N-aryltrifluoroacetimidoylphosphonates

Article abstract of DOI:10.1134/S1070363213030079

By reaction of N-aryltrifluoroacetimidoyl chlorides with trialkyl phosphites the corresponding N-aryltrifluoroacetimidoylphosphonates CF ₃C(=NAr)P(O)(OR)₂ existing as dynamic equilibrium mixture of Z,Eisomers [Z/E ～ (7-12):1] were pr

Full text of DOI:10.1134/S1070363213030079

ISSN 1070-3632, Russian Journal of General Chemistry, 2013, Vol. 83, No. 3, pp. 445–452. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © Ya.Ya. Khomutnik, P.P. Onys’ko, Yu.V. Rassukanaya, V.V. Pirozhenko, A.D. Sinitsa, 2013, published in Zhurnal Obshchei Khimii,
2013, Vol. 83, No. 3, pp. 391–398.
N-Aryltrifluoroacetimidoylphosphonates
Ya. Ya. Khomutnik, P. P. Onys’ko, Yu. V. Rassukanaya, V. V. Pirozhenko, and A. D. Sinitsa
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, ul. Murmanskaya 5, Kiev, 02094 Ukraine
e-mail: onysko@rambler.ru
Received January 26, 2012
Abstract―By reaction of N-aryltrifluoroacetimidoyl chlorides with trialkyl phosphites the corresponding N-
aryltrifluoroacetimidoylphosphonates CF3C(=NAr)P(O)(OR)2 existing as dynamic equilibrium mixture of Z,E-
isomers [Z/E ~ (7–12):1] were prepared. By 19F NMR spectroscopy kinetic and activation parameters of Z–E
isomerization were evaluated. Reaction of imidoylphosphonates with O- or S-centered nucleophiles leads to the
products of addition to C=N bond whereas cycloaddition with of nitrile oxide gives previously unknown
phosphorylated oxadiazolines.
DOI: 10.1134/S1070363213030079
Imidoylphosphonates, the esters of iminophosphonic
acids, remain comparatively poorly studied imines [1,
2]. At the same time, the presence of “oxidated”
fragment of α-aminophosphonic acid [>P(O)C=N]
capable of easy reductive functionalization opens new
opportunities for preparing various biologically
important derivatives of aminophosphonic acids. The
latter, being phosphorus-containing analogs of natural
amino acids, exhibit a large range of practically
important properties [3, 4]. They are potential enzyme
regulators and inhibitors of AIDS-protease, and due to
that they are nowadays intensivsly studied. Imidoyl
phosphonates containing trifluoromethyl group are
especially interesting because the modifying effect of
this group on chemical, physicochemical, and
pharmacological properties of compounds is well
known [5]. Previously we have developed methods for
preparing N–H, N-alkyl, N-acyl, and N-phosphoryltri-
fluoroacetimidoylphosphonates and showed the pos-
sibility of their use for preparing biologically promis-
ing derivatives of phosphonotrifluotoalanine [1, 2, 6, 7].
The reported data concerning the synthesis of N-
aryliminotrifluoroethylphosphonates [8–10] are scanty,
their chemical properties are practically not studied,
and 1H and 31P NMR spectral data are contradictory [8,
9]. In particular, the chemical shift of phosphorus
reported in [8] for diethyl N-phenyliminotrifluoroethyl-
phosphonate (δP 7.37) is not characteristic of trifluoro-
acetimidoylphosphonates (from –1 to –5 ppm [1, 11]).
In this work the synthesis of N-aryltrifluoroacet-
imidoylphosphonates is described and some of their
chemical and physicochemical properties are studied.
Most convenient approach to the target imidoylphos-
phonates is the reaction of synthetically available N-
aryltrifluoroacetimidoyl chlorides [12] with phos-
phorous acid esters. We have found that the reaction of
imidoyl chlorides Ia–Id with trialkyl phosphites IIa,
IIb in benzene or ether solution leads to imidoyl
phosphonates IIIa–IIIe in 80–94% yield (Scheme 1).
Scheme 1.
R
O
Cl
R
P(OR')3
P(OR')2
N
IIа, IIb
N
CF3
C6H6, 20°C
CF3
Iа_Id
IIIа_IIIe
I, R = 4-MeO (а), 3-MeO (b), 4-СN (c), H (d); II, R' = Me (a), Et (b); III, R' = Me, R = 4-MeO (a), 3-MeO (b), 4-СN (c);
R' = Et, R = H (d), 3-MeO (e).
445

446
KHOMUTNIK et al.
Monitoring the process by 19F and 31P NMR spec-
cases, for example for introduction of carboxy function
to the imine carbon atom, their use is preferred [12],
but these substances were not studied previously in the
reactions with trivalent phosphorus compounds. We
have for the first time investigated the reaction of
imidoyl iodide IV with triethyl phosphite (Scheme 2).
