The phosporylation of aniline derivatives in biphase systems

Article abstract of DOI:10.1080/10426500500536614

Aniline derivatives were phosphorylated in biphase systems using three methods. A comparative study was performed. The best results were obtained when a solid-liquid system was used. This method is the easiest and lead to higher yields (54-81%). Copyright

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Phosphorus, Sulfur, and Silicon
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The Phosporylation of Aniline
Derivatives in Biphase Systems
Gheorghe Ilia a , Mihaela Petric a , Lavinia Macarie a
, Smaranda Iliescu a & Adriana Popa a
a Institute of Chemistry , Timisoara, Romania
Published online: 01 Feb 2007.
To cite this article: Gheorghe Ilia , Mihaela Petric , Lavinia Macarie , Smaranda Iliescu
& Adriana Popa (2006) The Phosporylation of Aniline Derivatives in Biphase Systems,
Phosphorus, Sulfur, and Silicon and the Related Elements, 181:7, 1717-1723, DOI:
10.1080/10426500500536614
To link to this article: http://dx.doi.org/10.1080/10426500500536614
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Phosphorus, Sulfur, and Silicon, 181:1717–1723, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500536614
The Phosporylation of Aniline Derivatives
in Biphase Systems
Gheorghe Ilia
Mihaela Petric
Lavinia Macarie
Smaranda Iliescu
Adriana Popa
Institute of Chemistry, Timisoara, Romania
Aniline derivatives were phosphorylated in biphase systems using three methods.
A comparative study was performed. The best results were obtained when a solid–
liquid system was used. This method is the easiest and lead to higher yields (54–
81%).
Keywords Aniline derivatives; liquid–liquid; phosporylation; solid–liquid
INTRODUCTION
Phosphoramidic acid derivatives gained importance because of their
use as biological compounds and intermediates in organic synthesis.1−3
The general procedure developed by Atherton et al.4 and Todd5 for the
phosphorylation of amines uses as a base an amine and the system
phosphite/tetrahalomethane (Reaction 1).
REACTION 1
This method is useful for the phosphorylation of ammonia, but has
several drawbacks in the case of amines as the following:
1) From the two moles of amine used, one mole is inevitably lost as the
corresponding chlorohydrate.
Received February 22, 2005; accepted September 20, 2005.
Address correspondence to Gheorghe Ilia, Institute of Chemistry, 24 M. Viteazul Bv.,
Timisoara 300223, Romania. E-mail: ilia@acad-icht.tm.edu.ro
1717

1718
G. Ilia et al.
2) The separation of the amine salt is laborious and sometimes
ineffective.
3) The partial monodebenzylation6 occurs when dibenzylphosphite is
used.
Zwierzak7 has shown that the phosphorylation of amines can occur in
an aqueous system in the presence of a catalytic (about 5% mol) amount
of triethylbenzylammonium chloride.
In this article, we present the results obtained in the phosphorylation
of aniline derivatives in liquid–liquid systems and liquid–solid systems
(Reaction 2).
REACTION 2
RESULTS AND DISCUSSION
Three methods were used in this study. Methods A and B were per-
formed in a liquid–liquid system, and Method C was performed in a
liquid–solid system. The Method C is not mentioned in the literature
for the synthesis of such compounds.
Using the system phosphite/tetrachloromethane in the phosphoryla-
tion of aniline derivatives, the phosphite is oxidized to chlorophosphate,
which reacts with anilines by a nucleophilic substitution, and phospho-
ramidic derivatives are obtained (Reactions 3 and 4).
REACTION 3
REACTION 4
The hydrochloric acid is neutralized by the base.

Phosporylation of Anilines
1719
The use of standard 50% aqueous sodium hydroxide for the first two
methods led to side reactions with a formation of halocarbene followed
by its subsequent reaction with anilines8 (Reaction 5).
REACTION 5
Also, when this concentration was used, other side reactions were de-
tected: (a) the hydrolysis of phosphites, especially diphenyl, dibenzyl,
and long chain alkyl phosphites; and (b) the formation of dark-brown,
tarry contaminants. These possible side reactions could be reduced if
the concentration of the aqueous base was below 30% and the temper-
ature was kept below 10◦C during the addition of reagents. The use of
an excess of a phosphorylating agent was essential because some of the
phosphite was lost during the reaction by an anionic dealkylation in an
aqueous medium.
Also, the stirring speed and reaction time influenced the yields
(Figures 1 and 2).
The best results were obtained at 600rpm and reaction time of
2 h. The influence of a phase transfer catalyst was also studied.
The best results were obtained with tetrabutylammonium bromide
(Table I).
These studies allowed a few observations:
1) To obtain good yields, the concentration of aqueous sodium hydrox-
ide has to be below 30%.
FIGURE 1 The influence of the stirring speed on the yield.

