Convenient synthesis of α-perfluoroaryl and α-perfluorohetaryl substituted α-aminomethanephosphonates

Article abstract of DOI:10.1016/j.jfluchem.2012.01.004

Potassium salt of diethyl (diphenylmethyleneamino)methanephosphonate reacts with pentafluoropyridine, octafluorotoluene, diethoxymethylpentafluorobenzene, or octafluoronaphthalene to afford, on product hydrolysis, the corresponding α-perfluoro(het)aryl su

Full text of DOI:10.1016/j.jfluchem.2012.01.004

Journal of Fluorine Chemistry 136 (2012) 26–31
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Convenient synthesis of
a-perfluoroaryl and a-perfluorohetaryl substituted
a
-aminomethanephosphonates
*
*
Nataliya S. Goulioukina , Alexander Y. Mitrofanov, Irina P. Beletskaya
Department of Chemistry, Moscow State University, Leninskie Gory, GSP-1, Moscow 119991, Russia
A R T I C L E I N F O
A B S T R A C T
Article history:
Potassium salt of diethyl (diphenylmethyleneamino)methanephosphonate reacts with pentafluoropyr-
idine, octafluorotoluene, diethoxymethylpentafluorobenzene, or octafluoronaphthalene to afford, on
Received 22 September 2011
Received in revised form 17 December 2011
Accepted 21 January 2012
Available online 1 February 2012
product hydrolysis, the corresponding
a-perfluoro(het)aryl substituted derivatives in high yield and
regioselectivity. The method provides a new prospective route to fluorinated
a
-aminophosphonates. In
the case of N-benzylidenepentafluoroaniline the outcome of the reaction is different and results in the
formation of diethyl (pentafluorophenyl)amidophosphate.
Keywords:
ß 2012 Elsevier B.V. All rights reserved.
a
-Aminophosphonates
Fluorinated compounds
Nucleophilic aromatic substitution
Carbanions
1. Introduction
always accessible in terms of traditional synthetic approaches (for
instance, by the Kabachnik–Fields reaction [12]).
Schiff bases derived from phosphoglycine esters are among its
most popular synthetic equivalents that played an important role
Examples of described fluorine containing a-aminophospho-
nates are not numerous [13]; however, interest in them is
permanently increasing [14], because it is known that the
introduction of the fluorine atom (bioisosteric analog of hydrogen
and isoelectronic analog of hydroxyl group) into a molecule very
substantially changes such its properties as lipophilicity and
capability of hydrogen bonding, affects the metabolic degradation
ofbiologicallyactivecompounds,andfinally,makesitpossibletouse
the 19F NMR method for studying metabolism of these substances.
in the development of the chemistry of
a-aminophosphonic acids
[1]. They were introduced into the synthetic practice about thirty
years ago and nowadays undergo a kind of the Renaissance,
turning out to be convenient reactants for both the classical
organic synthesis and its modern directions, in particular, catalytic
and stereoselective methods [2–5]. This class of compounds and,
first of all, diethyl (diphenylmethyleneamino)methanephospho-
nate (1), was very actively applied in the reactions of alkylation [6]
and palladium-catalyzed allylation [2,3,6b,7], in the Michael
[4,6b,8] and Mannich [5] condensations, and finally, in sulfenyla-
tion [9]. However, the possibility of using phosphoglycine Schiff
bases in the reactions of nucleophilic aromatic substitution has not
been demonstrated so far. Moreover, examples of the reactions of
Herein we would like to report our results on the synthesis of
a-
perfluoroaryl- and -perfluorohetaryl substituted -aminometha-
a
a
nephosphonic esters, interesting objects of medicinal chemistry
and valuable intermediate reagents, by the nucleophilic aromatic
substitution reaction of perfluoroarenes with Schiff base 1.
nucleophilic aromatic substitution of
a-phosphoryl-stabilized
2. Results and discussion
carbanions with activated substrates described in the literature
are rare as a whole [10] and not always successful [11]. Meanwhile,
in the case of success, this reaction could form a basis for a new
Schiff base 1 was synthesized from accessible reagents via
Scheme 1, being a compilation of the known literature procedures
[6a,b,15]. A small modification (the use of diethyl aminometha-
nephosphonate instead of the corresponding hydrochloride as in
the literature prototype [6a]) offers more simple work up and
substantially enhances the yield of Schiff base 1.
