Nucleophilic substitution on 4-hydroxymethylanilines under 'neutral' conditions via aza quinone methide intermediate

Article abstract of DOI:10.1016/S0040-4039(02)01198-X

Substitution reaction of 4-hydroxymethylaniline derivatives with resonance-stabilized carbon nucleophiles and an acid-labile nucleophile, including β-ketoester, 1,3-diketone, α-nitroester, and silylenolether, proceeded efficiently upon heating at 80°C in a neutral solvent system. The reaction was successfully applied to the synthesis of 4-aminophenylalanine.

Full text of DOI:10.1016/S0040-4039(02)01198-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5751–5753
Nucleophilic substitution on 4-hydroxymethylanilines under
‘neutral’ conditions via aza quinone methide intermediate
Hiroyasu Takahashi, Nobuyuki Kashiwa, Hisayoshi Kobayashi, 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 10 May 2002; revised 10 June 2002; accepted 20 June 2002
Abstract—Substitution reaction of 4-hydroxymethylaniline derivatives with resonance-stabilized carbon nucleophiles and an
acid-labile nucleophile, including b-ketoester, 1,3-diketone, a-nitroester, and silylenolether, proceeded efficiently upon heating at
80°C in a neutral solvent system. The reaction was successfully applied to the synthesis of 4-aminophenylalanine. © 2002 Elsevier
Science Ltd. All rights reserved.
The substitution reactions of aromatic rings are impor-
tant in organic synthesis. We recently reported a novel
substitution reaction of dialkylaniline derivatives based
upon the Mannich-type condensation reaction between
tertiary aromatic amines 1 and resonance-stabilized car-
bon nucleophiles in the presence of formaldehyde (Fig.
1).1 In this reaction, the aza quinone methide intermedi-
ate 2 is thought to be the active intermediate, which is
formed via regioselective Friedel–Crafts-type reaction
with formaldehyde at the p-position of 1, followed by
dehydration.2 Though this reaction is a powerful
method for the formation of new carbon–carbon bonds
on aromatic rings,3 acidic conditions and a relatively
high temperature (e.g. acetic acid as a solvent at 80°C)
are required. Moreover, only formaldehyde (X=H in
Fig. 1) can be used as an aldehyde species, i.e. other
aldehydes, including acetaldehyde, do not form the
intermediate 2 because of their weaker electrophilicity.
Even though the aza quinone methide 2 is thought to
be a useful synthetic intermediate, practical generation
methods of 2 have not been well investigated. If we
could generate a variety of aza quinone methide inter-
mediates 2 (X is not only H, but also alkyl) under
milder conditions, ideally ‘neutral’ conditions, the scope
of that useful reaction would be expanded. With this in
mind, we have designed 4 as a precursor of 2. In this
communication, we present our novel method for gen-
eration of the reactive aza quinone methide species 2
(X=H, Me) from 4 under ‘neutral’ conditions, and its
subsequent substitution reaction with a variety of
nucleophiles.
To generate the aza quinone methide intermediate 2
under neutral reaction conditions, we chose the 4-
hydroxymethylaniline derivatives 44 as precursors for 2.
Firstly, the condensation reaction of N,N-dimethyl-4-
hydroxymethylaniline (4a) and ethyl acetoacetate (5a)
was investigated in various solvent systems. All reac-
tions were run at 80°C, and 1.5 equiv. of nucleophile 5a
was added. The results are summarized in Table 1.
When the reaction was performed in acetonitrile or
DMSO, the desired substituted 6a was obtained in
13–16% yield after 24 h, and the starting substrate was
recovered in 63–66% yield (entries 1 and 3). However,
addition of 1:1 v/v of H2O to the reaction system
resulted in a dramatic improvement of the yield. For
example, addition of H2O to the acetonitrile system
enhanced the yield of 6a from 16% to 52%, though the
dimer 7a5 was generated in 18% yield as a by-product
(entries 1 and 2). The enhancement was less masked
O
NR2
NR2
NR2
Nu
X
H
X
X
AcOH
Nu
1
2
3
(X = H)
Nu: Nucleophiles
NR2
X
OH
4
Figure 1. Novel Mannich-type condensation reaction.
* Corresponding author. Tel.: +81-3-5841-7848; fax: +81-3-5841-8495;
e-mail: nagasawa@iam.u-tokyo.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01198-X

