A New Robust and Efficient Ion-Tagged Proline Catalyst Carrying an Amide Spacer
centred under vacuum to give the title compound 7a as a
gummy solid; yield: 2.72 g (3.9 mmol, 92%); [a]2D0: À11.98 (c
0.70, CHCl3). 1H NMR (400 MHz, CDCl3, two conforma-
tional isomers): d=1.97–2.15 (m, 1H), 2.45–2.64 (m, 1H),
3.38–3.52 (m, 1H), 3.75–3.87 (m, 4H), 4.30–4.51 (m, 2H),
4.71–4.90 (m, 2H), 4.92–5.24 (m, 4H), 7.13–7.39 (m, 12H),
7.70–7.86 (d, J=7.0 Hz, 1H), 8.62–8.74 (s, 1H); 13C NMR
(100 MHz, CDCl3, two conformational isomers): d=33.2,
34.5, 35.5, 36.2, 48.2, 49.0, 50.8, 51.4, 51.7, 57.6, 58.0, 67.18,
67.24, 114.9, 118.0, 121.2, 122.8, 123.7, 124.4, 127.6, 127.7,
127.8, 127.9, 128.05, 128.07, 128.11, 128.2, 128.37, 128.40,
128.44, 128.5, 135.1, 135.3, 136.0, 136.1, 137.1, 154.0, 154.6,
163.8, 172.7, 172.8; anal. calcd. for C28H29F6N5O9S2 (757.68):
C 44.39, H 3.86, N 9.24; found: C 44.24, H 3.83, N 9.35.
4.09 (dd, J=9.1, 6.5 Hz, 1H), 4.44 (ddd, J=11.8, 6.7, 5.1 Hz,
1H), 4.99 (s, 2H), 7.52–7.65 (m, 2H), 8.90 (s, 1H); H NMR
1
(400 MHz, DMSO-d6): d=1.84–1.96 (dt, J=13.2, 7.4 Hz,
1H), 2.36–2.53 (m, 1H), 3.00–3.10 (dd, J=11.6, 6.5 Hz, 1H),
3.26–3.36 (dd, J=11.6, 7.0 Hz, 1H), 3.78–3.86 (t, J=8.3 Hz,
1H), 3.86–3.93 (s, 3H), 4.22–4.35 (m, 1H), 4.90–5.02 (d, J=
3.5 Hz, 2H), 7.65–7.72 (m, 2H), 8.88–8.95 (d, J=6.5 Hz,
1H), 9.04–9.11 (s, 1H); 13C NMR (100 MHz, DMSO-d6): d=
34.0, 35.8, 48.6, 48.9, 50.5, 59.4, 123.0, 123.7, 137.7, 165.0,
169.6; anal. calcd. for C13H17F6N5O7S2 (533.42): C 29.27, H
3.21, N 13.13; found: C 29.04, H 3.19, N, 13.14.
Imidazolium Tetrafluoroborate Catalyst (8b)
Following the same procedure reported for 8a, 8b was ob-
tained as a solid; yield: 96%; [a]2D0: À15.38 (c 0.36, H2O).
1H NMR (400 MHz, D2O): d=2.18–2.34 (dt, J=14.2, 6.2 Hz,
1H), 2.65–2.83 (ddd, J=14.1, 9.1, 7.0 Hz, 1H), 3.43–3.55
(dd, J=12.5, 5.0 Hz, 1H), 3.62–3.73 (dd, J=12.6, 6.9 Hz,
1H), 3.90–4.02 (s, 3H), 4.21–4.36 (dd, J=9.1, 6.8 Hz, 1H),
4.44–4.62 (ddd, J=12.2, 6.8, 5.4 Hz, 1H), 5.00–5.13 (s, 2H),
7.47–7.51 (s, 1H), 7.51–7.54 (s, 1H), 8.74–8.86 (s, 1H);
13C NMR (50 MHz, CD3OD): d=35.2, 36.6, 50.6, 50.7, 51.8,
61.4, 124.5, 125.0, 139.3, 167.2, 173.3; anal. calcd. for
C11H17BF4N4O3 (340.08): C 38.85, H 5.04, N 16.47; found: C
38.64, H 5.07, N 16.49.
Imidazolium Tetrafluoroborate Salt (7b)
Following the same procedure reported for 7a, 6 (0.14 g,
0.28 mmol) was reacted with sodium tetrafluoroborate
(0.037 g, 0.34 mmol) to afford 7b as a solid; yield: 0.15 g
(0.27 mmol, 95%); [a]2D0: À9.48 (c 0.58, CHCl3). 1H NMR
(200 MHz, CDCl3): d=1.87–2.16 (m, 1H), 2.31–2.64 (m,
1H), 3.18–3.50 (m, 1H), 3.57–3.91 (m, 4H), 4.19–4.47 (m,
2H), 4.63–4.88 (s, 2H), 4.89–5.24 (m, 4H), 7.08–7.57 (m,
12H), 8.45–8.64 (s, 1H); 13C NMR (100 MHz, CDCl3): d=
34.5, 35.4, 36.2, 48.1, 49.0, 50.8, 51.4, 51.6, 53.4, 57.7, 58.0,
67.2, 67.3, 122.78, 122.81, 123.6, 127.7, 127.91, 127.95, 128.00,
128.05, 128.11, 128.2, 128.3, 128.4, 128.5, 128.6, 135.3, 135.5,
136.2, 136.3, 137.4, 154.0, 154.6, 164.5, 164.5, 172.5, 172.7;
anal. calcd. for C26H29BF4N4O5 (564.34): C 55.34, H 5.18, N
9.93; found: C 55.43, H 5.21, N 9.97.
