Bimorpholine-Mediated Aldol Condensation
General Procedure of Preparation Bimorpholine Salts 5a-e
and 6b. To a solution of substituted bimorpholine (1 mmol) in
Et2O (4 mL), the corresponding acid (1 mmol) was added at 0 °C.
The precipitate was collected by filtration and dried in vacuum.
(3S,3′S)-4-Methyl-3,3′-bimorpholine Trifluoroacetic Acid Salt
(3S,3′S)-2-(3,3′-Bimorpholin-4-ylmethyl)phenol Trifluoroace-
tic Acid Salt (5d). mp 147-149 °C. [R]D ) +11.0 (c ) 1.84,
21
MeOH). IR (KBr): 3079, 2959, 2867, 2778, 2463, 1671, 1607,
1463, 1208, 1184, 1143, 1116, 995, 802, 762 cm-1. 1H NMR (CD3-
OD, 500 MHz): δ 7.25 (dd, 1H, J ) 1.2 and 7.4 Hz, H-6′′), 7.15
(ddd, 1H, J ) 1.2, 7.4, and 8.0 Hz, H-4′′), 6.84 (dt, 1H, J ) 1.0
and 2 × 7.4 Hz, H-5′′), 6.83 (dd, 1H, J ) 1.0 and 8.0 Hz, H-3′′),
4.11 and 4.04 (both d, 2H, J ) 12.5 Hz, Bn), 4.03 (m, 1H, H-2),
4.00 (m, 1H, H-2′), 3.90 (dt, 1H, J ) 2.4 and 2 × 11.8 Hz, H-6),
3.82 (m, 1H, H-6′), 3.80 (m, 1H, H-3′), 3.75 (m, 1H, H-2′), 3.70
(m, 1H, H-6′), 3.65 (dm, 1H, J ) 13.0 Hz, H-2), 3.55 (dm, 1H, J
) 11.3 Hz, H-6), 3.12 (ddd, 1H, J ) 3.7, 12.2, and 15.1 Hz, H-5),
3.02 (m, 1H, H-5′), 2.99 (m, 1H, H-3), 2.94 (ddd, 1H, J ) 3.2,
6.2, and 13.2 Hz, H-5′), 2.67 (dm, J ) 14.5 Hz, H-5). 13C NMR
(CD3OD, 125 MHz): δ 163.07 (q, J ) 34.7 Hz, COO), 157.25
(C-2′′), 133.03 (C-6′′), 130.46 (C-4′′), 124.92 (C-1′′), 120.89 (C-
5′′), 118.26 (q, J ) 293.2 Hz, CF3), 116.54 (C-3′′), 66.41 (C-2′),
65.08 (C-6′), 63.02 (C-6), 61.43 (C-2), 55.29 (C-3), 52.99 (Bn),
52.03 (C-3′), 45.59 (C-5), 42.46 (C-5′). MS (EI): m/z (%) ) 192
(32), 107 (38), 86 (100), 77 (11), 69 (14), 45 (17). HRMS (m/z):
[M + H+] calcd for (C11H14NO2)+, 192.1023; found: 192.1020.
Anal. Calcd for C17H23F3N2O5 (392.38): C, 52.04; H, 5.91; N, 7.14.
Found: C, 51.67; H, 5.92; N, 6.99.
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(5a). mp 104-105 °C. [R]D ) +9.8 (c ) 4.21, MeOH). IR
(KBr): 3448, 2963, 2761, 1682, 1431, 1207, 1114, 1102, 846, 724
1
cm-1. H NMR (CD3OD, 500 MHz): δ 4.84 (bs, OH), 4.08 (dd,
1H, J ) 3.3 and 12.7 Hz, H-2′), 3.95 (td, 1H, J ) 2 × 3.5 and
12.6 Hz, H-6′), 3.91 (dd, 1H, J ) 3.1 and 13.0 Hz, H-2), 3.83 (m,
1H, H-6), 3.78 (m, 1H, H-3′), 3.72 (ddd, 1H, J ) 3.3, 9.5 and 12.6
Hz, H-6′), 3.59 (dd, 1H, J ) 8.6 and 12.7 Hz, H-2′), 3.52 (m, 2H,
H-2,6), 3.24 (m, 1H, H-5′), 3.20 (m, 1H, H-5), 3.19 (m, 1H, H-5′),
2.67 (s, 3H, N-Me), 2.65 (m, 1H, H-3), 2.52 (dm, 1H, J ) 14.3
Hz, H-5). 13C NMR (CD3OD, 125 MHz): δ 67.27 (C-2′), 65.21
(C-6′), 62.88 (C-6), 61.30 (C-2), 58.39 (C-3), 53.03 (C-3′), 49.09
(C-5), 44.07 (C-5′), 41.67 (N-Me). MS (EI): m/z (%) ) 100 (100),
86 (16), 70 (19), 69 (14), 45 (17). HRMS (m/z): [M + H+] calcd
for (C5H10NO)+, 100.0762; found: 100.0762. Anal. Calcd for
C11H19F3N2O4 (300.28): C, 44.00; H, 6.38; N, 9.33. Found: C,
43.61; H, 6.41; N, 9.23.