5752
H. Takahashi et al. / Tetrahedron Letters 43 (2002) 5751–5753
Table 1. Substitution reaction of 4a with 5a under neutral
ined, THF, 2-propanol and toluene, gave poor results
(entries 5–8).6
conditions
O
NMe2
CO2Et
Using the ‘neutral’ solvent system, acetonitrile:H2O=
1:1, we next examined the scope and limitations of this
substitution reaction of the N,N-dimethyl-4-hydroxy-
methylaniline derivatives 4a and 4b, which have pri-
mary and secondary hydroxyl groups, respectively, with
various resonance-stabilized carbon nucleophiles 5a–e
and the acid-labile nucleophile 5f (Table 2). Reactions
of 4a and 4b with nucleophiles 5a–d in acetonitrile/H2O
(1:1) at 80°C gave 4-substituted aniline derivatives 6a–d
and 8a–d in moderate to good yields, respectively.7 In
the case of the secondary alcohol 4b, the dimerization
reaction of 4b was completely suppressed. When
dimethyl malonate (5e) was used as the nucleophile,
substitution reaction did not take place with 4a and 4b,
which is presumably due to the weaker nucleophilicity
of 5e compared with the others.1 It is noteworthy that
the acid-labile nucleophile 1-cyclohexenyloxy-trimethyl-
silane (5f) reacted with 4a and 4b to provide the con-
densed products 6f and 8f in 50 and 14% yields,
respectively.
NMe2
Me
NMe2
5a (1.5 equiv.)
+
O
CO2Et
OH
80 °C, 24 h
4a
Me
Me2N
7a
6a
Entry
Solvent
6a (%)
7a (%)
Recovery of 4a
(%)
1
2
3
4
5
6
7
8
CH3CN
16
52
13
25
6
8
5
4
9
18
12
19
8
21
17
20
63
22
66
56
81
70
73
75
CH3CN/H2Oa
DMSO
DMSO/H2Oa
THF
THF/H2Oa
2-Propanol
Toluene
a 1 equiv. volume of H2O was used.
This ‘neutral’ substitution reaction of N,N-dialkyl-4-
hydroxyanilines was successfully applied to the synthe-
sis of amino acid derivatives 10 (Scheme 1).
N,N-Dibenzyl-4-hydroxymethylaniline 4c was reacted
with DMSO (entries 3 and 4). The addition of H2O is
thought to be effective to accelerate the generation of
the aza quinone methide intermediate 2 by protonation
of the hydroxyl group of 4a. The other solvents exam-
Table 2. Substitution reaction of 4 with nucleophiles 5 under neutral conditions
NMe2
NMe2
NMe2
5
R
R
R
CH3CN-H2O (1 : 1)
O
80°C
OH
Nu
4a: R = H
4b: R = Me
6f: R = H
8f: R = Me
6a-e: R = H
8a-e: R = Me
equiv
Time (h) Products Yield (%)
5
4
NMe2
MeCOCH2CO2Et (5a)
MeCOCH2COMe (5b)
EtO2CCH2NO2 (5c)
NCCH2CN (5d)
3.0
2.3
2.3
2.3
2.0
2.3
27
24
3
6a
6b
6c
6d
6e
6f
74 (13)a
66 (28)a
98
OH
4a
18
48
24
80
0 (12)a
50 (30)a
MeO2CCH2CO2Me (5e)
1-Cyclohexenyloxy-
trimethylsilane (5f)
MeCOCH2CO2Et (5a)
MeCOCH2COMe (5b)
EtO2CCH2NO2 (5c)
NCCH2CN (5d)
1.5
1.5
1.5
2.0
2.0
1.6
24
18
4
8a
8b
8c
8d
8e
8f
58
54
97
93
NMe2
Me
OH
48
48
120
4b
MeO2CCH2CO2Me (5e)
complicated
14
1-Cyclohexenyloxy-
trimethylsilane (5f)
aThe yields in the parentheses are those of the dimers of the tertiary amines.

