Synthesis of new phosphonoamide and phosphonocaprolactam derivatives via the diethyl chlorophosphate-promoted beckmann rearrangement of γ-phosphonyloximes

Article abstract of DOI:10.1002/hc.21273

ABSTRACT: Herein, we report an efficient and straightforward synthesis of new phosphonoamide and phosphonocaprolactam derivatives, via the Beckmann rearrangement of γ-phosphonyloximes. The reaction proceeded smoothly in the presence of diethyl chlorophosp

Full text of DOI:10.1002/hc.21273

Heteroatom Chemistry
Volume 26, Number 6, 2015
Synthesis of New Phosphonoamide and
Phosphonocaprolactam Derivatives via the
Diethyl Chlorophosphate-Promoted Beckmann
Rearrangement of γ -Phosphonyloximes
Aymen Wahbi and Soufiane Touil
Laboratory of Heteroatom Organic Chemistry, Faculty of Sciences of Bizerte, University of
Carthage, 7021 Jarzouna, Tunisia
Received 21 March 2015; revised 12 May 2015
recognized as key intermediates for the synthesis
ABSTRACT: Herein, we report an efficient and
of amines [6], amides [7], nitriles [8], nitro com-
straightforward synthesis of new phosphonoamide
pounds [9], and azaheterocycles [10].
and phosphonocaprolactam derivatives, via the Beck-
The introduction of a phosphoryl group on
mann rearrangement of γ -phosphonyloximes. The re-
oximes may be very interesting for the enhancement
action proceeded smoothly in the presence of diethyl
of the biological and complexing properties of these
chlorophosphate as a promoter, to afford the title com-
molecules, and for synthetic transformations lead-
pounds in satisfactory yields. A mechanistic rational-
ing to phosphonylated amines, amides, and azahete-
ization for this reaction is provided allowing for the
rocycles, which are known to exhibit a variety of
ꢀC
prediction of its regiochemistry.
2015 Wiley Peri-
pharmacological properties [11,12].
odicals, Inc. Heteroatom Chem. 26:397–404, 2015;
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hc.21273
In view of the above, and in the continuation of
our studies on the synthetic applications of phospho-
nyl ketones [13–16], we report here for the first time
the synthesis of γ -phosphonyloximes from the base-
catalyzed reaction of hydroxylamine hydrochloride
with γ -ketophosphine oxides.
INTRODUCTION
Furthermore, and to explore the synthetic util-
ity of these oximes, we have investigated their
behavior in the Beckmann rearrangement, which
could represent an easy and direct access to novel
types of phosphonoamide and phosphonocaprolac-
tam derivatives with potential biological or techno-
logical importance. Indeed, phosphonoamides are
well known for their promising applications as an-
tibacterial, insecticidal, or acaricidal agents [17–
19]. Some of them are also useful as antiwear and
friction-reducing additives for lubricants and liquid
hydrocarbon fuels [20] and as plasticizer agents [21].
On the other hand, phosphonocaprolactams have
found uses as modifying additives in the synthe-
sis of phosphorus-containing polyamide-6, which
An increasing interest has been paid for several
years to the synthesis of oximes. Such interest has
been stimulated by their promising applications as
antimicrobial [1], anticancer [2], antioxidant [3],
and vasodilator [4] agents. Certain oxime deriva-
tives have also found applications in coordination
chemistry especially as uranium extractants [5]. On
the other hand, oximes and their derivatives are
Correspondence to: Soufiane Touil; e-mail: soufiane.touil@
fsb.rnu.tn.
Contract grant sponsor: Tunisian Ministry of Higher Education
and Scientific Research.
ꢀC
2015 Wiley Periodicals, Inc.
397

398 Wahbi and Touil
2
2
O
P
O
R
R
3
KOH
3
R
Ph
R
Ph P
2
2
HO-NH , HCl
+
2
EtOH, reflux, 24 h
1
1
O
R
N
R
OH
2
1
SCHEME 1 Synthesis of γ -phosphonyloximes 2.
TABLE 1 Substrate Scope for the Synthesis of Compounds 2
Entry
R1
R2
R3
Product
Yield (%)a
δ
31P (Z)b,c
δ
31P (E)
% Zd
% Ed
1
2
Ph
Ph
H
H
Me
Ph
2a
2b
84
71
34.3
35.7
34.2
34.3
44
17
56
83
3
H
Me
2c
69
33.4
33.0
43
57
4
H
Me
2d
73
33.2
33.6
42
58
5
6
Ph
(CH2)4
2e
2f
68
81
30.6
34.6
32.9
34.2
38
47
62
53
*
*
H
*R1 and R3: (CH2)3.
aIsolated yield.
b121.5 MHz, CDCl3.
cδ in ppm.
d Determined from the 31P NMR spectra.
possesses improved flame retardancy as well as im-
proved thermo- and thermooxidative resistance [22].
ochemistry of imines, hydrazones, and oximes, the
carbon adjacent to the C=N double bond resonates
at higher field when it is in the syn position to the
group on the nitrogen atom (OH in our case).
