A Novel Method for Biomimetic Synthesis of Mannich Bases
669, 543 cm-1 (According with lit.[13]).
3-(Dimethylamino)-1-phenylpropan-1-one
(6)
Colorless oil, yield 75.6%; 1H NMR (400 MHz, CDCl3)
δ: 2.32 (s, 6H, N(CH3)2), 2.80 (t, J=7.6 Hz, NCH2),
3.20 (t, J=7.2 Hz, COCH2), 7.47 (t, J=7.7 Hz, 2H,
m-ph-H), 7.57 (t, J=7.4 Hz, 1H, p-ph-H), 7.97 (d, J=
7.2 Hz, 2H, o-ph-H); IR (KBr) ν: 3061, 2972, 2943,
2861, 2819, 2768, 1684, 1597, 1581, 1451, 1379, 1330,
1286, 1206, 1068, 1040, 979, 869, 747, 692, 653, 572
cm-1 (According with lit.[13]).
2-(Piperidin-1-ylmethyl)cyclohexanone
(11)
Colorless oil, yield 25.4%; 1H NMR (400 MHz, CDCl3)
δ: 1.35—2.58 (m, 8H, cyclohexanone-H), 1.36—1.44
(m, 2H, piperidine-H), 1.51—1.57 (m, 4H, piperidine-
H), 2.17—2.42 (m, 6H, N(CH2)3), 2.75—2.80 (m, 1H,
COCH); IR (KBr) ν: 2932, 2855, 2773, 1709, 1447,
1378, 1353, 1303, 1222, 1121, 1057, 995, 865, 781, 669,
532 cm-1 (According with lit.[16]).
2-(Morpholinomethyl)cyclohexanone (12) Col-
3-(Diethylamino)-1-phenylpropan-1-one
(7)
1
Colorless oil, yield 72.1%; 1H NMR (400 MHz, CDCl3)
δ: 1.06 (t, J=7.4 Hz, 6H, CH2CH3), 2.58 (q, J=7.5 Hz,
4H, CH2CH3), 2.94 (t, J=7.8 Hz, 2H, NCH2), 3.16 (t,
J=7.6 Hz, 2H, COCH2), 7.46 (t, J=7.6 Hz, 2H,
m-ph-H), 7.56 (t, J=7.2 Hz, 1H, p-ph-H), 7.95 (d, J=
8.0 Hz, 2H, o-ph-H); IR (KBr) ν: 3061, 2969, 2930,
2872, 2808, 1683, 1597, 1448, 1378, 1281, 1219, 1069,
997, 744, 692, 653, 571 cm-1 (According with lit.[7a]).
orless oil, yield 23.3%; H NMR (400 MHz, CDCl3) δ:
1.38—2.58 (m, 8H, cyclohexanone-H), 2.37—2.46 (m,
6H, N(CH2)3), 2.79—2.84 (m, 1H, COCH), 3.68 (t, J=
4.0 Hz, 4H, O(CH2)2); IR (KBr) ν: 2932, 2855, 2808,
1708, 1450, 1364, 1296, 1118, 1069, 1009, 869, 669,
540 cm-1 (According with lit.[17]).
Results and Discussion
1-Phenyl-3-(piperidin-1-yl)propan-1-one
(8)
As shown in Scheme 3, when a mixture of 1,3-di-
methylimidazolidine, secondary amines and ketones with
active α-hydrogens was heated (CH3CN, reflux) in the
presence of acetic acid, the corresponding aminomethyla-
tion derivatives 2—12 were obtained (Table 1). All the
products were characterized by 1H NMR and IR spectra.
The yields of 2—12 were listed in Table 1, wherein those
of 10, 11 and 12 were low. Thus it could be seen that the
structure of ketone dominated the yield and the greater
steric effect would result in the lower yield.