Reaction proceeds according to the Scheme analogous
to that of corresponding imidoyl chloride Ib. It is the
first example of the Arbuzov reaction for imidoyl
iodides.
troscopy shows that the reaction rate increases with the
increase in the electron-acceptor properties of
substituents R in the benzene ring: 4-CN > 4-Cl, 3-Cl,
3-MeO > H, 3-Me, 4-Me > 4-OMe. Reaction proceeds
easily at room temperature (15–20°C) and requires no
heating (compare with [8–10]).
It was interesting to study the possibility to use
imidoyl iodides in this reaction. As is known, in some
Scheme 2.
MeO
I
NaI
IIb
Ib
N
acetone, 20°C
C6H6, 20°C
CF3
By the method of competing reactions we have
evaluated relative reactivity of imidoyl iodide IV and
the corresponding chloride Ib in the reaction with
triethyl phosphite. It occurred that iodide reacts
significantly faster (kIV/kIb ~ 3), and the ratio of E–Z
isomers of phosphonate IIIe prepared from imidoyl
chloride Ib and iodide IV is the same.
phorus (from 0.1 to –3.3 ppm) and fluorine (from
–66.2 to –70.2 ppm) are located upfield as compared to
the corresponding E-isomers (δP 1.5–4.8 ppm, δF –61
to –62 ppm). It follows from the obtained data that
chemical shift of phosphorus in the compound IIIa (δP
7.37 ppm) reported in [8] is not correct.
The registration of NMR spectra of imidoyl-
phosphonates III at elevated temperatures showed
significant broadening of signals of both isomers
indicating on the occurrence of dynamic process in the
solution of these compounds. We consider it to be Z,E-
isomerization. By 19F NMR line-shape analysis we
have for the first time calculated the rate constants of
this process in compounds III at different temperatures
(from –10 to –110°C). On the basis of these data using
Eyring equation we have found activation and
thermodynamic parameters of Z,E-isomerization in
toluene-d6 (see Scheme 3 and the table).
Imidoyl phosphonates IIIa-e are viscous light
yellow liquids which can be distilled in a high vacuum
without decomposition. The absorption band of C=N
bond vibrations in the IR spectra appears at 1580–
1610 cm–1.
Z-E isomerizm of N-aryltrifluoroacetimidoyl-
phosphonates. Recently we have for the first time
shown that some imidoyl phosphonates at room
temperature exist as a mixture of E,Z- isomers and
have established spectral properties permitting to
distinguish these isomers [13–15]. It was established
that NH and N-alkyltrifluoroacetimidoylphosphonates
exist mainly in Z-form [Z/E ~ (6–10):1] [14, 15] while
in the analogous benzimidoylphosphonates E-form is
preferred [13]. Such difference was connected with
large sterical demands of trifluoromethyl group
(compare [6, 16]). Analogous data was observed later
in [10]. We have found that N-trifluoroacetimidoyl-
phosphonates III also exist mainly in Z-form [Z/E ~
(7–12):1]. Performed studies showed that the
identification of isomers and evaluation of their ratio
can be most conveniently carried out by 19F and 31P
NMR spectroscopy. In the spectra of Z-isomers of
imidoylphosphonates III chemical shifts of phos-
It follows from the data presented in the table that
due to low activation barriers the isomerization relative
to the C=N bond in N-aryltrifluoroacet-imidoyl-
phosphonates III proceeds sufficiently fast at room
temperature (τ1/2 0.2–1.3 and 0.02–0.01 s for Z- and E-
isomers of compounds IIIa–IIIc respectively). The
increase in electron-donor properties of substituent R
leads to significant and approximately equal
acceleration of Z→E as well as of E→Z isomerization.
Due to that the equilibrium constant only insigni-
ficantly varies in going from most electron-donor 4-
MeO (σp –0.268) to most electron-acceptor 4-CN
substituent (σp 0.66) in the phenyl ring (ΔG0 6.3 and
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 3 2013

447
N-ARYLTRIFLUOROACETIMIDOYLPHOSPHONATES
Scheme 3.
R
O
P(OMe)2
CF3
O
k1
N
P(OMe)2
CF3
k-1
N
R
(Z)-III
(E)-III
R= 4-MeO (а), 3-MeO (b), 4-CN (c).
5.8 kJ mol–1). It is interesting to compare the results we
obtained with the data [17] related to the the
degenerate isomerization of p-substituted imines of
hexafluoroacetone. These compounds can be regarded
as the analogs of imidoylphosphonates III because tri-
fluoromethyl and diethoxyphosphoryl groups have
close polar characteristics (σI 0.38 and 0.37 respec-
tively [18]). It occurred that isomerization barriers in
compounds IIIa–IIIc are slightly higher than those in
the imines of hexafluoroacetone (ΔG# 62.3–64.6 kJ mol–1).
At the same time the values of activation entropies for
compounds IIIa–IIIc are positive, and for the imines
of hexafluoroacetone are negative (ΔS# varies from
–3.8 to –20.5 J mol–1 K–1). Greatest differences are
observed in the influence of substituents in N-phenyl
ring on the rate of the process. The increase in the
electron-acceptor properties of substituents leads to
significant deceleration of Z→E isomerization for
imines of hexafluoroacetone and to its acceleration for
the compounds IIIa–IIIc. Roberts et al. [17] attribute
the deceleration in the case of imines of hexa-
fluoroacetone to the existence of the rotational “out of
plane” mechanism of isomerization around the C=N
bond. Accelerating effect of electron-acceptor sub-
stituents on the isomerization of compounds III agrees
with the mechanism of “planar inversion” (com-
pare [17, 19]) with the linear transition state of the type
A.