strategy for the synthesis of potent bioactive
a-aminophospho-
nates containing in the -position various aromatic or heteroaro-
a
matic substituents (including polyfluorinated ones), which are not
The first problem we faced was the choice of an adequate
metallating agent. A whole range of bases was used in the
literature [2–9] for azomethine 1 (pKa = 23.0 (DMSO) [9]). A
specific feature of the reactions of CH-acids with perhaloaromatic
* Corresponding authors. Tel.: +7 495 939 48 28; fax: +7 495 932 88 46.
E-mail addresses: goulioukina@org.chem.msu.ru (N.S. Goulioukina),
beletska@org.chem.msu.ru (I.P. Beletskaya).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2012.01.004

N.S. Goulioukina et al. / Journal of Fluorine Chemistry 136 (2012) 26–31
27
Scheme 1. Synthesis of diethyl (diphenylmethyleneamino)methanephosphonate (1).
compounds is that the acidity of the product formed is consider-
ably higher than that of the initial substrate due to the electron-
completely the retention of the diethoxyphosphoryl moiety in the
product: the very intense band of C55? stretching vibrations lies at
1261 cmÀ1, two intense bands at 1043 and 1018 cmÀ1 correspond
to ?–E vibrations, and a medium-intensity bands of vibrations
withdrawing influence of the
a-ArF substituent. So, to gain the
quantitative conversion at least two equivalents of the base should
be used and the base should not be nucleophilic, i.e. it should not
react with perhaloarenes. This excludes the application not only n-
butyl- and phenyllithium but also potassium tert-butylate and
lithium diisopropylamide which rather easily react with perfluor-
oaromatic compounds to form the di- and trisubstituted deriva-
tives [16]. Taking into account these circumstances, the choice was
made in favor of alkaline metal hydrides, since it is known that
nucleophilic substitution in perfluoroarenes under the action of
hydride ion hardly occurs even at elevated temperatures [17].
It turned out that sodium hydride almost does not react with
Schiff base 1 in dimethoxyethane: no hydrogen evolution was
visually observed, the solution gained only weak yellow color,
probably due to the formation of the anion of the substrate in trace
amounts, and only the signal of the initial reactant was detected by
31P{1H} NMR spectroscopy. Perhaps, sodium salt of Schiff base 1 is
poorly soluble in DME, which results in blocking of the hydride
surface. The metallation of Schiff base 1 by sodium hydride in such
a well solvating solvent as DMF was spectrally detected by the
appearance in the 31P{1H} NMR spectrum of the signal at
n
(E–E) and n
(C–?) appear at 980 and 779 cmÀ1, respectively [18].
In the 31C NMR spectrum, the resonance of phosphorus undergoes
an upfield shift by DdP = 6.84 ppm relatively to the signal of the
initial Schiff base 1. In the 1= NMR spectrum, the doublet of the
methine proton with the characteristic spin-spin coupling
2
constant JP,H = 18.8 Hz lies at
d
= = 5.53 ppm. The ethoxy groups,
which were equivalent in Schiff base 1, become diastereotopic in
2a and appear as two sets of signals in the both 1= and 13E{1=}
spectra. The signal of the
a
-carbon atom with 1JP,E = 161.2 Hz is
characteristic in the carbon spectrum. An analysis of the 13E{1=}
NMR spectrum unambiguously suggests that the substitution in
pentafluoropyridine occurred in position (4): the characteristic
[19] spin–spin coupling constants with the fluorine nucleus
1JF,C = 263.0 and 246.2 Hz are observed only for two signals of
the quaternary carbon atoms of the aromatic ring.
The reaction of Schiff base 1 with octafluorotoluene is also
regiospecific affording diethyl (diphenylmethyleneamino)(2,3,5,6-
tetrafluoro-4-trifluoromethylphenyl)methanephosphonate (2b)
as the single product isolated in 71% yield (Table 1, Entry 2).
