Microwave-assisted synthesis of N,N-dialkyl-P-alkylphosphonamidic anhydrides

Article abstract of DOI:10.1080/10426500902953961

A new rapid, efficient, solvent-free, microwave-assisted, and high-yielding method for the synthesis of N,N-dialkyl-P-alkylphosphonamidic anhydrides has been developed. The method involves the use of 4-dimethylaminopyridine and water under microwave irrad

Full text of DOI:10.1080/10426500902953961

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Phosphorus, Sulfur, and Silicon and the
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Microwave-Assisted Synthesis of
N,N-Dialkyl-P-Alkylphosphonamidic
Anhydrides
Rajesh Kumar a , A. K. Gupta a & M. P. Kaushik a
a Process Technology Development Division , Defence R & D
Establishment , Gwalior, India
Published online: 23 Mar 2010.
To cite this article: Rajesh Kumar , A. K. Gupta & M. P. Kaushik (2010) Microwave-Assisted Synthesis
of N,N-Dialkyl-P-Alkylphosphonamidic Anhydrides, Phosphorus, Sulfur, and Silicon and the Related
Elements, 185:4, 765-771, DOI: 10.1080/10426500902953961
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Phosphorus, Sulfur, and Silicon, 185:765–771, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902953961
MICROWAVE-ASSISTED SYNTHESIS OF
N,N-DIALKYL-P-ALKYLPHOSPHONAMIDIC ANHYDRIDES
Rajesh Kumar, A. K. Gupta, and M. P. Kaushik
Process Technology Development Division, Defence R & D Establishment,
Gwalior, India
A new rapid, efficient, solvent-free, microwave-assisted, and high-yielding method for
the synthesis of N,N-dialkyl-P-alkylphosphonamidic anhydrides has been developed. The
method involves the use of 4-dimethylaminopyridine and water under microwave irradi-
ation. The reaction of N,N-dialkylaminoalkyl/phenyl phosphonochloridates 2a–h with 4-
dimethylaminopyridine (DMAP) gave pyridinium salts, which were converted into N,N-
dialkyl-P-alkylphosphonamidic anhydrides 4a–h.
Keywords N,N-Dialkylaminoalkyl/phenylphosphonochloridates; N,N-dialkyl-P-alkylphos-
phonamidic anhydrides; 4-dimethylaminopyridine (DMAP); microwave irradiation
INTRODUCTION
The chemistry of organophosphorus (OP) compounds is a rapidly developing area of
research because of their importance in industrial, agricultural, biochemical, and medicinal
applications.1 It is interesting to note that the variation in their physical, chemical, and bi-
ological properties is governed by the selection of the group attached to phosphorus atom.
Phosphorous compounds containing the P–C bond are not particularly abundant in nature;
nevertheless they have diverse biological activity, and as a consequence they have attracted
the attention of synthetic as well as medicinal chemists. Similarly, other OP compounds con-
taining the P–N–C linkage have also been reported as insecticides, fungicides, herbicides,
fire retardants, and lubricants.2 In particular, anhydrides of organophosphorus compounds
(pyrophosphates) having the P–O–P linkage are known to have a rich history both in terms
of their synthetic utility as well as their biological importance.3 Recently, these anhydrides
have been reported to serve as potent inhibitors and activators of enzymes.4–6 There are
several methods for the synthesis of pyrophosphates7–10 and phosphonamidic anhydrides.11
However, anhydrides of the N,N-dialkyl-P-alkylphosphonamidic acids have not been fully
explored. The biological activity of pyrophosphates has prompted us to develop the rapid
and efficient synthetic procedure for the synthesis of N,N-dialkyl-P-alkylphosphonamidic
Received 31 January 2009; accepted 5 April 2009.
The authors thank to Ms. Mamta Sharma and Avik Mazumder for NMR analysis.
