Chiral monomers with minimal functional group linkages for suspension co-polymerization: A Suzuki coupling approach

Article abstract of DOI:10.1055/s-2003-39893

A new strategy for the synthesis of chiral monomers for co-polymerization with styrene is described. Suzuki coupling of 4-vinylphenylboronic acid with chiral aryl triflates 5 and 13, and subsequent elaboration has resulted in chiral monomers 9 and 10. One of these monomers 10 has subsequently been incorporated into a polystyrene gel-type resin 16 with a functional group loading of 0.48 mmolg^-1.

Full text of DOI:10.1055/s-2003-39893

1096
LETTER
Chiral Monomers with Minimal Functional Group Linkages for Suspension
Co-polymerization: A Suzuki Coupling Approach
C
hira
l
Polystyrene
l
Monom
i
er Syn
s
thesis on N. Hulme,*a Sarah A. Barron,a Andrew J. Walkerb
a
School of Chemistry, The University of Edinburgh, West Mains Road, Edinburgh, EH9 3JJ, UK
b
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Fax +44(131)6504743; E-mail: Alison.Hulme@ed.ac.uk
Received 11 April 2003
part to the difficulty in achieving the required suspension
polymerization with standard laboratory apparatus.5
Abstract: A new strategy for the synthesis of chiral monomers for
co-polymerization with styrene is described. Suzuki coupling of 4-
vinylphenylboronic acid with chiral aryl triflates 5 and 13, and sub-
sequent elaboration has resulted in chiral monomers 9 and 10. One
of these monomers 10 has subsequently been incorporated into a
polystyrene gel-type resin 16 with a functional group loading of
0.48 mmolg–1.
Supported chiral 1,2-amino alcohols have been used ex-
tensively in the asymmetric addition of dialkylzinc re-
agents to aryl aldehydes.2a,b,6 However, a number of
weaknesses in the synthesis of supported chiral amino al-
cohols have been identified.7 The first is that tethering of
the amino alcohol to the support is frequently achieved
through either the amine or alcohol functionality, hence
affecting the catalytic activity with respect to the corre-
sponding solution phase analogue. This almost always
leads to a lowering of the observed enantioselectivity of a
particular catalytic system. This has been overcome re-
cently through the use of a chloro-(2-chloro)trityl polysty-
rene resin, in place of the traditional Merrifield resin,
which has been shown to eliminate the reduction in enan-
tioselectivity through the formation of a highly hindered
ether linkage to the solid support.7a Secondly, the incorpo-
ration of polar chiral side-chains may reduce the swelling
capacity of the resin in solvents, such as toluene, in which
the diethylzinc addition is most readily performed.7b Fi-
nally, and in order to be truly useful e.g. for use in auto-
mated synthesis or continuous flow reactors, the resins
must retain high levels of enantioselective induction
through several cycles of usage and hence any linkage
unit must be unreactive under a range of conditions.7c We
felt that a C-C bond linkage between the chiral side-chain
and polystyrene resin might successfully overcome these
difficulties and would offer a new and exciting strategy
for the synthesis of side-chain chiral polymers.8
Key words: palladium, polymers, amino alcohols, ligands, asym-
metric catalysis
Supported reagents and catalysts have found increasing
use in synthesis due to their ease of handling and general
applicability to automated parallel synthesis.1 A number
of polystyrene supported chiral catalysts have been re-
ported and these have been shown to catalyze reactions
such as the asymmetric addition of diethylzinc to alde-
hydes, asymmetric epoxidation and dihydroxylation reac-
tions, and the asymmetric reduction of ketones.2
Traditionally, two approaches to the synthesis of function-
alized polystyrenes with side-chain chirality have been
used. In the first, modification of an existing polystyrene
backbone leads to an appended chiral functionality.2
Grafting a chiral ligand offers the advantages of a pre-de-
termined polymer structure (degree of cross-linking, sur-
face area, pore size) and may allow an estimation of the
ligand/catalyst loading through assuming complete con-
version of a known mmolg–1 loading of the tether func-
tionality. However, the principle disadvantage of this
approach is that the tethering functionality (typically
ether, amine, ester or amide) remains and may therefore
affect the reaction to be catalyzed. In the second approach
a chiral monomer is copolymerized with styrene to gener-
ate polystyrene with the desired side-chain chirality.2c,3
With polymerization, any additional functionality beyond
the desired chiral ligand which is present in the side-chain
(ether, amine etc.) results from the synthesis of the chiral
monomer. A derivation of this approach makes use of
chiral cross-linking agents and a number of examples of
this strategy have appeared in the recent literature.2c,4
Overall, the polymerization of chiral monomers has re-
ceived less attention from the synthetic community due in
R
R
Me2N
OH
1
OR'
OR'
R
B
TfO
+
R
Me2N
OH
2
3a R = H
3b R = Me
3c R = Ph
Scheme 1 Functionalisation of a modified polystyrene resin to give
a supported amino alcohol.