(3S,3′S)-4-Isopropyl-3,3′-bimorpholine Trifluoroacetic Acid
21
Salt (5b). mp 113-115 °C. [R]D ) +11.7 (c ) 2.24, MeOH).
1
IR (KBr): 3427, 2493, 1672, 1623, 1208, 1129, 1107 cm-1. H
(3S,3′S)-4-Phenyl-3,3′-Bimorpholine Trifluoroacetic Acid Salt
21
(5e). mp 189-191 °C. [R]D ) +44.5 (c ) 2.2, MeOH). IR
NMR (CDCl3, 500 MHz): δ 9.0 (bs, 2H, NH), 4.11 (m, 1H, H-2′),
3.95 (m, 1H, H-6′), 3.84 (m, 2H, H-2,6′), 3.77 (m, 2H, H-2′,3′),
3.65 (m, 1H, H-6), 3.58 (m, 1H, H-6), 3.54 (m, 1H, H-2), 3.31 (m,
1H, H-5′), 3.22 (hept, 1H, J ) 6.6 Hz, i-Pr), 3.17 (m, 1H, H-5′),
3.04 (m, 2H, H-3,5), 2.73 (m, 1H, H-5), 1.12 and 1.09 (2d, 6H, J
) 6.6 Hz, i-Pr). 13C NMR (CDCl3, 125 MHz): δ 162.24 (q, J )
35.1 Hz, COO), 116.57 (q, J ) 292.8 Hz, CF3), 65.74 (C-2′), 64.90
(C-6), 63.64 (C-6′), 63.01 (C-2), 53.92 (C-3), 51.98 (C-3), 51.07
(i-Pr), 43.26 (C-5′), 41.50 (C-5), 21.66 and 19.97 (i-Pr). MS (EI):
m/z (%) ) 128 (100), 86 (68), 69 (30), 45 (51). HRMS (m/z): [M
+ H+] calcd for (C7H14NO)+, 128.1081; found: 128.1079. HRMS
(m/z): [M + H+] calcd for (C4H8NO)+, 86.0611; found: 86.0604.
(3S,3′S)-4-Isopropyl-3,3′-bimorpholine Trifluoromethane-
(KBr): 2981, 2861, 2496, 1682, 1599, 1501, 1200, 1131, 1107,
760, 720. 1H NMR (CDCl3, 500 MHz): δ 9.54 (bs, 1H, NH), 9.26
(bs, 1H, NH), 7.18 (m, 2H, m-), 6.85 (m, 2H, o-), 6.75 (t, 1H, J )
2 × 7.3 Hz, p-), 4.06 (dd, 1H, J ) 2.5 and 12.0 Hz, H-2′), 3.88
(m, 1H, H-3′), 3.83 (m, 1H, H-3), 3.70 (m, 1H, H-6′), 3.69 (m,
1H, H-2′), 3.63 and 3.61 (m, 2H, H-2), 3.52 and 3.50 (m, 2H, H-5′),
3.49 and 3.27 (m, 2H, H-6), 2.65 and 1.98 (m, 2H, H-5). 13C NMR
(CDCl3, 125 MHz): δ 161.29 (q, J ) 35.5 Hz, COO), 148.25 (C-
s), 129.49 (C-m), 119.27 (C-p), 116.03 (q, J ) 293.1 Hz, CF3),
115.93 (C-o), 66.12 (C-2′), 65.14 (C-6′), 63.51 (C-2), 63.12 (C-6),
54.06 (C-3), 51.74 (C-3′), 43.52 (C-5′), 43.19 (C-5). MS (EI): m/z
(%) ) 248 (4), 162 (100), 132 (28), 119 (26), 86 (38), 69 (37).
HRMS (m/z): [M + H+] calcd for (C10H12NO)+, 162.0913;
found: 162.0911. Anal. Calcd for C16H21F3N2O4 (362.34): C,
53.04; H, 5.84; N, 7.73. Found: C, 53.11; H, 5.87; N, 7.67.
General Procedure for the Organocatalytic Intramolecular
Aldol Condensation. Organocatalyst 5 (0.05 mmol) was added to
the stirred solution of triketone 7 (1.0 mmol) in anhydrous MeCN
(2.0 mL). The reaction mixture was refluxed for an appropriate
time. The reaction was monitored by capillary GC. After completion
of the reaction, toluene was added, the mixture was concentrated
in vacuum, and a crude product was purified by chromatography
on silica gel (30% EtOAc in petroleum ether).
