Synthesis of non-cross-linked polystyrene supported (4S)-4-substituted-4,5- dihydrooxazoline

Article abstract of DOI:10.3184/030823410X12653142350782

From N-Boc L-tyrosine ethyl ester, we synthesised (4 S)-4-[4-(4- vinylbenzyloxy)benzyl]-4,5-dihydrooxazoline, which was copolymerized with styrene to obtain non-cross-linked polystyrene supported 2-hydrogen oxazoline in 29.4% yield.

Full text of DOI:10.3184/030823410X12653142350782

86 RESEARCH PAPER
FEBRUARY, 86–87
JOURNAL OF CHEMICAL RESEARCH 2010
Synthesis of non-cross-linked polystyrene supported
(4S)-4-substituted-4,5-dihydrooxazoline
Jia Li, Cuifen Lu*, 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
From N-Boc L-tyrosine ethyl ester, we synthesised (4S)-4-[4-(4-vinylbenzyloxy)benzyl]-4,5- dihydrooxazoline, which
was copolymerized with styrene to obtain non-cross-linked polystyrene supported 2-hydrogen oxazoline in 29.4%
yield.
Keywords: non-cross-linked polystyrene, chiral ligand, support, 4-substituted-4,5-dihydrooxazoline
Chiral 4-substituted-4,5-dihydrooxazolines are important frag-
ments of chiral auxiliaries,1,2 or as key elements in numerous
ligands for asymmetric catalysis.3 However, their large-scale
application is limited due to the difficult procedure which
involves separation and recovery. In order to address this
problem, chiral ligands were attached to insoluble polymer
supports.4–6 But there were several shortcomings because of
non-linear kinetic behaviour, unequal distribution or access to
the chemical reaction, and synthetic difficulties in transferring
standard organic reactions to the solid phase. We have under-
taken a research program to synthesise chiral auxiliaries by
using non-cross-linked polystyrene (NCPS) as supports which
combines the superiorities of insoluble polymer support with
the advantages of classic liquid synthesis.7–9 But to the best
of our knowledge, there has been no report about chiral 4-
substituted-4,5-dihydrooxazolines supported on a polymer.
We now report how we synthesized NCPS supported (4S)-4-
substituted-4,5-dihydrooxazoline through five steps from the
material of N-Boc-L-tyrosine ethyl ester (Scheme 1).
Experimental
Melting points were measured on a WRS-1A digital melting point
apparatus and uncorrected; optical rotations were measured using the
sodium D line with a WZZ-2B Automatic Polarimeter; IR spectra
1
were recorded on a IR- spectrum one (PE) spectrometer; H NMR
(600 MHz) and 13C NMR (150 MHz) spectra were recorded on a
Varian Unity INOVA 600 spectrometer in CDCl3 using TMS as
internal standard; Elemental analyses were done on a VarioEL III
(Germany) analyser; HRMS data were collected on Q-star Elite,
ELI-LC-MS/MS (product from ABI, America).
N-Boc-O-(4-vinylbenzyl)-L-tyrosine ethyl ester (2): K2CO3 (7.40 g,
54 mmol), catalytic amounts of 18-crown-6 was added dropwise after
stirring for 30 min under N 4-vinylbenzyl chloride (4.3 mL, 30 mmol)
in DMF (20 mL) to a sol2u,tion of 1 (8.34 g, 27 mmol) in dry DMF
(60 mL) to the reaction mixture, which was stirred at 40 °C for 24 h.
The solvent was removed in vacuum and the residue diluted with
water (30 mL) and ethyl acetate (50 mL). The aqueous layer was
extracted with ethyl acetate (3 × 50 mL). The organic layers were
washed with brine, dried over MgSO , and concentrated in vacuum.
The residue was purified by silica4 gel column chromatography
(EtOAc/petroleum ether = 1/10) to give 2 as a milk white solid
Scheme 1 Synthesis of NCPS supported (4S)-4-substituted-4,5-dihydrooxazoline.
* Correspondent. E-mail: lucuifen1981@yahoo.cn

