Organocatalytic Mannich Reactions of Fluorinated Aldimines
tRanti: 43.72 min, tRsyn: 37.83 min); ee of the anti isomer: 98% (hex-
ane/2-propanol 95:5, tRmajor: 14.25 min, tRminor: 9.89 min); m.p. 64–
66 °C. [α]2D0 = +2.8 (c = 0.9, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 0.94 (t, J = 7.5 Hz, 3 H, Me–CH2), 1.59–1.65 (m, 3 H, Me–
CH2), 1.85–1.88 (m, 1 H, CH–Et), 3.74 (s, 3 H, Me–O), 3.81 (dd,
J = 11.3, 3.0 Hz, 1 H, CH2–O), 3.89–3.91 (m, 1 H, CH–CF3), 4.07
(dd, J = 11.1, 2.6 Hz, 1 H, CH2–O), 4.61 (br. s, 1 H, NH), 6.64 (d,
4.20 (br. s, 1 H, NH), 6.65 (d, J = 8.9 Hz, 2 H, Ar), 6.78 (d, J =
9.0 Hz, 2 H, Ar) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 15.1,
35.7, 56.1, 60.8 (q, JCF = 25.7 Hz), 65.5, 115.3, 115.4, 141.6,
2
153.3 ppm (the CF3 signal was obscured due to its low intensity).
19F NMR (282.4 MHz, CDCl3): δ = 72.6 (d, JFH = 7.7 Hz, 3 F)
ppm. Data of syn isomer: 19F NMR (282.4 MHz, CDCl3): δ =
–72.7 (d, JFH = 7.7 Hz, 3 F) ppm. HRMS (EI): calcd. for
J = 8.9 Hz, 2 H, Ar), 6.77 (d, J = 8.9 Hz, 2 H, Ar) ppm. 13C NMR C12H16F3NO2 [M]+ 263.1133; found 263.1127.
2
(75.5 MHz, CDCl3): δ = 12.1, 22.1, 41.3, 56.1, 59.7 (q, JCF
=
(2R,3S)-4,4,4-Trifluoro-3-(4-methoxyphenylamino)-2-(propyl)butan-
1-ol (5e): According to the general procedure, from 1a[24] (100 mg,
0.49 mmol) and pentanal (127 mg, 1.48 mmol), a mixture of anti
1
28.0 Hz), 62.8, 114.9, 115.2, 127.0 (q, JCF = 284.6 Hz), 142.0,
153.0 ppm. 19F NMR (282.4 MHz, CDCl3): δ = –72.9 (d, JFH
=
7.7 Hz, 3 F) ppm. HRMS (EI): calcd. for C13H18F3NO2 [M]+
277.1290; found 277.1282.
and syn diastereomers (97:3) was obtained (57 mg, 40% yield). The
anti
diastereomers were separated by HPLC (MeCN/H2O, 50:50, tR
:
(2R,3S)-2-Benzyl-4,4,4-trifluoro-3-(4-methoxyphenylamino)butan-1-
ol (5b): According to the general procedure, from 1a[24] (100 mg,
0.49 mmol) and 3-phenylpropanal (198 mg, 1.48 mmol), a mixture
of anti and syn diastereomers (92:8) was obtained (84 mg, 50%
yield). The diastereomers were separated by HPLC (MeCN/H2O,
48:52, tRanti: 42.25 min, tRsyn: 37.5 min); ee of the anti isomer: 98%
(hexane/2-propanol 95:5, tRmajor: 19.81 min, tRminor: 23.53 min);
m.p. 122–125 °C. [α]2D0 = –21.6 (c = 0.5, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 2.25–2.32 (m, 1 H, CH–Bn), 2.89 (d, J =
7.9 Hz, 2 H, CH2–Ph), 3.76 (s, 3 H, Me–O), 3.81 (dd, J = 11.1,
18.30 min, tRsyn: 16.35 min); ee of the anti isomer: Ͼ99% (hexane/
2-propanol 96:4, tRmajor: 16.34 min, tRminor: 9.60 min); m.p. 57–
59 °C. [α]2D0 = +2.9 (c = 0.9, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 0.89 (t, J = 7.2 Hz, 3 H, Me–CH2), 1.25–1.45 (m, 2 H, CH2–
CH2), 1.45–1.65 (m, 2 H, CH2–CH2), 1.93–2.05 (m, 1 H, CH–Pr),
3.75 (s, 3 H, Me–O), 3.79 (dd, J = 11.1, 3.8 Hz, 1 H, CH2–O), 3.89
(qd, J = 8.0, 4.0 Hz, 1 H, CH–CF3), 4.07 (dd, J = 11.1, 2.4 Hz, 1
H, CH2–O), 4.59 (br. s, 1 H, NH), 6.64 (d, J = 9.0 Hz, 2 H, Ar),
6.78 (d, J = 9.1 Hz, 2 H, Ar) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 14.0, 20.2, 30.9, 38.9, 55.7, 59.5 (q, 2JCF = 27.8 Hz), 62.7, 114.6,
1
2.9 Hz, 1 H, CH2–O), 3.85–3.87 (m, 1 H, CH–CF3), 4.10 (dd, J = 114.9, 126.7 (q, JCF = 284.8 Hz), 141.6, 152.6 ppm. 19F NMR
11.2, 2.8 Hz, 1 H, CH2–O), 6.57 (d, J = 9.0 Hz, 2 H, Ar–N), 6.76
(282.4 MHz, CDCl3): δ = –72.9 (d, JFH = 8.1 Hz, 3 F) ppm. HRMS
(d, J = 8.9 Hz, 2 H, Ar–N), 7.06–7.29 (m, 5 H, Ar–CH2) ppm. 13C (EI): calcd. for C14H20F3NO2 [M]+ 291.1446; found 291.1448.
