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Y.-Y. Zhou et al.
LETTER
Chem. 2009, 74, 6878. (g) Liu, Y.; Shang, D.; Zhou, X.; Liu,
X.; Feng, X. Chem. Eur. J. 2009, 15, 2055. (h) Hong, L.;
Wang, L.; Chen, C.; Zhang, B.; Wang, R. Adv. Synth. Chem.
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Wang, R. J. Org. Chem. 2009, 74, 6881. (j) Kang, Q.; Zhao,
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Org. Lett. 2008, 10, 1815. (o) Lee, S.; MacMillan, D. W. C.
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2007, 9, 2601. (t) Dong, H.-M.; Lu, H.-H.; Lu, L.-Q.; Chen,
C.-B.; Xiao, W.-J. Adv. Synth. Catal. 2007, 349, 1597.
(5.0 mL, 1.6 M in hexanes, 8.0 mmol) within 15–20 min at
–78 °C. The resulting yellow solution was stirred for 1 h at
the same temperature, then a solution of 2-chloromethyl
oxazoline 6a (1.99 g, 9.8 mmol) in THF (50 mL) was added
dropwise at –78 °C over 20 min. The mixture was slowly
warmed to room temperature and kept stirring for a further
36 h. The solvent was removed and the residue was diluted
with CH2Cl2 (100 mL), then washed with H2O (20 mL). The
aqueous layer was extracted with CH2Cl2 (2 × 20 mL), and
the combined organic phases were dried over Na2SO4,
filtered, and concentrated. Petroleum ether was added to
precipitate 2-chloromethyl oxazoline, the filtrate was
collected, and the solvent was removed in vacuo. The
residue was purified by flash chromatography (PE–EtOAc,
10:1→1:2) to give pure product as a white solid. Yield: 2.64
g (64%); [a]D20 –8.2 (c 1.00, CHCl3); IR (KBr): 2958, 2926,
2870, 1659, 1599, 1478, 1459, 1362, 1247, 1177, 1001, 752
cm–1; 1H NMR (400 MHz, CDCl3): d = 7.80 (d, J = 6.0 Hz,
1 H), 7.22–7.26 (m, 4 H), 7.08 (s, 2 H), 5.54 (d, J = 8.0 Hz,
1 H), 5.37 (t, J = 6.8 Hz, 1 H), 4.28 (t, J = 8.8 Hz, 1 H), 3.98
(t, J = 7.6 Hz, 1 H), 3.70–3.83 (m, 3 H), 3.35–3.55 (m, 4 H),
3.06–3.13 (m, 2 H), 2.68 (d, J = 14.8 Hz, 1 H), 1.67–1.76
(m, 1 H), 1.54–1.62 (m, 1 H), 1.26 (s, 18 H), 0.70–0.87 (m,
12 H); 13C NMR (100 MHz, CDCl3): d = 165.5, 165.3,
164.7, 150.0, 142.4, 140.1, 135.3, 128.2, 127.2, 125.4,
125.4, 124.9, 120.5, 82.9, 76.4, 71.7, 71.0, 70.0, 69.4, 46.0,
40.1, 38.3, 34.6, 32.4, 31.8, 31.5, 30.4, 18.8, 18.4, 17.6, 17.0;
MS (EI): m/z = 611 [M+]; HRMS (EI): m/z [M]+ calcd for
C39H53O3N3: 611.4087. Found: 611.4088.
Typical procedure for 2/Cu(OTf)2-catalyzed asymmetric
Friedel–Crafts reaction (9b as an example): To a Schlenk
tube was added 2 (18.4 mg, 0.030 mmol), Cu(OTf)2 (9.1 mg,
0.025 mmol), and s-BuOH (1.25 mL) under an N2 atmos-
phere, and the resulting blue-green solution was stirred at
room temperature for 2–3 h. The solution of catalyst was
transferred to 8b (62.5 mg, 0.25 mmol) under an air atmos-
phere and the mixture was allowed to stir at –25 °C for 15
min, then indole (36.0 mg, 0.30 mmol) was added. The
reaction was held at –25 °C until complete (reaction
monitored by TLC), then the mixture was concentrated
under reduced pressure, and the residue was submitted to
flash column chromatography on silica gel (CH2Cl2–PE, 1:1
then pure CH2Cl2) to afford the desired product 9b as a white
solid. Yield: 91.6 mg (99%); 94% ee [Chiralcel OD-H,
i-PrOH–hexane, 10:90, 0.90 mL/min, 254 nm: tR (minor) =
20.35 min, tR (major) = 24.73 min.]; 1H NMR (300 MHz,
CDCl3): d = 8.01 (br s, 1 H), 7.55 (d, J = 8.1 Hz, 1 H), 7.19–
7.38 (m, 6 H), 7.11–7.16 (m, 2 H), 7.01–7.06 (m, 1 H), 5.08
(d, J = 12 Hz, 1 H), 4.29 (d, J = 12 Hz, 1 H), 3.99 (m, 4 H),
1.00 (m, 6 H).
(10) Cornejo, A.; Fraile, J. M.; García, J. I.; Gil, M. J.; Martínez-
Merino, V.; Mayoral, J. A.; Pires, E.; Villalba, I. Synlett
2005, 2321.
(11) Cao, C.-L.; Zhou, Y.-Y.; Sun, X.-L.; Tang, Y. Tetrahedron
2008, 64, 10676.
(12) Procedure for the preparation of i-Pr-bisoxazoline:
2-(3,5-Di-tert-butylbenzyl)malononitrile (5.36 g, 20 mmol)
and Zn(OTf)2 (7.27 g, 20 mmol) in anhydrous toluene (150
mL) was stirred for 5 min under a nitrogen atmosphere. To
the mixture was added a solution of (S)-2-amino-3-methyl-
butan-1-ol (4.16 g, 40 mmol) in anhydrous toluene (50 mL)
and the resulting reaction mixture was heated at reflux for 72
h. After cooling to r.t., the mixture was washed with brine
(3 × 100 mL) and NaHCO3 (3 × 100 mL), dried over
Na2SO4, and concentrated. The residue was purified by flash
chromatography to give pure i-Pr-BOX as a buff-colored oil.
Yield: 6.07 g (69%). [a]D20 –34.1 (c 0.50, CHCl3); IR (neat):
2959, 2872, 1665, 1599, 1468, 1362, 1249, 1201, 991, 713
cm–1; 1H NMR (300 MHz, CDCl3): d = 7.24 (t, J = 1.8 Hz,
1 H), 7.08 (d, J = 1.8 Hz, 2 H), 4.17–4.26 (m, 2 H), 4.00 (t,
J = 7.8 Hz, 1 H), 3.80–3.97 (m, 4 H), 3.15–3.31 (m, 2 H),
1.69–1.80 (m, 1 H), 1.52–1.62 (m, 1 H), 1.30 (s, 18 H),
0.72–0.90 (m, 12 H); 13C NMR (75 MHz, CDCl3): d =
163.63, 163.60, 149.9, 136.7, 122.78, 120.0, 71.4, 71.4,
69.7, 69.6, 41.0, 35.9, 34.3, 31.9, 31.1, 18.1, 18.0, 17.4; MS
(EI): m/z = 440 [M+]; HRMS (EI): m/z [M]+ calcd for
C28H44O2N2 440.3403. Found: 440.3402.
Typical procedure for the synthesis of chiral hetero-
trisoxazoline 2: To a solution of bisoxazoline 5 (2.97 g, 7.0
mmol) in dried THF (90 mL) was added dropwise t-BuLi
Synlett 2011, No. 7, 935–938 © Thieme Stuttgart · New York