Microwave-assisted synthesis of 1-hydrazinophosphonates via the reaction of aldazines with dialkyl phosphite

Article abstract of DOI:10.1002/hc.21019

A simple, efficient, and novel method has been developed for the synthesis of 1-hydrazinophosphonic acids from aldazines. As described below, treatment of aldazines with diethyl phosphite gives the corresponding 1-hydrazinophosphonic acids in good yields. The reaction proceeds under microwave irradiation at 110°C and neutral condition without any additives such as base, acid, or catalyst. This method is easy, rapid, and gives good yields for the 1-hydrazinophosphonic acids.

Full text of DOI:10.1002/hc.21019

Heteroatom Chemistry
Volume 23, Number 3, 2012
Microwave-Assisted Synthesis of
1-Hydrazinophosphonates via the Reaction
of Aldazines with Dialkyl Phosphite
Babak Kaboudin and Soheil Alipour
Department of Chemistry, Institute for Advanced Studies in Basic Sciences, Gava Zang, Zanjan
45137-66731, Iran
Received 18 October 2011; revised 16 January 2012
Hydrazinophosphonic acids and their derivatives,
ABSTRACT:
A
simple, efficient, and novel
as an analog of 1-aminophosphonic acids, are an
important class of the compounds that exhibit
a variety of interesting and useful properties.
Some of these compounds show a good effect
against the phytotoxic action of chloroacetanilide
herbicides [5]. In contrast to the widely studied
aminophosphonic acid derivatives [6–9], relatively
few papers have reported on the chemistry of
1-hydrazinophosphonic acids. Synthetic routes to
1-hydrazinophosphonic acids involve base-catalyst
condensation of diethyl phosphite with aromatic
aldazines [10], nucleophilic substitution of 1-
mesylated phosphonates with hydrazine [11], and
reduction of 1-hydrazinophosphonates, prepared
from diethyl oxophosphonates, with sodium boro-
hydride or BH3 · THF [12]. However, these methods
have problems, including the use of chlorinated
solvents and strong bases, low yields, and side re-
actions. In addition, some of the starting materials
have to be synthesized and cleavage of a Et O P
bond of the product occurred in the reaction process
using strong bases [13].
Aldazines serve as a good precursor for the
synthesis of numerous organic compounds, espe-
cially heterocyclic compounds [14, 15]. Recently, al-
dazines have received significant attention due to
their utility in a number of interesting reactions,
their biological properties, and their potential appli-
cations in bond formation, liquid crystals, and non-
linear optical materials [16]. These easily accessible
precursors can be produced by the condensation of
aldehydes or ketones with hydrazine in ethanol so-
lution under reflux conditions [17].
method has been developed for the synthesis
of 1-hydrazinophosphonic acids from aldazines.
As described below, treatment of aldazines with
diethyl phosphite gives the corresponding 1-
hydrazinophosphonic acids in good yields. The
reaction proceeds under microwave irradiation at
110◦C and neutral condition without any addi-
tives such as base, acid, or catalyst. This method
is easy, rapid, and gives good yields for the 1-
ꢀ
C
hydrazinophosphonic acids.
2012 Wiley Periodicals,
Inc. Heteroatom Chem 23:304–308, 2012; View this article
online at wileyonlinelibrary.com. DOI 10.1002/hc.21019
INTRODUCTION
The organic chemistry of phosphorus compounds
has become increasingly useful and important in or-
ganic synthesis [1–3]. Aminophosphonic acids, the
phosphonic acid analogues of 1-amino carboxylic
acids, are an important class of compounds that
exhibit a variety of interesting and useful properties.
1-Aminophosphonic acids are valuable inter-
mediates for the preparation of medicinal
compounds and synthetic intermediates [4]. 1-
Correspondence to: Babak Kaboudin; e-mail: kaboudin@iasbs
.ac.ir
Contract grant sponsor: Institute for Advanced Studies in Basic
Sciences Research Council.
Contract grant number: G2010IASBS120.