Synlett 2003, No. 8, Print: 24 06 2003.
Art Id.1437-2096,E;2003,0,08,1096,1100,ftx,en;D08903ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chiral Polystyrene Monomer Synthesis
1097
As part of a program directed towards the synthesis of coupling of these chiral N,N-dimethyl amino alcohol and
supported chiral catalysts and auxiliaries we became in- amino ester derivatives suggested that this would not be
terested in the synthesis of tyrosine-derived chiral amino a particularly viable strategy for the synthesis of well-
alcohols 1 (Scheme 1, R = H, Me etc.) and their deriva- defined supported chiral amino alcohols.13
tives.9 We were initially attracted by the literature prece-
dent for Suzuki couplings carried out on supported
boronic esters10 (although the number of coupling reac-
tions involving the use of aryl triflates as required by the
9
OH
Me2N
Me2N
Me2N
strategy outlined in Scheme 1, are rather more limit-
ed).10b,11 Using this analysis we hoped to access the de-
sired chiral amino alcohols through coupling of a boronic
acid/ester functionalized polystyrene 2, with a triflate pre-
cursor such as 3. Our strategy would deviate significantly
from this literature precedent in that we would not be us-
ing a linker between the boronic acid functionality and the
polystyrene backbone, but would be reliant upon func-
tionalization of the polystyrene core itself, e.g. though
lithiation12 and reaction with a suitable boronic acid or
ester.8,13
b
a
O
5
11
12
OMe
X
Me
Me
OH
Scheme 3 Synthesis of monomer 9. Reagents and Conditions: (a)
4-vinylphenylboronic acid, K3PO4·H2O, PdCl2(dppf)·CH2Cl2, DME,
80 °C (82%) or 4-vinylphenyl-boronic acid, PdCl2(dppf)·CH2Cl2,
Na2CO3 (2 N aq), DMF, 80 °C (71%); (b) NaBH4, THF/MeOH, reflux
(78%).
O
TfO
TfO
X
Me2N
OMe
Me2N
OH
3a
5
a,b
X
c
In pursuit of an alternative approach to the desired func-
tionalized polystyrene resins, chiral monomers 9 and 10
were synthesized as outlined in Schemes 3 and 4, respec-
tively. Triflate 5 could be coupled with 4-vinylphenylbo-
ronic acid to give the Suzuki product 11 in excellent yield
(82%). This was readily reduced to give the parent mono-
mer 9. However, disappointing preliminary results in the
enantioselective addition of diethylzinc to a range of aro-
matic aldehydes catalyzed by the solution phase analogue
8 meant that polymerization of monomer 9 was not pur-
sued. Direct conversion of 11 to the gem dimethyl ana-
logue 12 was not possible due to significant levels of
concomitant anionic polymerization.17
p-Tol
O
HO
c,f,g
Me2N
OH
Me2N
OMe
4
8
d,e
O
Me
B
O
6
Me
Me
Me
Me
TfO
p-Tol
f
Me2N
OH
Me2N
OH
3b
7
Scheme 2 Model coupling reactions for amino alcohol attachment
to a polystyrene core. Reagents and Conditions: (a) LiAlH4, Et2O,
–78 °C (57%); (b) PhN(SO2CF3)2, Et3N, CH2Cl2, 0 °C to r.t. (17%);
(c) (CF3SO2)2O, py, CH2Cl2, 0 °C (87%); (d) MeMgI, Et2O, reflux
(81%); (e) PhN(SO2CF3)2, Et3N, CH2Cl2, 0 °C (74%); (f) 6,
PdCl2(dppf)·CH2Cl2, Na2CO3 (2 N aq), DMF, 80 °C (50% alcohol 3b,
66% ester 5); (g) LiBH4, THF, r.t. (65%).
