Diastereoselective synthesis of new dialkylphosphorylhydrazones

Article abstract of DOI:10.1080/10426500903444366

A series of 22 dialkylphosphorylydrazones (dialkyl ester, N′-[(1E)-(R1 phenyl)methylene]-phosphorohydrazidic acid), 20 of them new, along with three new N,N′-bis (diisobutylphosphorylthioamide)diamines (bis-[diisobutyl ester), N-thioxomethylene]-, diamine)phosphora-midic acid, were prepared and characterized by IR, ¹H NMR, ¹³C NMR, ³¹P NMR, and mass spectrometry. The analysis of ¹H NMR, ¹³C NMR, ³¹P NMR, and NOE spectra confirmed the observation of the single diastereoisomer E in the synthesis of dialkylphosphorylydrazones. The results of a molecular modeling study performed in order to investigate the mechanism of the synthesis of dialkylphosphorylydrazones are in agreement with the experimental results, i.e., the favored formation of diastereoisomer E over Z.

Full text of DOI:10.1080/10426500903444366

Phosphorus, Sulfur, and Silicon, 185:40–56, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903444366
DIASTEREOSELECTIVE SYNTHESIS OF NEW
DIALKYLPHOSPHORYLHYDRAZONES
Jana´ına Marques Rodrigues, Carlos Mauricio R. Sant’Anna,
Victor Marcos Rumjanek, and Joa˜o Batista Neves DaCosta
Departamento de Qu´ımica, Instituto de Cieˆncias Exatas, Universidade Federal
Rural do Rio de Janeiro, Rio de Janeiro, Brazil
A series of 22 dialkylphosphorylydrazones (dialkyl ester, Nꢀ-[(1E)-(R1 phenyl)methylene]-
phosphorohydrazidic acid), 20 of them new, along with three new N,Nꢀ-bis (diisobutylphos-
phorylthioamide)diamines (bis-[diisobutyl ester), N-thioxomethylene]-, diamine)phosphora-
midic acid, were prepared and characterized by IR, 1H NMR, 13C NMR, 31P NMR, and mass
spectrometry. The analysis of 1H NMR, 13C NMR, 31P NMR, and NOE spectra confirmed the
observation of the single diastereoisomer E in the synthesis of dialkylphosphorylydrazones.
The results of a molecular modeling study performed in order to investigate the mechanism of
the synthesis of dialkylphosphorylydrazones are in agreement with the experimental results,
i.e., the favored formation of diastereoisomer E over Z.
Keywords N,Nꢁ-bis(diisobutylphosphorylthioamide) diamines; dialkylphosphorylydrazones;
organophosphorus compounds
INTRODUCTION
Organophosphorus compounds and hydrazones have both attracted attention of var-
ious research groups during recent years. This growing interest may be attributed to the
chemical versatility shown by these compounds.1,2 Several organophosphorus compounds
have anticholinesterase activity, hence their major use as pesticides.3 They may act as
analgesics and antiinflammatory agents,4 anti-HIV agents,5,6 and they can be used in the
treatment of some bone diseases such as Paget’s or malign hypercalcemia, osteoporosis,
and metastatic and osteolytic diseases.7–11 Organophosphorus compounds have also been
reported in the use against rheumatoid arthritis12,13 and as antiproliferative against Try-
panosoma cruzi.14 Finally, they are also part of normal metabolism as in AMP, ADP, and
ATP15,16 or in adrenergic receptors.17 Furthermore, organophosphorus inhibits various en-
zymes such as glutamine synthase, dipeptidyl carboxypeptidase I, adenylosuccinate lyase,
alanine racemase,18 and tyrosinase.18,19
Received 23 October 2008; accepted 8 April 2009.
We thank the financial support from Conselho Nacional de Desenvolvimento Cient´ıfico e Tecnolo´gico
(CNPq), Coordenac¸a˜o de Aperfeic¸oamento de Pessoal de N´ıvel Superior (CAPES), and Fundac¸a˜o Carlos Chagas
Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ).
Address correspondence to Joa˜o Batista Neves DaCosta, Departamento de Qu´ımica, Instituto de Cieˆncias
Exatas, Universidade Federal Rural do Rio de Janeiro, BR 465 km 7 Serope´dica RJ 23890-000, Brazil. E-mail:
dacosta@ufrrj.br
40

