Simple and efficient approach for synthesis of hydrazones from carbonyl compounds and hydrazides catalyzed by meglumine

Article abstract of DOI:10.1080/00397911.2016.1258476

A simple, environmentally benign protocol for synthesis of hydrazones from carbonyl compounds and hydrazides has been developed in the presence of meglumine in aqueous-ethanol media at room temperature. The salient features of the present protocol are mild reaction conditions, short reaction time, high yields, operational simplicity, metal-free, applicability toward large-scale synthesis, and biodegradable and inexpensive catalyst.

Full text of DOI:10.1080/00397911.2016.1258476

A simple and efficient approach for synthesis of hydrazones from carbonyl
compounds and hydrazides catalyzed by meglumine
Mo Zhang1, Ze-Ren Shang1, Xiao-Tang Li1, Jia-Nan Zhang1, Yong Wang1, Kang Li1,
Yang-Yang Li1, Zhan-Hui Zhang1
1College of Chemistry and Material Science, Hebei Normal University, Shijiazhuang, P.
R. China
CONTACT: Z.-H. Zhang, College of Chemistry and Material Science, Hebei Normal
University, Shijiazhuang 050024, P. R. China. Email: zhanhui@126.com
Supplementary material for this article can be accessed on the publisher’s website.
Abstract
A simple, environmentally benign protocol for synthesis of hydrazones from carbonyl
compounds and hydrazides has been developed in the presence of meglumine in
aqueous-ethanol media at room temperature. The salient features of the present protocol
are mild reaction conditions, short reaction time, high yields, operational simplicity,
metal-free, applicability toward large-scale synthesis as well as the use of biodegradable
and inexpensive catalyst.
Graphical Abstract:
1

KEYWORDS: Hydrazones; Carbonyl compounds; Hydrazides; Meglumine; Metal-free;
Green and sustainable chemistry
INTRODUCTION
Hydrazone derivatives are a class of fundamental organic molecules and they can be used
as valuable building blocks for synthesis of bioactive natural products and functional
materials.[1] These hydrazone-based molecules have also shown a broad range of
biological properties such as monoamine oxidase inhibitory,[2] antiproliferative,[3]
antiplatelet aggregation,[4] amoebicide,[5] insecticidal,[6] antimicrobial activities,[7] EGFR
inhibitors,[8] antiinflammatory and analgesic agents.[9] In addition, they have been utilized
as dyes,[10] fluorescent sensor,[11] and ligands in chemical synthesis[12]. Besides, the
preparation of highly crystalline hydrazone derivatives has been known as a very effcient
method for the characterization, isolation, and purification of carbonyl compounds.[13]
As a classical approach for the synthesis of hydrazone derivatives, condensation of
carbonyl compounds and hydrazides is the most widely employed strategy, but it requires
harsh dehydrating conditions.[14] Some acid catalysts such as glacial acetic acid,[15]
SiO2/H2SO4,[16] polystyrene sulfonic acid,[17] Mg(ClO4)2,[18] zeolites,[19] Dowex (strongly
acidic cationic exchange resin) polymer,[20] choline chloride–oxalic acid[21] and
[Et3NH][HSO4],[22] have been developed to promote this reaction. This reaction has also
2

been performed under ultrasonic irradiation,[23] microwave irradiation,[24] or by kneading
ball-milling technique.[25] Although these protocols were efficient workednicely in many
cases for synthesis of hydrazone derivatives, sometimes, however, some methods suffer
from one or more disadvantages such as the use of volatile organic solvents,
unsatisfactory yields, overoxidization of aldehydes to the carboxylic acids, long reaction
times, high temperature, difficulties in the product isolation, the lack of generality or the
requirement of special apparatus. Especially, many protecting groups are deprotected
easily under acidic conditions. Thus, the development of a more efficient method for
synthesis of hydrazone derivatives under environmentally benign conditions is still highly
desirable.
Recently, significant attention has been focused on using bio-based materials as solvent
or catalyst in organic synthesis.[26] Meglumine is an attractive candidate as it possesses
environmentally benign properties such as bio-degradablity and physiological inertness.
It is an amino sugar derived from sorbitol and can be used in the formulation of
pharmaceuticals as an excipient and in conjunction with iodinated compounds in contrast
media due to its low toxicity. It has also important properties such as inexpensive,
non-corrosive, stable to air and moisture and readily available in the market. In 2012, Gu
et al. introduced meglumine and gluconic acid aqueous solution as a promoting medium
for the reaction of β-ketosulfones and formaldehyde.[27] Very recently, meglumine has
been used as an efficient catalyst for synthesis of functionalized 2-amino-4H-pyrans,[28]
3