O
(EtO)2P
N
R
F3C
A
The disappearance of sterical hindrances in going
from Z- or E-configuration to the transition state
A agrees with the positive value of activation entropies
ΔS# (see the table). The important difference of
compounds III from the imines of hexafluoroacetone
is the nonequivalence of Z-and E-configurations, and
Activation and thermodynamic parameters of Z,E-isomerization of N-trifluoroacetimidoylphosphonates IIIa–IIIc (toluene-d6,
298 K)
Substituent
4-MeO
3-MeO
4-CN
Z → E
81.9
23.7
74.8
6.3
E → Z
73.4
Z → E
75.1
13.4
71.6
6.0
E → Z
68.6
Z → E
70.1
1.9
E → Z
64.6
3.0
ΔH≠, kJ mol–1
ΔS≠, J mol–1 K–1
ΔG≠298, kJ mol–1
ΔGo298, kJ mol–1
k1 or k–1, s–1
τ1/2, s
16.5
10.1
68.5
65.6
69.5
5.8
63.8
0.5
1.7
0.4
4.1
6.0
0.1
20.1
0.03
10.1
41.5
0.02
1.3
0.2
K–1/k1
12.0
11.8
ΔТ a
nb
271–370
13
246–364
14
234–306
15
a
Temperature range of measurements, K. b Number of points used for calculation of thermodynamic parameters.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 3 2013

448
KHOMUTNIK et al.
hence Z,E-isomerization in this case is not degenerate.
For all compounds studied by us Z-isomers are
thermodynamically preferred at room temperature
where the N-aryl substituent is cis-located in relation to
more bulky phosphonyl group. Sterical constants R
that we calculated according to [20] for (MeO)2P(O)-
and CF3 groups are –2.07 and –1.39 respectively. As it
follows from the table, the entropic factor favors more
the Z→E isomerization than the reverse process.
Assuming that the variations in entropy are connected
mainly with the sterical influence of substituents at the
C=N bond it may be suggested that sterical factors
favor stabilization of E-isomer, and the preferred Z-
configuration of compounds III is caused by electron
effects of substituents. Indeed, the substitution of
trifluoromethyl substituent (Rs = –1.36) with more
bulky phenyl group (Rs = –2.39) is accompanied not
by the increase, but by the considerable decrease in the
content of Z-isomer. Z/E is 10:1 [14] and 1:17 [13] for
N-methyltrifluoroacet- and N-methylbenzimidoylphos-
phonates respectively. Hence, the above assumption on
the stercal stabilization of Z-configuration of trifluoro-
acetimidoylphosphonates [14] does not find experi-
mental confirmation because our data show that
sterically more hindered isomer is thermodynamically
preferred for compounds III.
Chemical properties. The presence of two elec-
tron-acceptor groups at the imine carbon atom of imidoyl-
phosphonates III causes sufficiently high electro-
philicity of these compounds. The reactivity of com-
pounds III with respect to nucleophilic reagents oc-
cupies intermediate position between the reactivity of
N-acyl (N-phosphoryl, N-sulfonyl) and N-alkyltri-
fluoroacetimidoylphosphonates. They do not react at
room temperature with dialkyl hydrogen phosphites
but easily add O- and S-centered nucleophiles to give
the adducts (V, VI) (see Scheme 4). Note that com-
pounds V are sufficiently stable in pure state and in
acetone solutions. At the same time while dissolved in
CDCl3 they partially dissociate to give the starting
components.
Scheme 4.
MeOH
20°C
O
Ar
N
P(OR)2
CF3
III
R'SH
C6H6, 20°C
V, Ar = Ph (a), 3-MeOC6H4 (b), R = Et (a), Me (b); VI, Ar = 4-MeOC6H4, R' = CH2COOMe (a), 4-FC6H4 (b).
We have for the first time shown that trifluoro-
acetimidoylphosphonates in the reactions with dipolar
compounds may act as dipolarophiles. For example,
reaction of compounds III with nitrile oxides opens
way to previously unknown phosphorylated oxadi-
azolines VII containing the fragment of aminophos-
phonic acid (Scheme 5).
EXPERIMENTAL
IR spectra were registered on an UR-20 spec-
trometer. NMR spectra were taken on spectrometers
Varian VXR-300 (1H), Bruker Avance DPX 500 (1H,
13C), and Varian Gemini-200 (31P) with the working
frequencies 299.95, 500.07, and 81.03 MHz
respectively. Chemical shifts are presented relative
internal TMS (1H, 13C), and external 85% phosphoric
acid (31P). All reactions were recorded in anhydrous
conditions under argon.
