E
Synlett
H. Dao Thi et al.
Letter
2
24. (d) Ji, Y.; Brueckl, T.; Baxter, R. D. Fujiwara Y.; Seiple, I. B.;
Su, S.; Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A.
011, 108, 14411.
of
cis-3-methoxy-1-(4-methoxyphenyl)-4-(trifluoro-
methyl)azetidine (4b, 0.15 g, 0.57 mmol, 1 equiv) in dry CH Cl2
2
2
(4 mL). After stirring for 2 h at room temperature, the solvent
was evaporated, and the resulting residue was redissolved in
MeCN (5 mL), after which NaOAc (0.19 g, 2.28 mmol, 4 equiv)
was added. After stirring at reflux temperature for 2 h, the reac-
(
(
(
5) (a) Mollet, K.; Catak, S.; Waroquier, M.; Van Speybroeck, V.;
D’hooghe, M.; De Kimpe, N. J. Org. Chem. 2011, 76, 8364.
(b) D’hooghe, M.; Dekeukeleire, S.; Leemans, E.; De Kimpe, N.
Pure Appl. Chem. 2010, 82, 1749. (c) Dekeukeleire, S.; D’hooghe,
M.; Törnroos, K. W.; De Kimpe, N. J. Org. Chem. 2010, 75, 5934.
tion mixture was poured into a sat. solution of NaHCO (5 mL),
3
extracted with CH Cl (3 × 5 mL), and washed with brine (3 × 5
2
2
(
d) Van Brabandt, W.; Van Landeghem, R.; De Kimpe, N. Org.
Lett. 2006, 8, 1105. (e) Van Brabandt, W.; De Kimpe, N. Synlett
006, 2039.
mL). Drying (MgSO ), filtration of the drying agent, and evapo-
4
ration of the solvent afforded syn-4,4,4-trifluoro-2-methoxy-3-
[N-(4-methoxyphenyl)-N-methylamino]butyl acetate (6b),
which was purified by means of preparative TLC (hexane–
2
6) (a) D’hooghe, M.; Dekeukeleire, S.; De Kimpe, N. Org. Biomol.
Chem. 2008, 6, 1190. (b) D’hooghe, M.; Dekeukeleire, S.; Mollet,
K.; Lategan, C.; Smith, P. J.; Chibale, K.; De Kimpe, N. J. Med.
Chem. 2009, 52, 4058. (c) Lee, H. K.; Chun, J. S.; Pak, C. S. Tetrahe-
dron Lett. 2001, 42, 3483. (d) Lee, H. K.; Chun, J. S.; Pak, C. S. Tet-
rahedron 2003, 59, 6445. (e) Chincholkar, P. M.; Kale, A. S.;
Gumaste, V. K.; Deshmukh, A. R. A. S. Tetrahedron 2009, 65,
EtOAc); pale yellow oil, yield 86%; R = 0.07 (PE–EtOAc, 95:5). IR
f
(ATR): ν
= 1745 (CO), 1512, 1242, 1097, 1053, 1038, 818 cm–1
.
max
1
H NMR (300 MHz, CDCl ): δ = 2.01 (3 H, s), 3.02 (3 H, s), 3.48 (3
3
H, s), 3.76 (3 H, s), 3.91 (1 H, qd, J = 5.5, 1.1 Hz), 4.14 (1 H, dd, J =
13
12.1, 6.6 Hz), 4.21–4.27 (2 H, m), 6.82 (4 H, br s). C NMR (75
MHz, CDCl ): δ = 20.6, 34.7, 55.6, 59.4, 61.9 (q, J = 26.9 Hz), 77.8,
3
2605.
114.6, 116.0, 125.9 (q, J = 288.5 Hz), 145.0, 152.9, 170.4. 19
F
7) (a) Ojima, I.; Slater, J. C. Chirality 1997, 9, 487. (b) Abouabdellah,
A.; Bégué, J.-P.; Bonnet-Delpon, D.; Thanh Nga, T. T. J. Org. Chem.