pyranopyrazole derivatives,[29] pyrazolopyranopyrimidines,[30] dihydropyridines[31] and
pyrazoles.[32] Under all these backgrounds and our research interests on the development
of environmentally benign methodologies for the preparation of bioactive and fine
chemicals,[33] herein, we descried the use of meglumine as a catalyst to promote the
condensation of hydrazides with carbonyl compounds for synthesis of hydrazones
(Scheme 1).
RESULTS AND DISCUSSION
For our initial investigation, benzaldehyde and phenylhydrazine were taken as the model
substrates to optimize the reaction conditions. We explored the reaction of an equimolar
of benzaldehyde and phenylhydrazine in aqueous-ethanol at room temperature in the
presence of various catalysts. As shown in Table 1, in the absence of the catalyst a low
yield (49%) of the expected (E)-1-benzylidene-2-phenylhydrazine (3a) was obtained
(Table 1, entry 1). Although all catalysts have provided the desired product 3a with yields
ranging from 56-90%, meglumine was proven to be the most effective. In addition, the
reaction could be shortened to 30 min using meglumine as a catalyst (entry 11).
Next, we found that the solvent played an important role in the success of this reaction.
The reaction using EtOH and water gave the corresponding product 3a in high yields
(Table 2, entries 4 and 5). While the results with other solvents such as CH2Cl2, glycerin,
4

and PEG 400 were not much impressive. Further studies showed that aqueous-ethanol
(1:1, v/v) was the best choice of solvent for this transformation (Table 2, entry 10). The
effect of catalyst loading was also evaluated in the model reaction. The results showed
that 15 mol% of catalyst was the best choice for the present reaction. Decreasing the
amount of catalyst to 10 mol% resulted in relatively low yield (entry 11). When the
reaction was conducted with increasing amounts of meglumine, the yield of 3a could not
be further increased. From the above investigations, the optimized reaction conditions
were established by employing benzaldehyde (1 mmol), and phenylhydrazine (1 mmol)
with meglumine (0.15 mmol) in aqueous-ethanol (1:1 v/v, 4 ml) at room temperature for
30 min.
In order to demonstrate the efficiency as well as the practical applicability of the catalytic
system, a reaction of benzaldehyde with phenylhydrazine was performed at the 100 mmol
scale with meglumine (15 mmol) in aqueous-ethanol (1:1, v/v) (400 mL). The
corresponding product 3a was obtained in 91% yield (Table 2, entry 13). By using these
optimized conditions, this process will be useful to industries for the larger-scale
production of various hydrazones.
Having identified the optimized reaction conditions, we next commenced exploring the
scope and generality of this process. As evidenced in Table 3, a variety of substituted
aromatic aldehydes, regardless of the presence of electron-donating or
5

electron-withdrawing functional groups attached to benzene rings could react with
phenylhydrazine to give the desired products in high to excellent yields. It is indicated
that the electron-withdrawing substitutent on aromatic rings has a positive effect on the
transformation. The reaction is slightly sensitive to the steric hindrance of benzaldehyde,
as 2-methoxybenzaldehyde displays lower reactivity than its para-substituted homologue.
Furthermore, aromatic heterocyclic aldehydes such as picolinaldehyde and
thiophene-2-carbaldehyde (Table 3, entries 12 and 13) could be applied as suitable
starting materials for this transformation and gave the corresponding products in high
yields. It is also important to note that the reactions were efficient for aliphatic and
, -unsaturated aldehydes (entries 14-16) under similar reaction conditions. Notably, the
method was found applicable for the preparation of bis-hydrazone by reaction of
terephthalaldehyde with 2 equivalents of phenylhydrazine, giving the corresponding
product 3q in 89% yield (entry 17).
Encouraged by these results, we next applied this protocol to less electrophilic ketones.
Without any optimization, we are pleased to find that cyclic ketones such as
cyclohexanone and adamantan-2-one as well as alkyl-alkyl ketones, and aryl-alkyl
ketones also underwent this conversion to afford the respective hydrazones in high yields
under these conditions. Notably, silyl ethers can be cleaved under acidic conditions. It is
quite exciting to find out that trimethylsilyl and triethylsilyl ethers were well tolerated in
this process and no desilylated products were detected (entries 29 and 30).
6

