suggests that the supported catalyst may
be compatible with membrane-separation systems in
which a reactor is repeatedly dosed with quantities of
substrates. There was, however, a deterioration of activ-
ity after the third addition of ketone substrate. This may
be a result of slow catalyst decomposition and will be
addressed in future studies of these reagents.
Finally, a short series of ketones was subjected to
asymmetric transfer hydrogenation using ligand 19, and
an interesting set of results was achieved (Figure 2). The
reduction of aryl/alkyl ketones gave consistently good
results, as would be expected from literature precedent.
In all cases, the ee values observed were similar to those
reported for the untethered reagents.
With this promising result in hand, we sought an
appropriate copolymer containing PEG groups for im-
proved solubility (Scheme 5). This was prepared from the
appropriate monomers HEMA and 16; we selected a PEG
monomer with a low molecular weight as we did not want
to increase the polymer bulk disproportionately relative
to the mass of the catalyst. The resulting copolymer 17
was tosylated without difficulty. Rather than employing
the palladium-catalyzed coupling route, however, we
instead carried out the direct reaction of TBDMS-
protected (1S,2R)-norephedrine with tosylated polymer
17 under the same conditions as employed for the
synthesis of 15. This proceeded well and delivered
product 18 in 62% yield, reducing the reaction sequence
by two steps. The subsequent desilylation completed the
synthesis of 19 in 65% yield.
In the first test as a ligand for transfer hydrogenation,
polymer 19 delivered a product of 81% ee in 52% isolated
yield (Table 1, entry 10) following an overnight reaction
time and represented the best result to date for this class
In the case of unsubstituted aromatic ketones, the
yields and ee’s were generally good; however, the intro-
5408 J . Org. Chem., Vol. 69, No. 16, 2004

Asymmetric Transfer Hydrogenation of Ketones
(1S,2R)-(+)-norephedrine 8 (4.0 g, 26.5 mmol) dissolved in THF
(20 mL). The white cloudy reaction mixture was heated at
reflux overnight. The resulting yellow reaction mixture was
allowed to cool before dilution with ethyl acetate (200 mL) and
washed with 1 M HCl solution (100 mL). The aqueous layer
was extracted using ethyl acetate (100 mL), and the combined
organic extracts were dried using magnesium sulfate, filtered,
and concentrated in vacuo to give the crude product as a yellow
oil. The crude product was purified using column chromatog-
raphy (SiO2, EtOAc/hexane gradient) to give the pure product
as a white solid (5.57 g, 79% yield): mp 218-220 °C; [R]22
)
D
+84.5 (c 1, CHCl3), lit21 [R]22 ) -44.1 (c 1, CHCl3, for 1R, 2S
D
isomer); IR (Nujol) 3240, 1581, 1499, 1377 cm-1; 1H NMR (250
MHz, CDCl3) δ 8.04 (br s, 2H), 7.38-7.25 (m, 5H), 5.01 (d, 1H,
J ) 3.7 Hz), 3.40 (qd, 1H, J ) 3.7, 6.7 Hz), 1.27 (d, 3H, J )
6.7 Hz), 0.95 (s, 9H), 0.22 (s, 3H); -0.21 (s, 3H); 13C NMR (75.5
MHz, CDCl3) δ 140.2, 128.6, 128.5, 127.1, 75.2, 54.2, 26.4, 18.5,
13.2, -4.5; MS (CI) m/z 266 (MH+); CI HRMS calcd for (C15H27
-
NOSi)+ 266.1940, found 266.1941.
(1S,2R)-2-(4-Br om oben zyla m in o)-1-p h en yl-1-[(ter t-bu -
tyld im eth ylsilyl)oxy]p r op a n e 7. Triethylamine (1.76 g, 2.42
mL, 18.5 mmol) was added to a solution consisting of (1S,2R)-
(+)-2-amino-1-[(tert-butyldimethylsilyl)oxy]propane, (4.63 g,
17.4 mmol) dissolved in THF (30 mL) and stirred for 30 min.
p-Bromobenzyl bromide (4.37 g, 17.5 mmol) was added to the
reaction mixture and heated at reflux overnight. The resulting
thick, white reaction mixture was allowed to cool before
dilution with EtOAc (200 mL). The reaction solution was then
washed with 1 M HCl solution (100 mL) and the sodium
hydrogen carbonate solution extracted with EtOAc (100 mL).
The combined organic extracts were dried using magnesium
sulfate, filtered, and concentrated in vacuo to give the crude
product as a yellow oil. The crude product was purified using
column chromatography to give the product 7 as a pale yellow
oil (4.81 g, 63% yield): [R]22D ) +26 (c 1, chloroform); IR (liquid
film) 3322, 2956, 2857, 2709, 2362, 1948, 1896, 1740, 1647,
1592, 1488, 1452, 1255, 1106, 1070 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.39 (d, 2H, J ) 8.5 Hz), 7.33-7.22 (m, 5H), 7.07 (d,
2H, J ) 8.5 Hz), 4.61 (d, 1H, J ) 5.0 Hz), 3.77 (d, 1H, J )
13.8 Hz), 3.64 (d, 1H, J ) 13.8 Hz), 2.73 (m, 1H), 1.40 (brs,
1H), 1.02 (d, 3H, J ) 6.0 Hz), 0.88 (s, 9H), 0.03 (s, 3H), -0.20
(s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 144.0, 138.5, 130.9,
129.9, 127.5, 127.3, 127.0, 120.1, 77.3, 59.7, 53.3, 25.6, 17.8,
9.0, -4.6; MS (CI) m/z 436 (MH+ Br81), 434 (MH+ Br79), 356
(MH+ - Br), 214, 212; CI HRMS calcd for (C22H32Br79NOSi)+
434.1515 found 434.1512.
