Magnesium perchlorate as an efficient catalyst for the synthesis of imines and phenylhydrazones

Article abstract of DOI:10.1016/j.tetlet.2004.08.097

Magnesium perchlorate has been found to be an efficient catalyst for the synthesis of imines and phenylhydrazones by the reaction of carbonyl compounds with amines and phenylhydrazine in high yields at room temperatures and in short times. The condensation of less electrophilic carbonyl compounds with poorly nucleophilic amines affords the imines in excellent yields.

Full text of DOI:10.1016/j.tetlet.2004.08.097

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7641–7644
Magnesium perchlorate as an efficient catalyst for the
synthesis of imines and phenylhydrazones
Asit K. Chakraborti,* Srikant Bhagat and Santosh Rudrawar
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER),
Sector 67, Punjab, SAS Nagar 160 062, India
Received 10 July 2004; revised 12 August 2004; accepted 17 August 2004
Abstract—Magnesium perchlorate has been found to be an efficient catalyst for the synthesis of imines and phenylhydrazones by the
reaction of carbonyl compounds with amines and phenylhydrazine in high yields at room temperatures and in short times. The con-
densation of less electrophilic carbonyl compounds with poorly nucleophilic amines affords the imines in excellent yields.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
carbonyl carbon in the firststep is reversible, the feasibil-
ity of imine formation largely depends on the rate of
removal of water in the final step (route A). The classical
synthesis of imines, originally reported by Schiff,6
involves condensation of a carbonyl compound with
an amine under azeotropic distillation7 to separate the
liberated water. Subsequently, removal of water was
facilitated by the use of molecular sieves.8 Recently an
in situ dehydration strategy has been adopted by the
use of dehydrating solvents such as tetramethyl orthosili-
cate9 and trimethyl orthoformate.10 In an alternative
approach (route B), the condensation reaction has been
carried out in the presence of ZnCl2,11 TiCl4,12 MgSO4–
PPTS,13 alumina,14 K-10 under microwave irradia-
tion,10b,15 Ti(OR)4,16 and CuSO4,16b which act as Lewis
acids to catalyze nucleophilic attack on the carbonyl
group by the amine as well as serving as dehydrating
agents to facilitate the removal of water in the final step.
The condensation of amines with carbonyl compounds
is a venerable and useful organic transformation1 as
the resultant imines are used as versatile components
in nucleophilic addition with organometallic reagents,2
in cycloaddition reactions,3 and have potential for thera-
peutic applications such as lipoxygenase inhibitors, anti-
inflammatory agents4 and anti-cancer agents.5 Various
synthetic routes for the synthesis of imines are depicted
in Scheme 1. As nucleophilic attack by the amine at the
Route A:
R1
R1
HO
H
N
-H2O
R1
LA
O + H2N R3
R3
NR3
R2
R2
R2
Route B:
R1
R1
R2
H2N R3
LA
HO
H
N
LA
R1
O
R3
O
The methodologies reported have disadvantages such as
the requirement for high reaction temperatures, pro-
longed reaction periods, an excess of costly dehydrating
reagents/catalysts, moisture sensitive catalysts, and spe-
cial apparatus. Moreover, the efficiency of the proce-
dures reported is limited to the reaction of highly
electrophilic carbonyl compounds and strongly nucleo-
philic amines.
R2
R2
LA
LA
H
H
H2O
R1
R2
O
NR3
R1
N
R3
R2
LA
Scheme 1. Synthetic routes for imine formation.
2. Results and discussion
Keywords:
Magnesium
perchlorate;
Catalyst;
Imines;
Phenylhydrazones.
*
We thought that the condensation between a carbonyl
compound and an amine leading to the formation of
Corresponding author. Tel.: +91 172 221 4683; fax: +91 172 221
4692; e-mail: akchakraborti@niper.ac.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.097