Hence, N-aryltrifluoroacetimidoylphosphonates exist
in a form of Z–E isomers and are convenient building
blocks for the synthesis of acyclic and heterocyclic
derivatives containing pharmacophoric fragment of
phosphonotrifluoroalanine.
Variable-temperature measurements of 19F NMR
spectra were carried out on a Varian VXR-300
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 3 2013

449
N-ARYLTRIFLUOROACETIMIDOYLPHOSPHONATES
Scheme 5.
Cl
O
CF3
O
N
OH
Ar
Ar
P(OMe)2
CF3
p-ClC6H4
N
P(OMe)2
N
O
Et2O, NEt3
p-ClC6H4
N
VIIа_VIIc
IIIа_IIIc
III, VII: Ar = 4-MeOC6H4 (а), 3-MeOC6H4 (b), 4-NCC6H4 (c).
spectrometer (282.2 MHz). Thermodynamic and
activation parameters of the process of Z-E
isomerization of compounds III were evaluated by the
Eyring equation [12] on the basis of calculated values
of rate constants of this process. The rate constants
were evaluated by comparison of experimental and
theoretical spectra using WINDMR program [22]. The
calculations of rate constants were performed on the
basis of line-shape analysis of trifluoromethyl groups
were analyzed. For more correct evaluation of rate
constants in the range of fast exchange the dependence
of chemical shifts and population of corresponding
isomers on temperature were taken into account. The
relative error of evaluation of values of free activation
energy was no more than 1%. Temperature-dependent
19F NMR spectra were registered with the digital
resolution 0.2 Hz per point. Accuracy of evaluation of
temperature was 1 K.
imidoylphosphonate (IIIa). Yield 84%, mp 115–117°C
(0.1 mm Hg). IR spectrum, ν, cm–1: 1050 (C–O–P),
1
1275 (P=O), 1585 (C=N). H NMR spectrum (CDCl3),
3
δ, ppm: 3.63 d (6H, JPH 11.4 Hz, POMe, Z), 3.83 s
3
(3H, MeOAr), 3.98 d (6H, JPH 11.4 Hz, POMe, E),
3
3
6.93 d (2H, JHH 8.4 Hz, Ar), 7.13 d (2H, JHH 8.4 Hz,
Ar). 13C NMR spectrum (CDCl3), δC, ppm: 53.54 d
(2JCP 7 Hz, MeOP), 55.35 s (MeO), 113.88 s (C3
,
Ar
C5Ar), 116.25 q.d (CF3, JCF 180, JPC 47), 121.50 s
1
2
(C2Ar, C6Ar), 139.92 d (3JCP 14 Hz, C1Ar), 149.73 d.q
(1JCP 159 Hz, JCP 35 Hz, C=N), 159.14 s (C4 Ar). 19F
2
NMR spectrum (CDCl3), δF, ppm: –68.86 (Z-isomer),
–61.75 (E-isomer). 31P NMR spectrum (CDCl3), δP,
ppm: 0.06 (Z-isomer), 4.78 (E-isomer). Calculated, %:
C 42.46, H 4.21, N 4.50. C11H13F3NO4P. Found, %: C
42.52, H 4.19, N 4.55.
O,O-Dimethyl-N-(3-methoxyphenyl)trifluoroacet-
imidoylphosphonate (IIIb). Yield 84%, bp 124–126°
C (0.1 mm Hg). IR spectrum, ν, cm–1: 1040 (C–O–P),
1280 (P=O), 1590 (C=N). 1H NMR spectrum (CDCl3),
Sterical constants Rs for (MeO)2P(O) and CF3
groups at C=N bond were calculated according to the
Eq. (1) [20].
3
δ, ppm: 3.58 d (6H, JPH 11.4, MeOP, Z), 3.82 s (3H,
MeOAr), 3.97 d (3JPH 11.4, MeOP, E), 6.56 s (1H, Ar),
6.58 d (1H, 3JHH 8.4 Hz, Ar), 6.78 d (1H, 3JHH 8.4. Ar),
6.30 t (1H, 3JHH 8.4, Ar). 13C NMR spectrum (CDCl3),
δC, ppm: 53.18 d (2JCP 7 Hz, MeOP), 55.11 s (MeO),
104.21 s, 110.88 s, 113.02 s (C2Ar, C4Ar, C6Ar), 120.13
ri2
n
Rs = 30log 1 – Σ —— .
(1)
4Ri2
i=1
In the course of calculation the covalent radii of
elements r presented in [23] were used. Parameter Ri,
the distance between the i-atom and the reaction
center, was evaluated from the optimized geometries
of molecules calculated by quantum chemical methods
(FireFly [24], PBE/6-311+G).
2
q.d (1JCF 280 Hz, JCP 46 Hz, CF3), 130.02 s (C5Ar),
149.35 d (3JCP 13 Hz, C1Ar), 153.73 d.q (1JCP 159 Hz,
3JCP 35 Hz, C=N), 160.05 s (C3Ar). 19F NMR spectrum
(CDCl3), δF, ppm: –69.95 (Z-isomer), –63.00 (E-
isomer). 31P NMR spectrum (CDCl3), δP, ppm: –0.78
(Z-isomer), 3.59 (E-isomer). Calculated, %: C 46.03; H
5.05; N 4.13. C13H17NO4P. Found, %: C 45.86; H 5.11;
N 4.12.