Isatin and its derivatives have been shown to possess a broad spectrum of bioactivity.
These interesting properties promoted us to further showcase the synthetic usefulness of
the developed method for isatins. As shown in Table 3, various isatins having
electron-neutral, electron-deficient, and electron-rich substituents on the aryl ring
underwent this transformation affording the expected hydrazones in high yields (entries
31-33).
Subsequently, arylhydrazines bearing different functional groups were evaluated.
Satisfactorily, aryhydrazines having either electron-donating or electron-withdrawing
group worked well and delivered expected products in high to excellent yields. Alkyl
substituted hydrazine such as tert-butylhydrazine was also investigated and the
corresponding product 3aq was obtained in 76% yield.
Furthermore, when phenylhydrazine was replaced by hydrazine,
(1E,2E)-1,2-dibenzylidenehydrazine (4) was obtained in 83% yield by reaction of 2
equivalents of benzaldehyde and hydrazine (Scheme 2).
The structures of the products were determined by spectroscopic analysis, and the
structure of product 3al (CCDC 1408548) was also confirmed by single-crystal X-ray
analysis (Figure 1).
7

CONCLUSION
In summary, we have developed a novel catalytic approach for synthesis of hydrazones
from carbonyl compounds and hydrazides in the presence of meglumine in
aqueous-ethanol media. This method is applicable to a wide range of aldehydes,
including aromatic, aliphatic, , -unsaturated and heterocyclic substrates, ketones and
isatins. The attractive features of this procedure are the mild reaction conditions, high
conversions, wide substrate scope, and use of inexpensive and environmentally friendly
catalyst, all of which make it an attractive strategy for large-scale industrial preparation
of hydrazones.
EXPERIMENTAL
Melting points were determined on an X-5 digital melting point apparatus and are
uncorrected. The FT-IR spectra were obtained as KBr pellets or liquid films on KBr
pellets with a Thermo Fisher is50 spectrometer. NMR spectra of the products were
recorded on a Bruker Avance III 500 in CDCl3 using tetramethylsilane as an internal
reference. The mass spectra were performed on a 3200 Qtrap instrument with an ESI
source.
8

General Procedure For Synthesis Of Hydrazones
To a mixture of carbonyl compound (1 mmol) and hydrazine (1 mmol) in
aqueous-ethanol (1:1, 4 ml) was added meglumine (0.15 mmol). The reaction mixture
was stirred at room temperature and monitored by TLC. After completion of the reaction,
water (5 ml) and ethyl acetate (5 ml) were added and the product was extracted with ethyl
acetate. The organic phase was dried over anhydrous Na2SO4, and the solvent was
removed under vacuum. The crude product was then purified by column chromatography
or recrystallized (petroleum ether–EtOAc).
Selected Spectral Data For (E)-1-(3,4-Dimethoxybenzylidene)-2-Phenylhydrazine
(3d)
Yellow solid, mp 136–138 °C; IR (KBr): 3303, 3054, 1747, 1598, 1508, 1463, 1418,
1022 cm-1; 1H NMR (DMSO-d6, 500 MHz) δ ppm: 10.07 (s, 1H), 7.84 (s, 1H), 7.32 (s,
1H), 7.21 (t, J = 8.0 Hz, 2H), 7.11-7.09 (m, 3H), 6.91 (d, J = 8.0 Hz, 1H), 6.72 (t, J = 7.0
Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H); 13C NMR (125 MHz, DMSO-d6) ppm: 161.5, 149.6,
149.5, 145.9, 137.4, 129.5, 129.2, 119.9, 119.0, 112.4, 112.0, 108.3, 55.8, 55.7; ESI-MS:
m/z = 283 (M+1)+; Anal. calcd. for C17H18N2O2: C, 72.32; H, 6.43; N, 9.92. Found: C,
72.08; H, 6.68; N, 10.15%.
9