F IGURE 2. 2. Alcohols formed by ketone reduction using19/
Ru(II).
duction of substitutents had a marked effect. p-Fluoro-
acetophenone, in particular, gave a product of very low
ee. In the last example, the introduction of a larger group
(than methyl) on the side of the ketone opposite the
aromatic ring also appears to reduce the enantioselec-
tivity. This is in agreement with literature precedent for
the reduction of such substrates using amino alcohol/Ru-
(II) systems10b and suggests that a steric effect is also
involved in the reduction process, in addition to the
known electronic effects.11f The slightly lower selectivity
observed for the ortho-substituted substrates also has
literature precedent.11a
Con clu sion
In conclusion, we have demonstrated that, through the
appropriate selection of monomers, methacryate copoly-
mers have the potential to act as competent soluble-
polymer supports for asymmetric catalysts. The polymers
may be prepared in large quantity through the use of
well-established radical polymerization chemistry with
the assistance of chain transfer catalysts and attached
to chiral ligands using routine organic transformations
and reagents. The materials may be conveniently ana-
lyzed using 1H NMR spectroscopy. More significantly, the
versatile and tolerant nature of the polymerization
methodology provides a means for the rapid preparation
and use of a “fine-tuned” reagent toward particular
applications through judicious selection of monomer
substitution. The polymer-supported reagents described
in this paper have the potential for use in a membrane-
separation reactor. This is currently the subject of
ongoing studies and our results will be reported in due
course.
(1S,2R)-2-(4′-An isylben zyla m in o)-1-p h en yl-1-[(ter t-bu -
tyld im eth ylsilyl)oxy]p r op a n e 11. (1S,2R)-2-(Bromobenzy-
lamino)-1-phenyl-1-[(tert-butyldimethylsilyl)oxy]propane, 7 (0.70
g, 1.61 mmol), was dissolved in THF (15 mL). To the stirred
solution was added dichloro[1,1-bisdiphenylphosphinoferrocene]-
palladium(II)‚DCM (0.04 g, 0.05 mmol), bis(pinacolato)diboron
(0.45 g, 1.77 mmol), and potassium acetate (0.47 g, 4.78 mmol).
The orange reaction mixture was heated at 80 °C for 2 h. The
resulting black reaction mixture was allowed to cool before the
addition of bromoanisole (0.6 g, 0.4 mL, 3.22 mmol), dichloro-
[1,1-bisdiphenylphosphinoferrocene]palladium(II)‚DCM (0.04
g, 0.05 mmol), and sodium carbonate (2 M, 4 mL). The reaction
mixture was then reheated at 80 °C overnight. The black
reaction mixture was allowed to cool before the product was
extracted with ethyl acetate (150 mL). The organic layer was
then washed with water (100 mL) and a brine solution (100
mL). The organic layer was dried using magnesium sulfate,
filtered, and concentrated in vacuo to give the crude product
as a yellow oil. This was purified by column chromatography
(SiO2, EtOAc/hexane gradient) to give the pure product, 11,
as a pale yellow oil (0.56 g, 76% yield): [R]22 ) +24 (c ) 1,
Exp er im en ta l Section
D
chloroform); IR (Nujol) 3300, 3028, 1883, 1646, 1610, 1583,
For general experimental details, see the Supporting Infor-
mation.
1526, 1500, 1291, 1181 cm-1; 1H NMR(300 MHz, CDCl3) δ 7.51
(1S,2R)-(+)-2-Am in o-1-[(ter t-b u t yld im et h ylsilyl)oxy]-
p r op a n e. tert-Butyldimethylsilyl chloride (4.79 g, 31.8 mmol)
and imidazole (4.51 g, 66.3 mmol) were added to a solution of
(21) Brussee, J .; van Benthem, R. A. T. M.; Kruse, C. G.; Gen, A.
Tetrahedron: Asymmetry 1990, 1, 163-166.
J . Org. Chem, Vol. 69, No. 16, 2004 5409

Bastin et al.
(d, 2H J ) 8.4 Hz), 7.46 (d, 2H J ) 8.1 Hz), 7.31-7.22 (m,
7H), 6.96 (d, 2H, J ) 8.8 Hz), 4.65 (d, 1H, J ) 5.0 Hz), 3.85 (d,
1H, J ) 13.5 Hz), 3.84 (s, 3H), 3.72 (d, 1H, J ) 13.5 Hz), 2.82
(m, 1H), 1.53 (brs, 1H), 1.06 (d, 3H, J ) 6.2 Hz), 0.89 (s, 9H),
0.07 (s, 3H), -0.19 (s, 3H); 13C NMR(75.5 MHz, CDCl3) δ 159.0,
142.9, 139.2, 139.1, 133.6, 128.2, 128.0, 127.9, 127.2, 126.9,
126.6, 114.2, 77.8, 58.7, 55.3, 50.7, 25.9, 18.2, 15.4, -4.5, -4.1;
1.80 (brm), 1.05-0.70 (brm); 13C (75.5 MHz, CDCl3) δ 177.8,
176.9, 145.1, 132.8, 130.0, 127.9, 67.2, 66.8, 62.2, 62.0, 54.2,
51.8, 44.9, 44.5, 21.7, 18.7, 16.7; m/z (GPC) Mn ) 4116, Pdi )
1.56; Tg Tg ) 51 °C (inflection point), 40 °C (Onset), heated
from 0 to 160 °C at 20 °C/min.