7642
A. K. Chakraborti et al. / Tetrahedron Letters 45 (2004) 7641–7644
Table 1. Condensation of 4-methoxybenzaldehyde with 4-nitroaniline
in the presence of various catalystsa
an imine should be a facile reaction due to the good elec-
trophilic and nucleophilic properties of the carbonyl and
amine groups, respectively, and may not require any
catalytic assistance in the absence of electronic/steric
factors that might decrease the electrophilicity/
nucleophilicity of the carbonyl/amine groups. Thus,
the condensation of aniline with benzaldehyde, 4-meth-
oxybenzaldehyde, 2-hydroxybenzaldehyde, and 4-
hydroxybenzaldehyde afforded 85–100% yields, in
5min–1h, under neat conditions at room temperature
without the requirement of any additional reagent/cata-
lyst although the reported procedures14,15 highlight the
need to use a catalyst for these reactions. The treatment
of aniline with 4-nitrobenzaldehyde and 4-dimethylami-
nobenzaldehyde afforded the corresponding imines in
75% and 97% yields in 1 and 6h, respectively, and a
quantitative yield was obtained during the reaction of
4-methoxyaniline with 4-nitrobenzaldehyde in 1h in
DCE at room temperature in the absence of catalyst.
Similarly, the reaction of benzaldehyde, 4-methoxybenz-
aldehyde, 4-dimethylaminobenzaldehyde, and cinnamal-
dehyde with (R)-(+)-a-methylbenzylamine resulted in
imine formation in >90% yields in DCE or under neat
conditions in the absence of catalyst in 0.25–0.5h
although the literature reports14 the use of catalyst for
the reaction of benzaldehyde with a-methylbenzylamine
and the reaction of cinnamaldehyde with the less steri-
cally hindered benzylamine. However, no significant
imine formation was observed (GC–MS) when 4-meth-
oxybenzaldehyde was treated with 4-nitroaniline either
under neat conditions or in DCE for 70h at room tem-
perature or under reflux in EtOH or PhMe for 24h.
Entry
Catalyst
Solvent
Yield (%)b
1
2Mg(ClO
Mg(ClO4)2
)
DCE
PhMe
THF
MeCN
EtOH
DCE
PhMe
EtOH
Neat
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Neat
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
100c
60d
50
4 2
3
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
None
4
60
5
60
6
Nile
Nilf
Nilf
Nilg
9
7
None
None
8
9
10
None
Mg(SO4)2
MgBr2
11
12Mg(OTf)
60
60h
16
2
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
LiClO4
Sc(OTf)3
Nil
66
Yb(OTf)3
InCl3
14
Zeolite (ZSM-5)
Zeolite (K/L)
Montmorillonite KSF
Montmorillonite K 10
Montmorillonite K 10
La2(SO4)3
Nili
Nili
Nili
23
Nilf,i
35
LaCl3Æ7H2O
ZrCl4
61
40
ZrOCl3Æ8H2O
ZnCl2
TiCl4
Ti(OPri)4
27
46
35
70
CuSO4ÆH2O
Neutral Al2O3
65
Nili
a An equimolar amount of the substrates were reacted in the presence
of 5mol% (except for entries 6–9, 17–21, and 30) of the catalyst at
room temperature (except for entries 7–9, 20) for 8h.
b Determined by 1H NMR and GC–MS.
c A 95% yield was obtained when carrying out the reaction under reflux
for 1h.
d An 80% yield was obtained when carrying out the reaction under
The presence of the methoxy group in 4-methoxybenzal-
dehyde reduces the electrophilicity of the carbonyl car-
bon through resonance and the strong electron
withdrawing property of the nitro group in 4-nitroani-
line decreases the nucleophilicity of the amine group.
Thus, the combination of these substrates constitutes a
model reaction for evaluating the efficiency of a catalyst.
Hence, 4-methoxybenzaldehyde was treated with 4-
nitroaniline under various conditions (Table 1). While
planning to select a suitable Lewis acid for catalyzing
the reaction, we thought that a catalyst known for acti-
vation of an electrophile should serve the purpose. Logi-
cally, we focused our attention toward acylation
catalysts. Recently, we reported that Mg(ClO4)2 effi-
ciently catalyzes the acylation of various phenols, alco-
hols, thiols, and amines.17 To our satisfaction we found
that the use of 5mol% of Mg(ClO4)2 resulted in quanti-
tative formation of the corresponding imine in DCE at
room temperature within 8h (entry 1). Increase in the
reaction temperature led to imine formation in compa-
rable yield, in 1h. Inferior yields were obtained when
carrying out the condensation reaction in other solvents
such as PhMe, THF, MeCN, and EtOH (entries 2–5).
The decrease in product yield in PhMe was due to the
poor solubility of the reactant 4-nitroaniline. However,
in case of THF, MeCN, and EtOH the inferior results
were due to the decreased catalytic efficiency of
Mg(ClO4)2 because of competitive coordination of
Mg2+ with the solvent. The distinct role of Mg(ClO4)2
in catalyzing the condensation reaction was demon-
reflux for 2.5h.
e The reaction was carried out for 70h at room temperature.
f The reaction was carried out for 24h under reflux.
g The reaction mixture was heated under microwave irradiation (BPL,
Model BMC 900T, 1.35KW, micromode, full power) for 5min.
h A 90% yield was obtained when carrying out the reaction under reflux
for 3h.
i The catalyst was used in 10% w/w with respect to the aldehydes.
strated by the lack of imine formation when carrying
out the reaction in DCE for 70h at room temperature,
and in PhMe or EtOH under reflux for 24h, and when
heating under microwave irradiation for 5min in the ab-
sence of Mg(ClO4)2 (entries 6–9). Next we explored the
catalytic efficiency of other magnesium derivatives such
as MgSO4, MgBr2, and Mg(OTf)2. However, MgSO4
did not exhibit any significant catalytic activity13 and
only a 60% yield was obtained in the presence of MgBr2
and Mg(OTf)2 establishing that amongst the various
magnesium salts used, Mg(ClO4)2 was the most effective
in catalyzing imine formation. This was further substan-
tiated by the observation that a 95% yield was obtained
when carrying out the reaction under reflux for 1h in the
presence of Mg(ClO4)2, whereas the corresponding reac-
tion carried out in the presence of Mg(OTf)2 required 3h

