Hydrolysis of Schiff bases promoted by UV light

Article abstract of DOI:10.1246/cl.2001.708

The first hydrolysis of Schiff base under 365 nm UV light is reported. The reaction was affected markedly by the solvent used. It has been successfully applied to the synthesis of compound 2c which is a useful antitumor agent.

Full text of DOI:10.1246/cl.2001.708

708
Chemistry Letters 2001
Hydrolysis of Schiff Bases Promoted by UV Light
Zhaohua Huang, Decheng Wan, and Junlian Huang*
The Key Laboratory of Molecular Engineering of Polymers, Education Ministry of China,
Department of Macromolecular Science, Fudan University, Shanghai 200433, P. R. China
(Received April 9, 2001; CL-010319)
The first hydrolysis of Schiff base under 365 nm UV light
is reported. The reaction was affected markedly by the solvent
used. It has been successfully applied to the synthesis of com-
pound 2c which is a useful antitumor agent.
Schiff bases have been widely used as protective group of
amino group in organic synthesis.1–4 The hydrolysis of Schiff
bases had been carefully investigated by Jencks.5,6 In most
cases, the cleavage reaction was carried out in acid or alkaline
conditions. In some cases, the Schiff base can be cleaved by
catalytic hydrogenation.2 However, these methods may suffer
from serious side reactions when multiple functionality is pres-
ent elsewhere in the substrate molecule. Thus it is meaningful
to develop new method for the convenient cleavage of Schiff
bases.
In our continuous effort to synthesize new antitumor agents,
Schiff base was selected as protective group of the aromatic
amine of sulfadiazine. It was noted that compound 1a was
gradually cleaved in the presence of sunlight when acetone was
used as solvent. Further investigation showed that the cleavage
of the Schiff base of 1a was due to the hydrolysis reaction,
which was supported by the fact that no cleavage reaction can
be observed in the absence of water. Furthermore, the reaction
was accelerated by the addition of water to acetone. The reac-
tion route is illustrated in Scheme 1 and the results are summa-
rized in Table 1.
The comparison of Entry 1 with Entry 4 suggests that sun-
light is a promoter for the hydrolysis since the reaction in the
dark is too slow to be detected. This can be further substantiat-
ed by the comparison of Entry 4 with Entry 3 that the reaction
under UV light was much more efficient. Therefore, it can be
concluded that the hydrolysis of 1a, in fact, was promoted by
UV light.
The hydrolysis of the Schiff bases was affected markedly
by the solvents used. As shown in Table 1, 1b and 1c were
completely hydrolyzed in acetone solution within 40 min
(Entries 5 and 6) while in THF solution only 31% and 25%
yields were obtained with other conditions unchanged (Entries
8 and 9). However, high yield can be achieved if the reaction
time is long enough (Entry 10). But, when DMF was used as
solvent the hydrolysis reaction did not occur at all, even the
reaction time was long enough (Entries 11 and 12). It seems
that the Schiff base is stabilized by DMF though the mechanism
is still unclear.
Accordingly, Condition C has been chosen as the prefer-
able reaction condition and acetone is taken as solvent for the
hydrolysis of the Schiff bases. It has been successfully applied
to the hydrolysis of 1a, lb, lc and 3 as listed in Entries 3, 5, 6
and 7, respectively.7,8 The advantage of this deprotection
method has been fully demonstrated in the synthesis of 2c,
since 2c, a potent antitumor agent, is sensitive to acid or alka-
