In this paper, we describe the preliminary results in
developing a concise and effective one-pot transformation
for preparation of the amino-substituted indazol-3,5-dione.
This method is based on the dehydrating agent initiated
intramolecular CꢀN formation and the subsequent nucleo-
philic conjugation addition of amine.
Table 1. Optimization of Reaction Conditions for Synthesis of 7e
molar ratio
dehydrating
agent
7eb
entry
solvent
(7/amine)
(%)
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2/1
2/1
2/1
0.5/1
1/1
2/1
5/1
10/1
5/1
5/1
ꢀ
ꢀ
HBTUa/ TEAd
EDCIa
40
42
43
39
57
61
38
11
8
3
4
DCCa
5
DCCa
6
DCCa
7
DCCa
8
DCCa
9
DCCa/DMAPc
DCCa/DMAPc/
TEAd
Figure 1. Structure of o-carboxyazobenzene (1ꢀ8).
10
11
12
13
14
15
16
17
CH2Cl2
CHCl3
THF
5/1
5/1
5/1
5/1
5/1
5/1
5/1
DCCa/HOBtd
DCCa
55
61
11
ꢀ
In order to investigate the scope of this rearrangement
reaction, a series of novel o-carboxyazobenzenes have been
designed and synthesized to react with different amines
(Figure 1). Among them, the o-carboxyazobenzene 7 and
p-toluidine are selected as the model substrates to screen
the experimental conditions for the optimization of dehy-
drating agents, solvents, and molar ratio of 7and p-toluidine
(Table 1).
DCCa
CH3CN
PhCH3
DMF
DCCa
DCCa
ꢀ
DCCa
41
7
DMSO
DCCa
a All reactions were carried out at room temperature for 2 h, and the
amount of dehydrating agent is 1.5 equiv vs that of 7. b Isolated yield
after purification by recrystallization. c Catalytic amount. d The amount
of TEA or HOBt is 1.0 equiv vs that of DCC.
When compound 7 (obtained from 3-hydroxybenzoic
acid and 4-methylbenzenediazonium) and p-toluidine are
dispersed in CH2Cl2 in the absence of dehydrating agent,
no desired product 7e is observed by the TLC (Table 1,
entry 1). After adding DCC or EDCI, 7e is obtained where
DCC appears to be a better activator compared with the
other two (Table 1, entries 2, 3, and 6). Subsequently, we
investigated the effect of different molar ratios of 7 and
p-toluidine in order to improve the yield of 7e (Table 1,
entries 4ꢀ8). The molarratioof5/1turns outtobe effective
to obtain an appropriate yield. In addition, the effects of
additives have been investigated (Table 1, entries 9ꢀ11). It
is found that the addition of DMAP and TEA negatively
impacts the performance of this reaction. It should be
noted that the solvents have a significant influence on the
outcome of the reaction. When 7 (5 equiv) is treated with
p-toluidine (1 equiv) and DCC (7.5 equiv) for 2 h at rt in
various solvents, such as CH2Cl2, CHCl3, THF, CH3CN,
PhCH3, DMF, and DMSO (Table 1, entries 7, 12ꢀ17),
CH3CN and PhCH3 are found to be poor reaction solvents
without formation of 7e (Table 1, entries 14, 15), while the
use of THF or DMSO gives 7e in yields of only 11% and
7%, respectively (Table 1, entries 13, 17). By contrast, the
employment of CH2Cl2 affords the desired product 7e with
an increased yield of 61%. Thus, we propose that the
optimal procedure for the preparation of amino-substi-
tuted indazol-3,5-dione is as follows: a mixture of o-car-
boxyazobenzene and amine (5/1, molar ratio) in CH2Cl2 is
stirred in the presence of DCC (1.5 equiv vs the case for
o-carboxyazobenzene) at rt.
Having established the optimization conditions, we in-
vestigated the limitation of this rearrangementreaction. As
shown in Table 2, this new reaction could be adapted to a
wide range of substrates. The rearrangement proceeds well
with o-carboxyazobenzene irrelevant of the electronic ef-
fects of the substituent on the benzene ring (Table 2, entries
2ꢀ8). Therefore, o-carboxyazobenzene with nitro, chloro,
bromo, methyl, and methoxyl substituents at the 4- or 2-
position of the benzene ring reacts to afford the correspond-
ing amino-substituted indazol-3,5-diones with a yield up to
88%. On the contrary, a significant substituent effect of
amine is observed and the reaction with 2-nitrophenylamine
gives only 33% of the target compound 7g (Table 2, entry
14). In the case of 2,6-dimethyl or 2,6-diethyl amine, a lower
reactivity is observed possibly due to the steric hindrance of
the bis ortho substituents (Table 2, entries 17, 19ꢀ20). The
steric hindrance effect has been further determined from the
poor yield if the anthraquinone is introduced in the o-carbo-
xyazobenzene (Table 2, entry 1).
(12) Dou, G. L.; Shi, D. Q. J. Comb. Chem. 2009, 11, 1073.
(13) Peters, M. V.; Stoll, R. S.; Goddard, R.; Buth, G.; Hecht, S.
J. Org. Chem. 2006, 71, 7840.
(14) Oakdale, J. S.; Solano, D. M.; Fettinger, J. C.; Haddadin, M. J;
Kurth, M. J. Org. Lett. 2009, 11, 2760.
(15) Kametani, T.; Sota, K.; Shio, M. J. Heterocycl. Chem. 1970, 7,
815.
(16) Li, C. J.; Feng, Y. Q.; Liu, X. J.; Zhang, T. Y. Chin. Chem. Lett.
2011, 22, 539.
In addition, the structure of the rearrangement product 1e is
clearly supported by the X-ray diffraction analysis (Figure 2).
480
Org. Lett., Vol. 14, No. 2, 2012
Li, Chengjie