A. K. Chakraborti et al. / Tetrahedron Letters 45 (2004) 7641–7644
7643
to afford a 90% yield (Table 1, compare footnotes c and
h). Being encouraged by the catalytic effect of
Mg(ClO4)2, we planned to evaluate the catalytic effi-
ciency in imine formation of other reported acylation
catalysts such as ZrCl4,18 InCl3,19 LiClO4,20 zeolite,21
Yb(OTf)3,22 montmorillonite clays,23 and Sc(OTf)3.24
None of these were found to be effective except for
Yb(OTf)3, which resulted in the formation of the imine
in 66% yield (entry 15). The use of other Lewis acids
such as La2(SO4)3, ZrOCl2Æ8H2O, ZnCl2,11 TiCl4,12
formation. However, treatment of phenylhydrazine with
4-methoxybenzaldehyde, 4-hydroxybenzaldehyde, 4-
nitrobenzaldehyde, furfural, thiophene-2-carboxalde-
hyde, and pyridine-3-carboxaldehyde either under neat
conditions or in DCE at room temperature for 0.5–2h
afforded the corresponding phenylhydrazones in 75–
95% yields without any catalytic assistance. Although
in each of these reactions quantitative formation of the
phenylhydrazones took place in 2–30min under the cat-
alytic influence of Mg(ClO4)2 (5mol%) in DCE at room
temperature, we decided to evaluate the catalytic effi-
ciency of Mg(ClO4)2 for the condensation of phenyl-
hydrazine with less electrophilic aldehydes/ketones
such as 3,4-dimethoxybenzaldehyde, 3,4,5-trimethoxy-
benzaldehyde, and acetophenone as no significant phen-
ylhydrazone formation was observed when these
substrates were treated with phenylhydrazine in the
absence of catalyst. The use of 5mol% of Mg(ClO4)2
afforded 98%, 90%, and 95% yields of the corresponding
phenylhydrazones in DCE at room temperature in 0.25–
2h from 3,4-dimethoxybenzaldehyde, 3,4,5-trimethoxy-
benzaldehyde, and acetophenone, respectively.
i
neutral alumina,14 Ti(OPr )4,16 and CuSO4
afforded
16b
lower yields (0–46%) and a 61% yield was obtained in
the presence of LaCl3Æ7H2O.
To establish the scope and limitations of Mg(ClO4)2 as a
catalyst for imine formation, structurally diverse carbo-
nyl compounds were treated with various amines such as
aniline (1), 4-methoxyaniline (2), 4-hydroxyaniline (3),
4-methylaniline (4), 4-chloroaniline (5), 4-nitroaniline
(6), and benzylamine (7) under the catalytic influence
of Mg(ClO4)2 and the results are summarized in Table
2. Excellent results were obtained in most cases.
Since, phenylhydrazones are important intermediates
for the synthesis of 1,3-diphenylpyrazoles with potential
antiparasitic activities,25 we next planned to extend the
application of Mg(ClO4)2 as a catalyst for hydrazone
3. Conclusion
In conclusion, Mg(ClO4)2 is a new and highly efficient
catalyst for the synthesis of imines and phenylhydra-
zones. The advantages include high yields, mild reaction
conditions and use of catalytic amounts of Mg(ClO4)2.
Table 2. Mg(ClO4)2-catalyzed reaction of carbonyl compounds with
aminesa
Caution: It should be mentioned that care must be taken
in handling perchlorates as they are potentially explo-
sive, when used in the presence of combustible sub-
stances at high temperature.26 However, some