In all cases, E isomers were the predominant
forms probably due to the steric hindrance between
the phosphonoethyl and hydroxyl groups, which
destabilizes the Z isomers.
With these oxime derivatives in hand, we next fo-
cused our efforts to investigate their behavior in the
Beckmann rearrangement to obtain new phospho-
noamide and phosphonocaprolactam derivatives,
which could have promising applications as precur-
sors of new phosphorus-containing polymers.
To optimize the reaction conditions for the
formation of the target compounds, we used γ -
phosphonyloxime 2a as a model substrate. The re-
action was studied with various promoters. The
results of these comparative experiments are sum-
marized in Table 2. It was found that performing
the model reaction using protonic and Lewis acids
as promoters did not yield the desired products but
this left the starting materials intact even after pro-
longed heating under reflux (Table 2, entries 1–6).
Also tested was the use of sulfonyl- and acyl chlo-
rides such as chlorosulfonic acid, tosyl-, and acetyl
RESULTS AND DISCUSSION
The starting γ -ketophosphine oxides
1
were
easily prepared from the reaction of P-
chlorodiphenylphosphine with α,β-unsaturated
ketones in refluxing acetic acid, according to the
reported procedure [23]. It was found that the
reaction of compounds 1 with hydroxylamine
hydrochloride, performed in refluxing ethanol, for
24 h, in the presence of an equimolar amount of
potassium hydroxide, led to γ -phosphonyloximes 2
(Scheme 1). The isolated yield of the reaction ranges
from 68 to 81% (Table 1).
Compounds 2 were characterized on the basis
of their IR, NMR (1H, 31P, 13C), and mass spectral
data, which indicate that they are obtained as a mix-
ture of Z and E isomers. Their relative proportions
were estimated from the 31P NMR spectra where a
singlet for each isomer is present (Table 1). The Z
and E configurations were assigned on the basis of
the 13C chemical shifts of carbons in α position with
respect to the C=N double bond. Indeed, according
to some literature data [24–28] concerning the stere-
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of New Phosphonoamide and Phosphonocaprolactam Derivatives 399
TABLE 2 Optimization of the Reaction Conditions
Entry
1
2
3
4
5
6
7
8
Promoter (1 equiv)
H2SO4
H2SO4
TsOH
H3NSO3
TsOH/ZnCl2
TsOH/ZnCl2
TsCl/ZnCl2
ClSO3H
AcCl
(EtO)2P(O)Cl
Solvent
H2O
Toluene
Toluene
MeCN
MeCN
1,4-Dioxane
MeCN
Temperature
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Time (h)a
Yield (%)b
24
24
24
24
24
24
24
24
24
2
0
0
0
0
0
0
5
10
14
52
Toluene
Toluene
Toluene
9
10
aThe progress of the reactions was monitored by TLC.
bOverall yield.
chloride, but lower than 14% overall yield was ob-
tained after refluxing the mixture for long periods of
time (Table 2, entries 7–9). A net improvement in the
yield was observed when using diethyl chlorophos-
phate as a promoter, in refluxing toluene, for 2 h. The
reaction furnished a mixture of two regioisomers 3a
and 3ꢀa in 52% overall yield (Table 2, entry 10).
With optimized reaction conditions in hand, we
next studied the scope of this methodology. A vari-
ety of structurally diverse γ -phosphonyloximes were
investigated, and a series of new phosphonoamide
(3a-d and 3ꢀa-d) and phosphonocaprolactam (3e,f
and 3ꢀe,f) derivatives were afforded in satisfactory
yields. In all cases, the reaction furnished a mixture
of two regioisomers 3 and 3’ in an approximate 3:1
ratio (Table 3).
A mechanistic rationalization for this reaction is
provided in Scheme 2. In this proposed mechanism,
the role of diethyl chlorophosphate is the conversion
of the oxime OH into a good leaving group via a
substitution reaction on the phosphorus atom. The
departure of this leaving group and the migration of
the organyl substituent on the C=N double bond to
the nitrogen atom then take place during a concerted
process; it is thus the organyl substituent anti to the
leaving group that migrates, resulting in a nitrilium
ion, which is converted into the final amide product,
during the basic hydrolysis.
the product ratio (3:3ꢀ) did not reflect exactly the
equilibrium distribution of the starting isomers
(E-2:Z-2). This can be explained taking into ac-
count the Curtin–Hammett principle. The Z-2/E-2
equilibrium, required for this principle, was eas-
ily confirmed by performing 31P NMR experiments
of oximes 2 at higher temperature and observing
changes in the Z/E ratio.
The proposed reaction mechanism was corrob-
orated by collecting an IR spectrum on the reac-
tion mixture (relative to oxime 2a) prior to the ba-
sic hydrolysis. The obtained spectrum revealed the
presence of an absorption band at 2296 cm−1 corre-
sponding to the proposed nitrilium intermediate.
In summary, we have successfully developed an
efficient and straightforward synthesis of new phos-
phonoamide and phosphonocaprolactam deriva-
tives via the diethyl chlorophosphate-promoted
Beckmann rearrangement of γ -phosphonyloximes.