1720
G. Ilia et al.
FIGURE 2 The influence of the reaction time on the yield.
2) The use of an excess of dialkylphosphite is necessary due to saponi-
fication reactions.
3) The order of reagent addition is important.
4) The solvent is important.
Also, the system of a liquid–solid was used. Solid potassium carbonate
was used as a base. In these cases, side reactions were reduced to a
minimum because potassium carbonate is a weaker base.
In accordance with the general procedures, reactions were performed
with different aniline derivatives and hydrogen phosphites in liquid–
liquid and liquid–solid systems. The obtained results are presented in
Table II.
TABLE I The Influence of the Catalyst on the Yield
R
R1
Catalyst
Yields, %
C2H5
H
p-NO2
H
p-NO2
H
p-NO2
H
p-NO2
TBAC
TBAC
TBAC
TBAC
TBAB
TBAB
TBAB
TBAB
71
57
70
55
78
65
75
62
C4H9
C2H5
C4H9
TBAC(B) = tetrabutylammonium chloride (bromide).

Phosporylation of Anilines
1721
TABLE II Results Obtained in the Phosphorylation of Aniline
Derivatives
31P
Method A Method B Method C NMR,a
Synth
R
R1
Yield, %
Yield, %
Yield, % δ, ppm
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
H
p-NO2
H
p-NO2
H
p-NO2
H
p-NO2
H
p-NO2
H
p-NO2
H
p-NO2
H
78 (777)
65
43 (357)
—
81
70
78
69
68
59
74
67
70
57
71
56
67
50
63
54
2.35
0.55
3.00
1.27
2.57
1.10
2.78
0.72
2.90
C2H5
C4H9
75
62
62
56
72
58
64
51
62
53
46
38
40
—
38
—
39
—
37
—
36
—
50
—
41
—
i-C4H9
C10H21
i-C8H17
CH3(CH2)3CH(C2H5)CH2
C6H5
0.83
3.40
0.91
−17.70
−17.74
2.55
48 (407)
40
C6H5 CH2
p-NO2
0.67
a31P NMR spectra were performed with Bruker Avance DRX 400 and were measured
in a CDCl3 solution using 85% H3PO4 as an external standard.
As is shown in the Table II, Method B led to the lowest yields. Phos-
phoramidates obtained by Methods A and C are formed in good yields.
The best results were obtained when potassium carbonate was used as
base. In these cases, side reactions were strongly reduced. Even alkyl
phosphites with longer chains were used, and the yields were higher.
No partial dealkylation was detected for these phosphites.
A mechanism for this method is proposed (Scheme 1).
SCHEME 1
The cation of the catalyst transfers the anion of the base in the or-
ganic media, where it reacts with the hydrochloric acid.

1722
G. Ilia et al.
The outlined synthetic procedures are particularly convenient for ob-
taining a wide range of phosphoramidates, especially using Method C,
which is the simplest and easy to perform.
EXPERIMENTAL
Method A
A solution of dialkylphosphite (0.011 moles) and the corresponding
amine (0.01 moles) in an appropriate solvent (5 mL) (dichloromethane
when aniline was used and ethyl acetate when nitroanilines were
used) was added dropwise to a stirred two-phase system consisting
of dichloromethane (5 mL), tetrachloromethane (5 mL), 25% aqueous
sodium hydroxide (5 mL), and a catalyst (0.02 g). The temperature
was kept at 0–10◦C by external cooling. After the addition was com-
pleted, stirring was continued for 1 h at 0–10◦C and then for another
2 h at r.t. The organic layer was separated, washed with 3% hydrochlo-
ric acid (2× 10 mL) and water (2 × 10 mL), and dried over anhydrous
magnesium sulfate, and the solvent evaporated.
Method B
A solution of 25% aqueous sodium hydroxide (5 mL) was added drop-
wise to a stirred and cooled (0–10◦C) mixture of dialkylphosphite (0.011
moles), corresponding amine hydrochloride (0.01 moles), an appropri-
ate solvent (5 mL) (dichloromethane when aniline was used and ethyl
acetate when nitoanilines were used), tetrachloromethane (5 mL), and
a catalyst (0.02 g). After the addition was completed, stirring was con-
tinued for 1 h at 0–10◦C and then for another 3 h at r.t. The organic
layer was separated, washed with 3% hydrochloric acid (2× 10 mL) and
water (2× 10 mL), and dried over anhydrous magnesium sulfate, and
the solvent evaporated.
Method C
A solution of dialkylphosphite (0.01 moles) and the corresponding
amine (0.01 moles) in an appropriate solvent (5 mL) (dichloromethane
when aniline was used and ethyl acetate when nitroanilnes were
used) was added dropwise to a stirred two-phase system consisting
of dichloromethane (5 mL), tetrachloromethane (5 ml), potassium car-
bonate (3 g), and a catalyst (0.02 g). The temperature was kept at 0–
10◦C by external cooling. After the addition was been completed, stir-
ring was continued for 1 h at 0–10◦C and then for another 3 h at r.t.

Phosporylation of Anilines
1723
The potassium carbonate and potassium chloride were filtered, and the
organic layer was separated, washed with 3% hydrochloric acid (2×
10 mL) and water (2× 10 mL), and dried over anhydrous magnesium
sulfate, and the solvent evaporated.
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