perchlorate salts have high thermal stability,27 [LiClO4]
is thermally stable at or above its melting point of
247°C and can be dried under vacuum at 160°C for a
prolonged period (ꢀ50h).28 Exposure to nominal levels
of perchlorate does not adversely affect health and
safety.27 Thus, in the present work the requirement of
catalytic quantities of Mg(ClO4)2 and the mild reaction
conditions (room temperature) should circumvent the
problems of the hazards associated with the use of
perchlorates.
Entry Substrate
Amine Time Yield
(%)b,c
(h)
R3
R2
CHO
R1
1
R1 = R3 = H; R2 = OMe
R1 = R3 = H; R2 = NMe2
R1 = R2 = OMe; R3 = H
R1 = R2 = OMe; R3 = H
R1 = R2 = OMe; R3 = H
R1 = OMe; R2 = OH; R3 = H
R1 = OMe; R2 = OH; R3 = H
R1 = OMe; R2 = OH; R3 = H
R1 = OMe; R2 = OH; R3 = H
R1 = R2 = OH; R3 = H
R1 = R2 = R3 = OMe
6
1
1
5
3
1
2
3
5
5
2
3
4
5
6
8
95
95
94
90
95
85
92
91
90
80
96
95
90
93
90d
2
0.25
4
3
4
8
5
8
6
4
7
5
8
8
9
4
4. Experimental
10
11
12R
13
14
15
8
6
1 = R2 = R3 = OMe
4
Typical procedure for imine formation: 4-Methoxybenz-
aldehyde (1.36g, 10mmol) was treated with 4-nitroani-
line (1.38g, 10mmol) in DCE (10mL) at rt for 8h
(GC–MS) with magnetic stirring in the presence of
Mg(ClO4)2 (0.1g, 0.5mmol, 5mol%). The reaction mix-
ture was diluted with DCE (10mL), filtered through a
bed of Na2SO4, and concentrated to afford the desired
product (2.43g, 95%) IR (KBr): m = 3482, 3362, 1679,
1627, 1599, 1508, 1335, 1165, 1109, 1028, 886,
R1 = R2 = R3 = OMe
4
R1 = R2 = R3 = OMe
8
R1 = R2 = R3 = OMe
1
O
16
7
8
90e
a The substrate (1equiv) was treated with amine (1equiv) in the pres-
ence of Mg(ClO4)2 (5mol%) in DCE at room temperature (except for
entry 15).
837cmÀ1 1H NMR (300MHz, CDCl3): d = 3.9 (s, 3
.
b Isolated yield of the corresponding imine.
H), 7.00 (d, J = 8.5Hz, 2H), 7.22 (d, J = 8.73Hz, 2H),
7.86 (d, J = 8.49Hz, 2H), 8.25 (d, J = 8.68Hz, 2H),
8.35 (s, 1H); EIMS m/z 256 (M+), identical with an
authentic sample of 4-nitro-N-(4-methoxybenzylid-
ene)aniline.29 This general procedure was followed for
c The compounds were characterized by IR, NMR, and MS.
d The reaction was carried out under reflux.
e The corresponding reaction, catalyzed by alumina, afforded 82% yield
at 120°C in 6h.14

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A. K. Chakraborti et al. / Tetrahedron Letters 45 (2004) 7641–7644
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the preparation of other imines. In most cases, the iso-
lated products gave satisfactory physical data (mp, IR,
NMR, and MS), which compared well with those of
the literature without any further purification. Wherever
applicable, purification was performed through crystalli-
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EtOH). N-(4-Dimethylaminobenzylidene)aniline (Table
2, entry 2),30 N-(4-hydroxy-3-methoxybenzylidine)ani-
line (Table 2, entry 6),31 4-methoxy-N-(4-hydroxy-
3-methoxybenzylidine)aniline (Table 2, entry 7),31a
4-hydroxy-N-(4-hydroxy-3-methoxybenzylidine)aniline
(Table 2, entry 8),31a 4-chloro-N-(4-hydroxy-3-meth-
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