Novel Mannich-type nucleophilic substitution reaction with tertiary aromatic amines

Article abstract of DOI:10.1016/S0040-4039(02)00447-1

A novel formaldehyde-mediated condensation reaction of N,N-dialkyl aromatic amines and resonance-stabilized carbon nucleophiles is described. A condensation reaction between N,N-dimethylaniline (4) and ethyl acetoacetate (8) in the presence of formaldehyd

Full text of DOI:10.1016/S0040-4039(02)00447-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2935–2938
Novel Mannich-type nucleophilic substitution reaction with
tertiary aromatic amines
Hiroyasu Takahashi, Nobuyuki Kashiwa, Yuichi Hashimoto and Kazuo Nagasawa*
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
Received 22 January 2002; revised 25 February 2002; accepted 1 March 2002
Abstract—A novel formaldehyde-mediated condensation reaction of N,N-dialkyl aromatic amines and resonance-stabilized
carbon nucleophiles is described. A condensation reaction between N,N-dimethylaniline (4) and ethyl acetoacetate (8) in the
presence of formaldehyde in acetic acid took place to give 2-(4-dimethylaminobenzyl)-3-oxo butyric acid ethyl ester (9) together
with the dimerization product 7 in 73 and 21% yields, respectively. This condensation reaction was further applied to the synthesis
of 4-substituted dialkylaniline derivatives. © 2002 Elsevier Science Ltd. All rights reserved.
The Mannich reaction is a classical and useful carbon–
carbon bond-forming reaction that involves the addi-
tion of resonance-stabilized carbon nucleophiles to
iminium salts and imines, and this method is widely
applied as a key step in the synthesis of numerous
pharmaceuticals and natural products.1 In the first step
of the Mannich reaction, a primary or secondary amine
1 is reacted with a nonenolizable aldehyde, usually
formaldehyde, to form the iminium salt intermediate 2,
and this electrophilic species 2 reacts with various kinds
of nucleophiles, such as carbanion, amine, thiol, phe-
nol, arylamines, and heterocycles to give condensed
products 3, known as ‘Mannich bases’. Under the usual
conditions of the Mannich reaction, tertiary amines
cannot be employed, since the formation of the
iminium salt with aldehyde at the first step of the
Mannich reaction is impossible. On the other hand, the
tertiary aromatic amine N,N-dimethylaniline (4) is
known to dimerize to give biphenylmethane 7 in the
presence of formaldehyde under acidic conditions.2 In
this formaldehyde-mediated dimerization reaction, aza
quinone methide 5 is thought to be the active interme-
diate, which is formed via regioselective Friedel–Crafts-
type reaction with formaldehyde at the p-position of 4,
followed by dehydration.3 We regarded this aza qui-
none methide intermediate 5, generated from the ter-
tiary aromatic amine and formaldehyde, as the iminium
salt equivalent of 2, and expected it to react with
various resonance-stabilized carbon nucleophiles to
provide a variety of aniline derivatives 6 which would
be useful intermediates for pharmaceuticals (Fig. 1).4
Though reactions of a quinone methide intermediate
with various nucleophiles have been reported,5 the reac-
tions of the aza quinone methide intermediate 5 have
not been well examined to our knowledge.6 In this
communication, we describe a novel Mannich-type con-
densation reaction of tertiary aromatic amines and
nucleophiles mediated by formaldehyde.
Initially the condensation reaction of N,N-dimethylani-
line (4) and ethyl acetoacetate (8) in the presence of
formaldehyde was investigated (Table 1). Under neutral
OH
R1
R1
R2
HCHO
HN
N
R2
N
O
1
2
3
OH
R2
N
R1
HCHO
R1
N
N
R2
O
4
5
6
N
N
4
7
Figure 1. Typical Mannich reaction and our novel Mannich-
* Corresponding author. Tel.: +81-3-5841-7848; fax: +81-3-5841-8495;
e-mail: nagasawa@iam.u-tokyo.ac.jp
type reaction with tertiary aromatic amine.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00447-1

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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.