Br om op h en yl-Der iva tized HEMA/MMA Solu ble Co-
p olym er 6. Sodium hydride (0.45 g, 18.79 mmol) was added
to THF (30 mL) and allowed to stir for 20 min before the
addition of bromophenol (1.63 g, 9.39 mmol). Tosylated HEMA/
MMA tosylated copolymer (1.60 g, 0.40 mmol) was added to
the reaction mixture, and the mixture was allowed to reflux
for 48 h. The reaction mixture was allowed to cool before being
filtered through a sinter funnel and the filtrate concentrated
in vacuo to give a pale brown solid. The pale brown solid was
redissolved in EtOAc (100 mL) and washed with water (100
mL). The organic layer was dried using magnesium sulfate
and concentrated in vacuo to give the crude product as a brown
solid. This was triturated using diethyl ether (60 mL) to give
the product 6 as a pale brown solid (0.95 g, 60% yield): IR
(Nujol) 2400-1800, 1729, 1591, 1489, 1273, 1245, 1150, 1066,
m/z 462 (MH+), 266, 240, 197, 134; CI HRMS calcd for C29H39
-
NO2Si 462.2828, found 462.2826.
(1S ,2R )-2-(4′-An is y lb e n zy la m in o )-1-p h e n y l-1-p r o -
p a n ol 12. TBAF (0.51 g, 1.95 mmol) was added to a solution
consisting of (1S,2R)-2-(bromobenzylamino)-1-phenyl-[(tert-
butyldimethylsilyl)oxy]propane 11 (0.25 g, 0.54 mmol) dis-
solved in THF (10 mL). The reaction mixture was allowed to
stir at room temperature overnight. The yellow reaction
mixture was diluted with EtOAc (150 mL) and washed with
water (200 mL). The water layer was extracted using EtOAc
(100 mL), and the combined organic extracts were dried using
magnesium sulfate, filtered, and concentrated in vacuo to give
the crude product as a green oil. The crude product was
purified by column chromatography (SiO2, EtOAc/hexane
gradient) to give the pure product 12 as a white solid (0.10 g,
1
824 cm-1; H (250 MHz, CDCl3) δ 7.40-7.30 (m), 6.90-6.80
(m), 4.35-4.25 (m), 4.25-4.10 (brm), 3.60 (brs), 2.05-1.80
(brm), 1.10-1.00 (brm), 1.00-0.80 (brm); 13C (75.5 MHz,
CDCl3) δ 177.7, 176.8, 176.4, 157.4, 132.2, 117.2, 116.3, 113.2,
65.6, 65.4, 63.1, 54.3, 51.7, 44.8, 44.4, 18.6, 16.3; m/z (GPC)
refractive index detector Mn ) 5192, Pdi ) 1.36; UV detector
Mn ) 4205, Pdi ) 1.48; Tg ) 76 °C (inflection point), 63 °C
(onset), heated from 0 °C to 160 °C at 20 °C/min.
54% yield): mp 110-112 °C; [R]22 ) +32 (c ) 1, chloroform);
D
IR (Nujol) 3373, 3312, 1887, 1737, 1604, 1463, 1377 cm-1; H
1
NMR(300 MHz, CDCl3) δ 7.54-7.50 (m, 4H), 7.39-7.22 (m,
7H), 6.98 (d, 2H, J ) 8.8 Hz), 4.83 (d, 1H, J ) 3.8 Hz), 3.92 (s,
2H), 3.85 (s, 3H), 3.03 (qd, 1H, J ) 6.6, 3.8 Hz), 2.67 (brs, 2H),
0.88 (d, 3H, J ) 6.6 Hz); 13C NMR(75.5 MHz, CDCl3) δ 159.1,
141.2, 139.8, 138.8, 138.1, 133.3, 128.5, 128.1, 128.0, 127.0,
126.8, 126.0, 114.2, 73.0, 57.7, 55.3, 50.8, 14.5; CI m/z 348,
Su zu k i Cou p lin g betw een Br om op h en yl-Der iva tized
H E MA/MMA 6 a n d (1S,2R)-2-(Br om ob en zyla m in o)-1-
p h en yl-[(ter t-bu tyld im eth ylsilyl)oxy]p r op a n e 7 To Give
P olym er 9. (1S,2R)-2-(Bromobenzylamino)-1-phenyl-[(tert-
butyldimethylsilyl)oxy]propane (0.25 g, 0.57 mmol), 7, and
dichloro[1,1-bis diphenylphosphinoferrocene]palladium(II)‚
DCM (0.012 g, 0.015 mmol) were dissolved in THF (10 mL).
Potassium acetate (0.17 g, 1.72 mmol) and bis(pinacolato)-
diboron (0.16 g, 0.63 mmol) were added to the reaction mixture
and heated at 80 °C for 2 h. The black reaction mixture was
allowed to cool before the addition of bromo-derivatized HEMA/
MMA copolymer 7 (0.13 g), sodium carbonate solution (2 M,
1.44 mL), and dichloro[1,1-bisdiphenylphosphinoferrocene]-
palladium(II)‚DCM (0.012 g, 0.017 mmol). The reaction mix-
ture was then heated at 80 °C overnight. The black reaction
mixture was allowed to cool before being concentrated in vacuo
to give the crude product as a black/gray solid. This was
redissolved in EtOAc (200 mL) and washed with water (100
mL). The organic layer was dried using magnesium sulfate,
filtered, and concentrated in vacuo to give the crude product
as a black oil. Methanol (2 × 50 mL) was added to the crude
product and stirred vigorously. The methanol extract was then
carefully removed to leave the purified product, 9, as a black
solid (0.11 g): IR (solid state) 2952, 1725, 1607, 1498, 1448,
330, 240, 197; CI HRMS calcd for
348.1964, found 348.1960.