SYNTHESIS OF NEW DIALKYLPHOSPHORYLHYDRAZONES
41
Hydrazones, on the other hand, show potential activity against cancer,20–22 malaria,20
bacteria,23,24 and fungi.24,25 These compounds are also used as DNA cleaving agents26 and
show many biological actions such as anticonvulsion,27 analgesic, anti-inflammatory, and
antithrombotic properties.28–30
Considering the widespread applications of both organophosphorus compounds and
hydrazones, the synthesis of compounds which possess both a P atom and a hydrazone
moeity may lead to new molecules with potential biological activity. Thus, in continuity of
our research work on the synthesis and evaluation of the applications of organophosphorus
compounds,31–33 we have synthesized and characterized a series of aromatic dialkylphos-
phorylhydrazones. In order to determine the applicability and limitations of these reactions,
we investigated the effect of substituents on the outcome of the reaction together with
molecular modeling.
RESULTS AND DISCUSSION
The synthesis of the dialkylphosphorylhydrazones was carried out in three steps,
according to Scheme 1. The first step involves the reaction of an aliphatic alcohol (1) with
PCl3 (2) to form the corresponding dialkylphosphonate (3). The second step is the biphasic
reaction between the hydrazine and the dialkylphosphonate (3) in CCl4 and a hydroalco-
holic solution of sodium hydroxide to form the different dialkylphosphorylhydrazides (5).
The last step involves an acid-catalyzed condensation reaction between different substituted
aromatic aldehydes (6) and the dialkylphosphorylhydrazides to yield the dialkylphospho-
rylhydrazones diastereoselectively with configuration E.
Scheme 1 Synthesis of phosphorylhydrazones.
The formation of the dialkylphosphorylhydrazones occurs by the nucleophilic attack
of the hydrazidic N atom on the carbonyl C atom so that the reaction is favored by electron-
attracting groups on the aromatic ring of the aldehyde. Thus, for these groups, the reactions
afforded the desired compounds in good yields in about 2 h, whereas for electron-donating
groups, satisfactory yields were only obtained with times of around 6 h (Table I).
Generally, the reaction of hydrazides with aldehydes occurs with ready precipitation
of the hydrazone. Formation of the reaction product from dialkylphosphorylhydrazine and
aromatic aldehydes probably involves the reaction intermediate a (Scheme 2).

42
J. M. RODRIGUES ET AL.
Scheme 2
Because of the possibility of occurrence of intramolecular coordination at P,34 we
propose that intermediate (a) can exist as two isomers, one with a tetracoordinated P atom
(at), and the other with a pentacoordinated P atom (ap) (Scheme 3).
Assuming an E2 mechanism for the dehydration step, an antiperiplanar conformation
between the N atom lone pair and the hydroxyl group attached to the chiral C atom would
Table I Yields obtained in the syntheses of dialkylphosphorylhydrazones
Yield
(%)
Melting Point
(◦C)
Reaction
time
Compound
R
Rꢁ
Color
7
8
9
Propyl
Propyl
Propyl
Propyl
Propyl
Propyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
o-NO2
m-NO2
p-NO2
82
82
74
61
76
68
80
94
84
87
57
95
22
67
39
71
14
49
84
61
70
79
60
56
77
55–57
100–102
73–75
65–67
167–169
85–87
102–104
151–152
150–152
107–109
192–194
112–114
84–85
Yellow
Yellow
Yellow
Yellow
White
Cream
Yellow
Yellow
Yellow
Yellow
White
Cream
White
White
White
White
Orange
Orange
White
Cream
Yellow
Yellow
Cream
Cream
Yellow
2 h
2 h
2 h
2 h
2 h
6 h
2 h
2 h
2 h
2 h
2 h
6 h
2 h
6 h
2 h
6 h
2 h
6 h
2 h
6 h
6 h
6 h
6 h
6 h
6 h
10
11
12
13
14
15
16
17
18
19
p-CN
p-COOH
OCH2O
o-NO2
m-NO2
p-NO2
p-CN
p-COOH
OCH2O
m-OCH3
—
79–80
—
127–129
—
20
21
Isopropyl
Isopropyl
p-OCH3
p-N(CH3)2
22
23
24
25
26
27
28
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Propyl
H
m-OH
p-OH
m-OH e p-OCH3
p-OH e m-OCH2CH3
m-OH e p-OCH3
p-OH e m-OCH2CH3
76–78
170–172
156–158
155–157
186–188
154–156
167–169
Propyl