Imidazolium Hexafluorophosphate Catalyst (8c)
Following the same procedure reported for 8a, 8c was ob-
tained as a solid; yield: 68%; [a]2D0: À14.28 (c 0.32, H2O).
1H NMR (400 MHz, CD3OD): d=2.17–2.29 (dt, J=13.0,
6.0 Hz, 1H), 2.56–2.73 (m, 1H), 3.37–3.46 (dd, J=12.2,
4.9 Hz, 1H), 3.47–3.58 (dd, J=12.2, 6.7 Hz, 1H), 3.91–4.01
(s, 3H), 4.01–4.13 (dd, J=9.0, 6.7 Hz, 1H), 4.36–4.52 (m,
1H), 4.93–5.11 (s, 2H), 7.52–7.62 (s, 2H), 8.79–8.94 (s, 1H);
13C NMR (100 MHz, CD3OD): d=35.4, 36.5, 50.75, 50.77,
51.8, 61.6, 124.4, 125.0, 138.5, 167.1, 173.6; anal. calcd. for
C11H17F6N4O3P (398.24): C 33.18, H 4.30, N 14.07; found: C
33.14, H 4.33, N 14.02.
Imidazolium Hexafluorophosphate Salt (7c)
Following the same procedure reported for 7a, 6 (0.11 g,
0.21 mmol) was reacted with potassium hexafluorophos-
phate (0.047 g, 0.26 mmol) to afford 7c as a solid; yield:
0.13 g (0.20 mmol, 97%); [a]2D0: À7.78 (c 0.67, CHCl3).
1H NMR (400 MHz, CDCl3, two conformational isomers):
d=2.00–2.15 (m, 1H), 2.40–2.60 (m, 1H), 3.40–3.58 (m,
1H), 3.72–3.85 (m, 4H), 4.30–4.54 (m, 2H), 4.59–4.78 (m,
2H), 4.96–5.26 (m, 4H), 7.03–7.15 (m, 2H), 7.17–7.41 (m,
10H), 8.39–8.47 (s, 1H); 13C NMR (100 MHz, CDCl3): d=
29.7, 33.9, 34.6, 35.4, 36.1, 48.1, 49.0, 50.8, 51.6, 51.8, 57.7,
58.0, 67.26, 67.30, 122.9, 123.6, 127.7, 127.9, 128.0, 128.07,
128.11, 128.24, 128.26, 128.38, 128.44, 128.5, 128.6, 135.3,
135.5, 136.2, 136.3, 137.1, 154.0, 154.7, 164.1, 172.8, 172.9;
anal. calcd. for C26H29F6N4O5P (622.50): C 50.17, H 4.70, N
9.00; found: C 55.33, H 4.72, N, 8.94.
Typical Procedure using Protocol A (Table 1,
Entry 14)
Cyclohexanone (0.10 mL, 1 mmol) was added to a solution
of catalyst 8a (5.3 mg, 0.01 mmol) in [bmim]ACTHNURGTNEUNG[NTf2] (0.3 mL)
and the mixture was allowed to stir for 10 min at room tem-
perature. 4-Nitrobenzaldehyde (0.075 g, 0.5 mmol) was then
added and the reaction mixture was stirred at room temper-
ature for 18 h. The product was extracted from ionic liquid
with diethyl ether (8ꢂ2 mL). The combined organic phases
were dried (Na2SO4) and evaporated to dryness. The pure
aldol product was obtained by flash-chromatography on
silica gel eluting with cyclohexane/ethyl acetate (7:3); yield:
0.113 g (0.46 mmol, 91%). The ee was determined by chiral
HPLC (CHIRALPAK AD column, hexane/2-propanol=
85:15, flow rate: 0.8 mLminÀ1, l=254 nm): tR syn=
11.1 min, tR syn=13.6 min, tR anti (minor)=14.6 min, tR anti
(major)=18.8 min.
Imidazolium Bis(trifluoromethylsulfonyl)imide
Catalyst (8a)
10% palladium on charcoal (0.19 g, 0.18 mmol) was added
to a solution of 7a (2.7 g, 3.6 mmol) in anhydrous CH3OH
(10 mL). The mixture was stirred under hydrogen at atmos-
pheric pressure overnight. The reaction mixture was then fil-
tered and washed with CH3OH (10 mL). The organic layer
was evaporated under vacuum to provide the catalyst as a
solid; yield: 1.83 g (3.56 mmol, 96%); [a]2D0: À20.48 (c 0.80,
CH3OH). 1H NMR (400 MHz, CD3OD): d=2.24 (dt, J=
13.7, 6.0 Hz, 1H), 2.63 (ddd, J=13.8, 9.2, 7.0 Hz, 1H), 3.41
(dd, J=12.2, 4.9 Hz, 1H), 3.54 (dd, J=12.2, 6.7 Hz, 1H),
Adv. Synth. Catal. 2011, 353, 3234 – 3240
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3239