Since the N,N-dimethylated tyrosinol analogues appeared
to be somewhat unstable with respect to aerial oxidation,
a Suzuki coupling approach towards the primary amino
alcohols was sought. A wide range of conditions for the
Suzuki coupling of triflate 1318 to 4-vinylphenylboronic
acid were investigated, and tetrakis(triphenylphosphine)
palladium(0) generated in situ was found to give the high-
est isolated yield of coupled product 14.19,20 Conversion to
the gem dimethyl derivative 10 was achieved in two
steps; Grignard addition,21 followed by aqueous acid
deprotection.22 The optical purity of the intermediate gem
dimethyl carbamate was assessed as >99.8%ee by com-
parison with a racemic sample by chiral HPLC. A solution
phase analogue 15 of the anticipated polymer supported
amino alcohol 16 was synthesized in an analogous man-
ner. Thus Suzuki coupling gave biphenyl derivative 17,18
and Grignard addition followed by TFA deprotection
yielded the desired amino alcohol 15.23
Two routes to the simplest amino alcohol coupling partner
3a from amino ester 414 were pursued (Scheme 2). But
both routes were plagued by low conversion to the desired
amino alcohol 3a in the second step. However, synthesis
of gem-dimethyl derivative 3b proceeded smoothly, with
Grignard addition to ester 4 followed by selective trifla-
tion of the phenol giving 3b in 53% overall yield from L-
tyrosine methyl ester. To model coupling to the polysty-
rene backbone, Suzuki couplings of 3b and also the tri-
flate of ester 4, with 4-methylphenyl boronic ester (6),15
were carried out using Giroux’s coupling conditions.16
The low yields associated with the solution phase Suzuki
Synlett 2003, No. 8, 1096–1100 ISSN 1234-567-89 © Thieme Stuttgart · New York

1098
A. N. Hulme et al.
LETTER
Preliminary results (Table 1) using amino alcohols 15 and
16 to catalyse the addition of diethylzinc to benzaldehyde
have shown that equivalent levels of enantioselectivity
may be obtained from both, although a slightly higher cat-
alyst mol% is required with the polymer supported cata-
lyst in order to achieve this. Curiously, the sense of
enantioselectivity is consistently overturned when the
polymer supported amino alcohol is employed, a result
which is observed whether the polymer is swollen in hex-
ane, or toluene. At this relatively low ligand loading (0.48
mmolg–1), it is possible that site isolation may lead to an
alternative mechanism for the reaction catalysed by the
supported metal-ligand complex.26
Me
Me
e,f
Ph
O
Ph
15
17
OMe
BocHN
OH
H2N
d
B(OH)2
TfO
O
a
13
OMe
BocHN
b,c
Me
Me
R
O
R
OMe
BocHN
R = (p-CH2CH)Ph
10
OH
14
H2N
This new approach to the synthesis of styrene-like mono-
mers for suspension polymerisation is particularly attrac-
tive due to the ready availability of a wide range of
coupling partners that may be linked with 4-vinylphenyl-
boronic acid via a Suzuki reaction. The procedure is
unique in that it allows the synthesis of monomers which
lack a linking functionality, but in which the side-chain
chirality is attached through a robust and inert carbon-car-
bon linkage. This approach will also allow the synthesis of
a range of bead morphologies (gel-type, macroporous
etc.) to be investigated.
R = (p-CH2CH)Ph
g
Me
Me
OH
H2N
16
Scheme 4 Synthesis of polymer 16 and its solution phase analogue
15. Reagents and Conditions: (a) 4-vinylphenylboronic acid,
Pd(OAc)2, PPh3, K2CO3, PhCH3, 85 °C (61%); (b) MeMgI, Et2O, re-
flux (82%); (c) HCl (3 N aq), MeCN, r.t. (87%); (d) PhB(OH)2,
Pd(OAc)2, PPh3, K2CO3, PhCH3, 85 °C (55%); (e) MeMgI, Et2O,
reflux (77%); (f) CF3CO2H, CH2Cl2, r.t. (87%); (g) i. H2O, PVA, 125
°C; ii. H2CCHPh, divinylbenzene, AIBN, THF/toluene, 0 °C to 80 °C
(53%).
Acknowledgment
We thank the EPSRC (Industrial CASE award to SAB, 97594538)
and GlaxoSmithKline for funding. We are grateful to Dr R. Brown
for carrying out isotherm measurements.