N-Aryltrifluoroacetylimidoylphosphonates (III).
To a solution of the corresponding imidoyl chloride I,
10 mmol, in 5 ml of anhydrous benzene 10 mmol of
triethyl phosphite was added with stirring. The
obtained reaction mixture was stirred at 20°C for 24 h,
evaporated under reduced pressure, and the residue
was distilled in a vacuum.
O,O-Dimethyl-N-(4-cyanophenyl)trifluoroacet-
imidoylphosphonate (IIIc). Yield 78%, bp 140–143°C
(0.1 mm Hg). IR spectrum, ν, cm–1: 1060 (C–O–P),
1280 (P–O), 1590 (C=N), 2170 (C≡N). 1H NMR spec-
3
trum (CDCl3), δ, ppm: 3.66 d (6H, JPH 11.4 Hz),
O,O-Dimethyl-N-(4-methoxyphenyl)trifluoroacet-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 3 2013

450
KHOMUTNIK et al.
3
MeOP, Z), 3.91 (3JPH 11.4 Hz, E), 7.01 s (2H, JHH
1H NMR spectrum (CDCl3), δ, ppm: 3.82 s (3H,
7.8 Hz, Ar), 7.70 d (2H, JHH 7.8 Hz, Ar). 19F NMR
MeO), 6.41 s (1H, Ar), 6.45 d (1H, JHH 8 Hz, Ar),
3
3
spectrum (CDCl3), δF, ppm: –70.20 (Z-isomer), –61.95
(E-isomer). 31P NMR spectrum (CDCl3), δP, ppm: –3.0
(Z-isomer), 1.75 (E-isomer). Calculated, %: C 42.46; H
4.21; N 4.50. C11H13F3NO4P. Found, %: C 42.52; H
4.19; N 4.10.
6.85 d (1H, 3JHH 8 Hz, Ar), 7.33 t (1H, 3JHH 8 Hz, Ar).
19F NMR spectrum (CDCl3), δF, ppm: –70.57.
Calculated, %: C 32.85; H 2.14; N 4.26. C9H7F3INO.
Found, %: C 32.92; H 2.19, N 4.24.
Phosphonates Va, Vb. A solution of 2 mmol of the
corresponding imidoylphosphonate III in 3 ml of
anhydrous methanol was stirred for 12 h at 20°C. Then
the solvent was evaporated and the residue washed
with petroleum ether.
O,O-Diethyl-N-phenyltrifluoroacetimidoylphos-
phonate (IIId). Yield 94%, bp 94–96°C (0.06 mm Hg).
IR spectrum, ν, cm–1: 1040 (C–O–P), 1285 (P=O),
1593 (C=N). 1H NMR spectrum (CDCl3), δ, ppm: 1.06
t (6H, JHH 6.8 Hz, 2CH3, Z), 1.32 t (3JHH 6.8 Hz,
3
O,O-Dimethyl-1-methoxy-1-(3-methoxyphenyl-
amino)-2,2,2-trifluoroethylphosphonate (Va). Yield
92%, mp 104–106°C. IR spectrum, ν, cm–1: 1040
(C–O–P), 3340 (N–H). 1H NMR spectrum (acetone-
d6), δ, ppm: 3.57 s (3H, MeOC), 3.77 s (3H, MeOAr),
3.84 d (3H, 3JPH 10.9 Hz, POMe), 3.87 d (3H, 3JPH 10.9
2CH3, E), 3.81 s (3H, MeO), 3.75-4.96 m (4H,
2CH2Me, Z), 4.93–4.3 m (2CH2Me, E), 6.90 d (2H,
3JHH 7.3 Hz, Ph), 6.60 t (1H, JHH 7.3, Ph), 6.77 t (2H,
3
4JHH 7.3 Hz, Ph). 13C NMR spectrum (CDCl3), δC,
ppm: 15.90 d (4JCP 6.5 Hz, CH3), 63.66 d (3JCP 6.7 Hz,
CH2), 118.18 s (C3Ar, C5Ar), 119.14 q.d (1JCF 280 Hz,
2JCP 47 Hz, CF3), 126.38 s (C4Ar), 128.64 s (C2Ar, C6Ar),
147.48 d (2JCP 14 Hz, C1Ar), 153.15 d.q (1JCP 160 Hz,
2JCP 35 Hz, C=N). 19F NMR spectrum (CDCl3), δF,
ppm: –69.17 (Z-isomer), –61.14 (E-isomer). 31P NMR
spectrum (CDCl3), δP, ppm: –3.0 (Z-isomer), 1.75 (E-
isomer). Calculated, %: C 46.61; H 4.89; N 4.53.
C12H13NO3P. Found, %: C 46.45; H 4.94; N 4.60.
3
Hz, POMe), 6.48 d (1H, JHH 7.9 Hz, Ar), 6.76 d (1H,
3JHH 7.2 Hz, Ar), 6.83 m (2H, Ar, NH), 7.12 m (1H,
19
Ar). F NMR spectrum (acetone-d6), δF, ppm: –71.41.