Address correspondence to M. P. Kaushik, Process Technology Development Division, Defence R&D
Establishment, Jhansi Road, Gwalior-474002 (MP), India. E-mail: mpkaushik@rediffmail.com
765

766
R. KUMAR ET AL.
anhydrides. Perusal of the literature revealed that reported methods for the synthesis py-
rophosphates are associated with several drawbacks, such as longer reaction times, use of
carcinogenic solvents, harsh reaction conditions, and tedious workup, and chromatographic
techniques are often used to afford the compounds of desired purity.7–11 Recently, there has
been considerable interest in the microwave (MW)-assisted synthesis of a variety of or-
ganic compounds due to the selective absorption of microwave energy by polar molecules.12
Microwave-assisted organic synthesis is known for the spectacular accelerations produced
in many reactions as a consequence of the heating rate, a phenomenon that can not be easily
reproduced by classical heating. As a result, higher yields, mild conditions, and shorter
reaction times can often be achieved.13
RESULTS AND DISCUSSION
Inspired by the concept of microwave heating, we thought that N,N-dialkyl-
P-alkylphosphonamidic anhydrides could be prepared from N,N-dialkylamino
alkyl/phenylphosphonic chlorides 2a–h.14 In this regard, initially, we prepared alkyl/phenyl
phosphonic dichloride 1 by a reported method by Kinnear and Parren.15 After obtaining
the N, N-dialkylamino alkyl/phenylphosphonic chlorides 2a–h, we optimized the reaction
conditions for the overall two-step process. In this regard, each of N,N-dialkylamino
alkyl/phenylphosphonic chlorides 2a–h were treated with various organic bases [dimethyl
aminopyridine (DMAP), pyridine, triethylamine, diethyl aniline, N-methyl imidazole, and
diisopropyl ethylamine] in presence of microwave irradiations under identical conditions.
The yield of product 4a–h was compared. However, the better yield was obtained when
DMAP was used to produce the pyridinium salts 3a–h. Best overall yields of N,N-
dialkyl-P-alkylphosphonamidic anhydrides 4a–h were obtained when N,N-dialkylamino
alkyl/phenylphosphonic chlorides were first treated with DMAP followed by water in the
molar ratio of 1:1:0.5 (Table I) at 180 W. The yields of products 4a–h were excellent
ranging from 85–93%. The purity of the compounds was checked on silica TLC plate
using a benzene:acetone mixture (8:2). The compounds 4a–h were characterized by IR,
NMR, GC-MS, and elemental analysis. The IR showed strong and broad bands in the range
of 975–969 cm−1, due to antisymmetric stretching of the P O P linkage.16 The other
frequencies assigned for P N C, P C, and P O linkage were found to be comparable
to those reported in the literature.17 It was observed that compounds 4a–h showed two
signals in 31P NMR due to the presences of two diastereotropic phosphorus atoms. The
results of other analyses of 4a–h are compiled in the Experimental section.
The results in Table I showed the novelty of the method, as compounds 4a–h can
be prepared in less than 10 min for each case with out isolating pyridinium salts 3a–h. A
further interesting aspect of this method is that the reactions are carried out in the absence
of an organic solvent, hence making a more environmentally attractive process.
CONCLUSION
In conclusion, we have developed a rapid and efficient method for the synthesis
of N,N-dialkyl-P -alkylphosphonamidic anhydrides 4a–h with excellent yields. The main
advantage of this method is that reactions were clean and had operational simplicity.
Since column chromatography was not required to get pure products, this reaction is more
attractive for organic chemists.

SYNTHESIS OF PHOSPHONAMIDIC ANHYDRIDES
767
Table I Synthesis of N,N-dialkyl-P-alkylphosphonamidic anhydrides 4a–h using microwave irradiations
Reaction
time (min.)