2
NMR (75.5 MHz, CDCl3): δ = 35.5, 41.6, 56.1, 58.8 (q, JCF
=
(2R,3S)-2-Ethyl-4,4,5,5,5-pentafluoro-3-(4-methoxyphenylamino)-
pentan-1-ol (5f): According to the general procedure, from 1b[25]
(100 mg, 0.39 mmol) and butyraldehyde (85 mg, 1.18 mmol), a mix-
ture of anti and syn diastereomers (93:7) was obtained (28 mg, 22%
yield). The diastereomers were separated by HPLC (MeCN/H2O,
28.7 Hz), 62.9, 115.0, 115.2, 126.9, 128.9, 129.6, 139.3, 141.6,
153.0 ppm (the CF3 signal was obscured due to its low intensity).
19F NMR (282.4 MHz, CDCl3): δ = –72.6 (d, JFH = 8.6 Hz, 3 F)
ppm. HRMS (EI): calcd. for C18H20F3NO2 [M]+ 339.1446; found
339.1446.
46:54, tRanti: 43.60 min, tRsyn: 43.41 min); ee of the anti isomer:
(R)-2-[(S)-2,2,2-Trifluoroethyl-1-(4-methoxyphenylamino)]pent-4- Ͼ99 % (hexane/2-propanol 98:2, tRmajor: 31.81 min, tR
:
minor
en-1-ol (5c): According to the general procedure, from 1a[24]
(100 mg, 0.49 mmol) and pent-4-enal (124 mg, 1.48 mmol), a mix-
ture of anti and syn diastereomers (95:5) was obtained (85 mg, 60%
yield). The diastereomers were separated by HPLC (MeCN/H2O,
48:52, tRanti: 19.98 min, tRsyn: 17.08 min); ee of the anti isomer: 97%
(hexane/2-propanol 95:5, tRmajor: 14.40 min, tRminor: 10.15 min);
m.p. 47–50 °C. [α]2D0 = +40.0 (c = 0.8, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 2.03–2.09 (m, 1 H, CH–allyl), 2.33 (t, J = 7.2 Hz, 2
H, CH2–CH=CH2), 3.74 (s, 3 H, Me–O), 3.81 (dd, J = 11.5, 3.7 Hz,
15.61 min); m.p. 65–67 °C. [α]2D0 = +10.2 (c = 0.4, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 0.92 (t, J = 7.5 Hz, 3 H, Me–CH2),
1.57–1.67 (m, 4 H, CH–CH2–Me, OH), 3.74 (s, 3 H, Me–O), 3.82
(dd, J = 11.5, 3.8 Hz, 1 H, CH2–O), 4.02–4.12 (m, 2 H, CH2–O,
CH–CF3), 4.55 (br. s, 1 H, NH), 6.60 (d, J = 8.9 Hz, 2 H, Ar), 6.76
(d, J = 8.9 Hz, 2 H, Ar) ppm. 13C NMR (75.5 MHz, CDCl3): δ =
2
12.2, 22.6, 41.7, 56.0, 57.2 (dd, JCF = 24.7, 20.1 Hz), 62.9, 114.5,
115.3, 141.8, 152.8 ppm (the CF3CF2 signals were obscured due to
their low intensity). 19F NMR (282.4 MHz, CDCl3): δ = –82.4 (s,
1 H, CH2–O), 3.90–3.95 (m, 1 H, CH–CF3), 4.07 (dd, J = 11.1, 3 F), –120.0 (dd, JFF = 273.3, JFH = 8.6 Hz, 1 F), –123.3 (dd,