NMR (282 MHz, CDCl ): δ = –68.36 (3 F, d, J = 7.9 Hz). MS (70
3
+
+
eV): m/z (%) = 336 (80) [M + H], 321 (100) [M – CH ]. ESI-
HRMS: m/z calcd for C15H21F3NO4 : 336.1417 [M + H] ; found:
3
+
+
1997, 62, 8826. (c) Abouabdellah, A.; Bégué, J.-P.; Bonnet-
Delpon, D. Synlett 1996, 399.
8) Li, B.; Wang, Y.; Du, D.-M.; Xu, J. J. Org. Chem. 2007, 72, 990.
9) Jiao, L.; Liang, Y.; Xu, J. J. Am. Chem. Soc. 2006, 128, 6060.
336.1433.
3
3
(
(
(14) syn-2-Benzyloxy-4,4,4-trifluoro-N -(4-methoxyphenyl)-N -
1
methyl-N -tert-butylbutane-1,3-diamine (7a)
(
10) Bonnet-Delpon, D.; Bégué, J. P.; Legros, J.; Crousse, B. WO
003095415, 2003; Chem. Abstr. 2003, 139, 381242
In a flame-dried flask under nitrogen atmosphere, Me O·BF4
(0.13 g, 0.88 mmol, 2 equiv) was added to an ice-cooled solution
3
2
(11) cis-3-Benzyloxy-1-(4-methoxyphenyl)-4-(trifluoro-
of
cis-3-benzyloxy-1-(4-methoxyphenyl)-4-(trifluoro-
methyl)azetidine (4a)
methyl)azetidine (4a, 015 g, 0.44 mmol, 1 equiv) in dry CH Cl2
2
To an ice-cooled solution of AlCl (2.22 g, 16.62 mmol, 3 equiv)
(3 mL). After stirring for 2 h at room temperature, the solvent
was evaporated, and the residue was redissolved in MeCN (3
mL), followed by the addition of tert-butylamine (0.13 g, 1.76
mmol, 4 equiv). After heating for 4 h at reflux temperature, the
reaction mixture was poured into a sat. solution of NaHCO3
(4 mL), extracted with CH Cl (3 × 3 mL), and washed with brine
3
in dry Et O (30 mL), LiAlH (0.63 g, 16.62 mmol, 3 equiv) was
2
4
carefully added dropwise under N . The reaction mixture was
2
allowed to reach room temperature and was then heated for 30
min at reflux temperature. Afterwards, the reaction mixture
was cooled to 0 °C and cis-azetidin-2-one 3a (1.94 g, 5.54 mmol,
2
2
1
equiv) was added. After stirring for 3 h at room temperature,
(3 × 3 mL). Drying (MgSO ), filtration of the drying agent, and
4
the reaction was quenched with H O (15 mL) and filtered
evaporation of the solvent yielded syn-2-benzyloxy-4,4,4-triflu-
oro-N -(4-methoxyphenyl)-N -methyl-N -tert-butylbutane-
1,3-diamine (7a), which was purified by means of preparative
2
®
3
3
1
through a short pad of Celite . Extraction with CH Cl (3 × 10
2
2
mL), drying (MgSO ), filtration of the drying agent, and evapora-
4
tion of the solvent afforded cis-3-benzyloxy-1-(4-methoxyphe-
nyl)-4-(trifluoromethyl)azetidine (4a) in 86% yield in high
purity (>95% based on NMR); orange crystals; yield 86%; mp
TLC (hexane–EtOAc, 95:5); pale yellow oil, yield 78%; R = 0.04
f
(PE–EtOAc, 95:5). IR (ATR): ν
= 3308 (NH), 1512, 1243, 1144,
max
–1 1
1113, 1029, 814, 739 cm . H NMR (300 MHz, CDCl ): δ = 0.95
3