The synthesized compounds could have promis-
ing applications as precursors of new phosphorus-
containing polymers, which are known for their
improved flame retardancy as well as improved
thermo- and thermooxidative resistance. These stud-
ies are ongoing in our laboratory and will be reported
in due course.
EXPERIMENTAL
This anti [1,2]-shift allows for the prediction
of the regiochemistry of this reaction and explains
the obtention of a mixture of two regioisomers
3 and 3ꢀ with the major isomer 3 arising from
the predominant E-stereoisomer of the starting γ -
phosphonyloxime. It is important to note here that
1H, 31P, and 13C NMR spectra were recorded with
CDCl3 as the solvent, on a Bruker AC-300 spectrom-
1
eter operating at 300.1 MHz for H, 121.5 MHz for
31P, and 75.5 MHz for 13C. The chemical shifts are
reported in ppm relative to TMS (internal reference)
Heteroatom Chemistry DOI 10.1002/hc

400 Wahbi and Touil
TABLE 3 Substrate Scope for the Synthesis of Compounds 3 and 3’
Entry
R1
R2
R3
Product
Yield (%)a
δ
31P(3)bb,c
δ
31P(3’)
% (3/3ꢀ)d
1
2
Ph
Ph
H
H
Me
Ph
3a + 3ꢀa
52
51
33.0
33.3
32.8
35.1
63/37
73/27
3b + 3ꢀb
3
H
Me
3c + 3ꢀc
3d + 3ꢀd
61
32.3
33.6
78/22
4
H
Me
68
32.2
32.2
74/26
5
6
Ph
(CH2)4
3e + 3ꢀe
3f + 3ꢀf
67
71
30.3
36.6
32.4
34.1
90/10
69/31
*
*
H
*R1 and R3: (CH2)3.
aIsolated overall yield.
b121.5 MHz, CDCl3.
cδ in ppm.
d Determined from the 31P NMR spectra of the crude product.
for 1H and 13C NMR and relative to 85% H3PO4 (ex-
ternal reference) for 31P NMR. The coupling con-
stants are reported in hertz. The multiplicities of sig-
nals are indicated by the following abbreviations: s,
singlet; d, doublet; t, triplet; m, multiplet. For the 13C
NMR data of aromatic carbons, the signals are listed
as they appear on the spectrum. Mass spectra were
determined on a Voyager DE STR spectrometer un-
der MALDI ionization conditions. Elemental analy-
ses (C, H, N) were performed on a CE440 elemen-
tal analyzer. IR spectra were recorded on a Nicolet
IR200 spectrometer. The progress of the reactions
was monitored by TLC. Purification of products was
performed by column chromatography using silica
gel 60 (Fluka).
der vacuum. The product obtained was washed with
petroleum ether.
1
2a: White solid; mp = 96–98°C; H NMR: δ =
1.27 (s, 3H, CH3–C=N, Z); 1.52 (s, 3H, CH3–C=N,
E); 2.71–3.09 (m, 2H, CH2–C=N); 3.84–3.92 (m, 1H,
CH-P, E); 4.13–4.21 (m, 1H, CH-P, Z); 6.88–8.01 (m,
15H, arom-H); 9.39 (br s, 1H, OH, E); 9.77 (br s, 1H,
OH, Z); 13C NMR: δ = 14.3 (s, CH3–C=N, E); 21.8 (s,
CH3–C=N, Z); 30.3 (s, CH2–C=N, Z); 35.5 (s, CH2–
C=N, E); 42.0 (d, 1JCP = 67.2, CH-P, Z); 44.0 (d, 1JCP
=
67.2, CH-P, E); 154.8 (d, 3JCP = 14.3, C=N, Z); 155.6
3
(d, JCP = 14.3, C=N, E); aryl carbons: 125.1, 125.4,
125.6, 125.7, 125.9, 126.1, 126.3, 126.5, 126.7, 126.8,
127.1, 127.3, 128.1, 128.9, 129.3, 129.9, 130.7, 130.9,
131.0, 131.2, 131.3, 131.5, 131.8, 131.9, 132.0, 132.6,
134.9, 135.1, 135.2, 135.7, 136.0, 136.6, 136.9, 138.0,
138.7, 139.5, 141.0, 141.1, 141.5, 141.7; IR (neat):
υP=O = 1270 cm−1; υC=N = 1662 cm−1; υOH = 3241
cm−1; MALDI-MS: m/z = 364.060 ([M + H]+).