2012 Wiley Periodicals, Inc.
c
ꢀ
304

Microwave-Assisted Synthesis of 1-Hydrazinophosphonates via the Reaction of Aldazines with Dialkyl Phosphite 305
TABLE 1 Addition Reaction of Diethyl Phosphite to Al-
O
O
dazines in Toluene at 110◦C under Microwave Irradiation
H
C
Toluene
MW, 110°C,
75–110 min
R
P(OEt)2
+ H P(OEt)2
R
R
C
H
N
N
C
H
Product Time (min) Yield (%)a
HN
Entry
R
N
c
1
2
3
4
5
6
7
8
C6H5-
C6H5-
3a
3a
3b
3c
3d
3e
3f
12b
75
90
80
90
–
R
75
78
83
76
68
73
62
–
–
–
–
–
p-MeC6H4-
p-MeOC6H4-
p-ClC6H4-
p-BrC6H4-
p-FC6H4-
p-NO2C6H4-
m-MeC6H4-
m-MeOC6H4-
m-NO2C6H4-
o-ClC6H4-
o-MeC6H4-
β-naphthyl
2-Thienyl
SCHEME 1 Treatment of aldazines with diethyl phosphite
under microwave condition.
105
85
110
110
110
110
110
110
110
110
110
3g
The application of microwave energy to acceler-
ate organic reactions is of increasing interest and of-
fers several advantages over conventional techniques
[18]. Syntheses that normally require for periods
can be achieved conveniently and very rapidly in a
microwave reactor. As part of our efforts to intro-
duce novel methods for the synthesis of organophos-
phorus compounds (for example, see Ref. [19]),
herein we report a new method for the synthesis
of 1-hydrazinophosphonates. We have found that
the microwave-assisted reaction of aldazines, pre-
pared by a novel solvent-free solid phase procedure,
with diethyl phosphite in toluene at 110◦C gives 1-
hydrazinophosphonates in good yields (Scheme 1).
d
9
–
–
–
–
d
10
11
12
13
14
15
16
d
d
d
–
d
–
–
–
–
d
–
e
PhCH2CH2-
–
aYields refer to the isolated pure products.
bReaction carried out at reflux in toluene.
cMixture of unknown compounds.
dProduct is very unstable in the column chromatography, and a mix-
ture of unknown compounds was obtained after purification.
eThe method used basic alumina as a solid but failed to give the
corresponding aliphatic diazine.
RESULTS AND DISCUSSION
the surface of basic alumina gave corresponding al-
dazine 2a in almost quantitative yields. The reaction
of aldazine 2a with diethyl phosphite in toluene at
reflux for 12 h gave a mixture of unknown products
(Table 1, entry 1). The 31P NMR spectrum of the re-
action mixture exhibited a mixture of the unknown
products. The reaction, when conducted under mi-
crowave irradiation for 75 min at 110◦C (Table 1,
entry 2), gave 3a, with a simple crystallization of
the reaction mixture from ethanol, in 75% isolated
yield. The 31P NMR spectrum of the product exhib-
ited one peak at δ 22.23 ppm for the compound 3a
The reaction of benzaldehyde (1a), chosen as
a model compound, with hydrazine dihydrochlo-
ride followed by treatment with diethyl phosphite
was studied under the various reaction conditions
(Scheme 2). The progress of the reaction was mon-
itored by TLC, and the experimental data for the
screening conditions are listed in Table 1. In re-
cent years, the use of reagents and catalysts immo-
bilized on solid supports has received considerable
attention. Such reagents not only simplify purifica-
tion processes but also help in preventing release of
reaction residues into the environment. Treatment
of benzaldehyde with hydrazine dihydrochloride on
1
(Scheme 2). The H NMR spectrum exhibited one
doublet peak at δ 4.91 ppm indicative of HC–P cou-
pling (JHP = 21.5 Hz). The 13C NMR spectrum ex-
hibited a doublet peak at δ63.4 (JCP = 149 Hz). The
structure was supported by elemental analysis.