SYNTHESIS OF NEW DIALKYLPHOSPHORYLHYDRAZONES
43
Scheme 3
favor the reaction. At room temperature, the pyramidal inversion of the N atoms should
occur rapidly, and the antiperiplanar conformation can be obtained for both configurations
of the second unsymmetrically substituted N atom by a simple rotation of the C-N bond, as
can be seen in Scheme 4 for the R configuration of the C chiral center, for example. These
different conformations will produce two diasteromeric products after the dehydration step.
Scheme 4
In order to rationalize the experimental results, we performed a molecular modeling
study on both reactions. After a previous full optimization at the AM1 semiempirical
level with the PC Spartan Pro program (Wavefunction, Inc.), the structures were fully
optimized at the HF/3–21G∗ level followed by a single point HF/6 – 31 + G∗ calculation
on the optimized geometries. The composition of an equilibrium mixture of the observable

44
J. M. RODRIGUES ET AL.
Table II Data from the molecular modeling study
Structure
ꢀE (3–21G∗/6–31+G∗)a
Nii/Nib
SNRC-at
RNRC-at
SNRC-ap
RNRC-ap
Z-b
0.0
–0.0042359
0.0
–0.0051457
0.0
–
89.1
–
234
–
E-b
–0.0054888
336
aIn Hartree.
bNumber of molecules of the present mixture component
relative to the previous one, at 298 K.
structures is determined by the free energy difference between them. Although ꢀG depends
on both entropy and enthalpy, there are many reactions for which the entropy contribution is
small and can be neglected. Thus, if this is the case, the composition of the reaction mixture
can be estimated directly from the energy difference between the mixture components
calculated in the present work (Table II).
As can be observed in Table II, the isomerization of the tetracoordinated form of
intermediate (a) to the pentacoordinated form would favor the formation of the E isomer.
After the isomerization, the relative concentration of the pentacoordinated intermediate that
will conduct to the E isomer (RNRC-ap, Scheme 3), is predicted to be enhanced 2.6 times
in the equilibrium mixture in comparison with the tetracoordinated form (SNRC-at). This
result is probably a consequence of enhanced crowding in the cyclized structures of (ap).
The energy relation indicates that the difference of concentration should be even greater
for the reaction product (b), where the concentration of the more stable isomer is 1.4 times
enhanced in comparison with the pentacoordinated isomer (ap). Both results suggest that
the E diastereomer should be the predominant isomeric form of the product obtained in the
reaction, in accordance with the experimental results.
The structural determination of the diakylphosphorylhydrazones 7–28 involved IR;
1H, 13C, and 31P NMR; and GC-MS spectroscopy. The characteristic IR absorption bands are
3100–3200 cm−1 (NH), 1250 cm−1 (P O), 1100 cm−1 (P O and C O), and 1520–1630
cm−1 (N C). Table III shows IR data for compounds 7–28.
1
Characteristic H NMR signals include δ = 7.7–9.3 ppm for the iminic hydrogen
( N C H) and δ = 7.0–10.0 ppm for the phosphoramidic hydrogen (P-N-H) with doublet
multiplicity (J = 26–30 Hz) due to coupling with the P atom. Tables IV and Table V show
1H NMR data for the dipropylphosphorylhydrazones and diisopropylphosphorylhydrazones
synthesized, respectively.
The 13C NMR spectra show signals in the 140–144 ppm range, assigned to the
imine carbon. This atom couples with the P atom affording a doublet with J = 18–21 Hz.
Tables VI and Table VII show, respectively, 13C NMR data for the dipropylphosphoryl-
hydrazones and the diisopropylphosphorylhydrazones synthesized. Finally, the 31P NMR
spectra show only a singlet for the different dialkylphosphorylhydrazones (Table VIII).
Generally, the synthesis of hydrazones from substituted aldehydes leads to the forma-
tion of two diastereoisomers (E and Z), which may interconvert as shown in Scheme 2. The
22 dialkylphosphorylhydrazones synthesized show only the E configuration, confirmed
1
by H NMR, NOE, and 31P NMR and also by the fragmentation pattern in their mass