The utility of this route for the synthesis of functionalised
polystyrene resins was ultimately demonstrated by the
suspension co-polymerization of 10 with styrene in the
presence of the cross-linking agent divinylbenzene. Opti-
mization of conditions for this procedure, led to the use of
a THF/toluene solvent mixture to promote the solubiliza-
tion of monomer 10 and poly(vinylalcohol) (PVA) to sta-
bilize the suspension.4,24,25 Elemental analysis confirmed
that the amino alcohol monomer had been successfully in-
corporated to produce the functionalized polymer 16, and
the functional group loading was determined to be 0.48
mmolg–1. The polystyrene resin 16 was found to have a
negligible surface area in the dry state as determined by
N2 adsorption and application of BET theory, thus indi-
cating a gel-type resin.
References
(1) Kirschning, A.; Monenschein, H.; Wittenberg, R. Angew.
Chem., Int. Ed. 2001, 40, 650.
(2) (a) McNamarra, C. A.; Dixon, M. J.; Bradley, M. A. Chem.
Rev. 2002, 102, 3275. (b) Mahdavain, A.-R.; Khoee, S.
React. Funct. Polym. 2002, 50, 217. (c) Clapham, B.;
Reger, T. S.; Janda, K. D. Tetrahedron 2001, 57, 4637.
(d) Abramson, S.; Bellocq, N.; Brunel, D.; Lasperas, M.;
Moreau, P. In Chiral Catalyst Immobilisation and
Recycling; De Vos, D. E.; Vankelecom, I. F. J.; Jaocbs, P.
A., Eds.; Wiley-VCH: Weinheim, 2000, 261.
(e) Shuttleworth, S. J.; Allin, S. M.; Wislon, R. D.;
Nasturica, D. Synthesis 2000, 1035. (f) Shuttleworth, S. J.;
Allin, S. M.; Sharma, P. K. Synthesis 1997, 1217.
(3) (a) Burguete, M. I.; García-Verdugo, E.; Vincent, M. J.;
Luis, S. V.; Pennemann, H.; Graf von Keyserling, N.;
Martens, J. Org. Lett. 2002, 4, 3947. (b) Cornejo, A.; Fraile,
J. M.; García, J. I.; García-Verdugo, E.; Gil, M. J.; Legarreta,
G.; Luis, S. V.; Martínez-Merino, V.; Mayoral, J. A. Org.
Lett. 2002, 4, 3927. (c) Orlandi, S.; Mandoli, A.; Pini, D.;
Salvadori, P. Angew. Chem. Int. Ed. 2001, 40, 2519.
(d) Itsuno, S.; El-Shehawy, A. A. Polym. Adv. Technol.
2001, 12, 670. (e) Itsuno, S.; Watanabe, K.; El-Shehawy, A.
A. Adv. Synth. Catal. 2001, 343, 89. (f) Altava, B.;
Burguete, M. I.; Fraile, J. M.; García, J. I.; Luis, S. V.;
Mayoral, J. A.; Vincent, M. J. Angew. Chem. Int. Ed. 2000,
39, 1503.
Table 1 Amino Alcohol Catalyzed Addition of Diethyl Zinc to
Benzaldehyde
O
OH
15 or 16
Et2Zn
H
Catalyst
15
mol%
5
Solvent
Yield
77
%eea
PhCH3
PhCH3
hexane
50 (R)
56 (S)
51 (S)
16
10
72
16
10
80
(4) Sellner, H.; Rheiner, P. B.; Seebach, D. Helv. Chim. Acta
2002, 85, 352.
a Major enantiomer indicated in parentheses.
Synlett 2003, No. 8, 1096–1100 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Chiral Polystyrene Monomer Synthesis
1099
(5) (a) Sherrington, D. C. Chem. Commun. 1998, 2275.
(b) Reger, T. S.; Kim, J. D. Bioorg. Med. Chem. Lett. 2002,
12, 837.
(6) Pu, L.; Yu, H. B. Chem. Rev. 2001, 101, 757.
(7) (a) Vidal-Ferran, A.; Bampos, N.; Moyano, A.; Pericàs, M.
A.; Riera, A.; Sanders, J. K. M. J. Org. Chem. 1998, 63,
6309. (b) Sung, D. W. L.; Hodge, P.; Stratford, P. W. J.