To determine the scope and limitations of the
present protocol, under the above optimized condi-
tions, aldazines were employed in the addition reac-
tion with diethyl phosphite. The obtained results are
summarized in Table 1 (Scheme 3). Treatment of dif-
ferent p-substituted aldazines with diethyl phosphite
under microwave irradiation in toluene at 110◦C
gave corresponding 1-hydrazinophosphonates in
good isolated yield (Table 1, entries 3–8). In the case
of other substituted aldazines, we could not obtain
any crystal, through crystallization from ethanol or
Al2O3 (b)
.
Ph
C
H
N
N
C
H
Ph
+ NH2NH2 2HCl
Ph
1a
C
O
15 min
grinding
H
2a
O
O
H
Toluene
MW, 110°C,
75 min
Ph
P(OEt)2
C
H
Ph +
P(OEt)2
Ph
C
H
N
N
C
H
HN
N
3a
2a
Ph
SCHEME 2 Reaction of aldazine 2a with diethyl phosphite
under microwave condition.
Heteroatom Chemistry DOI 10.1002/hc

306 Kaboudin and Alipour
Al2O3 (b)
mixture showed that the compound 3 was obtained
and the product is very unstable during the column
chromatography. We could not obtain any crystal,
via crystallization from ethanol or other solvents, for
more identification analysis.
.
R
C
H
N
N
C
H
R
+ NH2NH2 2HCl
R
C
H
1
O
15 min
grinding
2
O
P(OEt)2
O
H
Toluene
MW, 110°C,
75–110 min
H
R P(OEt)2
C
R
C
N
N
C
H
R +
H
EXPERIMENTAL
HN
N
All chemicals were commercial products and dis-
tilled or recrystallized before use. NMR spectra were
taken with a 250 and 400 Brucker Avance instru-
ment with the chemical shifts being reported as δ
ppm and couplings expressed in hertz. The chemical
3
2
R
SCHEME 3 Reaction of aldazines with diethyl phosphite
under microwave condition.
1
shift data for each signal on H NMR are given in
units of δ relative to CHCl3 (δ = 7.26) for CDCl3 so-
lution. For 13C NMR spectra, the chemical shifts in
CDCl3 are recorded relative to the CDCl3 resonance
(δ = 77.0). The chemical shifts of 31P are recorded
relative to external 85% H3PO4 (δ = 0) with broad-
other solvents, for more identification analysis. The
31P NMR data of the reaction mixture showed that
compound 3 was obtained, and the product is very
unstable in the column chromatography. A mixture
of unknown compounds was obtained after purifica-
tion using silica or alumina as an adsorbent in the
column chromatography (Table 1, entries 9–13).
1
band H decoupling. Silica gel column chromatog-
raphy was carried out with Silica gel 100 (Merck no.
10184). Merck silica-gel 60 F254 plates (no. 5744)
were used for the preparative TLC.
1-Naphthylcarbaldehyde
and
2-thiophene-
carbaldehyde, as a polynuclear and heteroaryl
aldehyde, gave the corresponding aldazine in
quantitative yield in the presence of alumina. In
these cases, we could not obtain any crystal, via
crystallization from ethanol or other solvents, for
more identification analysis (Table 1, entries 14 and
15).
We also examined the reaction of aliphatic alde-
hyde (Table 1, entry 16) in the presence of a mix-
ture of hydrazine dihydrochloride and basic alu-
mina. The reaction failed to give the corresponding
aldazine after 1 h of grinding.
In summary, we have developed a simple and
practical method for the preparation of aldazines
and 1-hydrazinophosphonates via the addition re-
action of diethyl phosphite to aldazines. Through
the condensation reaction of aldehydes with hy-
drazine dihydrochloride in the presence of basic
alumina, aldazines can be synthesized in quanti-
tative yields. This method is quite useful, in com-
parison with previously reported methods, because
it allows the use of a readily available inexpen-
sive reagent. In addition, by carrying out the ad-
dition reaction of diethyl phosphite with aromatic
aldazines (phenyl- and para-substituted aromatic al-
dazines) under microwave irradiation at 110◦C, we
achieved 1-hydrazinophosphonates without any ad-
ditives such as base or acid or catalyst. Other advan-
tages of this environmentally benign and safe proto-
col include a simple reaction setup and good yields of
1-hydrazinophosphonates. In the case of other sub-
stituted aldazines, the 31P NMR data of the reaction
General Procedure for the Preparation of
Aldazines Using Basic Alumina (2)
This solvent-free reaction method is operationally
simple. Five mmol of hydrazine dihydrochloride was
added to a mixture of basic alumina (Al2O3, 2 g) and
aldehyde (10 mmol) in a mortar and pestle by grind-
ing them together until a fine, homogeneous powder
was obtained (15 min). The mixture was extracted
with chloroform (3×50 mL); evaporation of solvent
gave the pure product as solid in almost quantitative
yields. All products gave satisfactory spectral data in
accordance with the assigned structures and litera-
ture reports [17].