31P NMR spectrum (acetone-d6), δP, ppm: 16.46. Cal-
culated, %: C 41.99; H 4.99, N 4.08. C12H17F3NO5P.
Found, %: C 41.80, H 5.04, N 4.05.
O,O-Diethyl-1-methoxy-1-phenylamino-2,2,2-tri-
fluoroethylphosphonate (Vb). Yield 95%, mp 81–83°C.
IR spectrum, ν, cm–1: 1030 (C–O–P), 1280 (P=O),
3325 (N–H). 1H NMR spectrum (acetone-d6), δ, ppm:
3.55 s (3H, MeOC), 1.16 t (6H, 3JHH 7 Hz, 2CH3), 3.82
O,O-Diethyl-N-(3-methoxyphenyl)trifluoroacet-
imidoylphosphonate (IIIe). Yield 80%, bp 135–137°C
(0.1 mm Hg). IR spectrum, ν, cm–1: 1045 (C–O–P),
1270 (P=O), 1580 (C=N). 1H NMR spectrum (CDCl3),
δ, ppm: 1.18 t (6H, 3JHH 7.2 Hz, 2CH3, Z), 1.42 t (3JHH
7.2 Hz, 2CH3, E), 3.81 s (3H, MeO), 3.84–4.11 m (4H,
2CH2Me, Z), 4.24-4.39 m (2CH2Me, E), 6.57 s (1H,
Ar), 6.60 d (1H, 2JHH 8.5 Hz, Ar), 6.77 d (1H, 3JHH 8.5 Hz,
3
m (4H, 2CH2Me), 6.92 d (2H, JHH 7.3 Hz, Ph), 6.65 t
(1H, 3JHH 7.3 Hz, Ph), 6.74 s (2H, 3JHH 7.3 Hz, Ph). 19F
NMR spectrum (acetone-d6), δF, ppm: –71.22. 31P
NMR spectrum (acetone-d6), δP, ppm: 13.75.
Calculated, %:
C
42.18,
H
4.83,
N
4.47.
Ar), 7.28 t (1H, JHH 8.5 Hz, Ar). 19F NMR spectrum
3
C13H15F3NO4P. Found, %: C 42.10, H 5.04, N 4.35.
(CDCl3), δF, ppm: –69.60 (Z-isomer), –61.65 (E-
isomer). 31P NMR spectrum (CDCl3), δP, ppm: –3.23
(Z-isomer), 1.48 (E-isomer). Calculated, %: C 45.75; H
5.61; N 4.10. C13H19F3NO4P. Found, %: C 45.83; H
5.53; N 4.12.
Phosphonates VI. To a solution of 10.0 mmol of
the corresponding imidoylphosphonate III in 5 ml of
anhydrous benzene 10.0 mmol of methyl thioglycolate
or 4-fluorophenol was added with stirring. The
obtained reaction mixture was stirred for a day at 20°C,
evaporated in a vacuum, and the residue was washed
with hexane.
N-(3-Methoxyphenyl)trifluoroacetimidoyl iodide
(IV). To a solution of 2.0 g of imidoyl chloride Ib in
20 ml of anhydrous acetone 3.9 g of anhydrous sodium
iodide was added with stirring. After stirring for 5 h at
20°C the reaction mixture was left overnight. Then
inorganic salts were filtered off, the filtrate was
evaporated under a reduced pressure, and the residue
was distilled in a vacuum. Yield 74%, bp 90–92°C
(10 mm Hg). IR spectrum, ν, cm–1: 1135, 1155 (C–F),
1715 (C=N).
O,O-Dimethyl-1-(methoxycarbonylmethylthio)-
1-(4-methoxyphenylamino)-2,2,2-trifluoroethylphos-
phonate (VIa). Yield 85%, mp 76–77°C. IR spectrum,
1
ν, cm–1: 1020 (POC), 1755 (C=O), 3370 (N–H). H
NMR spectrum (CDCl3), δ, ppm: 3.60 d (1H, 2JHH 11.4
3
Hz, SCH2), 3.68 s (3H, JPH 10.8 Hz, POMe), 3.77 s
(3H, MeOAr), 3.82 d (1H, 2JHH 11.4 Hz, SCH2), 3.92 d
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 3 2013

451
N-ARYLTRIFLUOROACETIMIDOYLPHOSPHONATES
3
3
(3H, JPH 10.8 Hz, POMe), 3.96 d (3H, JPH 10.8 Hz,
O,O-Dimethyl [4-(3-methoxyphenyl)-5-trifluoro-
methyl-3-(4-chlorophenyl)-4,5-dihydro-1,2,4-oxa-
diazol-5-yl]phosphonate (VIIb). Yield 80%, oil. IR
spectrum, ν, cm–1: 1012 (C–O–P), 1230 (P=O). 1H
3
POMe), 6.78 d (2H, JHH 8.4 Hz, Ar), 6.93 br s(1H,
NH), 7.16 d (2H, 3JHH 8.4 Hz, Ar). 19F NMR spectrum
(CDCl3), δF, ppm: –67.01. 31P NMR spectrum
(CDCl3), δP, ppm: 15.78. Calculated, %: C 40.29, H
4.59, N 3.36. C14H19F3NO6PS. Found, %: C 40.15, H
4.65, N 3.31.
