New practical synthesis of non-cross-linked polystyrene supported 2-phenylimino-2-oxazolidine

Article abstract of DOI:10.3184/174751912X13336487086374

A new practical method for the synthesis of a non-cross-linked polystyrene supported 2-phenylimino-2-oxazolidine chiral auxiliary is reported. This method started from the same material as in a previous synthesis, N-Boc-L-tyrosine ethyl ester, but the overall yield was 42.5%, which was higher than the copolymerisation method.

Full text of DOI:10.3184/174751912X13336487086374

276 RESEARCH PAPER
MAY, 276–277
JOURNAL OF CHEMICAL RESEARCH 2012
New practical synthesis of non-cross-linked polystyrene supported
2-phenylimino-2-oxazolidine
Cuifen Lu, Fuqiang Hu, Zuxing Chen* and Guichun Yang
Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules, Faculty of Chemistry and
Chemical Engineering, Hubei University, Wuhan 430062, P. R. China
A new practical method for the synthesis of a non-cross-linked polystyrene supported 2-phenylimino-2-oxazolidine
chiral auxiliary is reported. This method started from the same material as in a previous synthesis, N-Boc-L-tyrosine
ethyl ester, but the overall yield was 42.5%, which was higher than the copolymerisation method.
Keywords: practical, synthesis, non-cross-linked polystyrene, support, 2-phenylimino-2-oxazolidine
Asymmetric reactions using a chiral auxiliary have been
studied extensively and are now important and useful methods
for asymmetric carbon–carbon bond formation. Recently, a
new class of chiral auxiliary 2-phenylimino-2-oxazolidine
has been developed.1 The auxiliary provides a superior perfor-
mance to many other chiral auxiliaries currently in common
use, and has been proved to be particularly efficient in terms of
stereoselectivity and yield in asymmetric alkylations.2,3 How-
ever, in most cases, the chiral auxiliaries cannot be effectively
recovered after the reaction.
Insoluble polymer supports, such as the Merrifield resin and
Wang resin provide a simple procedure involving “filtration”
for rapidly achieving the isolation of desired compounds and
recovering expensive reagents or catalysts attached to a solid-
support for recycling.4,5 However, it is difficult with some
chiral auxiliaries to achieve a high degree of stereoselectivity
in solid-supported reactions.6 The soluble polymer supports,
which combine the benefits of an insoluble polymer support
with the advantages of classic liquid synthesis, have been
extensively studied by chemists.7–10 Our group has undertaken
a research program to develop several chiral auxiliaries using
non-cross-linked polystyrene (NCPS) as the support.11–14 We
have prepared NCPS supported 2-phenylimino-2-oxazolidine
chiral auxiliary by the copolymerisation method15. We now
report a new practical method to synthesise NCPS supported
2-phenylimino-2-oxazolidine chiral auxiliary (Scheme 1).
Results and discussion
As shown in Scheme 1, NCPS supported 2-phenylimino-2-
oxazolidine was synthesised using N-Boc-L-tyrosine ethyl
ester as the starting material. O-Benzyl-L-tyrosinol 4 can be
conveniently obtained from N-Boc-L-tyrosine ethyl ester 1
according to the reported procedure in 58.5% overall yield.16
Treatment of 4 with phenyl isothiocyanate yielded the thiourea
5 in 97% yield. 2-Phenylimino-2-oxazolidine 6 was easily
obtained in 93% yield by the cyclization of the thiourea 5 using
TsCl and NaOH. Removal of the benzyl group of 6 was
carried out by 20% Pd(OH)2/C and HCOONH4 to provide the
compound 7 in the yield of 95%. Then 7 was attached to the
functionalised NCPS 9 to afford NCPS supported 2-pheny-
limino-2-oxazolidine 8 in 85% yield. The overall yield was
42.5%. The functionalised NCPS 9 (Fig. 1) was prepared10 by
copolymerising 4-vinylbenzyl chloride and styrene in a ratio
of 1/3. The structure of the chiral auxiliary 8 was established
by IR, NMR and elemental analysis. The spectra were consis-
tent with the molecular structure.
We have previously reported15 the preparation and applica-
tion of a NCPS supported 2-phenylimino-2-oxazolidine chiral
auxiliary, which was synthesised from N-Boc-L-tyrosine ethyl
ester by a copolymerisation method in 28.8% overall yield.15
We now report a new practical method for the synthesis of an
NCPS supported 2-phenylimino-2-oxazolidine chiral auxiliary
using the same starting material, and with an overall yield of
42.5%, which is higher than copolymerisation method.
Scheme 1 Synthesis of NCPS supported 2-phenylimino-2-oxazolidine chiral auxiliary.
* Correspondent. E-mail: chzux@hubu.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2012 277
(S)-4-(4-Hydroxyl-benzyl)-2-phenylimino-2-oxazolidine (7): 20%