C23H26NO2 (M + H)
In itia l HEMA/MMA (3:7 Ra tio) Solu ble Cop olym er 4.
Sodium bis(2-ethylhexyl) sulfosuccinate (2.0 g) was added to
a 1 L flange flask glass reactor under a nitrogen atmosphere.
Water (450 mL) was added to the reactor, and the mixture
was heated to 80 °C and stirred using a turbine impeller at
150 rpm 4,4′-Azobis(4-cyanovaleric acid) (2.0 g) was added to
the reaction mixture immediately prior to the monomer/
catalyst feed. A solution of catalytic chain transfer agent
(CoBF) (0.024 g) in MMA (135 mL) and HEMA (65 mL) was
fed from a Schlenk tube via a FMI pump set at a rate of 3.33
mL min-1. The polymerization was left for 4 h, at which time
100% conversion was reached. The solvent was removed from
the polymer using an oven set at 150 °C to give the polymer,
4, as a yellow solid which when ground appeared as a white
powder (70.0 g): IR (Nujol) 3434, 1727, 1277, 1152, 1075 cm-1
;
1H (250 MHz, CDCl3) δ 6.30-6.20 (m), 5.60-5.50 (m), 4.20-
4.05 (m), 3.90-3.80 (m), 3.60 (brs), 2.10-1.80 (brm), 1.20-
0.80 (brm); 13C (75.5 MHz, CDCl3) δ 178.0, 176.8, 66.7, 60.2,
54.2, 51.7, 44.7, 44.4, 18.4, 16.5; m/z (GPC) Mn ) 2940, Pdi )
1.78; Tg ) 59 °C (Inflection point), 49 °C (Onset), heated from
0 to 160 °C at 20 °C/min.
1
1387, 1244, 1145, 1062; H NMR (300 MHz, CDCl3) δ 7.50-
6.80 (brm), 4.65-4.60 (m), 4.35-4.10 (brm), 3.55 (brs), 2.85-
2.80 (m), 2.05-1.80 (brm), 1.20-0.90 (brm), 1.00 (brs), 0.04
(brs), -0.20 (brs); 13C NMR (75.5 MHz, CDCl3) δ 178.0, 176.9,
176.1, 132.3, 134.1, 129.1, 128.2, 127.9, 127.2, 126.8, 126.6,
116.4-114.8, 113.2, 65.2, 63.2, 54.3, 51.8, 44.8, 44.5, 25.8, 24.8,
18.7, 18.1, 16.4, 15.2, -4.6, -5.0; GPC refractive index detector
Mn ) 5516, Pdi ) 2.23, UV detector Mn ) 3983, Pdi ) 2.50; Tg
onset 93 °C, inflection point 123 °C.
Rem ova l of th e TBDMS Gr ou p fr om th e HEMA/MMA-
Su p p or ted Ch ir a l Nor ep h ed r in e Der iva tive 9 To Give
10. The HEMA/MMA-supported TBDMS protected chiral
norephedrine derivative, 9 (0.26 g), was dissolved in THF (10
mL) before the addition of tetrabutylammonium fluoride (0.31
g, 1.19 mmol). The reaction mixture was allowed to stir for 4
h at room temperature. The black reaction mixture was
concentrated in vacuo to give the crude product as a black
solid. The crude product was redissolved in EtOAc (150 mL)
and washed with water (100 mL). The organic layer was dried
using magnesium sulfate, filtered, and concentrated in vacuo
Tosyla ted HEMA/MMA (3:7 Ra tio) Solu ble Cop olym er .
Triethylamine (4.85 g, 6.74 mL, 48 mmol) was added to HEMA/
MMA copolymer, 4 (10.0 g, 3.4 mmol), which was dissolved in
DCM (70 mL). Tosyl chloride (9.17 g, 48 mmol) and DMAP
(0.50 g, catalytic) were added to the reaction mixture, and the
reaction was allowed to stir for 2 days. The orange/red solution
was concentrated in vacuo to give a yellow solid. The yellow
solid was transferred to a sinter funnel and washed with
diethyl ether (200 mL) and hexane (100 mL). The pale yellow
solid was redissolved in DCM (100 mL) and washed with water
(300 mL), dried using magnesium sulfate, and concentrated
in vacuo to give a pale yellow solid. This was ground using a
pestle/mortar, transferred to a sinter funnel, and washed
further with diethyl ether (200 mL), methanol (200 mL), and
hexane (100 mL) to give the product as a white powder (10.60
g, 78% yield): IR (Nujol) 1730, 1598, 1275, 1244, 1177, 1150,
1
923, 815 and 748 cm-1; H NMR (250 MHz, CDCl3) δ 7.85-
7.80 (m), 7.39 (brd, J ) 14.0 Hz), 6.25-6.20 (m), 5.55-5.50
(m), 4.30-4.20 (m), 4.20-4.10 (m), 3.60 (brs), 2.47 (brs), 2.05-
5410 J . Org. Chem., Vol. 69, No. 16, 2004

Asymmetric Transfer Hydrogenation of Ketones
to give the crude product as a black solid. Methanol (2 × 50
mL) was added to the crude product and vigorously stirred.