SYNTHESIS OF NEW DIALKYLPHOSPHORYLHYDRAZONES
45
Table III IR absorption bands of the phosphorylhydrazones synthesized
Comp.
P
O
P
O
C
C
N
N
H
Substituent R’
7
8
9
1237.7 (st)
1232.4 (st)
1246.8 (st)
1014.9 (st)
1020.5 (st)
1021.5 (st)
1585.6 (st)
1602.1 (st)
1578.4 (st)
3116.5(st)
3117.0 (st)
3096.2 (st)
NO2 (st as) → 1521.4
NO2 (st si) → 1345.9
NO2 (st as) → 1530.8
NO2 (st si) → 1350.5
NO2 (st as) → 1518.0
NO2 (st si) → 1343
C≡N (st) → 2224.1
OH (st) → 3423.1
10
11
1231.4 (st)
1231.0 (st)
1013.9 (st)
1022.9 (st)
1596.9 (st)
1600.5 (st)
3137.2 (st)
3105.4 (st)
C
O
O (st) → 1690.5
12
13
14
15
1233.8 (st)
1237.5 (st)
1244.5 (st)
1247.4 (st)
1015.4 (st)
1000.3 (st)
1023.4 (st)
1024.5 (st)
1624.3 (st)
1526.0 (st)
1566.7 (st)
1578.1 (st)
3146.8 (st)
3143.6 (st)
3099.9 (st)
3097.8 (st)
CH2 O (st) → 938.4
CH (st) → 2967.6
NO2 (st as) → 1526.0
NO2 (st si) → 1350.6
NO2 (st as) → 1530.4
NO2 (st si) → 1350.5
NO2 (st as) → 1515.0
NO2 (st si) → 1342.1
C≡N (st) → 2226.7
OH (st) → 3446.3
16
17
1245.4 (st)
1274.2 (st)
1006.8 (st)
1011.0 (st)
1597.1 (st)
1603.8 (st)
3144.0 (st)
3196.3 (st)
C
O
O (st) → 1684.3
18
1244.2 (st)
1008.3 (st)
1624.8 (st)
3112.9 (st)
CH2 O (st) → 928.8
CH (st) → 2980.7 e 2930.2
19
20
1238.1 (st)
1238.0 (st)
1004.1 (st)
1010.7 (st)
1609.8 (st)
1606.9 (st)
3177.0 (st)
3119.6 (st)
—
OCH3 (C
OCH3 (C
O
O
C st as) → 1266.7
C st si) → 1084.4
21
1234.8 (st)
1008.1 (st)
1609.8 (st)
3114.4 (st)
OCH3 (st) → 2836.4
OCH3 (C
O
C st si) → 1083.0
22
23
1228.2 (st)
1225.2 (st)
991.2 (st)
1009.0 (st)
1609.0 (st)
1613.9 (st)
3194.3 (st)
3321.6 (st)
C
N (st) → 1076.2
OH (st) → 3183.6
COH (C O st) → 1198.5
OH (st) → 3180.6
24
25
1220.4 (st)
1278.8 (st)
974.2 (st)
1607.0 (st)
1613.9 (st)
3297.7 (st)
3178.9 (st)
COH (C O st) → 1164.8
OH (st) → 3180.6
1004.4 (st)
COH (C O st) → 1197.2
OCH3 (st) → 2839.5
OCH3 (C
OCH3 (C
O
O
C st as) → 1253.2
C st si) → 1025.0
26
27
1279.8 (st)
1276.9 (st)
1007.8 (st)
1015.8 (st)
1604.8 (st)
1615.8 (st)
3178.4 (st)
3168.0 (st)
OH (st) → 3285.6
COH (C O st) → 1184.5
OCH2 (C
OCH2 (C
O
O
C st as) → 1221.8
C st si) → 1036.4
OH (st) → 3285.6
COH (C O st) → 1213.2
OCH3 (st) → 2841.4
OCH3 (C
OCH3 (C
O
O
C st as) → 1243.8
C st si) → 1060.2
28
1280.8 (st)
1015.9 (st)
1605.2 (st)
3169.3 (st)
OH (st) → 3285.6
COH (C O st) → 1180.5
OCH2 (st) → 2898.6
OCH2 (C
OCH2 (C
O
O
C st as) → 1226.1
C st si) → 1060.7