H. Takahashi et al. / Tetrahedron Letters 43 (2002) 2935–2938
2937
Table 2. Condensation reaction with various tertiary aro-
matic amines
Table 3. Condensation reaction with various nucleophiles
Substrate
Products, yields
N
12-14 (1.5 eq)
HCHO (5 eq)
R
N
R
N
Nu
15-17
O
R
AcOH, 80°C
N
R
R = H
R = Et
R = CH2OH
a R = H
b R = Et
c R = CH2OH
4
10d
10e
EtO2C
a
11a R = H 48% (9%)
10a R = H
10b R = OH
a
11b R = OH 45% (trace)
15a R = H
15b R = Et
62% (22%)a
63% (20%)a
O2N
CO2Et
15c R = CH2OH 72% (15%)a
12 (pKa = 6)
N
O
N
O
O
EtO2C
16a R = H
16b R = Et
73% (19%)a
77% (10%)a
16c R = CH2OH 60% (32%)a
R
R
13 (pKa = 9)
a
a
a
61% (15%)
83% ( 4%)
89% (trace)
10c R = H
10d R = Me
10e R = OH
11c R = H
11d R = Me
11e R = OH
11f R = CO2Me
O
9
R = H
73% (21%)a
83% (4%)a
a
CO2Et
74% (17%)
10f R = CO2Me
11d R = Et
11e R = CH2OH 89% (trace)a
8 (pKa = 11)
O
N
N
17a R = H
17b R = Et
0% (30%)a,ref 7)
0% (65%)a
MeO2C
CO2Me
EtO2C
17c R = CH2OH 0% (60%)a
14 (pKa = 13)
a
10g
11g
24% (36%)
a
The yields in parentheses are those of the dimers of the tertiary amines.
R
N
R = Me
no reaction
no reaction
R = CO2Et
10h R = Me
10i R = CO2Et
Grants-in-Aid from Ministry of Education, Culture,
Sports, Science and Technology of Japan, and funds for
the Promotion of Fundamental Studies in Health Sci-
ence from the Organization for Pharmaceutical Safety
Research.
N
polymerized
10j
N
complex mixture
References
10k
1. For reviews see: (a) Arend, M.; Westermann, B.; Risch,
N. Angew. Chem., Int. Ed. 1998, 37, 1044; (b) Tramon-
tini, M.; Angiolini, L.; Mannich Bases, Chemistry and
Uses, CRC: Boca Raton, FL, 1994; (c) Tramontini, M.;
Angiolini, L. Tetrahedron 1990, 46, 1791; (d) Blicke, F.
F. Org. React. (NY) 1942, 1, 303; (e) Comprehensive
Organic Synthesis; Trost, B. M.; Fleming, I.; Heathcock,
C. H., Eds., Pergamon: Oxford, 1991; Vol. 2.
O
N
N
EtO2C
a
64% (27%)
O
11l
10l
EtO2C
N
N
2. Acid or base-catalyzed condensation of phenol or aniline
derivatives with formaldehyde is well known and widely
used for calixarene syntheses; see: (a) Sessler, J. L.;
Mozaffari, A.; Johnson, M. R. Organic Synthesis, John
Wiley and Sons: New York, 1992, Vol. 70; p. 68; (b)
Stewart, D. R.; Gutsche, C. D. J. Am. Chem. Soc. 1999,
121, 4136; (c) Bohmer, V. Angew. Chem., Int. Ed. Engl.
1995, 34, 713.
10m
a
11m 26% (32%)
a
The yields in parentheses are those of the dimers of the tertiary amines.
3. Takahashi, H.; Hashimoto, Y.; Nagasawa, K. Heterocy-
cles 2001, 55, 2305.
Acknowledgements
4. Ishioka, T.; Kubo, A.; Koiso, Y.; Nagasawa, K.; Itai,
A.; Hashimoto, Y. Bioorg. Med. Chem. 2002, 10, 1555.
The work in this paper was partially supported by

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H. Takahashi et al. / Tetrahedron Letters 43 (2002) 2935–2938
N
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Chem. 1988, 53, 891.
NMe2
18
NMe2
6. Condensation reaction of dimethylamine and N,N-dialkyl
toluidine derivatives with formaldehyde is reported. Mioc-
que, M.; Vierfond, J.-M. Bull. Soc. Chim. Fr. 1970, 5,
1907.
7. In the condensation reaction with 4 and 14, 18 was also
formed in 60% yield.
8. Ionization Constants of Organic Acids in Aqueous Solu-
tion, IUPAC Chemical Data Series; Serjeant, E. P.;
Dempsey, B., Eds., Pergamon Press: Oxford, 1979; Vol.
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