The Journal of Organic Chemistry
ARTICLE
chloride (537 mg, 1.57 mmol, 7.0 equiv) in THF (15 mL) was added n-
BuLi (2.5 M in hexane, 540 μL, 1.35 mmol, 6.0 equiv) at 0 °C. After
being stirred for 30 min at 0 °C, a solution of the crude aldehyde in THF
(10 mL) was added at 0 °C. After 1 h at rt, the reaction mixture was
neutralized by addition of a saturated aqueous solution of NaHCO3 and
then extracted with AcOEt (80 mL). The organic layer was dried over
MgSO4, filtered, and then evaporated under reduced pressure. The
residue was purified by flash chromatography on silica gel (hexane/
AcOEt 90/10 to 50/50) to give the products as yellow oils Z-17 (31 mg,
79 μmol, 35%) and E-17 (21 mg, 54 μmol, 24%). Rf 0.3 (PE/AcOEt 50/
Maffrand, J.-P.; Soubriꢀe, P.; Pascal, M. J. Pharmacol. Exp. Ther. 2002,
303, 1171–1179. (b) Steinberg, R.; Alonso, R.; Rouquier, L.; Desvignes,
C.; Michaud, J.-C.; Cudennec, A.; Jung, M.; Simiand, J.; Griebel, G.;
Emonds-Alt, X.; Le Fur, G.; Soubriꢀe, P. J. Pharmacol. Exp. Ther. 2002,
303, 1180–1188.
(4) For a review on C-substituted morpholine, see: Wijtmans, R.;
Vink, M. K. S.; Schoemaker, H. E.; van Delft, F. L.; Blaauw, R. H.; Rutjes,
F. P. J. T. Synthesis 2004, 641–662.
(5) Takemoto, T.; Iio, Y.; Nishi, T. Tetrahedron Lett. 2002,
41, 1785–1788 and references cited therein.
(6) Nishi, T.; Ishibashi, K.; Nakajima, K.; Iio, Y.; Fukazawa, T.
Tetrahedron: Asymmetry 1998, 9, 3251–3262.
1
50); IR (neat) 2924, 2855, 1631, 1427, 1271, 1078, 1027 cm-1; H
NMR (DMSO-d6 at 120 °C) δ 7.60 (d, J = 1.4 Hz, 1H), 7.55 (d, J = 8.4
Hz, 1H), 7.47-7.43 (m, 3H), 7.39-7.34 (m, 3H), 6.09 (d, J = 6.9 Hz,
1H), 4.51 (d, J = 6.9 Hz, 1H), 4.09 (d, J = 13.4 Hz, 1H), 3.85-3.79 (m,
2H), 3.70-3.60 (m, 2H), 3.39 (s, 3H), 3.33 (m, 1H); 13C NMR
(CDCl3) δ 170.4 (s), 148.9 (d), 143.6 (s), 135.4 (s), 132.2 (s), 131.1
(s), 130.0 (d), 129.9 (d), 128.5 (d), 128.2 (d), 127.0 (d, 2C), 125.5 (d, 2C),
106.7 (d), 77.26 (s), 61.2 (t), 60.5 (q), 49.9 (t), 47.5 (t); HRMS (ESI)
calcd for C20H20NO3Cl2 (M þ Hþ) 392.0815, found 392.0816.
(7) Okachi, T.; Murai, N.; Onaka, M. Org. Lett. 2003, 5, 85–87.
(8) Takamura, M.; Yabu, K.; Nishi, T.; Yanagisawa, H.; Kanai, M.;
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(9) For reviews, see: (a) Cossy, J.; Gomez Pardo, D. Chemtracts 2002,
15, 579–605. (b) Mꢀetro, T.-X.; Gomez Pardo, D.; Cossy, J. Chem.—
Eur. J. 2009, 15, 1064–1070. (c) Cossy, J.; Gomez Pardo, D.; Dumas,
C.; Mirguet, O.; Dechamps, I.; Mꢀetro, T.-X.; Burger, B.; Roudeau,
R.; Appenzeller, J.; Cochi, A. Chirality 2009, 21, 850–856. (d) Mꢀetro,
T.-X.; Duthion, B.; Gomez Pardo, D.; Cossy, J. Chem. Soc. Rev. 2010,
39, 89–102.
(10) For rearrangement of linear β-amino alcohols see: (a) Mꢀetro,
T.-X.; Appenzeler, J.; Gomez Pardo, D.; Cossy, J. Org. Lett. 2006,
8, 3509–3512. (b) Mꢀetro, T.-X.; Gomez Pardo, D.; Cossy, J. J. Org.