46

47

48

49

50

SYNTHESIS OF NEW DIALKYLPHOSPHORYLHYDRAZONES
51
Table VIII 31P NMR data of dialkylphosphorylhydrazones
δ in ppm
Compound
(multiplicity)—J in Hz
7
8
2.46
2.82
9
2.53
10
11
12
13
14
15
16
17
18
19
20
21
22
2.59
2.90
3.40
0.47
0.86
0.53
0.62
0.93
1.49
1.32
1.21
1.69
2.14
0.35 (dt)
JHP = 8.0 Hz
JHP = 27.2
0.79 (dt)
JHP = 8.0
JHP = 27.2
0.72 (dt)
JHP = 7.2
JHP = 26.4
0.75 (dt)
JHP = 8.0
JHP = 26.4
2.67 (dt)
JHP = 8.1
JHP = 27.5
2.62 (dt)
JHP = 7.29
JHP = 28.4
23
24
25
26
27
28
Figure 1 NOE enhancements for dialkylphosphorylhydrazones.

52
J. M. RODRIGUES ET AL.
spectra. The 1H NMR spectra show only one iminic hydrogen singlet at δ = 7.7–9.3 ppm
corresponding to the presence of a single diastereoisomer. This stereoselectivity is also
confirmed by the presence of a single signal for all P atoms of the different dialkylphos-
phorylhydrazones. The use of NOE difference experiments35 afforded the enhancements
shown in Figure 1, further confirming the E configuration.
Further evidence for the E configuration comes from the fragmentation pattern in the
mass spectra where, for all compounds, there is a peak at m/z+1 = 98, which is obtained
from a pseudo McLafferty rearrangement,36 only possible for the E isomer (Scheme 3).
CONCLUSION
The syntheses described in this work provide an efficient and easy access to di-
alkylphosphorylhydrazones substituted in the aromatic ring, making use of readily available
starting materials. These new dialkylphosphorylhydrazones may serve as intermediates in
the synthesis of new compounds with potential use in agriculture or medicinal chemistry.
EXPERIMENTAL
Synthesis of Dialkylphosphites37: General Procedure
In a two-necked 125 mL round flask equipped with an addition funnel and a reflux
condenser fitted with a bubbler, the alcohol was added. Through the funnel, freshly distilled
PCl3 was added dropwise with magnetic stirring so the temperature was kept around 0 ◦C.
After all the chloride was added, the mixture was kept under stirring at 50 ◦C for 2 h. The
mixture was then kept under vacuum to remove residual HCl, and finally the phosphonate
was removed with a rotary evaporator.
Dipropylphosphonate. 51.4 mL (41.2 g, 0.68 mmol) of propyl alcohol were
allowed to react with 20.5 mL (32.3 g, 0.23 mmol) of PCl3, affording 35.0 g (93%) of the
desired phosphonate as a colorless liquid.
Diisopropylphosphonate. 54.0 mL (42.12 g, 0.70 mmol) of isopropyl alcohol
were allowed to react with 20.5 mL (32.3 g, 0.23 mmol) of PCl3, affording 36.6 g (94%)
of a colorless liquid.
Synthesis of the Dialkylphosphorylhydrazides38: General Procedure
In a two-necked 125 mL round flask equipped with an addition funnel and reflux
condenser fitted with a bubbler, hydrazine hydrate and a solution of NaOH in equal volumes
of water and ethyl alcohol were added. A solution of the dialkylphosphonate and carbon
tetrachloride was then added dropwise with magnetic stirring maintaining the temperature
around 0 ◦C until all phosphonate was added. The reaction mixture was then kept at reflux
at 60 ◦C for 4 h. After this time, all the contents of the flask were transferred to a separation
funnel, and the organic phase was washed with CH2Cl2 (5 × 10 mL) and dried with sodium
sulfate. Then the solvents were removed under vacuum, and a yellow oil was obtained.
Dipropylphosphorylhydrazide. Dipropylphosphonate (8.8 g, 52.9 mmol), 2.64 g
(2.56 mL, 52.9 mmol) of hydrazine hydrate, 11.4 g (7.15 mL, 74 mmol) of carbon tetra-
chloride, and 2.12 g (52.9 mmol) of sodium hydroxide were dissolved in 10 mL of distilled
water and 10 mL of ethyl alcohol. The hydrazide was obtained in 47% yield (4.84 g) as a
yellow oil.