H. Takahashi et al. / Tetrahedron Letters 43 (2002) 5751–5753
5753
NBn2
2. Takahashi, H.; Hashimoto, Y.; Nagasawa, K. Heterocy-
cles 2001, 55, 2305.
O2N
CO2Et
NBn2
5c
3. The reaction of the aza quinone methido intermediate 2
with nucleophiles has not been well examined, though
the reaction with the quinone methido intermediate has
been reported. (a) Sanner, M. A.; Stansberry, M.;
Weigelt, C.; Michne, W. F. Tetrahedron Lett. 1992, 33,
5287; (b) Loubinoux, B.; Miazimbakana, J.; Gerardin, P.
Tetrahedron Lett. 1989, 30, 1939; (c) Angle, S. R.; Turn-
bull, K. D. J. Am. Chem. Soc. 1989, 111, 1136; (d) Poss,
A. J.; Belter, R. K. J. Org. Chem. 1988, 53, 891.
4. N,N-Dimethyl-4-hydroxymethylaniline derivatives 4a, 4b
were prepared from the corresponding aldehyde, 4-
(dimethylamino)benzaldehyde, by reduction with LiAlH4
or methylation with methylmagnesium bromide.
5. (a) Salmon, M.; Zavala, N.; Cabrera, A.; Cardenas, J.;
Gavino, R.; Miranda, R.; Martinez, M. J. Mol. Catal.
A: Chem. 1995, 104, L127; (b) Girard, P.; Yianni, P.;
Desvergne, J.-E.; Castellan, A.; B-Laurent, H. J. Chem.
Res. (S) 1985, 358.
6. When the reaction was performed in acetic acid as a
solvent, the dimer 7a was obtained in 30% yield, and the
starting 4a was recovered in 50% yield.
80 °C
O2N
NH2
CO2Et
OH
77%
4c
9
H2, Pd/C
rt
H2N
CO2Et
10
91%
Scheme 1. Synthesis of 4-aminophenylalanine (10).
with ethyl nitroacetate (5c) to give the condensed product
9, which was subsequently reduced with hydrogen in the
presence of palladium on carbon to give the 4-
aminophenylalanine ethyl ester (10)8 in a high yield.
In conclusion, we have developed a practical method for
generation of the reactive aza quinone methide interme-
diate
2 from N,N-dimethyl-4-hydroxymethylaniline
derivatives 4. We also have demonstrated that substitu-
tion reaction of 4 with a variety of nucleophiles 5 under
‘neutral’ conditions via the aza quinone methide interme-
diate 2. This reaction provides an efficient method for the
synthesis of b-aromatic amine-substituted ketone or ester
derivatives 6 and 8, which are useful intermediates for
syntheses of pharmaceuticals9 and natural products.
Further development and applications of this reaction
are under study in our laboratories.
7. Procedure for 6a: A mixture of 4a (100 mg, 0.66 mmol)
and ethyl acetoacetate (5a) (0.25 mL, 2.0 mmol) in ace-
tonitrile and H2O (1:1 v/v, 2 mL) was heated at 80°C
for 27 h. After cooling, the reaction mixture was concen-
trated in vacuo and the residue was purified by silica gel
chromatography with hexane/ethyl acetate as the eluent
to give 6a (130 mg, 74%). Spectral data for 6a: IR (neat)
1722, 1698 cm−1 1H NMR (CDCl3, 500 MHz) l 7.04
.
(d, J=8.5 Hz, 2H), 6.65 (d, J=8.5 Hz, 2H), 4.15 (m,
2H), 3.73 (t, J=7.5 Hz, 1H), 3.07 (d, J=7.5 Hz, 2H),
2.90 (s, 6H), 2.17 (s, 3H), 1.22 (t, J=7.2 Hz, 3). 13C
NMR (CDCl3, 125 MHz) l 202.99, 169.30, 149.41,
129.36, 125.78, 112.81, 61.65, 61.26, 40.63, 33.19, 29.59,
14.00. HRMS (FAB, M+) calcd for C15H21NO3
263.1521, found 263.1473.
Acknowledgements
This work was supported by Grants-in-Aid from the
Ministry of Education, Culture, Sports, Science and
Technology of Japan.
8. (a) Anilkumar, R.; Chandrasekhar, S.; Sridhar, M. Tet-
rahedron Lett. 2000, 41, 6665; (b) Sellergren, B.;
Andersson, L. J. Org. Chem. 1990, 55, 3381.
References
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