Colorless oil, yield 62.3%; 1H NMR (400 MHz, CDCl3)
δ: 1.44—1.48 (m, 2H, piperidine-H), 1.58—1.64 (m, 4H,
piperidine-H), 2.47 (br, 4H, piperidine-H), 2.82 (t, J=
7.4 Hz, 2H, COCH2), 3.22 (t, J=5.4 Hz, 2H, NCH2),
7.46 (t, J=7.6 Hz, 2H, m-ph-H), 7.56 (t, J=7.6 Hz, 1H,
p-ph-H), 7.97 (d, J=7.6 Hz, 2H, o-ph-H); IR (KBr) ν:
3060, 2934, 2852, 2798, 1684, 1597, 1580, 1447, 1377,
1353, 1241, 1206, 1115, 1040, 977, 865, 745, 692, 569
cm-1 (According with lit.[14]).
3-Morpholino-1-phenylpropan-1-one (9) Color-
less oil, yield 60.7%; 1H NMR (400 MHz, CDCl3) δ: 2.51
(t, J=4.0 Hz, 4H, N(CH2)2), 2.84 (t, J=7.4 Hz, 2H,
COCH2), 3.19 (t, J=7.6 Hz, 2H, NCH2), 3.72 (t, J=4.4
Hz, 4H, O(CH2)2), 7.47 (t, J=7.2 Hz, 2H, m-ph-H), 7.57
(t, J=8.0 Hz, 1H, p-ph-H), 7.96 (d, J=7.6 Hz, 2H,
o-ph-H); IR (KBr) ν: 3060, 2955, 2853, 2809, 1683, 1597,
1580, 1449, 1398, 1361, 1261, 1216, 1116, 1070, 980,
914, 869, 747, 692, 571 cm-1 (According with lit.[15]).
Table 1 Synthesis of Mannich bases
Entry Ketone
Amine
DMd
DEe
Time/h
10
Product
Yield/%
83.1
82.0
73.7
70.3
75.6
72.1
62.3
60.7
35.6
25.4
23.3
1
Aca
Ac
Ac
Ac
Apb
Ap
Ap
Ap
Chc
Ch
Ch
2
2
10
3
3
PIPf
10
4
4
MORg
10
5
5
DM
12
6
General procedure for the synthesis of compounds
10—12
6
DE
12
7
7
PIP
14
8
To a 100 mL flask was added 1,3-dimethylimida-
zolidine (1) (5 mmol), secondary amines (5 mmol),
cyclohexanone (11 mmol), acetic acid (10 drops) and
acetonitrile (40 mL). The mixture was refluxed for 20 h
with stirring. Acetonitrile was removed by distillation.
The residue was basified with 5% NaHCO3 solution to
make its pH 10 and then extracted with CH2Cl2 (15 mL
×5). The organic layer was dried over anhydrous
K2CO3 and concentrated in vacuo to obtain the crude
product, which was purified by silica gel column
chromatography (CH2Cl2/CH3OH, 20∶1, volume ra-
tio).
2-(N,N-dimethylaminomethyl)cyclohexanone (10)
Colorless oil, yield 35.6%; 1H NMR (400 MHz, CDCl3)
δ: 1.40—2.53 (m, 8H, cyclohexanone-H), 2.21 (s, 6H,
N(CH3)2), 2.23 (d, J=6.8 Hz, 2H, NCH2), 2.67—2.72
(m, 1H, COCH); IR (KBr) ν: 2936, 2859, 2818, 2765,
1709, 1453, 1382, 1307, 1263, 1218, 1126, 1029, 876,
8
MOR
DM
14
9
9
20
10
11
12
10
11
PIP
20
MOR
20
a Ac: acetone; b Ap: acetophenone; c Ch: cyclohexanone; d DM:
e
f
g
dimethylamine; DE: diethylamine; PIP: piperidine; MOR:
morpholine.
Protonation of 1,3-dimethylimidazolidine (1) in
trifluoroacetic acid produces an 82∶18 equilibrium
between the monoprotonated ring form (1-H+) and a
second form with Schiff-base, open-chain structure
(N-methyl-N-(2-methyl-amino)ethyl-N-methylene am-
monium trifluoroacetate).[18] The described herein car-
bon-transfer reaction should be derived from this ring-
chain tautomerism in 1,3-dimethylimidazolidine. So the
mechanism of formation of the aminomethylation de-
Chin. J. Chem. 2012, XX, 1—4
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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