21
sulfonic Acid Salt (6b). mp 104-105 °C. [R]D ) +13.4 (c )
2.50, MeOH). IR (KBr): 3437, 2860, 2525, 1279, 1245, 1153, 1103,
1031, 641, 519 cm-1. 1H NMR (CDCl3, 500 MHz): δ 6.8 (bs, 2H,
NH), 4.10 (m, 1H, H-2′), 3.98 (m, 1H, H-6′), 3.91 (m, 1H, H-6′),
3.80 (m, 2H, H-2,3′), 3.74 (m, 1H, H-2′), 3.60 (m, 2H, H-6), 3.58
(m, 1H, H-2), 3.34 (m, 1H, H-5′), 3.28 (m, 2H, H-5′, and i-Pr),
3.02 (m, 1H, H-3), 3.01 (m, 1H, H-5), 2.86 (m, 1H, H-5), 1.20 and
1.19 (2d, 6H, J )6 .5 Hz, i-Pr). 13C NMR (CDCl3, 125 MHz): δ
120.09 (q, J ) 318.9 Hz, CF3), 65.16 (C-2′), 64.46 (C-6), 63.57
(C-6′), 62.18 (C-2), 52.31 (C-3), 52.21 (i-Pr), 50.99 (C-3′), 42.35
(C-5′), 40.99 (C-5), 21.95 and 21.68 (i-Pr). MS (EI): m/z (%) )
215 (2), 128 (100), 86 (54), 69 (12). HRMS (m/z): [M + H+]
calcd for (C7H14NO)+, 128.1081; found: 128.1086. HRMS (m/z):
[M + H+] calcd for (C4H8NO)+, 86.0611; found: 86.0612.
(3S,3′S)-4-Benzyl-3,3′-bimorpholine Trifluoroacetic Acid Salt
General Procedure for the Organocatalytic Intermolecular
Aldol Condensation of Aromatic Aldehyde and Acetone. Or-
ganocatalyst 6b (0.09 mmol) was added to the solution of the
corresponding aromatic aldehyde 9a-i (0.3 mmol) in acetone (0.6
mL), and the mixture was stirred at room temperature for an
appropriate time (6-10 days). The reaction mixture was treated
with saturated NaCl solution and extracted with EtOAc or Et2O,
and the combined organic layers were dried. After filtration and
concentration in vacuum, the crude product 10a-i was purified by
chromatography on silica gel.
21
(5c). mp 105-108 °C. [R]D ) +6.9 (c ) 2.24, MeOH). IR
(KBr): 3428, 2850, 2518, 1668, 1454, 1198, 1175, 1138, 800, 724
1
cm-1. H NMR (CDCl3, 500 MHz): δ 7.33 (m, 4H, Bn o-, m-),
7.29 (m, 1H, Bn p-), 4.10 (dd, 1H, J ) 2.9 and 12.8 Hz, H-2′),
4.01 (dd, 1H, J ) 2.8, 12.9 Hz, H-2), 3.99 and 3.92 (both d, 2H,
J ) 13.3 Hz, Bn), 3.87 (m, 1H, H-3′), 3.81 (m, 1H, H-2′), 3.80
(m, 1H, H-6′), 3.79 (m, 1H, H-6), 3.67 (m, 1H, H-6′), 3.59 (m,
1H, H-2), 3.53 (m, 1H, H-6), 3.18 (m, 1H, H-5), 2.95 (m, 1H, H-3),
2.94 (m, 1H, H-5′), 2.68 (m, 1H, H-5′), 2.56 (dm, J ) 14.6 Hz,
H-5). 13C NMR (CDCl3, 125 MHz): δ 162.51 (q, J ) 35.0 Hz,
COO), 116.67 (q, J ) 292.8 Hz, CF3), 65.08 (C-2′), 63.72 (C-6′),
62.79 (C-6), 60.85 (C-2), 57.32 (Bn), 53.70 (C-3), 50.71 (C-3′),
45.85 (C-5), 41.33 (C-5′). MS (EI): m/z (%) ) 176 (49), 91 (100),
86 (12), 69 (12), 45 (30). HRMS (m/z): [M + H+] calcd for
(C11H14NO)+, 176.1075; found: 176.1079. Anal. Calcd for
C17H23F3N2O4 (376.38): C, 54.25; H, 6.16; N, 7.44. Found: C,
54.58; H, 6.16; N, 7.49.
Acknowledgment. The authors thank Estonian Science
Foundation (Grant Nos. 6662, 5628, and 6778) and the Ministry
of Education and Research (GrantNo. 0142725s06) for financial
support.
Supporting Information Available: Experimental details,
product characterization, and chromatographic data. This material
JO070524I
J. Org. Chem, Vol. 72, No. 14, 2007 5173