Schiff base 1 reacts with diethoxymethylpentafluorobenzene
with a lower selectivity: the 31P NMR spectrum of the reaction
mixture (after neutralization) reveals three signals with charac-
d
C = 30.80 ppm corresponding to the anion formed; however, in
this case, the degree of metallation did not exceed 43%.
Schiff base 1 is metallated completely within 30 min by
potassium hydride in THF at 0 8C: hydrogen is vigorously evolved,
an intensive orange color appears, and the single signal at dC
35.20 ppm corresponding to the anion appears in the 31C{1H} NMR
spectrum instead of the signal of the initial compound at
teristic splitting on fluorine nuclei at
dC = 18.54, 18.81, and
18.92 ppm with the ratio of integral intensities 88:8:4. They
possibly correspond to three regioisomers of the product. The
individual major isomer, diethyl (diphenylmethyleneamino)(4-
diethoxymethyl-2,3,5,6-tetrafluorophenyl)methanephosphonate
(2c), was isolated in 71% by crystallization from petroleum ether
and was completely characterized. para-Substitution in the
fluorinated aromatic ring is unambiguously proved by the date
of 13E{1=} spectroscopy: two and only two signals of quaternary
d
C = 15.95 ppm (Scheme 2).
The reaction of Schiff base 1 with pentafluoropyridine in the
presence of 3 equiv. of potassium hydride at 0 8C occurs
quantitatively and affords (after acidification of the reaction
mixture) diethyl (diphenylmethyleneamino)(2,3,5,6-tetrafluoro-
pyridin-4-yl)methanephosphonate (2a) as the single product
isolated in 70% yield (Table 1, Entry 1) (note, that the yield of
the desirable product 2a did not exceed 25% when potassium tert-
butylate was used as a base in the same reaction). It turned out that
product 2a is rather strong CH-acid: the anion formed in the
reaction is not protonated even with water, and acetic acid
(4 equiv.) was used for neutralization. Both anion 1 and anion 2a
are very readily oxidized with air oxygen and, hence, all
manipulations, including the neutralization stage, were carried
out using a vacuum experimental technique. In our hands, when
the reactions were performed under dry argon using Schlenk
techniques the yields were two times lower.
carbons at
dE = 144.37 and 144.83 ppm with the characteristic
constants 1JF,C = 251.2 and 255.4 Hz, respectively, are observed in a
low field.
The reaction of Schiff base 1 with octafluoronaphthalene results
in the predominant formation of diethyl (diphenylmethylenea-
mino)(1,3,4,5,6,7,8-heptafluoro-2-naphthyl)methanephosphonate
(2d) isolated in 75% yield. The selectivity of the process was also
estimated by 31P{1H} NMR: the spectrum of the crude reaction
mixture contains two signals corresponding to the reaction
products at dC = 18.49 and 18.65 ppm with the ratio of integral
intensities 96:4. The structure of individual isomer 2d was proved
by 19F NMR spectroscopy and was based on the remarkable fact
that in perfluorinated naphthalenes the values of spin–spin
coupling of the fluorine atoms in the peri-positions (1 and 8 or
4 and 5) are 50–70 Hz [20]. The 19F NMR spectrum of product 2d
The composition of product 2a was confirmed by elemental
analysis data, and its structure was determined by IR and 31C{1=},
19F, 1=, and 13E{1=} spectroscopy. The IR spectrum confirms
KH, THF, 0oC
Ph
Ph
100%
Ph
N
P(O)(OEt)2
Ph
N
P(O)(OEt)2
NaH, DME, 20oC
δP 35.20 ppm (THF-d8)
1, δP 15.95 ppm (THF-d8)
X
Scheme 2. Schiff base 1 metallation.

28
N.S. Goulioukina et al. / Journal of Fluorine Chemistry 136 (2012) 26–31
Table 1
Nucleophilic aromatic substitution reaction of the Schiff base 1 carbanion with perfluoroarenes and perfluorohetarenes.