JOURNAL OF CHEMICAL RESEARCH 2010 87
(9.48 g, 80%). M.p. 76.6–77.8 °C; [α]D20 = +0.9 (c 0.09, THF); IR
(NaCl): υ = 3377, 1740, 1716 cm−1; 1HNMR (CDCl3, 600 MHz):
δ 1.23 (3H, t, J = 7.2 Hz, CH ), 1.42 (9H, s, Boc), 3.02 (2H, q, J =
6.0 Hz, ArCH ), 4.15 (2H, q,3J = 6.6 Hz, OCH2 ), 4.51 (1H, d, J =
7.2Hz, CHN), 24.97 (1H, d, J = 7.2 Hz, Boc-NH) 5.02 (2H, s,ArCH O),
5.25 (1H, d, J = 11.4 Hz, = CH2), 5.75 (1H, d, J = 17.4 Hz, = CH2 ),
6.73 (1H, dd, J1 = 10.8 Hz, J = 17.4 Hz, = CH), 6.88 (2H, d, J2=
8.4 Hz, ArH), 7.04 (2H, d, J =27.8 Hz, ArH), 7.37 (2H, d, J = 7.8 Hz,
ArH) 7.42 (2H, d, J = 7.8 Hz, ArH); 13C NMR (CDCl , 150MHz):
δ 14.1, 28.3(3C), 37.5, 54.5, 61.2, 69.7, 79.8, 114.30(2C),114.8,
126.4(2C), 127.6(2C), 128.3(2C), 130.3, 136.4, 136.5, 137.3, 155.1,
157.8, 171.9; HRMS: Calcd for C25H32NO5[M+ + 1] 426.2280. Found
426.2283.
N-Boc-O-(4-vinylbenzyl)-L-tyrosinol (3): LiAlH4 (0.41 g, 10.8
mmol) in THF (20 mL) was added to a stirred solution of 2 (5.93 g,
13.5 mmol) in dry THF (40 mL) at –20 °C. After stirring at room tem-
perature for 12 h, the excess LiAlH4 was carefully destroyed by the
dropwise addition of 10% H2SO The solvent was removed under
vacuum and the residue diluted w4it. h water (30 mL) and ethyl acetate
(50 mL). The aqueous layer was extracted with ethyl acetate (3 ×
50 mL). The organic phase was washed with brine, dried over MgSO4,
and concentrated in vacuum. The residue was purified by silica gel
column chromatography (EtOAc/petroleum ether = 3/10) to give 3
as a white solid (3.88 g, 75%). M.p. 101.7–102.6 °C; [α]D20 = –2.1
(c 0.26, THF); IR (NaCl): υ = 3359, 1686 cm−1; 1HNMR (CDCl3,
600 MHz): δ 1.40 (9H, s, Boc), 1.52 (1H, s, OH), 2.76 (2H , d, J =
7.2Hz, ArCH ), 3.55 (1H, m, CH O), 3.68 (1H, m, CH2O), 3.80 (1H,
br s, CH-N), 24.78 (1H, s, CHN),25.02 (2H, s, ArCH2O), 5.24 (1H, d,
J = 11.4Hz, = CH ), 5.75 (1H, d, J = 17.4Hz, = CH2), 6.73 (1H, m,
= CH), 6.89 (2H, 2d, J = 8.4Hz, ArH), 7.10 (2H, d, J = 8.4Hz, ArH),
7.37 (2H, d, J = 7.8Hz, ArH) 7.41 (2H, d, J = 8.4Hz, ArH); 13C NMR
(CDCl3, 150MHz): δ 28.3(3C), 36.7, 54, 65, 69.8, 79.5, 114.0,
115.0(2C), 126.4(2C), 127.6(2C), 130.0, 130.2(2C), 136.4(2C), 136.6,
137.3, 157.5; HRMS: Calcd for C23H30NO4[M+ + 1] 384.2175. Found
384.2166.
reaction mixture was washed with 10% NaHCO3 (40 mL) and brine
(40 mL), and dried over Na2SO4. The residue was purified by silica
gel column chromatography (EtOAc/petroleum ether/triethylamine
= 1/4/1) to give 5 as a white solid (1.48 g, 72%). M.p. 144.4–145.0 °C
[α]D20 = –4.3 (c 0.13, THF); IR(NaCl): υ = 3047, 1635, 1116 cm−1; 1H
NMR (CDCl3, 600MHz): δ 2.88 (2H, m, ArCH2), 3.54 (1H, m, OCH2),
3.65 (1H, dd, J1 = 3.6Hz, J2 = 11.4 Hz, OCH2), 5.03 (2H, s, ArCH2O),
5.25 (1H, d, J = 10.8Hz, = CH2), 5.75 (1H, d, J = 7.8Hz, = CH2), 6.72
(1H, dd, J1 = 10.8Hz, J2 = 18.0 Hz, = CH), 6.91 (2H, d, J = 9.0Hz,
ArH), 7.09 (2H, d, J = 9.0Hz, ArH), 7.38 (2H, d, J = 7.8Hz, ArH),
7.42 (2H, d, J = 8.4Hz, ArH) , 8.17 (1H, s, CH = N); 13CNMR(CDCl3,
150MHz): δ 46.4, 49.4, 69.8, 114.1, 115.2(2C), 126.4(2C), 127.7(2C),
128.7, 130.2, 130.4(2C), 136.4(2C), 136.5, 137.4, 160.5; Elementary
analysis Calcd for Calcd for C19H19NO2: C, 77.79; H, 6.53; N, 4.77.
Found: C, 77.81; H, 6.54; N, 4.75%.
NCPS supported (4S)-4-substituted-4,5- dihydrooxazoline (6):
Styrene (1.99 mL, 17.52 mmol) and AIBN (16 mg) under N2 were
added to a solution of 5 (1.28 g, 4.38 mmol) in THF (20 mL). The
