Novel and efficient synthesis of N,N-dialkylamino-O-alkyl-2-(1-methyl-2- oxopropylidene)phosphorohydrazido oximes. Part 3

Article abstract of DOI:10.3390/12092193

A novel and efficient method has been developed for the synthesis of N,N-dialkylamino-O-alkyl-2-(1-methyl-2-oxopropylidene)phosphorohydrazido oximes 5. The reactions involve the condensation of diacetylmonoxime and N,N-dialkylamino-O-alkylphosphorohydrazides in the presence of activated silica and give the corresponding target oximes in excellent yields under mild conditions.

Full text of DOI:10.3390/12092193

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Molecules 2007, 12, 2193-2200
molecules
ISSN 1420-3049
© 2007 by MDPI
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Full Paper
Novel and Efficient Synthesis of N,N-dialkylamino-O-alkyl-2-(1-
methyl-2-oxopropylidene)phosphorohydrazido Oximes. Part 3
Rajesh Kumar, Arvind K. Gupta and Mahabir P. Kaushik*
Process Technology Development Division, Defence R & D Establishment, Jhansi Road, Gwalior-
474002 (MP), India; Tel. +91-751-2343972, Fax +91-751-2341148
* Author to whom correspondence should be addressed; e-mail: mpkaushik@rediffmail.com
Received: 15 August 2007; in revised form: 20 September 2007 / Accepted: 20 September 2007 /
Published: 21 September 2007
Abstract: A novel and efficient method has been developed for the synthesis of
N,N-dialkylamino-O-alkyl-2-(1-methyl-2-oxopropylidene)phosphorohydrazido oximes 5.
The reactions involve the condensation of diacetylmonoxime and N,N-dialkylamino-O-
alkylphosphorohydrazides in the presence of activated silica and give the corresponding
target oximes in excellent yields under mild conditions.
Keywords: Hydrazides, diacetylmonoxime, marine fish toxin, phosphorohydrazido
oximes.
Introduction
Two unusual naturally occurring phosphorus-containing fish toxins were isolated for the first time
from Gymnodinium breve and their structures established as O,O-dipropyl-(E)-2-(1-methyl-2-oxo-
propylidene)phosphorohydrazidothiolate-(E)-oxime [1] and O,O-diphenylcyclooctylphosphoramidate
(PB-1) on the basis of X-ray crystallography [2]. Due to the unique structure of these compounds and
their potent activities, much research has focused on their biological aspects [3, 4]. These naturally
occurring fish toxins are the only OP compounds that contains a P=O(S) moiety like that found in
insecticides [5] and they do not have any good leaving groups. Another interesting feature of these
compounds is the presence of free oximino functions, which were not found in the earlier reported

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toxic OP compounds. The non availability of a P=O(S) analogue of these naturally occurring fish
toxins [1] from the natural sources prompted us to develop a general synthetic method for the
preparation of these compounds and their analogues for complete toxicological and pharmacological
studies. In continuation of our ongoing research on the synthesis of new biologically active
compounds, the possibility of synthesizing new analogues of phosphorohydrazido oximes was
explored and recently, we have reported a method for the synthesis of various such derivatives [6-8].
Herein, we report a facile, cheap, extremely rapid and high-yielding procedure for the synthesis of
N,N-dialkylamino-O-alkyl-2-(1-methyl-2-oxopropylidene)phosphorohydrazido oximes
5
from
diacetyl-monoxime and N,N-dialkylamino-O-alkylphosphorohydrazides. To the best of our knowledge
there are no reports in the literature describing the synthesis of these compounds.
Result and Discussion
Retrosynthetic analysis of the target compounds suggested that they could be synthesized from the
corresponding phosphorohydrazides and butane-2,3-dione monoxime. We have thus followed the
sequence shown in Scheme 1 to obtain the N,N-dialkylamino-O-alkyl-2-(1-methyl-2-oxopropylidene)
phosphorohydrazidooximes 5a-j.
Scheme 1.
O
P
1
NR2
Cl
O
P
Cl
Cl
R21NH
(C2H5)3N
RO
(2)
RO
POCl3
R-OH
(C2H5)3N
(1)
Ethanol
NH2NH2
OH
O
1
O
NR2
N
C
CH3
CH3
1
RO
P
O
H3C
C
CH3
NR2
NHN
(4)
C
RO
P
C
N
NHNH2
Silica
(5)
(3)
OH
In order to follow the proposed synthetic plan for the synthesis of target compounds, the
intermediates 1-3 were prepared following literature procedures [9, 10]. After the synthesis of the
various N,N-dialkylamino-O-alkyl-phosphorohydrazides 3 we optimized the reaction conditions for the
synthesis of the target compounds 5. In this regard, we initially performed as a model the reaction of
diethylamino-O-butyl phosphorohydrazide with butane-2,3-dione monoxime in the presence of various
dehydrating reagents, while varying reaction times and temperatures. The efficiency of various
condensing agents such as Al2O3 (neutral, acidic, basic), SiO2, ZnCl2, H3PO3, KF-SiO2, POCl3, PTSA,
BiCl3, DCC, V2O5-SiO2 were studied using different molar ratios. The results of these experiments are
summarized in Table 1.
The results shown in Table 1 reveal that in comparison to other condensation reagents, the use of
silica gave the best results. Next, to study the effect of solvent in the model reaction, various solvents