FUNDING
Financial support from the National Natural Science Foundation of China (21272053),
the Natural Science Foundation of Hebei Province (B2015205182) and the Training
Programs of Innovation and Entrepreneurship for Undergraduates of Hebei Province is
grateful acknowledged.
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Table 1. Screening catalysts for the reaction of benzaldehyde and phenylhydrazinea
Entry
Catalyst
Time
(min)
60
Yield (%)
1
no
49
71
61
75
80
74
56
78
72
73
90
2
TsOH
60
3
L-(-)-Proline
Betaine HCl
Et3N
60
4
60
5
60
6
Piperidine
Na2CO3
60
7
60
8
Chitosan
Mannitol
1,3-Dimethylurea
Meglumine
60
9
60
10
11
60
30
a Experimental conditions: benzaldehyde (1 mmol), phenylhydrazine (1 mmol), catalyst
(0.15 mmol), EtOH: H2O (1:1, 4 ml), room temperature.
19

Table 2. Optimization of reaction conditionsa
Entry
Solvent
Catalyst loading
Time (min)
Yield (%)
(mol%)
15
1
CH2Cl2
CH3CN
MeOH
EtOH
60
60
60
60
60
60
60
60
60
30
60
30
40
62
68
70
72
80
56
53
73
70
90
82
90
91
2
15
3
15
4
15
5
H2O
15
6
Glycerin
PEG 400
15
7
15
8
Glycerin/H2O (1:1) 15
PEG 400/H2O (1:1) 15
9
10
11
12
13b
EtOH/H2O (1:1)
EtOH/H2O (1:1)
EtOH/H2O (1:1)
EtOH/H2O (1:1)
15
10
20
15
a Experimental conditions: benzaldehyde (1 mmol), phenylhydrazine (1 mmol), solvent
(4 ml), room temperature.b100 mmol scale.
20

Table 3. Scope of reaction of carbonyl compounds and hydrazides catalyzed by
meglumine
Entry
Carbonyl compounds
R3
Product Time
(min)
Yield
(%)a
90
1
PhCHO
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
30
65
55
65
70
25
25
25
30
30
25
40
40
40
25
30
3a
3b
3c
3d
3e
3f
2
2-OMeC6H4CHO
4-OMeC6H4CHO
3,4-(OMe)2C6H3CHO
2,3,4-(OMe)3C6H2CHO
4-FC6H4CHO
80
3
84
4
79
5
75
6
95
7
4-ClC6H4CHO
95
3g
3h
3i
8
4-BrC6H4CHO
96
9
2-NO2C6H4CHO
3-NO2C6H4CHO
4-NO2C6H4CHO
92
10
11
12
13
14
15
16
95
3j
95
3k
3l
85
80
3m
3n
3o
3p
86
86
90
21

17b
18
19
20
21
Ph
Ph
Ph
Ph
Ph
70
50
60
40
100
89
86
81
89
72
3q
3r
3s
3t
3u
22
23
24
25
26
27
28
29
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
40
25
40
40
35
25
35
90
82
88
84
82
82
90
82
75
3v
3w
3x
3y
O
O
3z
O
3aa
3ab
3ac
30
Ph
100
73
3ad
31
32
33
34
Ph
40
50
40
40
86
81
88
89
3ae
3af
3ag
3ah
Ph
Ph
PhCHO
3-MeC6H4
22

35
36
37
38
39
4-OMeC6H4CHO
4-ClC6H4CHO
PhCHO
3-MeC6H4
55
25
20
40
20
85
91
85
82
88
3ai
3-MeC6H4
3aj
3ak
3al
2,4,6-Cl3C6H2
2,4,6-Cl3C6H2
2,4,6-Cl3C6H2
2-OHC6H4CHO
4-ClC6H4CHO
3am
40
41
42
43
2-OMeC6H4
2-OMeC6H4
2,4,6-Cl3C6H2
tBu
20
30
40
50
86
85
80
76
3an
3ao
3ap
3aq
4-ClC6H4CHO
a Isolated yield. b2 equivalents of phenylhydrazine were used and bis-hydrazone was
obtained.
23

Scheme 1. Synthesis of hydrazones catalyzed by meglumine
24

Scheme 2. Synthesis of (1E,2E)-1,2-dibenzylidenehydrazine (4) catalyzed by meglumine.
25

Figure 1. X-ray crystal structural of compound 3al.
26