The methanol extract was then carefully removed from the
sample to leave the pure product, 10, as a black solid (0.17 g):
IR 3100, 2949, 1723, 1598, 1592, 1489, 1436, 1387, 1240, 1146,
1067; 1H NMR (300 MHz, CDCl3) δ 7.40-7.25 (m), 6.90-6.80
(m), 5.30-5.25 (m), 4.35-4.25 (brm), 4.25-4.05 (brm), 3.70-
3.50 (brs), 2.10-1.60 (brm), 1.40-0.85 (m); 13C NMR (75.5
MHz, CDCl3) δ 176.9, 176.5, 175.9, 164.6, 157.4, 156.8, 156.5,
131.3, 127.3, 127.0, 126.8, 115.4, 114.0, 113.9, 112.3, 72.1, 64.5,
62.2, 60.8, 53.5, 53.3, 50.1, 43.8, 43.5, 29.3, 28.7, 17.8, 16.7,
15.5, 13.1; GPC refractive index detector Mn ) 4335, PDi )
1.94, UV detector Mn ) 3270, PDi ) 1.96; Tg Onset 82 °C,
inflection point 96 °C.
16 (20.0 g, 18.6 mL, 40.7 mmol) were purged with N2 while
keeping the mixture at 0 °C. In a predried Schlenk tube was
weighed COBF (0.004 g, 0.009 mmol) and placed under
vacuum for 30 min before being dissolved in butanone (10 mL).
This Schlenk tube was then immersed in liquid nitrogen until
the solution had become a solid. The Schlenk tube was then
placed under vacuum and carefully immersed in a beaker
containing cold water ensuring that the total solid volume was
immersed in the water. The Schlenk tube was kept under
vacuum until the solution had just become liquid again and
then placed under nitrogen. This freeze/thaw process was
repeated three times to give the stock solution of COBF. COBF
stock solution (1 mL) was removed and further diluted with 9
mL of butanone (0.09 M). This was degassed using the same
freeze/thaw process a total of three times. Various volumes of
the diluted COBF solution were then used in the copolymer-
ization. The reaction mixture was then cooled to 0 °C for 30
min and diluted with butanone (10 mL). COBF solution (2.5
mL, 0.22 mmol) was added to the reaction mixture and allowed
to cool to 0 °C for 30 min. AIBN (0.048 g, 0.30 mmol) was then
added to the cooled reaction mixture. The reaction mixture
was then heated at 60 °C for 2 days. The reaction mixture
was cooled before removal of the solvent in vacuo to give the
crude product as an oil. The crude product was dissolved in
MeOH (50 mL) and precipitated out of solution using diethyl
ether (150 mL) to give a polymer layer at the base; the top
liquid layer was carefully removed. This process was repeated
to give the pure product (after drying), 17, as a white semisolid
(3.99 g): IR (solid state) 3473, 2929, 2868, 1722, 1485, 1449,
1386, 1350, 1273, 1245, 1105 cm-1; 1H NMR (300 MHz, CDCl3)
δ 6.25-6.20 (m), 5.55-5.50 (m), 4.15-4.05 (m), 3.85-3.80 (m),
3.75-3.60 (m), 3.55 (q, J ) 7.0 Hz), 1.95-1.80 (m), 1.19 (t, J
) 7.0 Hz), 1.10-1.00 (brm), 1.00-0.90 (brm); 13C NMR (75.5
MHz, CDCl3) δ 177.6, 176.7, 70.5, 70.4, 69.6, 68.4, 66.5, 63.9,
59.9, 54.2, 44.9, 44.6, 19.0, 16.8, 10.0; GPC Mn ) 4473, PDi )
1.59, Tg onset 61 °C.
Tosyla ted MeO-P EG5000 13. Poly(ethylene glycol) (PEG)
methyl ester 5000 (10.0 g, 2.0 mmol) was dissolved in DCM
(anhydrous, 40 mL) before the addition of tosyl chloride (0.76
g, 4.0 mmol) and triethylamine (0.49 g, 0.68 mL, 5.2 mmol).
DMAP (0.10 g, 0.82 mmol) was added to the reaction mixture
and stirred overnight. The reaction mixture was concentrated
in vacuo to give the crude product as a white solid. The crude
product was washed with MeOH (200 mL), which was then
carefully removed to give the pure product, 13, as a white solid
(9.27 g): IR (solid state) 2876, 1963, 1466, 1341, 1279, 1240,
1
1176, 1146, 1097 cm-1; H NMR (300 MHz, CDCl3) δ 7.80 (d,
2H, J ) 8.5 Hz), 7.35 (d, 2H, J ) 8.5 Hz), 4.17-4.14 (2H, m),
3.65-3.60 (m, satellite), 3.63-3.53 (brs, ca. 450H), 3.40-3.35
(m, satellite), 2.45 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 145.1,
130.2, 128.4, 92.4, 72.3, 71.5, 70.8, 69.6, 69.0, 59.4, 22.0; GPC
Mn ) 7319, PDi ) 1.05.
TBDMS-P r ot ect ed Nor ep h ed r in e MeOP E G5000 14.
