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H. Takahashi et al. / Tetrahedron Letters 43 (2002) 2935–2938
Table 1. Mannich-type condensation reaction with N,N-dimethylaniline
N
O
N
HCHO
N
+
O
EtO2C
7
CO2Et
4
9
8
N
Entry
Solvent
8 (equiv.)
Temp. (°C)
Time (h)
Yield (%)
9
7
i
DMF
1.5
1.5
1.5
5
100
80
80
80
80
4
5
0.5
0.5
2
–
6
ii
iii
iv
v
CH3CN
AcOH
AcOH
TFA
24
73
63
29
26
21
7
1.5
13
conditions (entries i and ii), the condensation reaction
did not proceed or gave only a low yield of the
desired 9 together with the dimer 7. On the other
hand, when the reaction was performed in acetic acid
at 80°C, the reaction was completed within 30 min
and gave 9 in 73% yield, together with dimerized
product 7 in 21% yield (entry iii). If the amount of
the nucleophile 8 was increased, the formation of the
dimer 7 was suppressed (entry iv). Switching the sol-
vent to TFA from acetic acid decreased the yield of 9
to 29% (entry v). Dimerization reaction of 4 took
place quantitatively in the absence of 8 in acetic acid
at 80°C.
tion reaction products. In the case of 2-substituted
aromatic amines (10h, 10i), formation of the aza qui-
none methide intermediate corresponding to 5 is
thought to be unstable by steric repulsion between
the N-alkyl group and the 2-substituents of the aro-
matic ring, and the starting aromatic tertiary amines
were recovered.
Reactions with other nucleophiles were examined
using non- or 3-substituted tertiary aromatic amines
4, 10d and 10e in the presence of formaldehyde
(Table 3). All reactions were performed in acetic acid
at 80°C, with 1.5 and 5 equiv., respectively, of nucleo-
philes (12–14 and 8) and formaldehyde, and the
results are summarized in Table 3. When ethyl
nitroacetate (12) and acetylacetone (13) were used as
nucleophiles, condensed products 15a–c and 16a–c
were obtained in 60–77% yield. On the other hand,
dimethyl malonate (14) did not react with any of the
aromatic tertiary amines 4, 10d and 10e and only
gave dimerization products of the tertiary aromatic
amines.7 This is probably because of the nucleophilic-
ity of 8 and 12–14. The pKa values of the active
methylene protons of the nucleophiles 8 and 12–14
are 11, 6, 9 and 13, respectively, in H2O,8 and consid-
ering the order of these values, the results in Table 3
suggest that the nucleophile in this condensation reac-
tion requires a nucleophilicity corresponding to a pKa
value of at least 11 of the active methylene protons.
Condensation reactions of various tertiary aromatic
amines and ethyl acetoacetate (8) (1.5 equiv.) with
formaldehyde (5 equiv.) were next examined. All reac-
tions were run in acetic acid at 80°C, and the results
are summarized in Table 2. Cyclic tertiary aromatic
amine derivatives 10a and 10b gave the condensed
products 11a and 11b in moderate yield. The 3-substi-
tuted aniline derivatives 10c, 10d, 10e and 10f gave
the corresponding condensed products 11c, 11d, 11e
and 11f in good yield with small amounts of dimers.
The sterically hindered 3,5-disubstituted derivative 10g
gave 11g in only 24% yield, and a 36% yield of the
dimerization product was obtained. The 2-substituted
aniline derivatives 10h and 10i did not react with
formaldehyde and the starting amines were recovered
quantitatively, whereas N-methylindoline 10j, a ring-
closed derivative of 10h, was polymerized under these
reaction conditions. The 4-substituted aniline 10k
gave multiple products, as detected on TLC. 1-Naph-
thylamine 10l and 2-naphthylamine 10m regioselec-
tively gave the condensed products 11l and 11m in 64
and 26% yields, respectively. Thus, the condensation
reaction occurred with non- or 3-substituted tertiary
aromatic amines, whereas 2- or 4-substituted tertiary
aromatic amines did not give the desired condensa-
In conclusion, we have developed a novel Mannich-
type condensation reaction, which is a regioselective
substitution reaction of tertiary aromatic amines and
resonance-stabilized carbon nucleophiles in the pres-
ence of formaldehyde. This one-pot reaction was
applied to the synthesis of various b-aromatic amine-
substituted ketone or ester derivatives. Further devel-
opment of this reaction and application to the
synthesis of natural products are in progress.