Yield
(%)a
Mp
(◦C)
31P NMR
(δ ppm)b
Substrate
Product
5
85
oil
27.14, 26.25
O
O
P
N(C3H7)2
N(C3H7)2
CH3
CH3
O
P
N(C3H7)2
CH3
P
Cl
O
4a
CH3
5
90
oil
27.00, 26.16
O
P
O
N(C4H9)2
N(C4H9)2
Cl
O
P
CH3
P
N(C4H9)2
O
CH3
4b
6
6
91
88
38
39
33.95, 33.34
33.48, 32.84
O
P
O
P
N(C3H7)2
N(C3H7)2
Cl
i
i
i
i
C3H7
O
P
N(C3H7)2
C3H7
O
4c
iC3H7
O
P
O
P
N(C4H9)2
O
N(C4H9)2
Cl
C3H7
C3H7
N(C4H9)2
iC3H7
O
P
4d
N(iC4H9)2
O
6
87
40
32.98, 32.56
N(iC4H9)2
Cl
O
P
O
P
i
N(iC4H9)2
iC3H7
i
C3H7
C6H5
C6H5
C3H7
C6H5
C6H5
O
P
4e
7
7
90
89
42
47
16.53, 16.23
16.74, 16.50
O
O
N(C2H5)2
N(C2H5)2
Cl
P
O
P
N(C2H5)2
P
O
C6H5
4f
O
P
O
P
N(C3H7)2
Cl
N(C3H7)2
O
N(C3H7)2
O
P
C6H5
4g
N(iC4H9)2
O
7
93
50
18.24, 17.99
N(iC4H9)2
Cl
O
P
O
P
N(iC4H9)2
C6H5
C6H5
C6H5
O
P
4h
aProduct yields.
b31P NMR spectra were recorded in CDCl3 at 162 MHz.
EXPERIMENTAL
Melting points were determined on a hot stage microscope and are uncorrected. IR
spectra were recorded on Bruker FT-IR spectrometer model Tensor 27 on KBr disk, and
1
solid compounds were analyzed by making KBr pellets. H, 13C, and 31P NMR spectra
were recorded in CDCl3 on a Bruker DPX Avance FT-NMR at 400, 100, and 162 MHz,
respectively, using tetramethylsilane as an internal standard for 1 H, 13C, and 85% H3PO4 as

768
R. KUMAR ET AL.
O
P
O
P
Cl
Cl
N(R1)2
HN(R1)2
R
R
N(C2H5)3
Cl
2a-h
MW
1
DMAP
180 W, 4 min.
O
N(R1)2
N
O
P
N(R1)2
H2O
R
P
Cl-
CH3
CH3
R
O
N(R1)2
180 W, 1min.
MW,
N
O
P
R
4a-h
3a-h
R = CH3, iC3H7, C6H5
R1 = C2H5 , C3H7, C4H9, iC4H9
Scheme 1
an external standard for 31P NMR. A Chemito GC model 1000 instrument was used with a
flame ionization detector (FID). A capillary column (30 m × 0.25 mm LD-BP5) packed with
5% phenyl and 95% dimethyl polysiloxane (SGE) coated on fused silica was employed.
The injection port and detector block were maintained at 280◦C and 260◦C, respectively,
and the column oven was at programmed temperature profile that began at 50◦C and ramped
up to 280◦C at 25◦C/min. Nitrogen was used as carrier gas (at a flow rate of 30 mL/min).
Air for FID was supplied at 300 mL/min and hydrogen at 30 mL/min. In all analyses,
0.1 µl sample was injected and peaks were recorded on Iris32 data acquisition station. The
GC-MS analyses were performed in EI (70 eV) in full scan mode with an Agilent 6890
GC equipped with a model 5973 mass selective detector (Agilent Technologies, USA). An
SGE BPX5 capillary column with 30 m length × 0.32 mm internal diameter × 0.25 µm
film thickness was used at temperature program of 80◦C (2 min)–20◦C/min–280◦C (3 min).