General Procedure for the Synthesis of
γ -Phosphonyloximes 2
1
2b: White solid; mp = 96–99°C; H NMR: δ =
To a mixture of hydroxylamine hydrochloride (0.01
mol, 0.695 g), potassium hydroxide (0.01 mol, 0.561
g), and dry ethanol (30 mL), a solution of γ -
ketophosphine oxide 1 [23] (0.01 mol, e.g., 1a: 3.484
g) was added dropwise with stirring, at 25°C, in dry
ethanol (20 mL). The reaction mixture was then
heated under reflux for 24 h. After cooling, the
solvent was removed under reduced pressure. The
residue obtained was diluted with CHCl3 (40 mL)
and washed with water (2×20 mL). The organic
phase was dried over Na2SO4 and concentrated un-
3.21–3.65 (m, 2H, CH2–C=N); 4.15–4.23 (m, 1H, CH-
P, E); 4.38–4.45 (m, 1H, CH-P, Z); 6.86–8.01 (m, 20H,
arom-H); 10.26 (br s, 1H, OH); 13C NMR: δ = 38.9 (s,
CH2–C=N, E); 41.1 (d, 1JCP = 54.3, CH-P, Z); 42.6 (d,
1JCP = 59.6, CH-P, E); 44.0 (s, CH2–C=N, Z); 155.7 (d,
3JCP = 12.8, C=N, Z); 155.8 (d, 3JCP = 12.8, C=N, E);
aryl carbons: 126.5, 127.0, 127.1, 127.9, 128.1, 128.4,
128.6, 128.7, 128.9, 129.0, 129.1, 129.4, 129.5, 129.6,
129.7, 129.8, 129.9, 130.0, 130.1, 130.2, 130.4, 130.5,
130.7, 130.8, 130.9, 131.0, 131.2, 131.5, 131.6, 131.7,
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of New Phosphonoamide and Phosphonocaprolactam Derivatives 401
3
3
R
R
O
H
O
O
C
N
C
N
Ph P-CH-CH
2
Ph P-CH-CH
2
O
H
(E)-2
1
2
1
2
(Z)-2
R
R
R
R
O
O
(EtO) P-Cl
-HCl
2
(EtO) P-Cl
2
-HCl
O
3
3
R
R
O
P(OEt)
2
O
O
C
N
O
C
N
Ph P-CH-CH
2
Ph P-CH-CH
2
O
P(OEt)
2
1
1
2
2
R
R
R
R
O
O
+
+
3
3
3
Ph P-CH-CH
N
R
N
R
Ph P-CH-CH
2
2
1
1
2
2
R
R
R
R
NaOH/H
O
H
NaOH/H
O
2
3
2
O
O
R
O
Ph P-CH-CH
N
Ph P-CH-CH
2
2
R
N
1
2
1
2
R
R
R
R
O
H
2
O
2
R
O
O
R
H
N
Ph P
2
+
3
Ph P
3
R
2
R
N
H
1
1
R
O
R
3' (min)
SCHEME 2 Proposed mechanism for the synthesis of compounds 3 and 3ꢀ.
3(maj)
131.9, 132.1, 132.5, 133.1, 133.3, 133.5, 133.7, 133.8,
133.9, 134.0, 134.2, 134.8, 134.9, 136.2; IR (neat):
υP=O = 1276 cm−1; υC=N = 1650 cm−1; υOH = 3211
cm−1; MALDI-MS: m/z = 426.087 ([M + H]+).
131.7, 131.8, 132.0, 132.1, 132.2, 136.5, 136.6, 136.8,
136.9; IR (neat): υP=O = 1283 cm−1; υC=N = 1674
cm−1; υOH = 3230 cm−1; MALDI-MS: m/z = 370.035
([M + H]+).
1
1
2c: Brown solid; mp = 92–94°C; H NMR: δ =
2d: Brown solid; mp = 90–92°C; H NMR: δ =
1.41 (s, 3H, CH3–C=N, Z); 1.65 (s, 3H, CH3–C=N,
E); 2.67–3.19 (m, 2H, CH2–C=N); 4.31–4.44 (m, 1H,
CH-P, E); 4.53–4.61 (m, 1H, CH-P, Z); 6.70–8.14 (m,
13H, arom-H); 9.83 (br s, 1H, OH, E); 10.07 (br s,
1H, OH, Z); 13C NMR: δ = 14.3 (s, CH3–C=N, E);
21.8 (s, CH3–C=N, Z); 31.6 (s, CH2–C=N, Z); 36.6 (s,
CH2–C=N, E); 37.4 (d, 1JCP = 69.4, CH-P, Z); 39.2 (d,
1JCP = 68.7, CH-P, E); 154.0 (d, 3JCP = 14.3, C=N, E);
1.40 (s, 3H, CH3–C=N, Z); 1.61 (s, 3H, CH3–C=N,
E); 2.63–3.02 (m, 2H, CH2–C=N); 4.12–4.29 (m, 1H,
CH-P, E); 4.33–4.45 (m, 1H, CH-P, Z); 6.00–7.92 (m,
13H, arom-H); 9.93 (br s, 1H, OH, E); 10.02 (br s,
1H, OH, Z); 13C NMR: δ = 13.9 (s, CH3–C=N, E);
21.0 (s, CH3–C=N, Z); 28.4 (s, CH2–C=N, Z); 33.6 (s,
CH2–C=N, E); 36.8 (d, 1JCP = 68.7, CH-P, Z); 38.4 (d,
1JCP = 69.4, CH-P, E); 155.2 (d, 3JCP = 12.1, C=N, Z);
3
3
155.5 (d, JCP = 12.8, C=N, Z); aryl carbons: 124.6,
154.0 (d, JCP = 13.6, C=N, E); aryl carbons: 108.9,
124.9, 125.0, 126.7, 126.8, 127.6, 127.7, 127.8, 127.9,
128.0, 128.1, 128.6, 128.7, 128.9, 130.0, 130.1, 130.2,
130.3, 130.9, 131.0, 131.1, 131.3, 131.4, 131.5, 131.6,
109.4, 109.5, 109.6, 110.7, 110.8, 110.9, 128.0, 128.1,
128.2, 128.3, 128.5, 128.6, 128.7, 129.7, 130.2, 130.8,
130.9, 131.0, 131.2, 131.3, 131.4, 131.6, 131.8, 132.0,
Heteroatom Chemistry DOI 10.1002/hc

402 Wahbi and Touil
132.1, 132.7, 132.9, 133.0, 141.5, 141.6, 141.8, 141.9;
chromatographed on silica gel column using a mix-
ture of ether and hexane 1:1 as an eluent.