3
NMR spectrum (CDCl3), δ, ppm: 3.60 d (3H, JPH
11.4 Hz, POMe), 3.73 s (3H, ArOMe), 3.86 d (3H, 3JPH
10.8 Hz, POMe), 6.79–6.85 m (3H, Ar), 7.18 t (1H,
3
3JHH 7.8 Hz, Ar), 7.36 d (2H, JHH 8.4 Hz, Ar). 19F
NMR spectrum (CDCl3), δC, ppm: –78.65. 31P NMR
spectrum (CDCl3), δP, ppm: 8.07. Calculated, %: C
46.52, H 3.69, N 6.03. C18H17ClF3N2O5P. Found, %: C
46.45, H 3.74, N 6.09.
O,O-Dimethyl-1-(4-methoxyphenylamino)-1-(4-
fluorophenylthio)-2,2,2-trifluoroethylphosphonate
(VIb). Yield 82%, mp 69–71°C. IR spectrum, ν, cm–1:
1035 (POC), 3410 (N–H). 1H NMR spectrum (CDCl3),
δ, ppm: 3.72 s (3H, MeOPC), 3.80 d (3H, 3JPH 10.5 Hz,
POMe), 3.85 d (3H, 3JPH 10.5 Hz, POMe), 6.84 m (4H,
ArF + ArOMe), 7.04 br (1H, NH), 7.26 m (4H, ArF +
ArOMe). 19F NMR spectrum (CDCl3), δF, ppm: –73.06
(3F), –117.2 (1F). 31P NMR spectrum (CDCl3), δP,
ppm: 16.32. Calculated, %: C 46.47, H 4.13, N 3.19.
C16H18F4NO4PS. Found, %: C 46.15, H 4.20, N 3.30.
O,O-Dimethyl [5-trifluoromethyl-3-(4-chlorophenyl)-
4-(4-cyanophenyl)-4,5-dihydro-1,2,4-oxadiazol-5-yl]-
phosphonate (VIIc). Yield 76%, oil. IR spectrum, ν,
cm–1: 1010 (C–O–P), 1240 (P=O). 1H NMR spectrum
3
(CDCl3), δ, ppm: 3.60 d (3H, JPH 11.4 Hz, POMe),
3.87 d (3H, 3JPH 10.Hz, POMe), 7.21–7.38 m (6H, Ar),
3
7.59 d (2H, JHH 8.7 Hz, Ar). 19F NMR spectrum
(CDCl3), δC, ppm: –78.96. 31P NMR spectrum
(CDCl3), δP, ppm: 6.68. Calculated, %: C 47.03, H
3.07, N 9.14.C18H14ClF3N3O4P. Found, %: C 47.20, H
3.02, N 9.05.
4,5-Dihydro-1,2,4-oxadiazoles (VIIa–VIIc). To a
solution of 20 mmol of the corresponding imidoyl-
phosphonate I and 22 mmol of triethylamine in 10 ml
of anhydrous diethyl ether 22 mmol of 4-chlorophenyl-
hydroxymoyl chloride was added with stirring at –20°C.
The reaction mixture was left overnight at room
temperature. The obtained precipitate was filtered off
and washed with ether (2x3 ml). The filtrate was
evaporated in a vacuum, and the residue was purified
by chromatography on silica gel, elution with 2:1 ethyl
acetate–hexane.
REFERENCES
1. Sinitsa, O.A., Kolotilo, M.V., and Onys’ko, P.P., Ukr.
Khim. Zh., 1998, vol. 65, no. 4, p.47.
2. Onys’ko, P.P., Rassukanay, Yu.V., Synytsya, A.O.,
Curr. Org. Chem., 2010, vol. 14, no. 12, p. 1223.
3. Aminophosphonic
and
Aminophoshinic
Acids.
Chemistry and Biological Activity, Kukhar, V.P. and
Hudson, H.R., Eds., New York: Wiley, 2000.
O,O-Dimethyl [4-(4-methoxyphenyl)-5-trifluoro-
methyl-3-(4-chlorophenyl)-4,5-dihydro-1,2,4-oxa-
diazol-5-yl]phosphonate (VIIa). Yield 74%, oil. IR
spectrum, ν, cm–1: 1015 (C–O–P), 1230 (P=O). 1H
4. Kafarski, P. and Lejczak, G., Phosphorus, Sulfur,
Silicon and the Related Elements, 1991, vol. 63, nos. 1–
2, p. 193.