3.0 Hz, 1 H, CH2–O), 4.58 (br. s, 1 H, NH), 4.98 (dd, J = 16.9,
JFF = 272.4, JFH = 20.7 Hz, 1 F) ppm. HRMS (EI): calcd. for
1.5 Hz, 1 H, CH=CH2), 5.07 (dd, J = 10.2, 1.2 Hz, 1 H, CH=CH2), C14H18F5NO2 [M]+ 327.1258; found 327.1261.
5.75 (ddt, J = 17.0, 10.1, 3.0 Hz, 1 H, CH=CH2), 6.63 (d, J =
(R)-2-[(S)-1-(2,2,3,3,3-Pentafluoropropyl-4-methoxyphenylamino)]-
9.0 Hz, 2 H, Ar), 6.76 (d, J = 8.9 Hz, 2 H, Ar) ppm. 13C NMR
pent-4-en-1-ol (5g): According to the general procedure, from 1b[25]
(100 mg, 0.39 mmol) and pent-4-enal (100 mg, 1.18 mmol), a mix-
ture of anti and syn diastereomers (95:5) was obtained (32 mg, 24%
yield). The diastereomers were separated by HPLC (MeCN/H2O,
46:54, tRanti: 35.56 min, tRsyn: 41.24 min); ee of the anti isomer: 98%
(hexane/2-propanol 95:5, tRmajor: 11.10 min, tRminor: 7.96 min); m.p.
58–60 °C. [α]2D0 = +24.0 (c = 0.2, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 2.12–2.17 (m, 1 H, CH–allyl), 2.21–2.39 (m, 3 H, CH2–
CH=CH2, OH), 3.74 (s, 3 H, Me–O), 3.82 (dd, J = 11.1, 4.1 Hz, 1
H, CH2–O), 4.03–4.17 (m, 2 H, CH2–O, CH–CF3), 4.96 (dd, J =
16.9, 1.5 Hz, 1 H, CH=CH2), 5.07 (dd, J = 10.1, 1.6 Hz, 1 H,
CH=CH2), 5.70 (ddt, J = 17.1, 9.9, 3.0 Hz, 1 H, CH=CH2), 6.60
2
(75.5 MHz, CDCl3): δ = 33.8, 39.5, 56.1, 59.1 (q, JCF = 28.7 Hz),
63.1, 115.1, 115.2, 118.6, 135.8, 141.7, 153.0 ppm (the CF3 signal
was obscured due to its low intensity). 19F NMR (282.4 MHz,
CDCl3): δ = –72.9 (d, JFH = 8.6 Hz, 3 F) ppm. HRMS (EI): calcd.
for C14H18F3NO2 [M]+ 289.1290; found 289.1285.
(2R,3S)-4,4,4-Trifluoro-3-(4-methoxyphenylamino)-2-methylbutan-
1-ol (5d): According to the general procedure, from 1a[24] (100 mg,
0.49 mmol) and propionaldehyde (86 mg, 1.48 mmol), a 86:14 mix-
ture of anti and syn diastereomers was obtained (53 mg, 41 %
yield). The diastereomers could not be separated. ee of the anti
isomer: Ͼ99%, as determined by chiral GC (tRmajor: 60.14 min).
1
Data of anti isomer: H NMR (300 MHz, CDCl3): δ = 1.15 (d, J
(d, J = 9.0 Hz, 2 H, Ar), 6.70 (d, J = 8.8 Hz, 2 H, Ar) ppm. 13C
2
= 7.2 Hz, 3 H, Me–CH), 1.58 (br. s, 1 H, OH), 2.11–2.19 (m, 1 H,
Me–CH), 3.68–3.73 (m, 1 H, CH2–O), 3.74 (s, 3 H, Me–O), 3.77–
3.87 (m, 1 H, CH–CF3), 3.94 (dd, J = 10.9, 3.6 Hz, 1 H, CH2–O),
NMR (75.5 MHz, CDCl3): δ = 34.1, 39.9, 56.0, 56.6 (dd, JCF
=
24.1, 19.5 Hz), 63.3, 114.7, 115.2, 118.6, 135.8, 141.5, 152.9 ppm
(the CF3CF2 signals were obscured due to their low intensity). 19F
Eur. J. Org. Chem. 2009, 5208–5214
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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