Chem. Soc., Perkin Trans. 1 1999, 1463. (c) Sung, D. W.
L.; Hodge, P.; Stratford, P. W. J. Chem. Soc., Perkin Trans.
1 1999, 2335.
(8) Suzuki coupling as a grafting strategy, see: Kell, R. J.;
Hodge, P.; Nisar, M.; Williams, R. T. J. Chem. Soc., Perkin
Trans. 1 2001, 3403.
(9) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,
835.
(10) (a) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. Rev. 2002, 102, 1359. (b) Hajduk, P. J.; Dinges,
J.; Miknis, G. F.; Merlock, M.; Middleton, T.; Kempf, D. J.;
Egan, D. A.; Walter, K. A.; Robins, T. S.; Shuker, S. B.;
Holzman, T. F.; Fesik, S. W. J. Med. Chem. 1997, 40, 3144.
(11) For solution phase Stille couplings of protected tyrosine
triflate, see: (a) Yao, Z.-J.; Gao, Y.; Burke, T. R. Jr.
Tetrahedron: Asymmetry 1999, 10, 3727. (b) Yokomatsu,
T.; Yamagishi, T.; Matsumoto, K.; Shibuya, S. Tetrahedron
1996, 52, 11725.
(12) Farrall, M. J.; Fréchet, J. M. J. J. Org. Chem. 1976, 41, 3877.
(13) Caze, C.; Moualij, N. E.; Hodge, P.; Lock, C. J.; Ma, J. J.
Chem. Soc., Perkin Trans. 1 1995, 345.
(14) Huguenin, R. L.; Boissonnas, R. A. Helv. Chim. Acta 1961,
44, 213.
35.5, 28.1 (3 C), 27.5, 26.5; m/z (FAB) 382 ([M + H]+, 2%),
373 (5), 309 (9), 301 (14), 193 (43), 57 (100); HRMS (FAB)
C24H32NO3 [M + H]+ requires 382.2382, found 382.2399.
(3S)-3-Amino-2-methyl-4-[p-(p-vinylphenyl)phenyl]-
butan-2-ol (10), Rf [CH2Cl2/MeOH (90:10)] 0.23; mp 114–
115 °C; [a]D –44.2 (c 0.5, MeOH); IR (CHCl3 solution)/
cm–1 3402, 3343, 3280, 2976, 1497, 1389; dH (200 MHz,
CD3OD) 7.57–7.44 and 7.32–7.28 (8 H, m), 6.75 (1 H, dd,
J = 17.8 Hz, 10.8 Hz), 5.79 (1 H, d, J = 17.8 Hz), 5.22 (1 H,
d, J = 10.8 Hz), 3.02 (1 H, dd, J = 13.2 Hz, 2.7 Hz), 2.88 (1
H, dd, J = 10.7 Hz, 2.7 Hz), 2.34 (1 H, dd, J = 13.2 Hz, 10.7
Hz), 1.27 (3 H, s), 1.23 (3 H, s); dC (62.9 MHz, CD3OD)
139.6, 138.7, 138.0, 136.0, 135.8, 128.9 (2 C), 126.1 (2 C),
126.0 (2 C), 125.8 (2 C), 112.1, 71.5, 61.3, 37.1, 24.7, 22.9;
m/z (FAB) 282 ([M + H]+, 56%), 264 (17), 222 (19), 193
(100), 88 (31), 43 (27); HRMS (FAB) C19H24NO [M + H]+
requires 282.1858, found 282.1858; Anal. Calcd for
C19H23NO: C, 81.10; H, 8.24; N, 4.98, found C, 80.59; H,
8.16; N, 4.73.
(23) (3S)-4-Biphenyl-3-N-(tert-butoxycarbonyl)-2-methyl-
butan-2-ol, Rf [hexane/EtOAc (80:20)] 0.14; mp 137–138
°C; [a]D –61.2 (c 1.0, CHCl3);IR (CHCl3 solution)/cm–1
3442, 2980, 1700, 1503, 1368, 1169; dH (250 MHz, CDCl3)
7.58–7.25 (9 H, m), 4.65 (1 H, d, J = 9.6 Hz), 3.80–3.69 (1
H, m), 3.13 (1 H, dd, J = 14.2 Hz, 3.4 Hz), 2.71 (1 H, br s),
2.62 (1 H, d, J = 14.2 Hz), 1.41–1.25 (15 H, m); dC (62.9
MHz, CDCl3) 156.3, 141.0, 139.0, 137.9, 129.5, 128.6 (3 C),
126.9 (5 C), 79.2, 72.8, 60.2, 35.3, 28.1 (3 C), 27.4, 26.5;
m/z (FAB) 356 ([M + H]+, 19%), 300(57), 282(75),
167(100), 57(91); HRMS (FAB) C22H30NO3 [M + H]+
requires 356.2225, found 356.2225; Anal. Calcd. for
C22H29NO3: C, 74.33; H, 8.22; N, 3.94, found C, 73.82; H,
8.24; N, 4.06.
