PAPER
Regioselective Dealkylation of 2-Alkoxybenzoic Acid and Its Amide Derivatives with Aliphatic Amines
245
Table 2 Cleavage of Anisic Acid and Amide Derivatives with Piperazine in Dimethylacetamide (Scheme 2)
Entry
Anisic Acid and Anisamide Derivatives
Reaction Time
(h)
Yield
(%)a
mp (°C)
reported
X
R1
R2
found
1
2
3
OH
Me
Me
Me
Me
Me
Me
Me
Et
i-Pr
MOMd
Bzl
Me
Me
Me
Me
Me
Me
Bzl
Me
H
H
H
H
H
H
H
H
1
24
24
8
13
24
5
12
24
0.5
1
0.2
0.2
1
18
10
0.2
0.5
0.5
4
84
12b
0c
74
67
0c
95
74
0c
93
91
94
89
93
0e
160
159
–
142
88
16019
–
ONa
OEt
NH2
NHMe
NMe2
NHPh
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
–
4
14420
8822
–
521
623
724
8
–
135
159
–
160
159
150
161
142
–
172
183
183
143
193
–
13525
16019
–
9
H
H
H
1026
11
12
13
14
15
1630
1732
1833
19
20
21
22
16019
16019
15227
16128
14129
–
3-MeO
4-MeO
5-MeO
6-MeO
6-Me
4-BzlO
4-BzlO
4-MOMO
4-MeO
52
93
95
93f
96g
0c
17231
18232
18232
–
–
–
p-NHPhCO2Et Me
m-anisic acid
p-anisic acid
24
24
0c
–
–
a Yield of isolated product.
b Starting material was recovered in 81% yield as a free acid. The product and the starting material were separated by column chromatography
(silica gel, CHCl3 /MeOH, 9:1).
c Starting material was recovered.
d MOM: methoxymethyl.
e Complex mixture was obtained, and the starting material was recovered in 5% yield.
f MS: m/z = 198 (M+), 180 (M - 18), 150 (M - 48).
1H NMR (CDCl3): d = 3.49 (s, 3 H, OCH3), 5.22 (s, 2 H, OCH2O), 6.60 (dd, 1 H, J = 2 Hz, 9 Hz, H-5), 6.64 (d, 1 H, J = 2 Hz, H-3), 7.72 (d, 1
H, J = 9 Hz, H-6). The methylene signal at d = 5.22 showed NOE correlation to H-3 at d = 6.64 and H-5 at d = 6.60, respectively.
IR (KBr): n = 2995, 1661, 1622, 1456, 1260, 1146, 1073, 994 cm-1.
Anal. Calcd for C, 54.55; H, 5.09. Found: C, 54.33; H, 5.03.
g MS: m/z = 315 (M+), 270(M - 45), 165(M - 150), 151(M - 164).
1H NMR (DMSO-d6): d = 1.33 (t, 3 H, J = 7 Hz, OCH2CH3), 3.81 (s, 3 H, OCH3), 4.30 (q, 2 H, J = 7 Hz, OCH2CH3), 6.53 (d, 1 H, J = 2 Hz,
H-3), 6.58 (dd, 1 H, J = 2 Hz, 9 Hz, H-5), 7.98 (d, 1 H, J = 9 Hz, H-6), 7.85-7.98 (m, 4 Harom), 10.46 (br, 1 H, NH), 12.14 (br, 1 H, OH). The
methyl signal at d = 3.81 showed NOE correlation to H-3 at d = 6.53 and H-5 at d = 6.58, respectively.
IR (KBr): n = 3316, 2995, 1713, 1615, 1541, 1516, 1254, 1175, 1105, 1030 cm-1.
Anal. Calcd for C, 69.12; H, 5.39. Found: C, 69.02; H, 5.55; N, 5.45.
IR (KBr): n = 3349, 1713, 1659, 1595, 1541, 1291, 1250, 1123
(3) Williard, P. G.; Fryhle, C. B. Tetrahedron Lett. 1980, 21,
3731.
cm-1.
(4) Nagaoka, H.; Schmid, G.; Iio, H.; Kishi, Y. Tetrahedron Lett.
1981 22, 899.
(5) Parker, K. A.; Petraitis, J. J. Tetrahedron Lett. 1981, 22, 397.
(6) Node, M.; Nishide, K.; Sai, M.; Ichikawa, K.; Fuji, K.; Fujita,
E. Chem. Lett. 1979, 97.
(7) Node, M.; Nishide, K.; Fuji, K.; Fujita, E. J. Org. Chem. 1980,
45, 4275.
(8) For reviews See:
Dealkylation of 2-Alkylsubstituted o-Anisic Acids; General
Procedure
A mixture of the starting material (1 equiv) and piperazine (3 equiv)
in DMA (1 mL/mmol) was heated at 150°C under argon. When the
starting material had disappeared (TLC monitoring), the solvent
was removed in vacuo, and the residue was acidified with 1 N HCl
at 0°C. The resulting precipitate was collected by filtration, washed
with H2O and dried in vacuo.
Maercker, A. Angew. Chem. 1987, 99, 1002; Angew. Chem.
Int. Ed. Engl. 1987, 26, 972.
Ticco, M. Synthesis 1988, 749.
(9) Feutrill, G. I.; Mirrington, R. N. Tetrahedron Lett. 1970, 16,
1327.
(10) McCarthy, J. R.; Moore, J. L.; Cregge, R. J. Tetrahedron Lett.
1978, 52, 5183.
(11) Mann, F. G.; Pragnell, M. J. Chem.& Ind. (London) 1964,
1386.
References
(1) Greene, T. W.; Wuts, P. G. M.; Protective Groups in Organic
Synthesis, Wiley: New York, 2nd ed. 1991, pp 145-149.
(2) For review See: Bhatt, M. V.; Kulkarni, S. U. Synthesis 1983,
249.
Synthesis 2000, No. 2, 243–246 ISSN 0039-7881 © Thieme Stuttgart · New York