A 4-Hydroxy Pyrrolidine-Catalyzed Mannich Reaction of Aldehydes
FULL PAPER
7.08 (m, 5H), 7.00–6.96 (m, 2H), 5.81 (s, 1H), 4.22 (m, 1H), 3.96 (dd, J=
3.1, 11.2 Hz, 1H), 3.59 (dd, J=4.6, 11,2 Hz, 1H), 2.38 (s, 3H), 1.98 (m,
1H), 0.82 ppm (d, J=7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=
142.9, 139.9, 137.3, 129.6, 129.2, 128.2, 127.1, 126.4, 64.9, 61.5, 40.9, 21.4,
14.5 ppm; the enantiomeric purity of the major diastereoisomer was de-
termined by HPLC analysis (Daicel Chiralpak IA, hexane/2-propanol
95:5): flow rate=0.8 mLminÀ1; retention times: 36.7 (minor), 43.7 min
(major).
(t, J=7.4, 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=142.7, 140.1,
137.7, 129.1, 128.2, 127.7, 127.1, 123.8, 61.2, 60.2, 47.4, 21.4, 21.2, 21.0,
11.6 ppm; the enantiomeric purity of the major diastereomer was deter-
mined by HPLC analysis (Daicel Chiralpak IA, hexane/2-propanol 98:2):
flow rate=0.7 mLminÀ1; retention times: 91.1 (minor), and 98.8 min
(major).
N-[(1S,2R)-1-(4-Chlorophenyl)-2-(hydroxymethyl)heptyl]-4-methylben-
zene sulfonamide (34d): Prepared according to the general procedure by
starting from heptanal (0.21 mL, 1.5 mmol) and N-tosyl-4-chlorophenyli-
mine (23d) (147 mg, 0.5 mmol). The crude material was purified by flash
column chromatography on silica gel (eluting with hexane/ethyl acetate
80:20) and then disgregated with Et2O to give the compound as a white
solid. Yield: 76% (161 mg); m.p. 120–1248C; [a]2D0 =À58.9 (c=1 in
CH2Cl2); 1H NMR (300 MHz, CDCl3): d=7.54 (d, J=8.3 Hz, 2H), 7.13
(m, 4H), 7.01 (d, J=8.5 Hz, 2H), 6.39 (d, J=7.4 Hz, 1H), 4.40 (t, J=
7.0 Hz, 1H), 3.81 (d, J=11.2 Hz, 1H), 3.61 (m, 1H), 2.40 (s, 3H), 2.31
(m, 1H), 1.65 (m, 1H) 1.40–1.05 (m, 8H), 0.86 ppm (t, J=7.0 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=143.1, 139.2, 137.7, 132.8, 129.3, 128.3,
127.0, 61.9, 60.1, 45.6, 31.8, 28.2, 26.7, 22.4, 21.4, 14.0 ppm; the enantio-
meric purity of the major diastereomer was determined by HPLC analy-
sis (Daicel Chiralpak AD-H, hexane/2-propanol 95:5): flow rate=
0.8 mLminÀ1; retention times: 31.7 (minor), 49.1 min (major).
N-[(1S,2R)-2-(Hydroxymethyl)-1-p-tolylbutyl]-4-methylbenzenesulfona-
mide (32a): Prepared according to the general procedure by starting
from butanal (0.14 mL, 1.5 mmol) and N-tosyl-tolylimine (23a) (137 mg,
0.5 mmol). The crude material was purified by flash column chromatog-
raphy on silica gel (eluting with hexane/ethyl acetate 80:20) to give the
title compound as a yellow oil. Yield: 77% (134 mg); [a]2D0 =À19.8 (c=
1
0.5 in CH2Cl2); H NMR (300 MHz, CDCl3): d=7.54 (d, J=8.3 Hz, 2H),
7.13 (d, J=8.2 Hz, 2H), 6.97 (d, J=7.9 Hz, 2H), 6.87 (d, J=8.1 Hz, 2H),
5.81 (d, J=7.9 Hz, 1H), 4.35 (t, J=7.8, Hz, 1H), 3.93 (d, J=11.1 Hz,
1H), 3.72–3.63 (m, 1H), 2.39 (s, 3H), 2.30 (s, 3H), 1.66–1.53 (m, 1H),
1.44–1.18 (m, 2H), 0.88 ppm (t, J=7.4, 7.4 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=142.8, 137.7, 137.4, 136.8, 129.2, 128.9, 127.1, 126.6, 61.2, 60.0,
47.6, 29.7, 21.4, 21.0, 11.6 ppm; the enantiomeric purity of the major dia-
stereomer was determined by HPLC analysis (Daicel Chiralpak AD-H,
hexane/2-propanol 95:5): flow rate=0.8 mLminÀ1; retention times: 51.5
(minor), 61.8 min (major).