Helium was used as the carrier gas at a constant flow rate of 1.2 mL/min. The samples were
analyzed in split less mode at injection temperature. For these studies, a microwave oven
(Samsung CE 2977N operating at 2450 MHz with an oven cavity of 336 × 241 × 349 mm
and 28 L volume) at a power level of 180 W, equipped with inverter technology was used.
The purity of compounds was checked on TLC plate (silica gel coated on aluminium plate)
using benzene/acetone mixture (8:2), and the Rf value for each final product was found at
0.6–0.77.
General Procedure for the Preparation of N,N-Dipropyl-P-methylphos-
phonamidic Anhydride (4a–h)
To 4-dimethylaminopyridine (1.22 g, 0.01 M) in a conical flask was added N,N-
dipropyl methylphosphonochloridate (1.97 g, 0.01 M) and the resulting mixture was mixed
well. Following this, the mixture was irradiated with microwaves of 180 W energy for
4 min, resulting in salt production. Water (900 µL, 0.005 M) was added to the resultant

SYNTHESIS OF PHOSPHONAMIDIC ANHYDRIDES
769
salt, and the reaction mixture was shaken until dissolution occurred. The mixture was
further irradiated at 180 W for 1 min. The progress of the reaction was monitored by
31P NMR until the signal of N, N-dipropyl methylphosphonochloridate disappeared. The
reaction mass was washed and extracted with n-pentane (4 × 25 mL), and the solvent was
evaporated to afford N,N-dipropyl-P-methylphosphonamidic anhydride. The product was
triturated with pentane to get analytical purity.
N,N-Dipropyl-P-methylphosphonamidic anhydride (4a). Anal. Calcd.
C14H34N2O3P2: C, 49.40; H, 10.07; N, 8.23. Found: C, 49.43; H, 10.05; N, 8.25. IR
(KBr): 694(P C), 971 (P O P), 1089, 1152 (P N C), 1237 (P O), 1434 (C N),
2885 (C H) cm−1; 1H NMR (400 MHz, CDCl3) : δ 0.88 (t, J = 7.3 Hz, 12H, CH3), 1.53
3
(m, J = 7.3 Hz, 8H, CH2), 1.67 (d, JP = 18.6 Hz, 6H, CH3), 2.98 (m, JP = 11.4
H
H
Hz, 8H, CH2); 13C NMR (100 MHz, CDCl3): δ 10.53 (CH3), 18.90 (CH2), 21.06 (JP
C
= 150.5 Hz, CH3), 46.50 (3JP = 5.5 Hz, CH2); GCMS (EI); m/z (%): 340 (4.46), 240
C
(78.57), 226 (20.53), 162 (41.07), 168 (22.32), 100 (100), 43 (19.64).
N,N-Dibutyl-P-methylphosphonamidic anhydride (4b). Anal. Calcd.
C18H42N2O3P2: C, 54.53; H, 10.68; N, 7.07. Found : C, 54.50; H, 10.65; N, 7.08. IR
(KBr): 698(P C), 970 (P O P), 1080, 1150 (P N C), 1235 (P O), 1435 (C N), 2889
1
(C H) cm−1; H NMR (400 MHz, CDCl3) : δ 0.93 (t, J = 7.2 Hz, 12H, CH3), 1.27 (m,
J = 7.2 Hz, 8H, CH2), 1.33 (m, J = 7.0 Hz, 8H, CH2), 1.63 (d, JP H = 18.6 Hz, 6H, CH3),
3.01 (m, 3JP = 11.4 Hz, 8H, CH2); 13C NMR (100 MHz, CDCl3): δ 10.35 (CH3),15.73
H
(CH2), 18.95 (CH2), 20.09 (JP C = 150.5 Hz, CH3), 44.67 (3JP C = 5.5 Hz,CH2); GCMS
(EI); m/z (%): 396 (4.46), 318 (6.25), 275 (100), 190 (74.10), 148 (38.28), 128 (74.10),
106 (22.32), 92 (31.25), 41 (24.10).
