The Mannich-type reaction between N,O-acetals and carbon nucleophiles under solvent-free conditions

Article abstract of DOI:10.3987/COM-05-S(T)34

The Mannich-type reaction for 1-methoxycarbonyl- or 1-benzyloxy-carbonyl-2-methoxylpyrrolidine with carbon nucleophiles such as acetylacetone, methyl acetoacetate, dimethyl malonates, benzoylacetone, dibenzoylmethane, or cyclohexane-1, 3-dione proceeded b

Full text of DOI:10.3987/COM-05-S(T)34

HETEROCYCLES, Vol. 67, No. 1, 2006
113
HETEROCYCLES, Vol. 67, No. 1, 2006, pp. 113 - 117. © The Japan Institute of Heterocyclic Chemistry
Received, 14th July, 2005, Accepted, 5th September, 2005, Published online, 6th September, 2005. COM-05-S(T)34
THE MANNICH-TYPE REACTION BETWEEN N,O-ACETALS AND
CARBON NUCLEOPHILES UNDER SOLVENT-FREE CONDITIONS
Yoshihiro Matsumura,* Takashi Ikeda, and Osamu Onomura
Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences,
Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Abstract-The Mannich-type reaction for 1-methoxycarbonyl- or 1-benzyloxy-
carbonyl-2-methoxylpyrrolidine with carbon nucleophiles such as acetylacetone,
methyl acetoacetate, dimethyl malonates, benzoylacetone, dibenzoylmethane, or
cyclohexane-1, 3-dione proceeded by acid catalysis under solvent-free conditions
with more efficiency than that in dichloromethane.
The Mannich-type reactions between N-acyliminium ions generated from N,O-acetals and nucleophiles
have been frequently utilized to introduce substituents at the α-position of various amines.1,2 We have
already exploited some reactions between N,O-acetals prepared by electrochemical oxidation3 and various
nucleophiles to afford some important α-substituted amines.4 Those reactions were carried out in large
volume of organic solvents which seemed to be environmentally unsuitable and uneconomical.5 So we
examined solvent-free6 processes for such reactions, and found that the Mannich-type reaction for
N,O-acetals (2a,b) proceeded through acyliminium ions under solvent-free conditions more efficiently
than ones in organic solvents (Eq. 1). We report herein the detail of the results and the comparison with
the corresponding reactions carried out using organic solvents.
-2e
acid
Nu
+
(1)
Nu
OMe
N
Z
1a,b
N
Z
N
N
Z
3a,b
in MeOH
solvent-free
Z
2a,b
a: Z=CO2Me
b: Z=CO2CH2Ph
The preparation of 2a,b was easily achieved by electrochemical oxidation of 1-methoxycarbonyl- or
benzyloxycarbonylpyrrolidines (1a,b) in methanol.2 With 2a,b in hand, we first examined the reactions of
2a with liquid active methylene compounds (4p-q) (3 equiv. to 2a),7-9 a kind of carbon nucleophiles, in
the presence of a catalytic amount of some acids under solvent-free10 and solvent (CH2Cl2) conditions to
afford the products (3ap-ar)7 (Eq. 2). The results are summarized in Table 1 which shows the yields based
on 2a. The yields depended on the reaction conditions, that is, the yields of the coupling product (3ap)11
in the case using acetylacetone (4p) under solvent-free conditions were much higher than under solvent
conditions (entries 1-4), and the yields of 3aq and 3ar in the cases using acetoacetate (4q) and dimethyl
malonate (4r) under solvent-free conditions were similar to or better than under solvent conditions.12,13
*
Corresponding author, Tel +81-95-819-2429, Fax+81-95-819-2476, E-mail matumura@net.nagasaki-u.ac.jp

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HETEROCYCLES, Vol. 67, No. 1, 2006
Lewis acid or Brønsted acid
X
Y
X
Y
(0.1 equiv.)
OMe
(2)
+
N
N
solvent-free or in CH2Cl2
rt, 12 h
CO2Me
4p-r (3.0 equiv.)
p: X=Y=COMe
q: X=COMe, Y=CO2Me
r: X=Y=CO2Me
CO2Me
3ap-ar
2a
Table 1. Solvent-free and solvent reaction of N,O-acetal (2a) with active methylene compounds (4p-r)
in the presence of acid
yield (%)
acida
entry
nucleophile
product
solvent-free
in CH2Cl2
1
2
4p
4p
4p
3ap
3ap
3ap
89
84
77
70
TiCl4
16d
TiCl2(O-i-Pr)2
CF3SO3H
3
44
4
4p
4q
4q
4q
4q
3ap
94
93
87
93
74
67
87
94
56
61
p-TsOH
3aqc
3aqc
3aqc
3aqc
TiCl4
5
6
TiCl2(O-i-Pr)2
CF3SO3H
p-TsOH
7
8
b
9
4r
4r
4r
3ar
3ar
3ar
76
80
57
TiCl4
10
11
61
TiCl2(O-i-Pr)2
p-TsOH
traced
traced
a
b
c
0.1 equiv. Et3N (0.1 equiv.) was added. The ratio of diastereomer for product (3aq) was
d
about 2:1. Conversions were very low.
Furthermore, we found that the coupling reaction of 2a with solid 1,3-diketones (4s-u) was possible under
solvent free conditions (Eq. 3), in which the amount of 2a was 3 equivalent to 1,3-diketones (4s-u) and
the yields of the products (3as-3au)14 were obtained based on 4s-u. The results indicate the advantage of
solvent-free conditions in the Mannich-type reaction between 2a and 4s-u in comparison with the reaction
in CH2Cl2 (Eq. 3).
p-TsOH
(1/30 equiv.)
X
Y
X
(3)
+
2a
N
Y
4s-u
solvent-free or in CH2Cl2
rt, 12 h
CO2Me
3as-au
(1/3 equiv)
s: X=COMe, Y=COPh
t: X=Y=COPh
solvent-free
in CH2Cl2
u: X-Y=CO(CH2)3CO
3as
3at
3au
77%
63%
82%
19%
42%
67%
The solvent-free conditions were applicable to the Mannich-type reaction between N,O-acetal (2b) and
(4p,q,t) to afford the coupling products (3bp,14bq,8bt14) in good yields (Eq. 4).