SYNTHESIS OF NEW DIALKYLPHOSPHORYLHYDRAZONES
53
Diisopropylhydrazide. Diisopropylphosphonate (11.57 g, 69.7 mmol), 3.48 g
(3.38 mL, 69.7 mmol) of hydrazine hydrate, 15 g (9.4 mL, 97 mmol) of carbon tetra-
chloride, and 2.80 g (70 mmol) of sodium hydroxide were dissolved in 10 mL of distilled
water and 10 mL of ethyl alcohol. The corresponding hydrazide was obtained in 39% yield
(5.34 g) as a yellow oil.
Synthesis of the Dialkylphosphorylhydrazones39: General Procedure
In a one-neck 50 mL round flask, 2.70 mmol of dialkylphosphorylhydrazide, 8 mL
of ethyl alcohol, 2.55 mmol of the corresponding aldehyde, and three drops of 37.5% HCl
were added. This mixture was kept under magnetic stirring at room temperature for the
times described in Table I. After those times, six drops of sodium bicarbonate 10% were
added, and the mixture was poured into 10 mL of cold distilled water and kept in an ice bath
for 30 min. The resulting solid was filtered and dried under vacuum. For benzoic aldehyde,
no bicarbonate was added.
N-[(1E)-(o-Nitrophenylmethanol)phosphorohydrazidic acid dipropyl es-
ter (7). Dipropylphosphorylhydrazine (0.53 g, 0.00270 mol) was allowed to react with
0.38 g (0.00252 mol) of o-nitrobenzaldehyde, ethanol (8 mL), and hydrochloric acid (3
drops, 37%) for 2 h. The product was obtained in 82% yield ( 0.69 g).
Nꢀ-[(1E)-(m-Nitrophenyl)methylene]phosphorohydrazidic acid dipropyl
ester (8). Dipropylphosphorylhydrazine (0.53 g, 0.00270 mol) was allowed to react with
0.38 g (0.00252 mol) of m-nitrobenzaldehyde, ethanol (8 mL), and hydrochloric acid (3
drops, 37%) for 2 h. The product was obtained in 82% yield (0.69 g).
Nꢀ-[(1E)-(p-Nitrophenyl)methylene]-phosphorohydrazidic acid dipropyl
ester (9). Dipropylphosphorylhydrazine (0.53 g, 0.00270 mol) was allowed to react with
0.38 g (0.00252 mol) of m-nitrobenzaldehyde, ethanol (8 mL), and hydrochloric acid (3
drops, 37%) for 2 h. The product was obtained in 74% yield (0.62 g).
Nꢀ-[(1E)-(p-Cyanophenyl)methylene]-phosphorohydrazidic acid dipr-
opyl ester (10). Dipropylphosphorylhydrazine (0.53 g, 0.00270 mol) was allowed to
react with 0.33 g (0.00252 mol) of p-cyanobenzaldehyde, ethanol (8 mL), and hydrochloric
acid (3 drops, 37%) for 2 h. The product was obtained in 61% yield (0.48 g).
Nꢀ-[(1E)-(p-Carboxyphenyl), mehylene]-phosphorohydrazidic acid dipr-
opyl ester (11). Dipropylphosphorylhydrazine (0.53 g, 0.00270 mol) was allowed to react
with 0.38 g (0.00253 mol) of p-carboxybenzaldehyde, ethanol (8 mL) and hydrochloric
acid (3 drops, 37%) for 2 h. The product was obtained in 76% yield (0.64 g).
Nꢀ-[(1E)-(1,3-Benzodioxol-5-ylmethylene)]-phosphorohydrazidic
acid
dipropyl ester (12). Dipropylphosphorylhydrazine (0.53 g, 0.00270 mol) was allowed
to react with 0.54 g (0.00360 mol) of piperonal, ethanol (8 mL), and hydrochloric acid (3
drops, 37%) for 6 h. The product was obtained in 68% yield (0.79 g).
Nꢀ-[(1E)-(o-Nitrophenyl)methylene]-phosphorohydrazidic acid diiso-
propyl ester (13). Diisopropylphosphorylhydrazine (0.53 g, 0.00270 mol) was allowed
to react with 0.38 g (0.00252 mol) of o-nitrobenzaldehyde, ethanol (8 mL), and hy-
drochloric acid (3 drops, 37%) for 2 h. The desired product was obtained in 80% yield
(0.67 g).
Nꢀ-[(1E)-(m-Nitrophenyl)methylene]phosphorohydrazidic acid diiso-
propyl ester (14). Diisopropylphosphorylhydrazine (0.53 g, 0.00270 mol) was allowed
to react with 0.38 g (0.00252 mol) of m-nitrobenzaldehyde, ethanol (8 mL), and