N-[(1S,2R)-2-(Hydroxymethyl)-3-methyl-1-p-tolylbutyl]-4-methylben-
zene sulfonamide (35a): Prepared according to the general procedure by
starting from isovaleraldehyde (0.16 mL, 1.5 mmol) and N-tosyl-tolyli-
mine (23a) (137 mg, 0.5 mmol). The crude material was purified by flash
column chromatography on silica gel (eluting with hexane/ethyl acetate
80:20) and then disgregated with Et2O to give the title compound as a
white solid. Yield: 76% (134 mg); m.p. 145–1488C; [a]2D0 =À70.8 (c=1 in
CH2Cl2); 1H NMR (300 MHz, CDCl3): d=7.50 (d, J=8.2 Hz, 2H), 7.08
(d, J=8.1 Hz, 2H), 6.97–6.90 (m, 4H), 6.70–6.55 (brs, 1H), 4.60 (d, J=
6.8 Hz, 1H), 3.82–3.68 (m, 2H), 2.36 (s, 3H), 2.28 (s, 3H), 1.80–1.65 (m,
1H), 1.46–1.36 (m, 1H), 1.34–1.24 (brs, 1H), 0.92 ppm (dd, J=6.7,
20.5 Hz, 6H); 13C NMR (125 MHz, CDCl3): d=142.6, 138.0, 137.7, 136.4,
129.0, 128.7, 127.0, 126.9, 60.3, 59.6, 53.5, 51.9, 25.7, 21.3, 20.9, 18.8 ppm;
the enantiomeric purity of the major diastereomer was determined by
HPLC analysis (Daicel Chiralpak IA, hexane/2-propanol 95:5): flow
rate=0.5 mLminÀ1; retention times: 50.1 (minor), 54.4 min (major).
N-[(1S,2R)-2-(Hydroxymethyl)-1-(4-methoxyphenyl)butyl]-4-methylben-
zene sulfonamide (32b): Prepared according to the general procedure by
starting from butanal (0.14 mL, 1.5 mmol) and N-tosyl-4-methoxyphenyli-
mine (23b) (145 mg, 0.5 mmol). The crude material was purified by flash
column chromatography on silica gel (eluting with hexane/ethyl acetate
80:20) and then disgregated with Et2O to give the title compound as a
white solid. Yield: 63% (114 mg); m.p. 117–1218C; [a]2D0 =À54.8 (c=1 in
CH2Cl2); 1H NMR (300 MHz, CDCl3): d=7.53 (d, J=8.3 Hz, 2H), 7.13
(d, J=8.0 Hz, 2H), 6.91 (d, J=8.6 Hz, 2H), 6.68 (d, J=8.7 Hz, 2H), 5.97
(d, J=7.8 Hz, 1H), 4.33 (t, J=7.7, 7.7 Hz, 1H), 3.94 (d, J=11.19 Hz,
1H), 3.77 (s, 3H), 3.68 (d, J=8.0 Hz, 1H), 2.38 (s, 3H), 2.29 (s, 1H),
1.67–1.55 (m, 1H), 1.44–1.16 (m, 2H), 0.87 ppm (t, J=7.4, 7.4 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=158.7, 142.8, 137.7, 132.5, 129.2, 127.9,
127.1, 113.6, 61.3, 59.8, 55.2, 47.6, 21.4, 21.0, 11.6 ppm; the enantiomeric
purity of the major diastereomer was determined by HPLC analysis
(Daicel Chiralpak IA, hexane/2-propanol 95:5): flow rate=
0.75 mLminÀ1; retention times: 79.6 (minor), 92.3 min (major).
N-[(1S,2R)-3-Hydroxy-2-methyl-1-p-tolylpropyl]-2-nitrobenzenesulfona-
mide (30a): Prepared according to the general procedure by starting
from propanal (0.12 mL, 1.5 mmol) and N-o-nosyl-p-methyl-phenylimine
(24a) (152 mg, 0.5 mmol). The crude material was purified by flash
column chromatography on silica gel (eluting with hexane/ethyl acetate
80:20) to give the title compound as a yellowish oil and as a diastereo-
meric mixture syn/anti in a ratio of 7:93. Yield: 61% (111 mg); spectro-
N-[(1S,2R)-2-(Hydroxymethyl)-1-phenylbutyl]-4-methylbenzenesulfona-
mide (32c): Prepared according to the general procedure by starting
from butanal (0.14 mL, 1.5 mmol) and N-tosyl-phenylimine (23c)
(129 mg, 0.5 mmol). The crude material was purified by flash column
chromatography on silica gel (eluting with hexane/ethyl acetate 80:20)
and then disgregated with Et2O to give the compound as a white solid.