5
4
1
3
4
9 °C. Elem. Anal. calcd. for C18H18F NO : C 64.09, H 5.38, N
(9 H, s), 2.68 (1 H, dd, J = 12.1, 7.2 Hz), 2.77 (1 H, dd, J = 12.1, 5.5
Hz), 3.04 (3 H, s), 3.77 (3 H, s), 3.98–4.01 (1 H, m), 4.51 (1 H, dq,
J = 8.4, 5.0 Hz), 4.59 and 4.67 (2 × 1 H, 2 d, J = 11.6 Hz), 6.83 and
3
2
.15; found: C 63.96, H 5.14, N 4.12. IR (ATR): ν
= 1510, 1242,
max
–1 1
124, 813, 735 cm . H NMR (300 MHz, CDCl ): δ = 3.75 (3 H, s),
3
13
.93 (1 H, dd, J = 8.3, 7.7 Hz), 4.17 (1 H, dd, J = 8.3, 4.4 Hz), 4.43–
.61 (2 H, m), 4.52 and 4.68 (2 × 1 H, 2 d, J = 11.6 Hz), 6.50–6.56
6.89 (2 × 2 H, 2 d, J = 8.8 Hz), 7.29–7.36 (5 H, m). C NMR (75
MHz, CDCl ): δ = 28.9, 34.8, 42.4, 50.5, 55.8, 62.1 (q, J = 26.6 Hz),
3
13
and 6.79–6.86 (4 H, 2 m), 7.29–7.38 (5 H, m). C NMR (75 MHz,
CDCl ): δ = 55.7, 59.7, 67.4 (q, J = 31.2 Hz), 67.8, 72.3, 113.1,
73.6, 79.1, 114.7, 115.7, 126.4 (q, J = 288.4 Hz), 127.9, 128.5,
1
9
138.2, 145.2, 152.6. F NMR (282 MHz, CDCl ): δ = –67.85 (3 F,
3
3
+
114.7, 124.8 (q, J = 281.5 Hz), 127.6, 128.0, 128.5, 137.2, 142.5,
d, J = 9.2 Hz). MS (70 eV): m/z (%) = 425 (100) [M + H]. ESI-
HRMS: m/z calcd for C23H32F N O : 425.2410 [M + H] ; found:
19
+
+
153.0. F NMR (282 MHz, CDCl ): δ = –70.03 (3 F, d, J = 6.6 Hz).
3
3 2 2
+
MS (70 eV): m/z (%) = 338 (100) [M + H]. ESI-HRMS: m/z calcd
for C18H19F3NO2 : 338.1362 [M + H] ; found: 338.1365.
425.2421.
+
+
(15) (a) Laguerre, M.; Boyer, C.; Carpy, A.; Léger, J. M.; Panconi, E.;
Vaugien, B.; Cognic, F. Eur. J. Med. Chem. 1993, 28, 77.
(b) Sharma, D.; Sharma, R. K.; Bhatia, S.; Tiwari, R.; Mandal, D.;
Lehmann, J.; Parang, K.; Olsen, C. E.; Parmar, V. S.; Prasad, A. K.
Biochimie 2010, 92, 1164. (c) Lee, C. E.; Kick, E. K.; Ellman, J. A.
J. Am. Chem. Soc. 1998, 120, 9735.
(
12) (a) Lensen, N.; Marais, J.; Brigaud, T. Org Lett. 2015, 17, 342.
(b) Ngoc Tam, N. T.; Magueur, G.; Ourévitch, M.; Crousse, B.;
Bégué, J.-P.; Bonnet-Delpon, D. J. Org. Chem. 2005, 70, 699.
(c) Jiang, J.; Shah, H.; DeVita, R. J. Org Lett. 2003, 5, 4101.
(
d) Bravo, P.; Fustero, S.; Guidetti, M.; Volonterio, A.; Zanda, M.
J. Org. Chem. 1999, 64, 8731.
13) syn-2-Methoxy-3-[N-(4-methoxyphenyl)-N-methylamino]-
(16) (a) Bredikhina, Z. A.; Pashagi, A. V.; Savel’ev, D. V.; Bredikhin, A.
A. Russ. Chem. Bull. Int. Ed. 2001, 50, 436. (b) Weglicki, W. B. US
1998187334, 1999; Chem. Abstr. 1999, 131, 63464
(c) Bundgaards, H. WO 8807044 A1, 1988; Chem. Abstr. 1989,
110, 75519.
(
4,4,4-trifluorobutyl Acetate (6b)
In a flame-dried flask under nitrogen atmosphere, Me O·BF
3
4
(0.17 g, 1.14 mmol, 2 equiv) was added to an ice-cooled solution
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F