54
J. M. RODRIGUES ET AL.
hydrochloric acid (3 drops, 37%) for 2 h. The desired product was obtained in 94% yield
(0.79 g).
Nꢀ-[(1E)-(p-Nitrophenyl)methylene]-phosphorohydrazidic acid diiso-
propyl ester (15). Diisopropylphosphorylhydrazine (0.32 g, 0.00163 mol) was allowed
to react with 0.23 g (0.00152 mol) of p-nitrobenzaldehyde, ethanol (8 mL), and hy-
drochloric acid (3 drops, 37%) for 2 h. The desired product was obtained in 84% yield
(0.42 g).
Nꢀ-[(1E)-(p-Cyanophenyl)methylene]-phosphorohydrazidic acid diiso-
propyl ester (16). Diisopropylphosphorylhydrazine (0.53 g, 0.00270 mol) was allowed
to react with 0.33 g (0.00252 mol) of p-cyanobenzaldehyde, ethanol (8 mL), and
hydrochloric acid (3 drops, 37%) for 2 h. The desired product was obtained in 87% yield
(0.69 g).
Nꢀ-[(1E)-(p-Carboxyphenyl),mehylene]-phosphorohydrazidic acid diiso-
propyl ester (17). Diisopropylphosphorylhydrazine (0.53 g, 0.00270 mol) was allowed
to react with 0.38 g (0.00253 mol) of p-carboxybenzaldehyde, ethanol (8 mL), and hy-
drochloric acid (3 drops, 37%) for 2 h. The product was obtained in 57% yield (0.48 g).
Nꢀ-[(1E)-(1,3-Benzodioxol-5-ylmehylene)]-phosphorohydrazidic acid di-
isopropyl ester (18). Diisopropylphosphorylhydrazine (0.53 g, 0.00270 mol) was al-
lowed to react with piperonal (0.33 g, 0.00252 mol), ethanol (8 mL), and hydrochloric acid
(3 drops, 37%) for 6 h. The product was obtained in 95% yield (0.75 g).
Nꢀ-[(1E)-(phenyl)methylene]-phosphorohydrazidic acid diisopropyl es-
ter (19). Diisopropylphosphorylhydrazine (0.74 g, 0.00378 mol) was allowed to react
with 0.38 g (0.00358 mol) of benzaldehyde, ethanol (8 mL), and hydrochloric acid (3
drops, 37%) for 2 h. The product was obtained in 84% yield (0.85 g).
Nꢀ-[(1E)-(m-Methoxyphenyl)
mehylene]-phosphorohydrazidic
acid
diisopropyl ester (20). Diisopropylphosphorylhydrazine (0.53 g, 0.00270 mol) was
allowed to react with 0.35 g (0.00257 mol) of m-methoxybenzaldehyde, ethanol (8 mL),
and hydrochloric acid (3 drops, 37%) under two different conditions: (i) reaction time: 2 h
affording a yield of 22% (0.18 g); (ii) reaction time: 6 h affording a yield of 67% (0.54 g).
Nꢀ-[(1E)-(p-Methoxyphenyl) mehylene]-phosphorohydrazidic acid diiso-
propyl ester (21). Diisopropylphosphorylhydrazine (0.53 g, 0.00270 mol) was allowed
to react with 0.35 g (0.00257 mol) of m-methoxybenzaldehyde, ethanol (8 mL), and hy-
drochloric acid (3 drops, 37%) under two different conditions: (i) reaction time: 2 h affording
a yield of 40% (0.32 g); (ii) reaction time: 6 h affording a yield of 71% (0.57 g).
N’-[(1E)-[4-(N,N’-Dimehylamino) phenyl]mehylene]-phosphorohydrazi-
dic acid diisopropyl ester (22). Diisopropylphosphorylhydrazine (0.57 g,
0.00291 mol) was allowed to react with 0.41 g (0.00257 mol) of 4-N,Nꢁ-
dimethylaminobenzaldehyde, ethanol (8 mL), and hydrochloric acid (3 drops, 37%)
under two different conditions: (i) reaction time: 2 h affording a yield of 14% (0.13 g); (ii)
reaction time: 6 h affording a yield of 49% (0.44 g).
Nꢀ-[(1E)-(m-Hydroxyphenyl) methylene]-phosphorohydrazidic acid di-
isopropyl ester (23). Diisopropylphosphorylhydrazine (0.30 g, 0.00153 mol) was al-
lowed to react with 0.19 g (0.00156 mol) of m-hydroxybenzaldehyde, ethanol (8 mL), and
hydrochloric acid (3 drops, 37%) for 6 h. The product was obtained in 61% yield (0.28 g).
Nꢀ-[(1E)-(p-Hydroxyphenyl) methylene]-phosphorohydrazidic acid diiso-
propyl ester (24). Diisopropylphosphorylhydrazine (0.30 g, 0.00153 mol) was allowed
to react with 0.19 g (0.00156 mol) of p-hydroxybenzaldehyde, ethanol (8 mL), and
hydrochloric acid (3 drops, 37%) for 6 h. The product was obtained in 70% yield (0.32 g).