line conditions and is unstable at relatively high temperature.
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
709
In conclusion, we have developed a new efficient method
for the hydrolysis of Schiff bases by the employment of 365 nm
UV light. The application of this method to the synthesis of 2c
has been successful. Further research focusing on the mecha-
nism of this reaction is in progress.
(dd, 1H, pyrimidyl), 8.61 (dd, 1H, pyrimidyl), 8.63 (s, 1H,
ArCH=N); MS (EI) m/z (RI) 382 (M+, 6), 348 (19), 279
(46), 260 (100), 244 (38), 196 (82), 180 (85), 152 (55), 109
(31). 2b: mp: 224–226 °C; 1H NMR (300 MHz, DMSO-d6)
δ 3.73 (t, 2H, J = 4.5 Hz, CH2CH2OH), 4.07 (t, 2H, J = 4.5
Hz, CH2CH2OH), 5.02 (t, 1H, J = 5.4 Hz, CH2CH2OH),
5.66 (br s, 2H, NH2), 6.51 (d, 2H, J = 8.7 Hz, phenyl), 6.73
(dd, 1H, J = 2.4 Hz, J = 4.2 Hz, pyrimidinyl), 7.51 (d, 2H,
J = 8.7 Hz, phenyl), 8.23 (dd, 1H, J = 2.4 Hz, J = 4.2 Hz,
pyrimidyl), 8.58 (q, 1H, J = 2.4 Hz, pyrimidyl); MS (EI)
m/z (RI) 295 ([M+H]+, 15), 172 (60), 156 (100), 108 (29),
References and Notes
1
2
P. Bey and J. P.Vevert, Tetrahedron Lett., 18, 1455 (1977).
R. A. Lucas, D. F. Dickel, M. J. Dziemian, B. L. Hensle,
and H. B. MacPhillamy, J. Am. Chem. Soc., 82, 5688
(1960).
1
3
4
5
6
G. W. J. Fleet and I. Fleming, J. Chem. Soc., C, 1969,1758.
B. Bezas and L. Zervas, J. Am. Chem. Soc., 83, 719 (1961).
W. P. Jencks, J. Am. Chem. Soc., 81, 475 (1959).
B. M. Anderson and W. P. Jencks, J. Am. Chem. Soc., 82,
1773 (1960).
108 (83), 92 (81), 65 (68). 1c: mp:141–142 °C; H NMR
(300 MHz, Acetone-d6) δ 1.83 (m, 2H, CH2CH2CH2), 2.32
(t, 2H, J = 7.2 Hz, O=CCH2CH2CH2), 2.50 (t, 2H, J = 7.2
Hz, CH2CH2CH2Ph), 3.80 (m, 8H, N(CH2CH2Cl)2), 4.51
(t, 2H, J = 2.1 Hz, NCH2CH2O), 4.59 (t, 2H, J = 2.1 Hz,
NCH2CH2O), 6.74 (d, 2H, J = 8.7 Hz, phenyl), 6.79 (dd,
1H, J = 2.4 Hz, J = 4.2 Hz, pyrimidinyl), 7.04 (d, 2H, J =
8.7 Hz, phenyl), 7.32 (d, 2H, J = 8.7 Hz, phenyl), 7.59 (m,
3H, phenyl), 8.02 (d, 2H, J = 3 Hz, phenyl), 8.07 (d, 2H, J
= 3 Hz, phenyl), 8.38 (dd, 1H, J = 2.4 Hz, J = 4.2 Hz,
pyrimidyl), 8.60 (s, 1H, ArCH=NAr), 8.62 (q, 1H, J = 2.4
7
Typical procedure for the hydrolysis of the Schiff bases
under UV light: To a solution of 1c (3 g) in acetone (60
mL) was added distilled water (5 mL). With nitrogen gas
slightly bubbling through, the reaction solution was irradi-
ated by a 300 W high-pressure mercury lamp for 40 min at
r.t. Cupric sulfate aqueous solution was used as the
photofilter to obtain 365 nm monochromatic light. After
the removal of the solvent, the crude product was washed
with ethyl ether to remove benzaldehyde, then the residue
was dried at vacuum. 2c was obtained as white solid in
yield of 99%.
1
Hz, pyrimidyl). 2c: mp: 97–98 °C; H NMR (300 MHz,
CDCl3) δ 1.81 (m, 2H, CH2CH2CH2), 2.23 (t, 2H, J = 7.2
Hz, O=CCH2CH2CH2), 2.53 (t, 2H, J = 7.2 Hz,
CH2CH2CH2Ph), 3.60 (t, 4H, J = 6.0 Hz, N(CH2CH2Cl)2),
3.70 (t, 4H, J = 6.0 Hz, N(CH2CH2Cl)2), 4.25 (t, 2H, J =
4.5 Hz, NCH2CH2O), 4.43 (t, 2H, J = 4.5 Hz,
NCH2CH2O), 5.64 (br s, 2H, NH2), 6.46 (dd, 1H, J = 2.4
Hz, J = 4.2 Hz, pyrimidinyl), 6.64 (dd, 4H, J = 8.4 Hz, J =
2.4 Hz, phenyl), 7.00(d, 2H, J = 6.9 Hz, phenyl), 7.66 (dd,
1H, J = 2.4 Hz, J = 4.2 Hz, pyrimidyl),7.81 (d, 2H, J = 6.9
Hz, phenyl), 8.58 (q, 1H, J = 2.4 Hz, pyrimidyl).
8
Satisfactory analyses (within ±0.4%) were obtained for all
new compounds. Selected data for 1b: mp: 186–187 °C; 1H
NMR (300 MHz, DMSO-d6) δ 3.77 (t, 2H, CH2CH2OH),
4.15 (t, 2H, CH2CH2OH), 5.06 (t, 1H, CH2CH2OH), 6.84
(dd, 1H, pyrimidinyl), 7.30 (d, 2H, phenyl), 7.58 (m, 3H,
phenyl), 7.89 (d, 2H, phenyl), 7.95 (dd, 2H, phenyl), 8.32