General Procedure for the Addition of Diethyl
Phosphite to Aldazines under Microwave
Irradiation (3)
Diethyl phosphite (15 mmol) was added to a mixture
of aldazine (5 mmol) and toluene (25 mL), and the
solution was stirred for 75–110 min at 110◦C at am-
bient pressure in a microwave reactor (a Milestone
Micro Synth (Italy) microwave labstation for syn-
thesis; a microwave reactor was used for all exper-
iments). The solvent was evaporated under reduced
pressure, ethanol (10 mL) was added to a crude mix-
ture, and the solution was then left in the refrigerator
for 1 h. The solid was collected, and the pure product
could be obtained after the solid was further washed
by hexane and ethanol, and vacuum dried. All prod-
ucts gave satisfactory spectral data in accordance
Heteroatom Chemistry DOI 10.1002/hc

Microwave-Assisted Synthesis of 1-Hydrazinophosphonates via the Reaction of Aldazines with Dialkyl Phosphite 307
(m, 4H), 7.69 (s, 1H); 31P NMR (CDCl3–H3PO4, 162
MHz), δ: 21.68; 13C NMR (CDCl3–TMS, 100.6 MHz),
δ: 16.2 (d, JPC = 6.0 Hz), 16.4 (d, JPC = 6.0 Hz), 61.2
(d, JPC = 150.0 Hz), 63.2 (d, JPC = 7.0 Hz), 63.3 (d,
JPC = 7.0 Hz), 127.5, 127.9, 128.0, 128.4, 128.6, 130.0,
135.2, 135.5, 140.3.
with the assigned structures and literature reports
[11].
Diethyl
[(2E)-2-benzylidenehydazino](phenyl)
methyl phosphonate (3a). White solid, mp = 97–
1
99◦C; H-NMR (CDCl3–TMS, 250 MHz), δ: 1.11 (t,
3H, J = 7.2 Hz), 1.29 (t, 3H, J = 7.2 Hz), 3.72–4.16
(m, 4H), 4.92 (d, 1H, JHP = 21.5 Hz), 6.05 (s, 1H,
NH), 7.24–7.47 (m, 10H), 7.63 (s, 1H); 31P NMR
(CDCl3-H3PO4, 101.25 MHz), δ: 22.23; 13C NMR
(CDCl3–TMS, 62.9 MHz), δ: 18.6 (d, JPC = 6.3 Hz),
18.8 (d, JPC = 6.3 Hz), 63.4 (d, JPC = 149.0 Hz), 65.5
(d, JPC = 3.8 Hz), 65.6 (d, JPC = 3.8 Hz), 128.5, 130.4,
130.5 (d, JPC = 6.3 Hz), 130.8, 130.9, 131.0, 137.5,
137.8, 142.7.
