LETTER
Mitsunobu Diol Cyclisation to Chiral Morpholines and Dioxanes
2153
N-(3,4-Dichlorobenzyl)-2(S)-(chloromethyl)morpholine·HCl
(16)
Cl
Cl
NPhth
OH OH
O
N
O
To N-(3,4-dichlorobenzyl)ethanolamine 4 (5 g) was added (R)-(–)-
epichlorohydrin (3.2 mL 1.8 equiv) and the reaction mixture stirred
at 20 °C for 18 h. Then, TPP (7.72 g, 1.3 equiv) was added, the so-
lution cooled to 0 °C, and DIAD (5.15 mL, 1.15 equiv) added drop-
wise over 5 min. The reaction was warmed to 20 °C, stirred for 1 h,
and toluene (25 mL) added. In a separate flask, acetyl chloride (3.2
mL, 2 equiv) was added to i-PrOH (25 mL) with cooling, then this
solution added slowly to the reaction mixture. The slurry was aged
for 15 min, isolated by filtration, and the cake washed with toluene
(2 × 20 mL). After drying the product 16 was recovered as a white
crystalline powder (5.52 g, 73%). 1H NMR (DMSO-d6): d = 12.1 (1
H, br), 8.01 (1 H, s), 7.76 (1 H, d, J = 8 Hz), 7.65 (1 H, d, J = 8 Hz),
4.39 (2 H, m), 4.16 (1 H, m), 4.00 (2 H, m), 3.80 (1 H, d, J = 3.5, 12
PhthNK
65%
Cl
see
text
N
N
Cl
Cl
Cl
Cl
Cl
15
16
17
NH2
i) NaN3
O
ii) Ph3P
81%
N
Cl
Hz), 3.71 (1 H, d, J = 5, 12 Hz), 3.30 (2 H, m), 2.99 (2 H, m). 13
NMR (DMSO-d6): d = 133.5, 132.4, 131.9, 131.3, 130.9, 130.2,
71.7, 62.8, 57.6, 51.6, 50.1, 44.5. HRMS: m/z calcd for
C12H15NOCl3: 294.0219 [MH]; found: 294.0222 [MH+].
C
Cl
2
Scheme 7 Completion of chiral route from epichlorohydrin to 2
Acknowledgment
N-(3,4-Dichlorobenzyl)-2(S)-(phthalimidomethyl)morpholine
(9)
Ian Steeples and Marianna Nott are acknowledged for important
contributions. Mike Hindson, Simon Watson, Judith Careirra and
Eleanor Roberts are thanked for analytical support.
N-(3,4-Dichlorobenzyl)ethanolamine (4, 65 g) was slurried in tolu-
ene (360 mL) and heated to 82 °C until complete dissolution. The
toluene solution was washed with H2O (100 mL) and concentrated
to 130 mL by atmospheric distillation. (S)-N-(2,3-Epoxypropyl)ph-
thalimide (7, 59.4 g, 0.99 equiv) was added, and the mixture heated
to 122 °C for 5 h. Post cooling to 100 °C, toluene (160 mL) was
added, followed by TPP (89 g, 1.15 equiv). The solution was cooled
to 55 °C, and DIAD (67 mL, 1.15 equiv) added over 1 h. After
warming to 75 °C, n-PrOH (490 mL) was added, and the mixture
concentrated to 375 mL. Then, EtOH (585 mL) was added, the mix-
ture refluxed for 15 min, then cooled to 50 °C over 90 min. The slur-
ry was held at this temperature for 30 min, cooled to 0 °C over 90
min, and held for 30 min. Isolation by filtration was followed by
washing with chilled EtOH (2 × 260 mL). Post drying the product 9
was recovered as a white crystalline powder (101.5 g, 84.4%). IR
(neat): 1708, 1465, 1421, 1388 cm–1. 1H NMR (CDCl3): d = 7.87 (4
H, m), 7.58 (1 H, d, J = 8 Hz), 7.55 (1 H, d, J = 1 Hz), 7.31 (1 H, dd,
J = 1, 8 Hz), 3.78–3.70 (3 H, m), 3.58–3.40 (4 H, m), 2.78 (1 H, d,
J = 11 Hz), 2.52 (1 H, m), 2.10 (1 H, apparent dt), 1.94 (1 H, appar-
ent t). 13C NMR (DMSO-d6): d = 168.3, 139.7, 135.0, 131.9, 131.3,
131.0, 130.9, 130.0, 129.5, 123.6, 72.9, 66.1, 61.0, 56.2, 52.6, 40.3.
HRMS: m/z calcd for C20H19N2O3Cl2: 405.0773 [MH]; found:
405.0762 [MH+].
References
(1) Ancliff, R. A.; Cook, C. M.; Eldred, C. D.; Gore, P. M.;
Harrison, L. A.; Hayes, M. A.; Hodgson, S. T.; Judd, D. B.;
Keeling, S. E.; Lewell, X. Q.; Mills, G.; Robertson, G. M.;
Swanson, S.; Walker, A. J.; Wilkinson, M. PCT Int. Appl.
WO 2003082861, 2003; Chem. Abstr. 2003, 139, 307777.
(2) Kato, S.; Morie, T.; Hino, K.; Kon, T.; Naruto, S.; Yoshida,
N.; Karasawa, T.; Matsumoto, J.-I. J. Med. Chem. 1990, 33,
1406.
(3) Loftus, F. Synth. Commun. 1980, 10, 59.
(4) Chiral morpholine synthesis via tosylation, see: Myers, A.
G.; Lanman, B. A. Org. Lett. 2004, 6, 1045.
(5) Hayes, M. A.; Mills, G.; Swanson, S.; Walker, A. J.;
Wilkinson, M. PCT Int. Appl. WO 2003082835, 2003;
Chem. Abstr. 2003, 139, 307774.
(6) For other routes, see: Wilkinson, M. C. Tetrahedron Lett.
2005, 46, 4773.
Synlett 2006, No. 13, 2151–2153 © Thieme Stuttgart · New York