TBDMS-protected (1S,2R)-(+)-norephedrine (0.21 g, 0.79 mmol)
was dissolved in MeCN (40 mL, distilled) before the addition
of tosylated MeO-PEG5000, 13 (2.0 g, ca. 0.4 mmol), and
potassium carbonate (0.12 g, 0.88 mmol). The reaction mixture
was heated at reflux for 2 days. After 2 days of reflux, the
reaction mixture was allowed to cool before dilution with
EtOAc (150 mL). The reaction mixture was then filtered to
remove the insoluble material. The reaction mixture was
concentrated in vacuo to give the crude product as an oil. The
crude product was washed with diethyl ether (250 mL) and
the diethyl ether removed carefully. The crude product was
dissolved in DCM (60 mL) and precipitated using diethyl ether
(100 mL) to give the product, 14, as a white solid (1.96 g): IR
(solid state) 2877, 1466, 1341, 1359, 1279, 1241, 1146, 1094,
Syn th esis of Tosyla ted P EG Eth yl Ester /HEMA Co-
p olym er . PEG ethyl ester MMA/HEMA copolymer, 17, (3.92
g) was dissolved in DCM (anhydrous, 30 mL) before the
addition of triethylamine (2.09 g, 2.9 mL, 20.68 mmol). Tosyl
chloride (3.95 g, 20.7 mmol) and DMAP (0.2 g, 1.6 mmol) were
added to the reaction mixture and stirred at room temperature
for 2 days. The orange/red solution was concentrated in vacuo
to give a yellow solid. The yellow solid was transferred to a
sinter funnel and washed with diethyl ether. The pale yellow
solid was redissolved in DCM (200 mL) and washed with water
(100 mL), dried using magnesium sulfate, and concentrated
in vacuo to give a pale yellow solid. This was ground using a
pestle/mortar, transferred to a sinter funnel, and washed
further with diethyl ether (200 mL) to give the product as a
pale yellow semisolid (2.21 g): IR (solid state) 2971, 2867,
1725, 1647, 1597, 1448, 1357, 1271, 1149 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.80-7.70 (m), 7.40-7.30 (m), 6.25-6.20 (weak
m), 5.35-5.30 (weak m), 4.25-4.15 (m), 4.15-4.05 (m), 3.70-
3.50 (brm), 3.45 (q, J ) 7.0 Hz), 2.45 (brs), 1.22 (t, J ) 7.0
Hz), 1.10-1.00 (brm), 1.00-0.85 (brm); 13C NMR (75.5 MHz,
CDCl3) δ 177.2, 176.0, 145.0, 132.6, 130.3, 128.2, 70.6, 70.5,
69.7, 68.4, 66.5, 63.9, 62.2, 54.2, 45.0, 44.6, 21.7, 18.5, 16.6;
used directly in next step.
1
1059 cm-1; H NMR (300 MHz, CDCl3) δ 7.67-7.60 (m, 3H),
7.33-7.09 (m, 2H), 4.89 (m, 1H), 4.60 (m, 2H), 4.10-3.55 (brm,
ca. 450H), 2.75-2.70 (m, 1H), 2.60 (brs, 2H), 1.01 (brd, 3H, J
) 6.0 Hz), 0.91 (brs, 9H), 0.04 (brs, 3H), -0.20 (brs, 3H); 13C
NMR (75.5 MHz, CDCl3) δ 127.7, 126.6, 125.9, 91.8, 71.7, 70.9,
70.6, 65.6, 58.8, 48.9, 42.5, 25.7, 15.1, 0.8, -3.9, -4.7; GPC
Mn ) 7366, PDi ) 1.062.
Nor ep h ed r in e-F u n ct ion a lized
MeO-P E G5000 15.
TBDMS (1S,2R)-(+)-norephedrine-functionalized PEG poly-
mer, 14 (0.7 g), was dissolved in THF (20 mL) before the
addition of TBAF (0.7 g, 2.22 mmol). The reaction mixture was
stirred at room temperature overnight. The reaction mixture
was concentrated in vacuo before being redissolved in MeOH
(50 mL) and precipitated out of solution using diethyl ether
(100 mL). The crude product was redissolved in DCM (250 mL)
and washed with brine solution (70 mL). The organic layer
was dried using MgSO4, filtered, and concentrated in vacuo
to give the pure product, 15, as a white solid (0.56 g): IR (solid
Rea ction betw een TBDMS-P r otected Nor ep h ed r in e
a n d Tosyla ted P EG/HEMA Cop olym er . Tosylated PEG
ethyl ester/HEMA copolymer (7.35 g) was placed under
vacuum for 30 min before being dissolved in MeCN (70 mL,
distilled and stored over molecular sieves). (1S,2R)-(+)-2-
Amino-1-[(tert-butyldimethylsilyl)oxy]propane (6.36 g, 23.9
mmol) and potassium carbonate (4.27 g, 30.89 mmol) were
added to the reaction vessel and heated at reflux for 2 days.
After 2 days of reflux, the cloudy reaction mixture was allowed
to cool before being diluted with EtOAc (150 mL). The reaction
mixture was filtered to remove insoluble material and washed
with water (3 × 50 mL). The organic layer was dried over
MgSO4 and the solvent removed in vacuo to give the crude
state) 2877, 1466, 1455, 1341, 1278, 1240, 1146, 1094 cm-1
;
1H NMR (250 MHz, CDCl3) δ 7.35-7.30 (brm, 5H), 4.78 (d,
1H J ) 4.0 Hz), 4.00-3.95 (m, 2H), 3.65-3.55 (brm, ca. 350h),
2.95-2.90 (m, 1H), 2.33 (brs, 2H), 0.81 (d, 3H, J ) 6.0 Hz);
13C NMR (75.5 MHz, CDCl3) δ 128.3, 127.3, 126.3, 72.2-63.5,
59.3, 49.4, 21.6; GPC Mn ) 4476, PDi ) 1.36.
Syn th esis of Eth yl P EG Ester Meth a cr yla te/HEMA
Cop olym er (7:3 Ra tio) 17. 2-Hydroxyethyl methacrylate
(2.26 g, 1.56 mL, 17.4 mmol) and PEG ethyl ether methacrylate
J . Org. Chem, Vol. 69, No. 16, 2004 5411

Bastin et al.
product as a pale yellow oil. The crude product was dissolved
in a minimum amount of diethyl ether and precipitated with
hexane to give the product 18 as an oil (5.1 g, 62% yield): IR
(S)-1-(1′-Na p h t h yl)et h a n ol:10a 51% ee (S) by HPLC
(Chiracel OD, ethanol:hexane ) 5:95 (1 mL/min), S isomer 14.1
min, R isomer 21.9 min; 100% yield; 1H NMR (300 MHz,
CDCl3) 8.16-8.09 (m, 1H), 7.91-7.84 (m, 1H), 7.80-7.77 (d,
1H, J ) 8.14 Hz), 7.70-7.67 (d, 1H, J ) 7.3 Hz), 7.56-7.45
(m, 3H), 5.68 (q, 1H, J ) 6.4 Hz), 1.91 (br s, 1H), 1.68 (d, 3H,
J ) 6.4 Hz).