Yield: 68% (122 mg); m.p. 123–1258C; [a]2D0 =À72.7 (c=1 in CH2Cl2);
1H NMR (300 MHz, CDCl3): d=7.53 (d, J=8.3 Hz, 2H), 7.17–7.08 (m,
5H), 7.02–6.99 (m, 2H), 5.95 (d, J=8.07 Hz, 1H), 4.42 (t, J=7.7, 7.7 Hz,
1H), 3.91 (m, 1H), 3.38 (m, 1H), 2.38 (s, 3H), 1.69–1.59 (m, 1H), 1.49–
1.21 (m, 2H), 0.89 ppm (t, J=7.4, 7.4 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=142.8, 140.4, 137.7, 129.2, 128.3, 127.0, 126.7, 61.3, 60.2, 47.5,
21.4, 21.1, 11.6 ppm; the enantiomeric purity of the major diastereomer
was determined by HPLC analysis (Daicel Chiralpak IA, hexane/2-prop-
1
scopic data of the major anti diastereomer: H NMR (300 MHz, CDCl3):
d=7.76–7.67 (m, 2H), 7.62–7.53 (m, 1H), 7.48–7.40 (m, 1H) 6.98–6.83
(m, 4H), 6.62 (d, J=8.7 Hz, 1H), 4.49 (t, J=8.3 Hz, 1H), 4.00—3.88 (m,
1H), 3.74–3.62 (m, 1H), 2.22 (s, 3H), 2.08–1.90 (m, 2H), 0.95 ppm (d, J=
7.0, 3H); 13C NMR (125 MHz, CDCl3): d=137.2, 136.2, 134.7, 132.5,
132.2, 130.8, 130.6, 128.9, 126.8, 124.8, 64.5, 62.2, 40.7, 20.9, 14.6 ppm; the
enantiomeric purity of the major diastereomer was determined by HPLC
analysis (Daicel Chiralpak IC, hexane/2-propanol 70:30): flow rate=
0.5 mLminÀ1; retention times: 108.5 (minor), 116.5 min (major).
N-[(1S,2R)-3-Hydroxy-2-methyl-1-phenylpropyl]-4-nitrobenzenesulfona-
mide (31c): Prepared according to the general procedure by starting
from propanal (0.12 mL, 1.5 mmol) and N-p-nosyl-phenylimine (25c)
(145 mg, 0.5 mmol). The crude material was purified by flash column
chromatography on silica gel (eluting with hexane/ethyl acetate 80:20) to
give the title compound as a white solid and as a diastereomeric mixture
syn/anti in a ratio of 9:91. Yield: 59% (90 mg); spectroscopic data of the
major anti diastereomer: 1H NMR (300 MHz, CDCl3): d=8.12–8.05 (m,
2H), 7.75–7.69 (m, 2H), 7.19–7.10 (m, 3H), 7.04–6.98 (m, 2H), 4.43 (d,
J=7.7 Hz, 1H), 3.93–3.83 (m, 1H), 3.70–3.62 (m, 1H), 2.05–1.95 (m,
1H), 0.91 ppm (d, J=7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=
149.5, 146.7, 139.3, 128.4, 128.1, 127.7, 127.1, 123.6, 65.4, 63.0, 40.3,
14.7 ppm; the enantiomeric purity of the major diastereomer was deter-
mined by HPLC analysis (Daicel Chiralpak IC, hexane/2-propanol
anol 95:5): flow rate=0.75 mLminÀ1
; retention times: 51.3 (minor),
57.7 min (major).
N-[(1S,2R)-2-(Hydroxymethyl)-1-m-tolylbutyl]-4-methylbenzenesulfona-
mide (32e): Prepared according to the general procedure by starting
from butanal (0.14 mL, 1.5 mmol) and N-tosyl-3-methylphenylimine
(23e) (137 mg, 0.5 mmol). The crude material was purified by flash
column chromatography on silica gel (eluting with hexane/ethyl acetate
80:20) to give the title compound as a yellow oil. Yield: 60% (104 mg);
[a]2D0 =À39.8 (c=1 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=7.51 (d,
J=8.3 Hz, 2H), 7.13–7.01 (m, 3H), 6.94 (d, J=7.5 Hz, 1H), 6.83 (d, J=
7.6 Hz, 1H), 6.68 (s, 1H), 6.10 (d, J=8.1 Hz, 1H), 4.33 (t, J=7.9, 7.9 Hz,
1H), 3.93 (d, J=11.1 Hz, 1H), 3.68 (d, J=10.7 Hz, 1H), 2.51 (brs, 1H),
2.37ACHTUNGTRENNUNG(s, 3H), 2.17ACHTUNGTRENNUNG(s, 3H), 1.70–1.57 (m, 1H), 1.47–1.20 (m, 2H), 0.88 ppm
Chem. Eur. J. 2010, 16, 5333 – 5342
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5339