(15) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 2000,
65, 164.
(16) Giroux, A.; Han, Y.; Prasit, P. Tetrahedron Lett. 1997, 38,
3841.
(3S)-3-Amino-4-biphenyl-2-methyl-butan-2-ol (15), Rf
[CH2Cl2/MeOH (90:10)] 0.23; mp 65–66 °C; [a]D –40.2 (c
1.0, CHCl3); IR (nujol)/cm–1 3404, 3341, 3270, 1487, 754;
dH (200 MHz, CD3OD) 7.60–7.54 and 7.44–7.29 (9 H, m),
3.03 (1 H, d, J = 13.4 Hz), 2.89 (1 H, d, J = 11.0 Hz), 2.35 (1
H, dd, J = 13.4 Hz, 11.0 Hz), 1.28 (3 H, s), 1.24 (3 H, s); dC
(50.3 MHz, CD3OD) 142.3, 140.7 (2 C), 130.8 (2 C), 129.9
(2 C), 128.2 (3 C), 127.9 (2 C), 73.5, 63.2, 39.0, 26.6, 24.8;
m/z (FAB) 256 ([M + H]+, 85%), 238 (35), 196 (20), 167
(100), 88 (24), 43 (28); HRMS (FAB) C17H22NO [M + H]+
requires 256.1701, found 256.1706.
(17) Wünsch, J. R. Rapra Review Reports 2000, 10, Report 112.
(18) Shieh, W.-C.; Carlson, J. A. J. Org. Chem. 1992, 57, 379.
(19) The conditions previously optimised for the coupling of
methyl ester 5 and 4-vinylphenylboronic acid were found to
give incomplete conversion to Suzuki product 14 resulting in
a tricky separation of unreacted triflate 13 and product 14.
(20) Methyl (2S)-2-N-(tert-butoxycarbonyl)-3-[p-(p-
vinylphenyl)phenyl]-propanoate (14), Rf [CH2Cl2:MeOH
(95:5)] 0.92; mp 110 °C; [a]D +61.6 (c 0.6, CHCl3); IR
(CHCl3 solution)/cm–1 3429, 3365, 2979, 1740, 1712, 1498,
1366, 1166, 756; dH (250 MHz, CDCl3) 7.57–7.44 and 7.25–
7.17 (8 H, m), 6.75 (1 H, dd, J = 17.6 Hz, 10.9 Hz), 5.78 (1
H, dd, J = 17.6 Hz, 0.9), 5.27 (1 H, dd, J = 10.9 Hz, 0.9 Hz),
5.02 (1 H, d, J = 7.7 Hz), 4.62 (1 H, d, J = 7.9 Hz), 3.73 (3
H, s), 3.19–3.05 (2 H, m), 1.42 (9 H, s); dC (62.9 MHz,
CDCl3) 172.2, 155.0, 139.9, 139.3, 136.4, 136.2, 135.0,
129.6 (2 C), 126.9 (4 C), 126.5 (2 C), 113.8, 79.9, 54.2, 52.2,
37.8, 28.2 (3 C); m/z (FAB) 382 ([M + H]+, 7%), 326 (25),
193 (25), 154 (100), 57 (28); HRMS (FAB) C23H28NO4 [M
+ H]+ requires 382.2018, found 382.2004.
(21) Bull, S. D.; Davies, S. G.; Jones, S.; Polywka, M. E. C.;
Prasad, R. S.; Sanganee, H. J. Synlett 1998, 519.