N,N-Dipropyl-P-isopropylphosphonamidic anhydride (4c). Anal. Calcd.
C18H42N2O3P2 : C, 54.53; H,10.68; N, 7.07. Found : C, 54.50; H,10.65; N 7.09. IR
(KBr): 696 (P C), 975 (P O P), 1088, 1153 (P N C), 1237 (P O), 1437 (C N),
2888 (C H) cm−1; 1H NMR (400 MHz, CDCl3) : δ 0.82 (t, J = 6.3 Hz, 12H, CH3), 1.10
(dd, 3JP = 21.4 Hz, 12H, CH3), 1.54 (m, J = 6.3 Hz, 8H, CH2), 2.05 (m, J P-H = 19.9
H
Hz, 2H, CH), 3.0 (m, 3JP = 11.3 Hz, 8H, CH2); 13C NMR (100 MHz, CDCl3): δ 10.23
H
(CH3), 15.97 (3JP = 10.0 Hz, CH3), 18.45 (CH2), 21.05 (JP-C = 144.3 Hz, CH), 44.56
C
(3JP C = 5.6 Hz, CH2); GCMS (EI); m/z (%): 396 (3.6), 353 (5.45), 296 (24.54), 254 (50),
224 (12.72), 190 (18.18),148 (25.45), 100 (100), 43 (23.63).
N,N-Dibutyl-P-isopropylphosphonamidic anhydride (4d). Anal. Calcd.
C22H50N2O3P2: C, 58.38; H,11.14; N, 6.19. Found: C, 58.35; H,11.15; N 6.20. IR (KBr):
705(P C), 978 (P O P), 1090, 1155 (P N C), 1235 (P O), 1435 (C N), 2887(C H)
cm−1; 1H NMR (400 MHz, CDCl3) : δ 0.75 (t, J = 6.4 Hz, 12H, CH3), 1.05 (dd, 3JP
=
H
21.4 Hz, 12H, CH3), 1.10 (m, J = 6.4 Hz, 8H, CH2), 1.52 (m, J = 6.5 Hz, 8H, CH2), 2.05
(m, JP H = 19.9 Hz, 2H, CH), 3.02 (m, 3JP H = 11.3 Hz, 8H, CH2); 13C NMR (100 MHz,
CDCl3): δ 9.98 (CH3), 14.36 (3JP = 10.0 Hz,CH3), 18.36 (CH2), 21.05 (JP = 144.2
C
Hz, CH), 23.06 (CH2), 46.50 (3JP-CC= 5.5 Hz, CH2); GCMS (EI); m/z (%): 452 (4.5), 409
(3.6), 324 (18.18), 282 (12.72), 176 (20.90), 141 (18.18),128 (100), 41 (10.35).
N,N-Diisobutyl-P-isopropylphosphonamidic anhydride (4e). Anal. Calcd.
C22H50N2O3P2 : C, 58.38; H,11.14; N, 6.19. Found: C, 58.35; H,11.15; N 6.20. IR (KBr):
698 (P C), 980 (P O P), 1090, 1150 (P N C), 1240 (P O), 1436 (C N), 2885 (C H)
cm−1; 1H NMR (400 MHz, CDCl3) : δ 0.80 (d, J = 6.5 Hz, 12H, CH3), 1.05 (dd, 3JP-H
=
21.4 Hz, 12H, CH3), 1.52 (m, J = 6.1Hz, 4H, CH), 2.05 (m, JP = 19.9 Hz, 2H, CH),
H
3.02 (m, 3JP = 11.3 Hz, 8H, CH2); 13C NMR (100 MHz, CDCl3): δ 9.98 (CH3), 14.36
H
(3JP C = 10.0 Hz,CH3), 19.56 (CH), 21.05 (JP C = 144.2 Hz, CH), 46.47 (3JP C = 5.5 Hz,

770
R. KUMAR ET AL.
CH2); GCMS (EI); m/z (%): 452 (7.23), 409 (4.56), 324 (24.28), 282 (14.24), 176 (20.90),
141 (18.18),128 (100), 41 (10.35).