SYNTHESIS OF NEW DIALKYLPHOSPHORYLHYDRAZONES
55
Nꢀ-[(1E)-(m-Hydroxy-p-methoxyphenyl)methylene]-phosphorohydrazi-
dic acid diisopropyl ester (25). Diisopropylphosphorylhydrazine (0.39 g,
0.00199 mol) was allowed to react with 0.30 g (0.00197 mol) of m-hydroxy-p-
methoxybenzaldehyde, ethanol (8 mL), and hydrochloric acid (3 drops, 37%) for 6 h. The
product was obtained in 79% yield (0.51 g).
Nꢀ-[(1E)-(m-Ethoxy-p-hydroxyphenyl)methylene]-phosphorohydrazidic
acid diisopropyl ester (26). Diisopropylphosphorylhydrazine (0.42 g, 0.00214 mol)
was allowed to react with 0.36 g (0.00217 mol) of m-ethoxy-p-hydroxybenzaldehyde,
ethanol (8 mL), and hydrochloric acid (3 drops, 37%) for 6 h. The product was obtained in
60% yield (0.45 g).
Nꢀ-[(1E)-(m-Hydroxy-p-methoxyphenyl)methylene]-phosphorohydrazi-
dic acid diisopropyl ester (27). Diisopropylphosphorylhydrazine (0.51 g,
0.00260 mol) was allowed to react with 0.40 g (0.00263 mol) of m-hydroxy-p-
methoxybenzaldehyde, ethanol (8 mL), and hydrochloric acid (3 drops, 37%) for 6 h. The
product was obtained in 56% yield (0.49 g).
Nꢀ-[(1E)-(m-Ethoxy-p-hydroxyphenyl) methylene]-phosphorohydrazidic
acid dipropyl ester (28). Dipropylphosphorylhydrazine (0.47 g, 0.00240 mol) was
allowed to react with 0.40 g (0.00241mol) of m-ethoxy-p-hydroxybenzaldehyde, ethanol
(8 mL), and hydrochloric acid (3 drops, 37%) for 6 h. The product was obtained in 77%
yield (0.64 g).
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