IR (neat): υP=O = 1279 cm−1; υC=N = 1658 cm−1
;
υOH = 3255 cm−1; MALDI-MS: m/z = 354.028 ([M +
3a: Yellow solid; mp = 161–163°C; 1H NMR: δ =
1.66 (s, 3H, CH3–C=O); 3.80–3.98 (m, 2H, CH2–NH);
4.06–4.12 (m, 1H, CH-P); 7.05–7.88 (m, 15H, arom-
H); 7.95 (br s, 1H, NH); 13C NMR: δ = 21.5 (s, CH3–
H]+).
1
2e: Yellow solid; mp = 100–102°C; H NMR: δ
= 1.14–3.85 (m, 10H, cyclic-H and CH-P); 6.96–8.12
(m, 15H, arom-H); 9.95 (br s, 1H, OH, Z); 10.18 (br
s, 1H, OH, E); 13C NMR: δ = 20.3 (s, (CH2)2–CH2–
CH2–C=N, Z); 21.7 (s, (CH2)2–CH2–CH2–C=N, E);
22.7 (s, (CH2)3–CH2–C=N, E); 23.3 (s, (CH2)3–CH2–
C=N, Z); 24.9 (s, CH2–CH2–(CH2)2–C=N, E); 25.9
1
C=O); 35.4 (s, CH2–NH); 43.4 (d, JCP = 67.2, CH-
P); 170.9 (s, NH–C=O); aryl carbons: 127.2, 127.6,
128.1, 128.3, 128.7, 128.9, 129.7, 129.9, 130.8, 131.0,
131.2, 131.4, 131.6, 131.8, 132.1, 132.5, 132.8, 133.2,
133.4, 134.5; IR (neat): υP=O = 1276 cm−1; υC=O
=
1
1670 cm−1; υNH = 3447 cm−1; MALDI-MS: m/z =
364.026 ([M + H]+); elemental analysis calcd (%) for
C22H22NO2P: C 72.71, H 6.10, N 3.85; found: C 72.80,
H 6.17, N 3.79.
(s, CH2–CH2– (CH2)2–C=N, Z); 30.8 (d, JCP = 82.3,
CH-P, E); 41.2 (s, CH–C=N, E); 42.2 (d, 1JCP = 70.2,
CH-P, Z); 43.2 (s, CH–C=N, Z); 43.6 (s, CH2–(CH2)3–
3
3
C=N); 156.9 (d, JCP = 12.1, C=N, Z); 157.9 (d, JCP
= 12.1, C=N, E); aryl carbons: 125.9, 126.2, 126.6,
127.1, 127.3, 127.5, 127.6, 127.7, 127.9, 128.0, 128.2,
128.3, 130.1, 130.2, 130.3, 130.4, 130.5, 130.6, 130.7,
130.9, 131.1, 131.2, 131.3, 132.3, 132.7, 133.5, 133.9,
1
3b: White solid; mp = 208–210°C; H NMR: δ
= 3.93–4.26 (m, 2H, CH2–NH); 4.40–4.45 (m, 1H,
CH-P); 7.14–8.01 (m, 20H, arom-H); 10.28 (br s, 1H,
1
NH); 13C NMR: δ = 41.4 (s, CH2–NH); 45.0 (d, JCP
135.0, 136.6; IR (neat): υP=O = 1281 cm−1; υC=N
=
= 67.2, CH-P); 167.7 (s, NH–C=O); aryl carbons:
123.4, 126.9, 127.4, 128.0, 128.2, 128.6, 128.9, 129.1,
129.7, 130.4, 130.9, 131.1, 131.3, 131.5, 131.9, 132.1,
132.5, 132.9, 133.7, 134.0, 135.0, 135.8, 136.4, 139.0;
1654 cm−1; υOH = 3270 cm−1; MALDI-MS: m/z =
404.081 ([M + H]+).
2f: Yellow solid; mp = 99–101°C; 1H NMR: δ
= 1.61–3.45 (m, 9H, cyclic-H); 7.40–8.81 (m, 10H,
arom-H); 10.13 (br s, 1H, OH, Z); 10.28 (br s, 1H,
OH, E); 13C NMR: δ = 22.5 (s, CH2–CH2–CH2–C=N);
23.8 (s, (CH2)2–CH2–C=N, Z); 24.1 (s, (CH2)2–CH2–
C=N, E); 25.2 (s, CH2–(CH2)2–C=N, E); 26.7 (s, CH2–
(CH2)2–C=N, Z); 30.2 (s, CH–CH2–C=N, Z); 31.5 (s,
IR (neat): υP=O = 1266 cm−1; υC=O = 1667 cm−1
;
υNH = 3309 cm−1; MALDI-MS: m/z = 426.051 ([M +
H]+); elemental analysis calcd (%) for C27H24NO2P:
C 76.22, H 5.69, N 3.29; found: C 76.36, H 5.81, N
3.16.