1. KH (3 eq.), THF, 0oC, 30 min
2. ArFF (1.5 eq.), 0oC, 1.5 h
P(O)(OEt)2
Ph ArF
CH3COOH
Ph ArF
P(O)(OEt)2
Ph
Ph
N
P(O)(OEt)2
Ph
N
Ph
N
1
2a-d
Entry
1
ArFF
Regioselectivity
Regiospecifically
Isolated product
Isolated yield (%)
70
N
N
F5
F4
Ph
Ph
Ph
N
N
P(O)(OEt) 2
2a
CF3
CF3
F4
2
Regiospecifically
25a
Ph
F5
P(O)(OEt)2
2b
CH(OEt)2
F4
CH(OEt)2
F5
3
88:8:4
71
Ph
Ph
Ph
Ph
N
P(O)(OEt)2
2c
F4
F4
F3
4
94:4
71
F4
N
P(O)(OEt)2
2d
a
tBuOK was used instead of KH.
contains three well discernible doublets with the characteristic
constants at F = 148.78 (JF,F = 57.4 Hz), 146.37 (JF,F = 57.4 Hz), and
143.64 ppm (JF,F = 71.5 Hz) along with the broadened signal at
F = 116.01 ppm. Its position and width (ꢀ150 Hz) allow one to
attribute it to the -CNfF atom. The signal broadening and, as a
of the hydrochloric salt. The same was observed earlier for salts of
a-aminophosphonates (see, e.g. [6a]); however, the nature of this
effect is not discussed in the literature.
The reaction of Schiff base 1 with N-benzylidenepentafluor-
oaniline gave an unexpected result: diethyl (pentafluoropheny-
l)amidophosphate (4) was isolated in 72% yield instead of
d
d
a
consequence, the unresolved constant are related, probably, to
steric overloading of the molecule and hindered rotation about the
the expected products of
a-arylation or Mannich addition.
b
-CNf–CP bond.
It is known [15] that Schiff bases carbanions derived from
phosphoglycine esters react with carbonyl compounds
according to the Horner–Wadsworth–Emmons reaction type.
Probably, the aza variant [21] of the same condensation takes
place in this case. The plausible mechanism is presented in
Scheme 4.
The diphenylmethylene protective group is easily removed by
hydrolysis. Thus, the product 2a was treated with a mixture of 1 N
hydrochloric acid and THF to give diethyl amino(2,3,5,6-tetra-
fluoropyridin-4-yl)methanephosphonate hydrochloride (3) in 71%
isolated yield (Scheme 3).
Interestingly, no diastereotopism of the ethoxy groups of the
diethoxyphosphoryl moiety is manifested in the 1= NMR spectrum
We failed to introduce pentafluorobenzene into the reaction
with Schiff base 1. The reason is evidently related to the known
N
N
1. 1N HCl, THF, 0oC, 1 h
F4
F4
Ph
2. NaHCO3
3. HCl, EtOH
-Cl +H3N
3, 71%
P(O)(OEt)2
Ph
N
P(O)(OEt)2
2a
Scheme 3. Removal of diphenylmethylene protective group; a representative example.

N.S. Goulioukina et al. / Journal of Fluorine Chemistry 136 (2012) 26–31
29
C6F5N CHPh
Ph
Ph
KH
THF
Ph
N
P(O)(OEt)2
Ph
N
P(O)(OEt)2
Ph
1
Ph
Ph
NC6F5
Ph
C6F5
N
Ph
N
P(OEt)2
Ph
N
P(OEt)2
O
O
H+
P(OEt)2
O
C6F5N
C6F5NH P(O)(OEt)2
Ph
_
4, δP 1.01
Ph
Ph
N
Scheme 4. A plausible mechanism of diethyl (pentafluorophenyl)amidophosphate (4) formation.
CH-acidity of this aromatic compound and, as a consequence,
metallation of the latter by carbanion 1 and/or potassium hydride.
inert atmosphere for 48 h. The solvent was distilled off on a rotary
evaporator, and the product was recrystallized from petroleum
ether. Schiff base 1 was obtained as colorless crystals in a yield of
3. Conclusions
6.35 g (80%). IR (Nujol):
NMR (400 MHz, CDCl3):
n ;
1260, 1040, 1025, 980, 795 cmÀ1 1H
d
1.34 (t, 3JH,H = 7.1 Hz, 6=, E=3), 3.95 (d,
In summary, the results obtained indicate that potassium salt of
phosphoglycine Schiff base 1 is the suitable nucleophile for the
2JH,C = 17.5 Hz, 2=, CE=2), 4.19 (m, 4=, ?E=2), 7.22 (m, 2=, arom.),
7.33 (t, 3JH,H = 7.4 Hz, 2=, arom.), 7.38–7.50 (m, 4=, arom.), 7.64 (d,
direct preparation of the phosphonic analogues of
a
-C-perfluor-
3JH,H = 7.5 Hz, 2=, arom.); 31P NMR (162 MHz, CDCl3):
d 23.73.