3601, 2929, 2859, 2359, 2342, 1725, 1456, 1248 and 1107 cm-1
1H NMR (300 MHz, CDCl3) 7.30-7.20 (m), 4.55-4.50 (m),
4.25-4.15 (m), 4.15-4.05 (m), 3.70-3.60 (brm), 3.55 (q, J )
7.0 Hz), 2.80-2.70 (m), 1.95-1.75 (brm), 1.21 (t, J ) 7.0 Hz),
1.10-1.00 (m), 1.00-0.85 (brm), 0.95 (brs), 0.05 (brs), -0.20
(brs); 13C (75.5 MHz, CDCl3) 128.5, 127.5, 71.1, 71.0, 70.2, 67.0,
59.1, 56.8, 56.1, 55.9, 55.7, 45.1, 45.0, 44.7, 44.6, 26.3, 15.6,
-4.1, -6.2; GPC Mn ) 7500, PDi ) 1.93, Tg onset 130 °C.
Rem ova l of th e TBDMS Gr ou p fr om th e P EG/HEMA-
Su ppor ted TBDMS-P r otected Nor eph edr in e 18. The PEG/
HEMA-supported TBDMS-protected chiral norephedrine de-
rivative 18 (4.95 g) was dissolved in THF (70 mL) before the
addition of tetrabutylammonium fluoride (3.0 g). The reaction
mixture was allowed to stir overnight at room temperature.
The reaction mixture was concentrated in vacuo to give the
crude product as an oil. The crude product was redissolved in
EtOAc (150 mL) and washed with water (2 × 100 mL). The
organic layer was dried over magnesium sulfate, filtered, and
concentrated in vacuo to give the crude product 19 as a yellow
oil (2.82 g, 65% yield): IR 3424, 2973, 2868, 1724, 1449, 1244,
1103 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.35-7.25 (m), 6.25-
6.20 (weak m), 5.55-5.50 (weak m), 4.85-4.80 (m), 4.15-4.00
(brm), 3.70-3.50 (brm), 3.55 (q, J ) 7 Hz), 2.95-2.90 (m),
2.00-1.80 (brm), 1.18 (brt, J ) 7 Hz), 1.15-1.00 (m), 1.00-
0.85 (m); 13C NMR (75.5 MHz, CDCl3) δ 177.5, 176.5, 128.5,
128.0, 127.9, 127.0, 126.1, 70.5, 70.5, 70.3, 69.7, 68.3, 66.4, 63.8,
53.6, 44.5, 18.5, 15.0, 14.0; GPC Mn ) 5262, DPi ) 1.66, Tg
onset 103 °C.
;
(S)-1-P h en ylp r op a n ol:10a 74% ee (S) by HPLC (Chiracel
OD, ethanol/hexane ) 5:95 (1 mL/min), S isomer 9.3 min, R
1
isomer 8.2 min; 91% yield; H NMR (300 MHz, CDCl3) 7.36-
7.23 (m, 5H), 4.60 (t, 1H, J ) 6.6 Hz), 1.91-1.69 (m, 2H), 1.88
(br s, 1H), 0.92 (t, 3H, J ) 7.5 Hz).
(S)-1-Tetr a lol:10a 87% ee (S) by HPLC (Chiracel OD,
ethanol/hexane ) 3:97 (1 mL/min), S isomer 8.9 min, R isomer
9.6 min; 57% yield; 1H NMR(300 MHz, CDCl3) 7.46-7.41 (m,
1H), 7.23-7.17 (m, 2H), 7.12-7.09 (m, 1H), 4.79 (br s, 1H),
2.87-2.69 (m, 2H), 1.99-1.60 (m, 5H).
(S)-1-(4-Nitr op h en yl)eth a n ol:22 60% ee (S) by GC (oven
170 °C), (R) isomer 18.06 min, (S) isomer 18.75 min; 78% yield;
1H (400 MHz, CDCl3) 8.20 (dd, 2H, J ) 9, 2 Hz), 7.55 (dd, 2H,
J ) 9, 2 Hz), 5.03 (quartet, 1H, J ) 7 Hz), 2.02 (brs, 1H), 1.53
(dd, 3H, J ) 7, 2 Hz).
4-((S)-1-Hyd r oxyeth yl)ben zon itr ile:11b 61% ee (S) by GC
(oven 160 °C) (R) isomer 16.70 min, (S) isomer 17.64 min; 76%
1
yield; H (400 MHz, CDCl3) 7.64 (d, 2H, J ) 9 Hz), 7.49 (d,
2H, J ) 9 Hz), 4.96 (quartet, 1H, J ) 6 Hz), 1.94 (brm, 1H),
1.50 (dd, 3H, J ) 6, 2 Hz).
(S)-1-(2-Ch lor op h en yl)eth a n ol:23 68% ee (S) by GC (oven
140 °C) (R) isomer 8.71 min, (S) isomer 9.74 min; 99% yield;
1H (400 MHz, CDCl3) 7.59 (dd, 1H, J ) 8, 2 Hz), 7.32-7.28
(m, 2H), 7.22 (dd, 1H, J ) 8, 2 Hz), 5.29 (dq, 1H, J ) 6.5, 3.8
Hz), 1.99 (d, 1H, J ) 3.8 Hz), 1.49 (d, 3H, J ) 6.5 Hz).