3c: Brown solid; mp = 177–178°C; 1H NMR: δ =
1.70 (s, 3H, CH3–C=O); 3.80–3.99 (m, 2H, CH2–NH);
4.50–4.64 (m, 1H, CH-P); 6.70–8.04 (m, 13H, arom-
H); 5.50 (br s, 1H, NH); 13C NMR: δ = 22.8 (s, CH3–
1
CH–CH2–C=N, E); 36.1 (d, JCP = 72.5, CH-P, Z);
37.4 (d, 1JCP = 72.5, CH-P, E); 157.2 (d, 3JCP = 12.8,
3
C=N, E); 157.5 (d, JCP = 14.3, C=N, Z); aryl car-
1
bons: 128.6, 128.8, 129.0, 129.1, 130.1, 130.2, 130.5,
130.7, 130.8, 130.9, 131.0, 131.1, 131.4, 131.7, 131.8,
C=O); 41.6 (s, CH2–NH); 40.3 (d, JCP = 67.9, CH-
P); 171.1 (s, NH–C=O); aryl carbons: 124.9, 126.6,
126.8, 127.5, 127.7, 128.1, 128.3, 128.9, 130.5, 130.7,
130.9, 131.2, 131.5, 131.9, 132.3, 132.7, 133.7, 134.5,
131.9, 132.0, 132.1; IR (neat): υP=O = 1177 cm−1
;
υC=N = 1660 cm−1; υOH = 3188 cm−1; MALDI-MS:
m/z = 314.017 ([M + H]+).
135.8, 137.0; IR (neat): υP=O = 1269 cm−1; υC=O
=
1687 cm−1; υNH = 3297 cm−1; MALDI-MS: m/z =
369.987 ([M + H]+); elemental analysis calcd (%)
for C20H20NO2PS: C 65.02, H 5.46, N 3.79; found: C
65.19, H 5.55, N 3.60.
General Procedure for the Synthesis of
Phosphonoamides and Phosphonocaprolactams
3 and 3ꢀ
1
3d: Brown solid; mp = 195–197°C; H NMR: δ
= 2.24 (s, 3H, CH3–C=O); 3.87–4.09 (m, 2H, CH2–
NH); 4.27–4.44 (m, 1H, CH-P); 5.80 (br s, 1H, NH);
6.08–7.86 (m, 13H, arom-H); 13C NMR: δ = 21.5 (s,
CH3–C=O); 35.9 (d, 1JCP = 70.2, CH-P); 40.8 (s, CH2–
NH); 172.9 (s, NH–C=O); aryl carbons: 108.7, 109.3,
110.8, 117.8, 126.6, 128.1, 128.3, 128.5, 128.8, 129.0,
129.4, 129.8, 130.4, 131.1, 131.4, 131.6, 131.9, 132.7,
The γ -phosphonyloxime 2 (5 mmol, e.g. 2a: 1.817
g) and toluene (1 mL) were charged into a 50-mL
two-necked round-bottomed flask equipped with a
magnetic stirrer, under nitrogen atmosphere. The
reaction was heated to reflux with stirring, and di-
ethyl chlorophosphate (5 mmol, 0.863 g) was added
dropwise to the mixture. Stirring was continued for
2 h under reflux. After cooling to room temperature,
a 5% aqueous NaOH solution (10 mL) was added
and the mixture was extracted with CHCl3 (10 mL).
The organic phase was dried over Na2SO4 and con-
centrated under vacuum. The crude obtained was
137.8, 140.4; IR (neat): υP=O = 1290 cm−1; υC=O
=
1670 cm−1; υNH = 3419 cm−1; MALDI-MS: m/z =
354.003 ([M + H]+); elemental analysis calcd (%) for
C20H20NO3P: C 67.98, H 5.70, N 3.96; found: C 68.17,
H 5.83, N 3.78.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of New Phosphonoamide and Phosphonocaprolactam Derivatives 403
3e: Yellow solid; mp = 221–223°C; 1H NMR: δ =
C 76.22, H 5.69, N 3.29; found: C 76.30, H 5.86, N
3.18.