HETEROCYCLES, Vol. 67, No. 1, 2006
115
X
Y
p-TsOH
X
Y
+
(4)
N
N
OMe
(0.1 equiv.)
solvent-free
rt, 12 h
CO2CH2Ph
CO2CH2Ph
4p,q (3.0 equiv.)
4t (1/3 equiv.)
2b
3bp: 82%
3bq: 78%
3bt: 81%
Furthermore, it was found that the yield (57%) of 5 for the solvent-free allylation reaction15 of 2a was
much superior to that (21%) in CH2Cl2 (Eq. 5). In this type of reaction, interestingly, a chiral Lewis acid,
(S)-BINOL-Ti complex,16 gave 5 with higher enantioselectivity (enriched isomer; R) under solvent-free
conditions than that in CH2Cl2, though the ee’s were very low.17
acid (0.1 equiv.)
SiMe3
+
(5)
2a
N
solvent-free or in CH2Cl2
rt, 12 h
(3.0 equiv.)
CO2Me
5
Yield (%) of 5
acid
p-TsOH
solvent-free
in CH2Cl2
21
57
66
75
Cl
O
O
(11% ee)
(20% ee)
Ti
Cl
enriched isomer : R
Although there have not been any data to explain the reason why solvent–free conditions gave higher
yields of products than those in CH2Cl2 in the Mannich-type reaction between N,O-acetals (2a,b) and
carbon nucleophiles (4p-u), we presume that it might be due to faster trapping of N-acyliminium ions
generated from 2a,b with 4p-u than in the reactions in CH2Cl2 because of high density of nucleophiles
under solvent-free conditions.
In summary the Mannich-type reactions for N,O-acetals (2a,b) under solvent-free conditions proceeded
more efficiently than in CH2Cl2. The characteristics and advantages of the Mannich-type reaction under
solvent-free conditions will be applied into preparations of some biologically important α-substituted
cyclic amine derivatives.
ACKNOWLEDGEMENT
Y. M. and O.O. thank the Ministry of Education, Culture, Sports, Science and Technology, Japan for
Scientific Research on Priority Areas, (No. 420: Reaction Control of Dynamic Complexes) and the Japan
Society for the Promotion of Science for Scientific Research (C) (15550094).
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HETEROCYCLES, Vol. 67, No. 1, 2006
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3as: 1.60-2.33 (m, 4H), 2.19 (s, 3H), 2.85-3.80 (m, 2H), 3.66 and 3.69 (2s, 3H), 4.30-4.40, 5.10-5.18
and 5.58-5.62 (3m, 1H), 4.65-4.80 (m, 1H), 7.38-7.65 (m, 3H), 7.82-8.11 (m, 2H).
3at: 1.62-1.82 (m, 2H), 2.00-2.28 (m, 1H), 2.35-2.48 (m, 1H), 2.85-3.10 (m, 1H), 3.25-3.50 (m, 1H),
3.58 and 3.61 (2s, 3H), 4.58-4.82 (m, 1H), 5.78 and 6.40 (2d, J=4.0 and 4.0 Hz, 0.25H and 0.75H),
7.38-7.62 (m, 6H), 7.85-8.05 (m, 4H).
3au: 1.49-2.63 (m, 10H), 3.40-3.80 (m, 5.5H), 4.69-4.78 (m, 1H), 10.78 (br s, 0.5H).
3bp: 1.78-2.30 (m, 4H), 2.17 (br s, 6H), 3.30-3.40 (m, 1H), 3.45-3.52 (m, 1H), 4.00-4.50 (m, 1H), 4.45
(br s, 1H), 5.13 (br s, 2H), 7.36 (s, 5H).
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7.20-7.45 (m, 10H), 7.50-7.58 (m, 2H), 7.65-7.75 (m, 1H), 7.90-8.00 (m, 2H).
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HETEROCYCLES, Vol. 67, No. 1, 2006
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flow rate: 1.0 mL/min, detection at 210 nm, retention time: 10 min for (R)-(+)-isomer and 13 min for
(S)-(-)-isomer.