mixture was stirred at 70 °C for 4 days. Then most of the solvent was
removed under reduced pressure. The residue was poured dropwise
into a beaker of cold and stirring ethanol (50 mL) to precipitate white
solid. The solid was filtrated and washed in ethanol (3 × 8 mL) to
remove any micromolecules (TLC detecting) and dried in a vacuum
to give polymer 6 (1.2 g, 80%). IR(NaCl): υ = 3302, 1671 cm−1;
1HNMR (CDCl3, 600MHz): δ 1.10–2.10 (bm, polymer-CH2), 2.64
(2H, br s, ArCH2), 3.47 (1H, s, CH2O), 3.64 (1H, s, CH2), 4.18 (1H, s,
CH), 4.92 (2H, s, ArCH2O), 6.50–7.25 (bm, polymer-ArH); 13C NMR
(CDCl3,150 MHz): δ 23.0, 29.9, 32.0, 40.5, 52.0, 70.2, 110.0, 115.0,
125.9, 127.8, 128.2, 130.5, 145.5, 158.0; Elementary analysis Calcd
for polymer 6: C, 86.28; H,7.24; N, 1.97. Found: C, 85.95; H, 7.38; N,
2.08%. Compound 5 was copolymerised with styrene with the radio
of 1/4, the theoretical structural unit of polymer 6 was composed of
1 mol 5 and 4 mol styrene, so the calculated analysis of polymer 6
was obtained by calculating the contents of C, H, N in the sum of
1 mol 5 and 4 mol styrene.
O-(4-vinylbenzyl)-L- tyrosinol 4: Acetyl chloride (1.48 mL, 20.8
mmol) in ethyl acetate (15 mL) was added dropwise to a solution of
3 (3.98 g, 10.4 mmol) in mixed solvents of ethyl acetate (15 mL) and
methanol (60 mL) at 0 °C. After stirring for 30 min at 0 °C, the reac-
tion mixture was warmed up to room temperature and stirred continu-
ally for 24 h. To the yellow mixture was added excess 1.5 M NaOH.
The solvent was removed under vacuum and the residue diluted
with water (30 mL) and ethyl acetate (50 mL). The aqueous layer
was extracted with ethyl acetate (3 × 50 mL). The organic phase was
washed with brine, dried over MgSO4, and concentrated in vacuum.
The residue was purified by silica gel column chromatography (MeOH
/CH Cl2 = 1/20) to give 4 as a white solid (2.50 g, 85%). M.p. 145.5–
146.21 °C; [α]D20 = –0.8 (c 0.12, MeOH); IR(NaCl): υ = 3334, 3271，
1509，1176 cm−1; 1HNMR (CDCl3,600 MHz): δ 1.50 (2H, s, C–NH2),
2.47 (1H, m, ArCH ), 2.72 (1H, m, ArCH ), 3.35 (1H, d, J = 3.6Hz,
CH2O), 3.49 (1H, s,2OH), 3.61 (1H, m, CH22O), 5.03 (2H, s, ArCH2O),
5.26 (1H, d, J = 10.8Hz, = CH2), 5.75 (1H, d, J = 18.0Hz, = CH ), 6.71
(1H, dd, J1 = 10.8Hz, J2 = 18Hz, CH2 = CH), 6.90 (2H, d, J =27.8Hz,
ArH), 7.09 (2H, d, J = 7.8Hz, ArH), 7.37 (2H, d, J = 7.8Hz, ArH) 7.41
(2H, d, J = 7.2Hz, ArH); 13C NMR(CDCl , 150MHz): δ 41.9, 54.0,
68.5, 70.9, 114.3, 114.4(2C), 126.5(2C), 1237.1(2C), 129.2(2C), 130.4,
136.2(2C), 140.3, 158.0; Elementary analysis Calcd for C H21NO2:
C, 76.29; H, 7.47; N, 4.94. Found: C, 76.35; H, 7.43; N, 4.8198%.
(4S)- 4-[4-(4-vinylbenzyloxy)benzyl]-4,5-dihydrooxazoline (5):
DMF-DMA (1.02 mL, 7.7 mmol), and TsOH (50 mg) under N were
added to a solution of 4 (2.0 g, 7.01 mmol) in toluene (80 mL2). The
solution was refluxed for 48 h in a flask equipped with a Soxhlet
extraction device containing 20 g 4A molecular sieves under N2. The
We gratefully acknowledge financial support from the National
Natural Sciences Foundation of China (No: 20772026) and
the 2007 Excellent Mid-youth Innovative Team Project of the
Education Department of Hubei Province (No. T200701).
Received 1 December 2009; accepted 29 January 2010
Paper 090891 doi: 10.3184/030823410X12653142350782
Published online: 1 March 2010
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