N,N-Diethyl-P-phenylphosphonamidic anhydride (4f). Anal. Calcd.
C20H30N2O3P2: C, 58.82; H, 7.40; N, 6.86. Found: C, 58.80; H, 7.39; N, 6.87. IR (KBr):
698 (P C), 975 (P O P), 1089, 1150 (P N C), 1240 (P O), 1437 (C N), 2888
1
(C H), 2995 (C6H5), cm−1; H NMR (400 MHz, CDCl3) : δ 1.02(t, J = 6.5 Hz, 12H,
CH3), 2.99 (m, 3JP = 11.3 Hz, 8H, CH2), 7.44–8.23(m, JP = 20.1 Hz, 10H, Ar H);
H
H
13C NMR (100 MHz, CDCl3): δ 10.32 (CH3), 47.15 (3JP = 5.5 Hz, CH2), 128–135
C
(JP = 147.2 Hz,Ar C); GCMS (EI); m/z (%): 408 (8.89), 336 (18.15), 260 (9.34), 196
C
(28.10), 124 (9.72), 72 (100), 43 (10.56).
N,N-Dipropyl-P-phenylphosphonamidic anhydride (4g). Anal. Calcd.
C24H38N2O3P2 : C, 62.06; H, 8.25; N, 6.03. Found : C, 62.07; H, 8.24; N 6.05. IR (KBr):
698 (P C), 974 (P O P), 1085, 1150 (P N C), 1240 (P O), 1441(C N), 2890
(C H), 2975 (C6H5) cm−1; 1H NMR (400 MHz, CDCl3) : δ 0. 76 (t, J = 6.5 Hz, 12H,
CH3), 1.65 (m, J = 6.7 Hz, 8H, CH2), 3.05 (m, 3JP-H = 11.3 Hz, 8H, CH2), 7.35–7.95 (m,
JP-H = 20.1Hz,10H, Ar H); 13C NMR (100 MHz, CDCl3): δ 10.32 (CH3), 18.25 (CH2),
46.45 (3JP = 5.6 Hz, CH2), 128–135 (JP = 147.4 Hz, Ar C); GCMS (EI); m/z (%):
C
C
464 (3.55), 364 (24.27), 292 (7.76), 224 (24.27), 150 (14.50), 140 (14.72), 100 (100), 43
(14.56).
N,N-Diisobutyl-P-phenylphosphonamidic anhydride (4h). Anal. Calcd.
C28H46N2O3P2 : C, 64.60; H, 8.91; N, 5.38. Found: C, 64.62; H, 8.90; N, 5.40. IR (KBr):
690 (P-C), 969 (P-O-P), 1085, 1150 (P-N-C), 1238 (P = O), 1437 (C-N), 2889 (C-H), 2988
(C6H5) cm−1; 1H NMR (400 MHz, CDCl3) : δ 0. 75 (d, J = 6.5 Hz, 12H, CH3), 1.92 (m, J
3
= 6.6 Hz, 4H, CH), 2.95 (m, JP-H = 11.3 Hz, 8H, CH2), 7.35–7.85 (m, JP-H = 20.1Hz,
10H, Ar-H); 13C NMR (100 MHz, CDCl3): δ 10.35 (CH3), 18.25 (CH), 44.46 (3JP-C = 5.7
Hz, CH2), 128–135 (JP-C = 147.4 Hz, Ar-C); GCMS (EI); m/z (%): 520 (4.43), 392 (100),
338 (9.70), 252 (14.56), 217 (4.58), 196 (14.56), 152 (19.40), 128 (68.93), 57 (16.47), 41
(18.44).
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