Diethyl [(2E)-2-(4-methylbenzylidene)hydazino]
(4-methylphenyl)methyl phosphonate (3b). White
solid, mp = 98–99◦C; 1H NMR (CDCl3-TMS, 400
MHz), δ: 1.15 (t, 3H, J = 6.8 Hz), 1.32 (t, 3H, J =
6.8 Hz), 2.38 (s, 6H), 3.79–4.21 (m, 4H), 4.95 (d, 1H,
JHP = 21.0 Hz), 6.68 (s, 1H, NH), 7.25–7.30 (m, 4H),
7.47–7.51 (m, 4H), 7.69 (s, 1H); 31P NMR (CDCl3–
H3PO4, 162 MHz), δ: 21.90; 13C NMR (CDCl3–TMS,
Diethyl [(2E)-2-(4-flourobenzylidene)hydazino]
(4-flourophenyl) methyl phosphonate (3f). White
1
solid, mp = 112–114◦C; H NMR (CDCl3–TMS, 250
MHz), δ: 1.14 (t, 3H, J = 7.0 Hz), 1.29 (t, 3H, J = 7.0
Hz) 3.78–4.17 (m, 4H), 4.87 (d, 1H, JHP = 21.2 Hz),
5.72 (s, 1H, NH), 6.93–7.07 (m, 4H), 7.40–7.46 (m,
4H), 7.62 (s, 1H); 31P NMR (CDCl3–H3PO4, 101.25
MHz), δ: 21.77 (d, JFP = 5.1); 13C NMR (CDCl3–TMS,
62.9 MHz), δ: 16.2 (d, JPC = 5.6 Hz), 16.4 (d, JPC
= 5.6 Hz), 60.3 (d, JPC = 150.3 Hz), 63.1 (d, JPC
=
6.3 Hz), 63.2 (d, JPC = 6.3 Hz), 115.3, 115.7, 127.7,
127.8, 129.7 (d, JFC = 6.3 Hz), 129.8 (d, JFC = 6.3
Hz), 131.2, 139.5, 162.8 (d, JFC = 252 Hz).
Diethyl [(2E)-2-(4-nitrobenzylidene)hydazino](4-
nitrophenyl) methyl phosphonate (3g). White solid,
mp = 165–167◦C; 1H NMR (CDCl3–TMS, 400 MHz),
δ: 1.18 (t, 3H, J = 7.2 Hz), 1.32 (t, 3H, J = 7.2 Hz),
3.83–4.18 (m, 4H), 4.89 (d, 1H, JHP = 21.2 Hz), 5.55
(s, 1H, NH), 6.98–7.09 (m, 4H), 7.44–7.48 (m, 4H),
7.64 (s, 1H); 31P NMR (CDCl3–H3PO4, 162 MHz), δ:
21.24; 13C NMR (CDCl3–TMS, 100.6 MHz), δ: 16.3 (d,
100.6 MHz), δ: 16.2 (d, JPC = 6.8 Hz), 16.4 (d, JPC
=
6.8 Hz), 22.2, 22.3, 61.3 (d, JPC = 150.0 Hz), 63.2 (d,
JPC = 7.0 Hz), 63.3 (d, JPC = 7.0 Hz), 127.6, 127.9,
128.1, 128.5, 128.6, 130.1, 135.3, 135.8, 140.3.
Diethyl [(2E)-2-(4-methoxybenzylidene)hydazino]
(4-methoxyphenyl) methyl phosphonate (3c). White
JPC = 6.0 Hz), 16.4 (d, JPC = 6.0 Hz), 60.5 (d, JPC
=
1
solid, mp = 110–112◦C; H NMR (CDCl3–TMS, 250
149.0 Hz), 63.2 (d, JPC = 7.0 Hz), 63.3 (d, JPC = 7.0
Hz), 115.4, 115.6, 127.8, 129.8, 129.9, 131.2, 139.4,
161.7, 164.1.
MHz), δ: 1.10 (t, 3H, J = 7.5 Hz), 1.29 (t, 3H, J = 7.5
Hz), 3.74 (s, 6H), 3.78–4.17 (m, 4H), 4.86 (d, 1H, JHP
= 22.5 Hz), 5.72 (s, 1H, NH), 6.93–7.07 (m, 4H), 7.40–
7.46 (m, 4H), 7.62 (s, 1H); 31P NMR (CDCl3–H3PO4,
101.25 MHz), δ: 22.23; 13C NMR (CDCl3–TMS, 62.9
MHz), δ: 16.3 (d, JPC = 6.9 Hz), 16.4 (d, JPC = 6.9
Hz), 55.4, 56.5, 60.9 (d, JPC = 149.0 Hz), 63.1 (d, JPC
= 4.4 Hz), 63.5 (d, JPC = 4.4 Hz), 126.1–128.7 (m,
Ar), 135.1, 135.4, 140.2, 153.0, 153.9.
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