(S)-1-(4-F lu or op h en yl)eth a n ol:22 39% ee (S) by GC (oven
115 °C) (R) isomer 9.26 min, (S) isomer 9.93 min; 91% yield;
1H (400 MHz, CDCl3) 7.36-7.32 (m, 2H), 7.03 (dt, 2H, J )
8.8, 2.0 Hz), 4.89 (dq, 1H, J ) 6.5, 3.0 Hz), 1.83 (t, 1H, J ) 3.0
Hz), 1.49 (d, 3H, J ) 6.5 Hz)
Gen er a l P r oced u r e for Tr a n sfer H yd r ogen a t ion of
Keton es. Ligand (1 mol % or level indicated in relevant table)
and (p-cymene)ruthenium(II) dichloride dimer (0.0077 g, 0.125
mmol) were dissolved in dry IPA (5 mL). The reaction mixture
was then heated at 80 °C for 60 min. At this stage, a cosolvent
(10 mL) was used to help solubilization of the polymer ligand.
The reaction mixture was then transferred via cannula to a
solution of acetophenone (0.6 g, 5 mmol) dissolved in IPA (45
mL). KOH/IPA (0.1 M, 1.25 mL) was then added to the reaction
mixture and allowed to stir for 3 h or overnight in the case of
the polymer ligands. The reaction mixture was passed through
a thin plug of silica before removal of the solvent in vacuo to
furnish the crude product as a brown oil. The crude product
was purified using column chromatography using a solvent
gradient of EtOAc in hexane to give the pure product.
Enantiomeric excesses were determined by chiral GC or HPLC
against racemic standards prepared by reduction with NaBH 4.
Absolute configurations were confirmed by comparison of the
GC or HPLC data with that previously reported for each
compound. It should be noted that the mol % of ligand was, in
each case, calculated by inspection of the relevant 1H NMR
spectrum for the polymer used. The integral of the peaks
characteristic of the ephedrine unit (e.g., methines adjacent
to OH or N) compared to that of the methyl groups on the
polymer backbone provides a useful quantitative measurement
process. The relative number of moles of ephedrine per gram
of polymer, and hence the loading, is relatively easy to
calculate using this method.
(S)-2-Meth yl-1-p h en ylp r op a n -1-ol:10a 33% ee (S) by GC
(oven 115 °C) (R) isomer 18.77 min, (S) isomer 19.35 min; 72%
1
yield; H (400 MHz, CDCl3) 7.36-7.25 (m, 5H), 4.37 (dd, 1H,
J ) 6.8, 3.0 Hz), 1.96 (heptet, 1H, J ) 6.8 Hz), 1.80 (d, 1H, J
) 3.0 Hz), 1.00 (d, 3H, J ) 6.8 Hz), 0.80 (d, 3H, J ) 6.8 Hz).
(S)-1-(4-Ch lor op h en yl)eth a n ol:10j,23 63% ee (S) by GC
(oven 140 °C) (R) isomer 10.56 min, (S) isomer 11.06 min; 84%
1
yield; H (400 MHz, CDCl3) 7.35-7.25 (m, 4H), 4.89 (dq, 1H,
J ) 6.3, 2.8 Hz), 1.79 (t, 1H, J ) 2.8 Hz), 1.48 (d, 3H, J ) 6.3
Hz).
Ack n ow led gm en t. We thank the DTI and Evote-
cOAI for generous financial support through the LINK
ACCP program and Professor D. Games and Dr. B.
Stein of the EPSRC National Mass Spectroscopic service
(Swansea) for HRMS analysis of certain compounds. We
acknowledge the use of the EPSRC Chemical Database
Service at Daresbury.24 J ohnson-Matthey are thanked
for a loan of ruthenium salts.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
all polymer-supported reagents and 1H and 13C NMR of all
new compounds lacking elemental analyses. This material is
available free of charge via the Internet at http://pubs.acs.org.
(S)-1-P h en yleth a n ol:10a 79% ee (S) by HPLC (Chiracel OD,
ethanol/hexane ) 5:95 (1 mL/min), S isomer 9.0 min, R isomer
7.9 min; 46% yield; 1H NMR (300 MHz, CDCl3) 7.37-7.25 (m,
5H), 4.86 (q, 1H, J ) 6.4 Hz), 1.92 (br s, 1H), 1.48 (d, 3H, J )
6.4 Hz).
J O049479U
(S)-1-(2′-Na p h t h yl)et h a n ol:10a 77% ee (S) by HPLC
(Chiracel OD, ethanol/hexane ) 5:95 (1 mL/min), S isomer 13.5
min, R isomer 15.2 min; 81% yield; 1H NMR (300 MHz, CDCl3)
7.86-7.81 (m, 4H), 7.53-7.42 (m, 3H), 5.07 (dq, 1H J ) 3.20,
6.39 Hz), 1.94 (d, 1H, J ) 3.20 Hz), 1.59 (d, 3H, J ) 6.68 Hz).
(22) Homann, M. J .; Vail, R. B.; Previte, E.; Tamarez, M.; Morgan,
B.; Dodds, D. R.; Zaks, A. Tetrahedron 2004, 60, 789-797.
(23) Xie, J .-H.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Fan, B.-M.; Duan,
H.-F.; Zhou, Q.-L. J . Am. Chem. Soc. 2003, 125, 4404-4405.
(24) Fletcher, D. A.; McMeeking,; R. F. Parkin, D. J . Chem. Inf.
Comput. Sci. 1996, 36, 746-749.
5412 J . Org. Chem., Vol. 69, No. 16, 2004