o(het)aryl-substituted glycine esters via SNAr reaction with
perfluoro(het)arenes. The new synthetic method provides the
diethyl (diphenylmethyleneamino)(perfluoro(het)aryl)methane-
phosphonates under mild reaction conditions in high yields and
with high regioselectivity.
4.3. Diethyl (diphenylmethyleneamino)(2,3,5,6-tetrafluoropyridin-4-
yl)methanephosphonate (2a); general procedure
A
flame-dried, one-necked, 50-mL round-bottom flask
equipped with a magnetic stirrer and filled with argon was
charged with Schiff base 1 (300 mg, 0.91 mmol) and a microbeaker
containing potassium hydride (with 65% paraffin oil, 310 mg,
2.71 mmol). The flask was connected to a vacuum line and
thoroughly evacuated. THF (8 mL) was transferred by freezing
from a volumetric ampule along the vacuum line. The reaction
mixture was defrozen in an ice bath and stirred for 30 min. A
weighed sample (237 mg, 1.40 mmol) of pentafluoropyridine was
degassed by three cycles of freezing–evacuation–defreezing and
then transferred into the reaction flask. The reaction mixture was
stirred at 0 8C for 1.5 h and neutralized with acetic acid (240 mg,
4.00 mmol), which was preliminarily degassed and then trans-
ferred into the reaction flask as indicated above. Volatile
components of the reaction mixture were removed in vacuo. The
reaction flask was disconnected from the vacuum line, and
benzene (15 mL) was added. The precipitate was filtered off and
washed with benzene on the filter. The mother liquor was
4. Experimental
4.1. General
1H, 13C{1H}, 19F, and 31P{1H} NMR spectra were recorded on a
Bruker Avance-400 instrument. Chemical shifts (d) are reported in
ppm relative to TMS (0 ppm for 1H NMR), solvent CDCl3 (77.0 for
13C NMR), residual CHCl3 (7.25 for 1H NMR) or HDO (4.75 for 1H
NMR), external 85% H3PO4 (0 ppm for 31P NMR) and CFCl3 (0 ppm
for 19F NMR). Infrared spectra were obtained using SPECORD 75 IR
and Carl Zeiss UR-20 spectrophotometers. Elemental analysis was
performed on an Elementar Vario MICRO Cube analyzer.
THF was distilled from and stored under sodium benzophenon
ketyl. Ethanol was dried over calcium ethoxide. Glacial acetic acid
was purified by reiterated fractional freezing. Pentafluoropyridine,
octafluorotoluene, octafluoronaphthalene, pentafluorobenzalde-
hyde, pentafluoroaniline, potassium hydride (with 65% paraffin oil,
Merck), sodium hydride (60% dispersion in mineral oil, Aldrich),
potassium tert-butoxide (98%, Acros), and hydrazine monohydrate
(98%, Aldrich) are commercially available and were used as
received.