(22) (3S)-3-N-(tert-Butoxycarbonyl)-2-methyl-4-[p-(p-
vinylphenyl)phenyl]-butan-2-ol, Rf [CH2Cl2/MeOH
(90:10)] 0.51; mp 150–151 °C; [a]D –69.0 (c 2.0, CHCl3); IR
(CHCl3 solution)/cm–1 3377, 2980, 1669, 1529, 1172, 757;
dH (200 MHz, CDCl3) 7.52–7.45 and 7.29–7.26 (8 H, m),
6.76 (1 H, dd, J = 17.5 Hz, 10.8 Hz), 5.79 (1 H, d, J = 17.5
Hz), 5.27 (1 H, d, J = 10.8 Hz), 4.66 (1 H, d, J = 9.2 Hz),
3.74–3.70 (1 H, m), 3.12 (1 H, d, J = 13.8 Hz), 2.68 (1 H, d,
J = 13.8 Hz), 2.58 (1 H, br s), 1.30 (15 H, m); dC (50.3 MHz,
CDCl3) 156.5, 140.4, 138.6, 138.2, 136.4 (2 C), 129.6 (2 C),
127.0 (2 C), 126.8 (2 C), 126.6 (2 C), 113.8, 79.4, 72.9, 60.3,
(24) Suzuki, T.; Narisada, N.; Shibata, T.; Soai, K. Polym. Adv.
Technol. 1999, 10, 30.
(25) A dry 500 mL 3-necked flask equipped with overhead
stirrer, condenser and septum was charged with distilled
water (135 mL) which was subsequently degassed and
purged with argon. PVA (675 mg, 87–89% hydrolysed,
average MW = 85000–146000) was added and the reaction
mixture was stirred at 125 °C for 10 minutes before being
cooled to 0 °C. Two further dry flasks were separately
charged with THF (50 mL) and toluene (50 mL), each being
degassed and purged with argon. The amino alcohol
monomer 10 (1.84 g, 6.55 mmol) was added to the THF
ensuring dissolution before addition of the toluene. AIBN
(211 mg, 1.28 mmol), styrene (9.94 mL, 86.7 mmol) and
divinylbenzene (5.25 mL, 29.5 mmol) were then added to
the organic phase with each of the monomers being washed
with 1% aqueous NaOH (10 mL) and water (2 × 10 mL)
immediately prior to use. The monomer phase was added via
cannulation over a period of 10 minutes to the cooled
aqueous phase which was stirred at 350 RPM. The height of
the paddle impeller was positioned ~ 3 cm below the surface
of the reaction mixture as this depth was found to visually
reduce horizontal flow. Stirring was then continued at 0 °C
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1100
A. N. Hulme et al.
LETTER
for 1 hour. The reaction mixture was then heated to 80 °C
with constant stirring at 350 RPM under argon for 18 hours.
The polymer beads were collected by filtration through a 100
micron mesh sieve and washed with water (500 mL), THF
(500 mL) and methanol (500 mL). The polymeric material
was then dried under reduced pressure at 40 °C to constant
mass and sieved between 500 and 100 micron mesh sieves
affording cross-linked amino alcohol polymer(16) as
colourless free flowing beads (3.40 g, 23%), IR (KBr disc)/
cm–1 3446, 3025, 2923, 1601, 1493, 1452, 758, 698; Anal.
Calcd. for polymer: C, 90.69; H, 7.81; N, 0.70, found C,
89.74; H, 8.05; N, 0.67, loading = 0.48 mmolg–1; N2 BET
adsorption < 10 m2g–1; resin swelled to 5.2 times its own
volume in CH2Cl2.
A significant proportion of the polymeric product was found
to contain larger colourless beads mixed with plastic residue
which were retained in the 500 micron mesh sieve (4.34 g,
30%), IR (KBr disc)/cm–1 3446, 3025, 2918, 1601, 1493,
1452, 758, 699; Anal. Calcd. for polymer: C, 90.69; H, 7.81;
N, 0.70, found C, 89.89; H, 8.08; N, 0.70, loading = 0.50
mmolg–1; N2 BET adsorption < 10 m2g–1; resin swelled to 4.7
times its own volume in CH2Cl2.
(26) For a discussion of the mechanism of catalysis by primary
amine containing amino alcohols, see: Itsuno, I.; Sakurai, Y.;
Ito, K.; Maruyama, T.; Nakahama, S.; Fréchet, J. M. J. J.
Org. Chem. 1990, 55, 304.
Synlett 2003, No. 8, 1096–1100 ISSN 1234-567-89 © Thieme Stuttgart · New York