5. Organophosphorus Compounds in Medicinal Chemistry
and Biomedical Applications, Filler, R., Kobayashi, Y.,
and Yagupolski, M., Eds., Ansterdam: Elsevier, 1993
3
NMR spectrum (CDCl3), δ, ppm: 3.57 d (3H, JPH
11.4 Hz, POMe), 3.77 s (3H, ArOMe), 3.89 d (3H, 3JPH
3
10.2 Hz, POMe), 6.79 d (2H, JHH 8.7 Hz, Ar), 7.20 d
3
3
(2H, JHH 9.0 Hz, Ar), 7.24 d (2H, JHH 8.7 Hz, Ar),
6. Onysko, P.P., Rassukanaya, Yu.V., and Sinitsa, A.D.,
7.30 d (2H, JHH 9.0 Hz, Ar). 13C NMR spectrum
3
Zh. Org. Pharm. Khim., 2009, vol. 7, no. 2(26), p. 37.
(CDCl3), δC, ppm: 54.25 d (2JCP 7 Hz, MeOP), 55.39
(MeOC), 55.51 d (2JCP 7 Hz, MeOP), 96.70 d.q (1JCP
183 Hz, 2JCP 34 Hz, C5), 114.13 s (C3, ArOMe), 121.79
7. Rassukanaya, Yu.V., Onys’ko, P.P., Kolotilo, M.V.,
Sinitsa, A.D., Lyzwa, P., and Mikolajczyk, M.,
Tetrahedron Lett., 2009, vol. 50, no. 3, p. 288.
8. Huang, W., Zhang, Y., and Yang, C., Phosph, Sulfur,
Silicon, 1995, vol. 107, nos. 1–4, p.21.
9. Shchegel’skii, V.F., Sokolov, V.V., Shataeva, G.A., and
Fetisov, V.I., Khim. Farm. Zh., 1996, vol. 30, no. 11,
p. 26.
10. Goulionkina, N.S., Bondarenko, G.N., Lyubimov, S.E.,
Davankov, V.A., Gavrilov, K.N., and Beletskaya, I.P.,
Adv. Synth. Catal., 2008, vol. 350, no. 3, p. 482.
s (C1, ArCl), 121.82 q.d (2JCP 36 Hz, JCF 290 Hz, CF3),
1
128.47 d (2JCP 1 Hz, C1, ArOMe), 128.95, 128.95 s
(C2, C3, ArCl), 131.17 s (C2, ArOMe), 137.13 s (C4,
ArCl), 155.98 d (3JCP 2 Hz, C3), 159.36 s (C4,
ArOMe).19F NMR spectrum (CDCl3), δC, ppm: –78.47.
31P NMR spectrum (CDCl3), δP, ppm: 8.30. Calculated,
%: C 46.52, H 3.69, N 6.03. C18H17ClF3N2O5P. Found,
%: C 46.45, H 3.74, N 6.09.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 3 2013

452
KHOMUTNIK et al.
11. Onys’ko, P.P., Kim, T.V., Kiseleva, E.I., and Sinitsa, A.D.,
17. Roberts, J.D., Hall, G.E., and Middleton, W.J., J. Am.
Chem. Soc., 1971, vol. 93, no. 19, p. 4778.
Zh. Obshch. Khim., 2004, vol. 74, no. 12, p. 1981.
12. Uneyama, K., J. Fluor. Chem., 1999, vol. 97, nos. 1–2,
18. Hansch, C., Leo, A., and Taft, R.W., Chem. Rev., 1991,
p. 11.
vol. 91, no. 2, p. 165.
13. Onys’ko, P.P., Kim, T.V., Rassukanaya, Yu.V.,
Kiseleva, E.I., and Sinitsa, A.D., Zh. Obshch. Khim.,
2004, vol. 74, no. 9, p. 1447.
14. Onys’ko, P.P., Kim, T.V., Kiseleva, E.I., Pustovit, Yu.M.,
and Sinitsa, A.D., Zh. Obshch. Khim., 2005, vol. 75,
no. 8, p. 1263.
19. Kessler, H. and Lebfritz, D., Tetrahedron, 1970, vol. 26,
no. 8, p. 1805.
20. Galkin, V.I., Sayakhov, R.D., and Cherkasov, R.A.,
Metallorg. Khim., 1990, vol. 3, no. 5, p. 986.
21. Eyring, H., J. Chem. Phys., 1935, vol. 3, no. 2, p. 107.
15. Rassukanaya, Yu.V., Kolotilo, M.V., Sinitsa, O.A.,
Pirozhenko, V.V., and Onys’ko, P.P., Synthesis, 2007,
no. 17, p. 2627.
16. Asensio, A., Bravo, P., Crucianelli, M., Farina, A.,
Fustero, S., Soler, J., Meille, S., Panzeri, W., Viani, F.,
Volonterio, A., and Zanda, M., Eur. J. Org. Chem.,
2001, no. 8, p. 1449.
22. Reich, H.J., J. Chem. Educ., 1995, vol. 72, no. 12,
p. 1086.
23. Cordero, B., Gomez, V., Platero-Prats, A.E., Reves, M.,
Echeverria, J., Cremades, E., Berragan, F., and Alvarez, S.,
Dalton Trans., 2008, no. 21, p. 2832.
24. Granovsky, A.A., Firefly version 7.31G, 2011.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 3 2013