1.16–3.15 (m, 8H, cyclic-H); 3.52–3.57 (m, 1H, CH-
P); 3.85 (br s, 1H, NH); 3.95–4.02 (m, 1H, CH–NH);
7.03-7.84 (m, 15H, arom-H); 13C NMR: δ = 21.8 (s,
CH2–CH2–(CH2)2–C=O); 28.1 (s, (CH2)2–CH2– CH2–
C=O); 32.3 (s, CH2– (CH2)3–C=O); 35.5 (s, (CH2)3–
CH2–C=O); 49.5 (d, 1JCP = 67.2, CH-P); 53.8 (s, CH–
NH); 175.8 (s, NH–C=O); aryl carbons: 124.4, 124.8,
125.4, 125.8, 126.0, 126.9, 127.1, 127.5, 127.8, 128.9,
129.8, 130.0, 130.3, 130.5, 131.5, 133.0, 133.7, 134.0,
1
3ꢀc: Brown solid; mp = 258–260°C; H NMR: δ
= 1.97 (s, 3H, CH3–NH); 2.48–3.00 (m, 2H, CH2–
C=O); 3.42–3.63 (m, 1H, CH-P); 7.05–7.88 (m, 13H,
arom-H); 9.80 (br s, 1H, NH); 13C NMR: δ = 26.1 (s,
CH3–NH); 35.5 (d, 1JCP = 70.9, CH-P); 38.5 (s, CH2–
C=O); 170.3 (d, 3JCP = 14.3, O=C–NH); aryl carbons:
124.7, 125.1, 126.6, 127.3, 127.6, 128.0, 128.2, 128.8,
130.1, 130.6, 130.8, 131.1, 131.3, 131.8, 132.1, 132.6,
132.9, 133.9, 135.7, 136.9; IR (neat): υP=O = 1269
cm−1; υC=O = 1671 cm−1; υNH = 3222 cm−1; MALDI-
MS: m/z = 369.990 ([M + H]+); elemental analysis
calcd (%) for C20H20NO2PS: C 65.02, H 5.46, N 3.79;
found: C 65.14, H 5.58, N 3.64.
135.7, 136.7; IR (neat): υP=O = 1266 cm−1; υC=O
=
1668 cm−1; υNH = 3406 cm−1; MALDI-MS: m/z =
404.065 ([M + H]+); elemental analysis calcd (%) for
C25H26NO2P: C 74.42, H 6.50, N 3.47; found: C 74.48,
H 6.59, N 3.36.
1
3ꢀd: Brown solid; mp = 285–287°C; H NMR: δ
1
3f: Yellow solid; mp = 148–149°C; H NMR: δ
= 2.31 (s, 3H, CH3–NH); 2.76–2.90 (m, 2H, CH2–
C=O); 3.22–3.43 (m, 1H, CH-P); 3.80 (br s, 1H, NH);
6.08–7.86 (m, 13H, arom-H); 13C NMR: δ = 30.2 (s,
CH3–NH); 34.4 (d, 1JCP = 70.2, CH-P); 40.8 (s, CH2–
C=O); 170.9 (d, 3JCP = 13.8, O=C–NH); aryl carbons:
107.7, 108.8, 110.7, 117.6, 125.3, 126.8, 128.2, 128.4,
128.7, 128.9, 129.1, 129.6, 130.1, 130.9, 131.2, 131.5,
131.7, 132.2, 134.1, 138.0; IR (neat): υP=O = 1290
cm−1; υC=O = 1670 cm−1; υNH = 3400 cm−1; MALDI-
MS: m/z = 354.006 ([M + H]+); elemental analysis
calcd (%) for C20H20NO3P: C 67.98, H 5.70, N 3.96;
found: C 68.15, H 5.88, N 3.70.
= 1.19–2.15 (m, 6H, cyclic-H); 3.02–3.17 (m, 1H,
CH-P); 4.30–4.62 (m, 2H, CH2–NH); 6.60 (br s, 1H,
NH); 7.00–7.84 (m, 10H, arom-H); 13C NMR: δ =
22.9 (s, CH2–CH2–CH2–C=O); 28.4 (s, CH2– (CH2)2–
1
C=O); 33.2 (d, JCP = 70.2, CH-P); 35.3 (s, (CH2)3–
CH2–C=O); 42.1 (s, CH2–NH); 178.2 (s, NH–C=O);
aryl carbons: 128.6, 128.9, 129.1, 129.3, 129.6, 129.9,
130.2, 130.4, 130.8, 131.0, 131.3, 131.6, 131.9, 132.1;
IR (neat): υP=O = 1268 cm−1; υC=O = 1661 cm−1
;
υNH = 3392 cm−1; MALDI-MS: m/z = 314.009 ([M +
H]+); elemental analysis calcd (%) for C18H20NO2P:
C 69.00, H 6.43, N 4.47; found: C 69.11, H 6.49, N
4.33.