Chem. 2007, 72, 6556–6561. (c) Mꢀetro, T.-X.; Gomez Pardo, D.; Cossy,
J. Synlett 2007, 2888–2890. (d) Duthion, B.; Mꢀetro, T.-X.; Gomez
Pardo, D.; Cossy, J. Tetrahedron 2009, 65, 6696–6706.
(11) For rearrangement of cyclic β-amino alcohols see: (a) Cossy, J.;
Dumas, C.; Michel, P.; Gomez Pardo, D. Tetrahedron Lett. 1995,
36, 549–552. (b) Cossy, J.; Dumas, C.; Gomez Pardo, D. Eur. J. Org.
Chem. 1999, 1693–1699.
(12) (a) Cossy, J.; Dumas, C.; Gomez Pardo, D. Bioorg. Med. Chem.
1997, 7, 1343–1344. (b) Dechamps, I.; Gomez Pardo, D.; Karoyan, P.;
Cossy, J. Synlett 2005, 1170–1172. (c) Dechamps, I.; Gomez Pardo, D.;
Cossy, J. Arkivoc 2007, v, 38–45. (d) Dechamps, I.; Gomez Pardo, D.;
Cossy, J. Tetrahedron 2007, 63, 9082–9091. (e) Mꢀetro, T.-X.; Gomez
Pardo, D.; Cossy, J. J. Org. Chem. 2008, 73, 707–710. (f) Cochi, A.;
Burger, B.; Navarro, C.; Gomez Pardo, D.; Cossy, J.; Zhao, Y.; Cohen, T.
Synlett 2009, 2157–2161.
[2-(3,4-Dichlorophenyl)-2-((E)-2-methoxyvinyl)mor-
pholin-4-yl]phenylmethanone (E-17): Rf 0.5 (PE/AcOEt 50/
1
50); IR (neat) 2924, 2860, 1629, 1430, 1221, 1076, 1027 cm-1; H
NMR (DMSO-d6 at 100 °C) δ 7.60-7.58 (m, 2H), 7.47-7.45 (m, 3H),
7.37 (dd, J = 8.5 and 1.8 Hz, 1H), 7.34-7.31 (m, 2H), 6.47 (d, J = 12.9
Hz, 1H), 4.89 (d, J = 12.9 Hz, 1H), 3.98 (d, J = 13.7 Hz, 1H), 3.85 (m,
1H), 3.81 (d, J = 13.7 Hz, 1H), 3.62 (m, 1H), 3.54 (m, 1H), 3.52 (s, 3H),
3.42 (m, 1H); 13C NMR (CDCl3) δ 170.0 (s), 151.5 (d), 143.1 (s),
135.1 (s), 132.6 (s), 131.6 (s), 130.5 (d), 130.0 (d), 128.7 (d), 128.6 (d),
127.1 (d), 126.9 (d), 125.9 (d), 125.3 (d), 105.1 (d), 77.24 (s), 61.0 (t),
56.4 (q), 48.9 (t), 47.5 (t); HRMS (ESI) calcd for C20H20NO3Cl2 (M þ
Hþ) 392.0815, found 392.0816.
’ ASSOCIATED CONTENT
S
Supporting Information. NMR spectra of compounds 2,
b
4-6, and 17 and SFC spectra of compound 6. This material is
(13) Ooi, T.; Takeuchi, M.; Ohara, D.; Maruoka, K. Synlett 2001,
1185–1187.
’ AUTHOR INFORMATION
(14) Shuman, R. T.; Rothenberger, R. B.; Campbell, C. S.; Smith,
G. F.; Gifford-Moore, D. S.; Gesellchen, P. D. J. Med. Chem. 1993,
36, 314–319.
Corresponding Author
*E-mail: domingo.gomez-pardo@espci.fr; janine.cossy@espci.fr.
(15) Kukolja, S.; Draheim, S. E.; Pfeil, J. L.; Cooper, R. D. G.; Graves,
B. J.; Holmes, R. E.; Neel, D. A.; Huffman, G. W.; Webber, J. A.; Kinnick,
M. D.; Vasileff, R. T.; Foster, B. J. J. Med. Chem. 1985, 28, 1886–1896.
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G. W.; Cram, D. J. J. Am. Chem. Soc. 1978, 100, 4555–4568.
(17) Look, G. C.; Murphy, M. M.; Campbell, D. A.; Gallop, M. A.
Tetrahedron Lett. 1995, 36, 2937–2940.
’ ACKNOWLEDGMENT
Sanofi-Aventis is greatly acknowledged for financial support
(T.-X.M.). The authors also wish to thank Dr. Vincent Ferey and
Sylvie Vigne (Sanofi-Aventis) for furnishing a sample of SSR
241579.
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915–945.(e) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001.
DEDICATION
†Dedicated to Professor Carmen Najerꢀa on the occasion of her
60th birthday.
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