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like THF, dioxane, hexane, diethyl ether, benzene, DCM, chloroform and CCl4 were used and it was
observed that benzene afforded the best results. During this study we observed that that yield of 5 was
affected by changing the nature of solvent. It was also revealed that the use of DCM, chloroform and
CCl4 gave more or less similar yields of 5 (35-40%). However, when the reaction time was increased
the isolation of products became difficult due to formation of some unidentified side products and
unreacted starting materials. Diethyl ether and hexane were found to be poor solvents due to the
limited solubility of the reactants in both the solvents, even under reflux conditions.
Table 1. Condensation agent optimization for the synthesis of compounds 5a.
Molar ratio of compound
Entry Dehydrating agent
Solvent
Converson (%)
3:4: dehydrating agents
1
2
Al2O3(neutral)
Al2O3(basic)
Al2O3(acidic)
H3PO3
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
1:1:1
1:1:1
1:1:1
1:1:0.5
1:1:1
1:1:2
1:1:1
1:1:1
1:1:1
1:1:0.5
1:1:1
1:1:1
1:1:4
1:1:6
32
18
42
17
19
15
45
10
15
8
3
4
5
ZnCl2
6
DCC
7
PTSA
8
V2O5-SiO2
BiCl3
9
10
11
12
13
14
POCl3
ZnCl2
29
52
78
78
SiO2
SiO2
SiO2
10. All the reactions were performed for a constant time (3 hr) and temperature (100 °C) and
reactions were monitored by 31 P-NMR in C6D6 at 162 MHz.
After optimization of reaction conditions, various N,N-dialkylamino-O-alkyl phosphorohydrazides
were condensed with diacetylmonoxime in presence of activated silica in benzene, to give N,N-
dialkylamino-O-alkyl-2-(1-methyl-2-oxopropylidene) phosphorohydrazido oximes 5a-j in excellent
yield (Table 2).
Conclusions
In summary, we have described a general and efficient method for the synthesis of structurally
complex and diverse N,N-dialkylamino-O-alkyl-2-(1-methyl-2-oxopropylidene)phosphorohydrazido
oximes. It was found that procedure offers several advantages, including the possibility of obtaining
pure products in high yields without the use of column chromatography, operational simplicity and
cleaner reactions, which makes it a useful and attractive process for the synthesis of these compounds.

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The assignment of the configuration and the detailed biological activity is under progress and will be
reported in due course.
Table 2. Physical data of the newly synthesized compounds 5a.
1
O
NR2
CH3
CH3
RO P
NHN
C
C
N
OH
Reaction
time (h)
m. p.
(°C)
Entry
R
R1
31P-NMRb
Yieldc (%)
5a
5b
5c
5d
5e
5f
OC4H9
OC4H9
OC4H9
OC4H9
OC4H9
OC3H7
OC3H7
OC3H7
OC3H7
OC3H7
C2H5
C3H7
iC3H7
C4H9
iC4H9
C2H5
C3H7
iC3H7
C4H9
iC4H9
2.8
2.9
3.0
3.0
3.2
2.7
2.8
3.0
3.0
3.0
9.95
10.11
10.14
10.27
9.88
103
112
105
118
121
110
120
123
113
130
78
75
83
86
79
72
73
83
69
81
10.15
10.04
10.03
9.98
5g
5h
5i
5j
10.02
a) All the reactions were performed in benzene under reflux conditions; b)
31P-NMR data were recorded at 162 MHz using either CDCl3 or DMSO-d6
as solvents; c) isolated yields
Acknowledgements
The authors thank Ms. Mamta Sharma and Avik Mazumder for NMR analysis.
Experimental
General
31
1H-, P- and 13C-NMR spectra were recorded in CDCl3 or DMSO-d6 solutions on a Bruker
AVANCE 400 NMR spectrometer operating at 400, 162 and 100 MHz, respectively. LCMS analysis
(EI, 70V) were performed on a Hewlett-Packard HP 5971 instrument. IR spectra were recorded on a
Bruker model Tensor 27 FT-IR spectrometer as KBr pellets.