3ꢀe: Yellow solid; mp = 264–265°C; 1H NMR: δ =
1.16–3.29 (m, 9H, cyclic-H); 3.66–3.69 (m, 1H, CH-
P); 3.86 (br s, 1H, NH); 7.03–7.84 (m, 15H, arom-H);
13C NMR: δ = 21.4 (s, CH2–CH2–(CH2)2–NH); 27.8 (s,
CH2– (CH2)3–NH); 31.0 (s, (CH2)2–CH2–CH2–NH);
3ꢀa: Yellow solid; mp = 188–190°C; 1H NMR: δ =
1.82 (s, 3H, CH3–NH); 2.75–2.99 (m, 2H, CH2–C=O);
3.06–3.13 (m, 1H, CH-P); 7.05–7.88 (m, 15H, arom-
H); 7.97 (br s, 1H, NH); 13C NMR: δ = 31.4 (s, CH3–
NH); 31.5 (s, CH2–C=O); 42.8 (d, 1JCP = 67.2, CH-P);
166.3 (d, 3JCP = 13.8, O=C–NH); aryl carbons: 127.5,
128.0, 128.2, 128.4, 128.8, 129.1, 129.8, 130.4, 130.9,
131.1, 131.3, 131.5, 131.7, 132.0, 132.2, 132.6, 133.1,
1
35.5 (d, JCP = 67.1, CH-P); 41.8 (s, (CH2)3–CH2–
NH); 53.7 (s, CH–C=O); 175.5 (d, 3JCP = 16.4, O=C–
NH); aryl carbons: 124.2, 124.6, 124.9, 125.6, 125.9,
126.7, 127.0, 127.4, 127.7, 127.9, 129.5, 129.9, 130.1,
130.4, 131.0, 132.2, 133.4, 133.9, 135.4, 135.8; IR
(neat): υP=O = 1266 cm−1; υC=O = 1660 cm−1; υNH
= 3300 cm−1; MALDI-MS: m/z = 404.069 ([M +
H]+); elemental analysis calcd (%) for C25H26NO2P:
C 74.42, H 6.50, N 3.47; found: C 74.55, H 6.64, N
3.41.
133.3, 133.7, 134.6; IR (neat): υP=O = 1276 cm−1
;
υC=O = 1669 cm−1; υNH = 3284 cm−1; MALDI-MS:
m/z = 364.029 ([M + H]+); elemental analysis calcd
(%) for C22H22NO2P: C 72.71, H 6.10, N 3.85; found:
C 72.82, H 6.23, N 3.73.
3ꢀb: White solid; mp = 248–250°C; 1H NMR: δ =
3.02–3.09 (m, 2H, CH2–C=O); 3.71–3.75 (m, 1H, CH-
P); 7.14–8.01 (m, 20H, arom-H); 10.28 (br s, 1H, NH);
13C NMR: δ = 36.9 (s, CH2–C=O); 42.5 (d, 1JCP = 69.4,
CH-P); 168.7 (d, 3JCP = 15.8, O=C–NH); aryl carbons:
119.6, 126.3, 127.1, 127.5, 128.1, 128.3, 128.8, 129.0,
129.2, 129.8, 130.8, 131.0, 131.2, 131.4, 131.7, 132.0,
132.4, 132.6, 133.4, 133.9, 134.9, 135.8, 135.9, 138.8;
3ꢀf: Yellow solid; mp = 271–273°C; 1H NMR: δ =
1.19–3.30 (m, 8H, cyclic-H); 3.82–4.17 (m, 1H, CH-
P); 6.50 (br s, 1H, NH); 7.00–7.84 (m, 10H, arom-H);
13C NMR: δ = 22.7 (s, CH2–CH2–CH2–NH); 29.4 (s,
CH2–(CH2)2–NH); 35.8 (s, (CH2)3–CH2–NH); 39.9 (d,
1JCP = 67.2, CH-P); 41.9 (s, CH2–C=O); 176.4 (d, 3JCP
= 18.9, O=C–NH); aryl carbons: 128.4, 128.7, 129.0,
129.2, 129.4, 129.8, 130.0, 130.3, 130.7, 130.9, 131.1,
IR (neat): υP=O = 1266 cm−1; υC=O = 1687 cm−1
;
131.5, 131.8, 132.0; IR (neat): υP=O = 1268 cm−1
;
υNH = 3271 cm−1; MALDI-MS: m/z = 426.057 ([M +
υC=O = 1655 cm−1; υNH = 3300 cm−1; MALDI-MS:
H]+); elemental analysis calcd (%) for C27H24NO2P:
Heteroatom Chemistry DOI 10.1002/hc

404 Wahbi and Touil
m/z = 314.011 ([M + H]+); elemental analysis calcd
(%) for C18H20NO2P: C 69.00, H 6.43, N 4.47; found:
C 69.07, H 6.54, N 4.35.
[13] Wahbi, A.; Mhamdi, A.; Hassen, Z.; Touil, S. Green
Chem Lett Rev 2014, 7, 73–78.
[14] Chebil, E.; Chamakhi, M.; Touil, S. J Sulfur Chem
2011, 32, 249–256.
[15] Said, N.; Touil, S.; Zantour, H. Phosphorus, Sulfur
Silicon Relat Elem 2004, 179, 2487–2496.
[16] Touil, S.; Zantour, H. Phosphorus, Sulfur Silicon Re-
lat Elem 2003, 178, 353–360.
[17] (a) Solodenko, V. A.; Kukhar, V. P. Tetrahedron Lett
1989, 30, 6917–6918; (b) Polyak, M. S. Antibiot Med
Biotek 1987, 32, 66–75.
[18] Gutman, A. D.; Freiberg, A. H. U.S. Patent 3517088,
June 23, 1970.
[19] Gutman, A. D.; Freiberg, A. H. U.S. Patent 3692900,
September 19, 1972.
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Heteroatom Chemistry DOI 10.1002/hc