Pd(OH)2/C (0.43 g) and HCOONH4 (1.15 g, 38.16 mmol) were added
to a solution of compound 6 (3.26 g, 9.10 mmol) in EtOAc (20 mL)
and CH3OH (15 mL). The mixture was stirred at reflux for 3 h. After
filtration of the catalyst and evaporation of the solvent, the crude prod-
uct was further purified by column chromatography (CH3OH/CH2Cl2,
1/30, v/v) to give 7 (2.31 g, 95%) as a colourless liquid. [α]2D5 = –87.5
(c 0.008, CH2Cl2); IR (NaCl): υ = 3288, 1667, 1595, 1551, 737,
1
695 cm−1; H NMR (CDCl3, 600 MHz): δ 7.25–7.17 (5H, m, ArH),
6.99 (2H, d, J = 7.8 Hz, ArH), 6.69 (2H, d, J = 8.4 Hz, ArH), 5.62 (2H,
s, NH, OH), 4.42 (1H, m, CH), 4.15 (2H, d, J = 4.8 Hz, CH2O), 2.75
(2H, d, J = 6.0 Hz, CH2Ar); 13C NMR (CDCl3, 150 MHz): δ 157.1,
155.7, 130.1, 128.9 (2C), 127.6 (2C), 123.1 (2C), 121.4 (2C), 115.8
(2C), 72.2, 61.3, 40.7; Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01;
N, 10.44. Found: C, 71.75; H, 5.92; N, 10.25%.
Fig. 1 Functionalised NCPS.
Conclusion
This chiral auxiliary induced asymmetric alkylation reactions
in good yield and stereoselectivity, and it was easily recovered
and could be reused several times. The further application of
the NCPS supported 2-phenylimino-2-oxazolidine chiral aux-
iliary to other asymmetric reactions, such as aldol reactions,
Michael reactions and Diels–Alder reactions, is underway in
our laboratory.
NCPS supported 2-phenylimino-2-oxazolidine (8): Functionalised
NCPS 9 (5.12 g), anhydrous K2CO3 (16.26 g, 11.78 mmol), and 18-
crown-6 (catalytic amount) were added to a solution of compound 7
(1.58 g, 5.89 mmol) in DMF (30 mL). The resulting mixture was
stirred at 60 °C for 20 h. Then most of the solvent was removed under
reduced pressure. The viscous solution was dropped into cold ethanol
(150 mL), and the precipitated solid was filtered and dried at 65 °C
for 2 h under vacuum to afford polymer 8 (5.7 g, 85%). IR (NaCl):
1
υ = 3321, 2925, 1680, 1598, 1509, 1241, 756, 699cm−1; H NMR
Experimental
(CDCl3, 600 MHz): δ 7.30–7.18 (9H, m, ArH), 7.15–6.48 (bm,
polymer-ArH); 6.15 (1H, s, NH), 4.23 (2H, m, CH2O), 2.98 (2H, d,
J = 8.4 Hz, CH2Ar), 2.73 (1H, m, CH), 2.14–1.25 (bm, polymer-CH2);
13C NMR (150 MHz, CDCl3): δ 157.3, 156.9, 148.5, 146.2, 134.2,
131.0, 129.4, 128.5, 126.8, 120.5, 114.4, 72.9, 70.3, 67.5, 40.2; Anal.
Calcd for C49H48N2O2: C, 84.45; H, 6.94; N, 4.02. Found: C, 84.55; H,
6.92; N, 4.08%. The molecular formula was calculated by adding the
sum of 1 mol 4-vinylbenzyl chloride and 3 mol styrene (C33H33Cl)
to the molecular formula of 7 (C16H16N2O2) and then deducting HCl.
The number average molecular weight (Mn) and molecular weight
distribution (Mw/Mn) of polymer 8 were found to be 9000 and 1.4,
respectively (gel permeation chromatographic analyses, calibrated by
polystyrene standards).
All solvents were obtained from commercial sources and dried or
purified by standard procedures before use. Melting points were mea-
sured on a WRS-1A digital melting point apparatus and are uncor-
rected; optical rotations were measured using the sodium D line on
WZZ-2B Automatic Polarimeter; IR spectra were recorded on a PE
IR-spectrum one spectrometer. H NMR (600 MHz) and 13C NMR
1
(150 MHz) spectra were recorded on a Varian Unity INOVA 600 spec-
trometer in CDCl3 using TMS as the internal standard; elemental
analyses were carried out with a VarioEL III (Germany) analyser. Gel
permeation chromatographic analyses (GPC) were carried out on a
µ-styragel preparative liquid chromatography (China) with a multi-
angel laser photometer (DAWN HELEOS II, Wyatt, USA) and
refractive index (RI) detector (Optilab Rex, Wyatt, USA) using a
polystyrene standards.
O-Benzyl-L-tyrosinol (4): Obtained16 from N-Boc-L-tyrosine ethyl
ester 1 in 58.5% overall yield. The spectroscopic data of 4 correspond
with those reported.16
We gratefully acknowledge the National Natural Sciences
Fundation of China (No. 20772026 and 21042005) and the
Natural Sciences Foundation of Hubei province in China (No.
2010CDA019) for financial support.
N-2-(S)-(4-(4-Benzyloxy) benzyl) hydroxyethyl-N′-phenylthioureas
(5): Phenyl isothiocyanate (2.0 mL, 16.34 mmol) in THF (10 mL)
dropwise was added to a solution of compound 4 (3.5 g, 13.62 mmol)
in THF (30 mL) and the mixture was stirred at 25 °C for 6 h. The
solvent was removed under reduced pressure to afford a white solid.
The crude product was further purified by column chromatography
(EtOAc/PE, 1/5, v/v) to give 5 (5.30 g, 97%). m.p. 82.0–82.5 °C;
[α]D25 = –85.7 (c 0.05, CH2Cl2); IR (NaCl): υ = 3367, 3250, 1732, 1610,
Received 22 October 2011; accepted 9 March 2012
Paper 1100947 doi: 10.3184/174751912X13336487086374
Published online: 10 May 2012
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