concentrated on
a rotary evaporator, and the residue was
recrystallized from petroleum ether. The crystals precipitated
were filtered off and washed with hexane. Product 2a was obtained
as white crystals in a yield of 305 mg (70%). IR (Nujol):
n
1261,
1043, 1018, 980, 779 cmÀ1 1H NMR (400 MHz, CDCl3):
; d 1.23 (t,
3JH,H = 7.1 Hz, 3H, CH3), 1.36 (t, 3JH,H = 7.1 Hz, 3H, CH3), 4.14 (m, 2H,
2
4.2. Diethyl (diphenylmethyleneamino)methanephosphonate (1)
CH2), 4.32 (m, 2H, CH2), 5.53 (d, JP,H = 18.8 Hz, 1H, PCH), 7.15
3
(br.m, 2H, arom.), 7.35 (t, JH,H = 7.6 Hz, 2H, arom.), 7.42–7.48 (m,
A solution of diethyl aminomethanephosphonate (prepared
4H, arom.), 7.71 (d, 3JH,H = 7.9 Hz, 2=, arom.); 13E NMR (101 MHz,
from
diethyl
N-phthalimidomethanephosphonate
(7.16 g,
CDCl3): d
16.04 (3JC,E = 5.9 Hz, CH3), 16.21 (3JC,E = 6.0 Hz, CH3),
24.0 mmol) and hydrazine monohydrate (1.5 mL, 31.7 mmol)
according to protocol [15]) in benzene (50 mL) was cooled to
10 8C and diphenylmethyleneimine (4.8 mL, 28.7 mmol) was
added with stirring. Warning: Due to hazardous properties of
benzene, all work should be performed in well ventilated chemical
fume-hood. The mixture was stirred at room temperature under an
58.65 (1JC,E = 161.2 Hz, CP), 63.30 (2JC,E = 6.9 Hz, CH2), 64.26
(2JC,E = 6.3 Hz, CH2), 127.28 (2CH arom.), 128.06 (2CH arom.),
128.72 (2CH arom.), 128.93 (2CH arom.), 129.18 (CH arom.),
130.03 (EArF), 131.04 (CH arom.), 134.63 (C arom.), 138.42 (C
arom.), 140.17 (1JF,E = 263.0 Hz, 2EF), 143.42 (1JF,E = 246.2 Hz, 2EF),
174.23 (3JC,E = 17.6 Hz, E55N); 19F NMR (376 MHz, CDCl3):
d
À91.17

30
N.S. Goulioukina et al. / Journal of Fluorine Chemistry 136 (2012) 26–31
3
(2F), À139.27 (2F); 31P NMR (162 MHz, CDCl3):
d
16.89. Anal. Calcd.
7.44 (m, 4H, arom.), 7.72 (d, J=,= = 7.8 Hz, 2=, arom.); 13E NMR
for C23H21F4N2O3P: E, 57.51; H, 4.59; N, 5.76. Found: E, 57.50; H,
(101 MHz, CDCl3):
d
16.24 (3JC,E = 5.9 Hz, CH3), 16.35 (3JC,E = 6.0 Hz,
4.41; N, 5.83.
CH3), 58.26 (1JC,E = 165.1 Hz, CP), 63.28 (2JC,E = 6.6 Hz, CH2), 63.91
(2JC,E = 6.2 Hz, CH2), 107.66 (EArF), 110.93 (EArF), 115.30 (EArF),
127.42 (2CH arom.), 128.11 (2CH arom.), 128.68 (2CH arom.),
128.99(2CH arom.), 129.07(CH arom.), 130.92(CH arom.), 135.13 (C
arom.), 138.80 (C arom.), 138.53 (1JF,E = 255.4 Hz, EF), 139.63
4.3.1. Diethyl (diphenylmethyleneamino)(2,3,5,6-tetrafluoro-4-
trifluoromethylphenyl)methanephosphonate (2b)
Synthesized similarly to 2a in 71% yield from Schiff base 1
(300 mg, 0.91 mmol), potassium hydride (with 65% paraffin oil,
310 mg, 2.71 mmol), and octafluorotoluene (333 mg, 1.40 mmol).
Acetic acid (240 mg, 4.00 mmol) was used for neutralization.
(1JF,E = 254.6 Hz, EF), 140.84 (1JF,E = 251.2 Hz, 2EF), 141.34 (1JF,E
258.8 Hz, EF), 146.55 (1JF,E = 257.1 Hz, EF), 150.32 (1JF,E = 256.3 Hz,
=
EF), 173.64 (3JC,E = 18.2 Hz, E55N); 19F NMR (376 MHz, CDCl3):
d
White crystals. IR (Nujol):
n
1270, 1165, 1055, 1030, 990,
À155.91 (1F), À153.43 (1F), À148.78 (4JF,F = 57.4 Hz, 1F), À146.37
795 cmÀ1 1H NMR (400 MHz, CDCl3):
;
d 1.23 (t, JH,H = 7.1 Hz,
(4JF,F = 57.4 Hz, 1F), À143.64 (4JF,F = 71.5 Hz, 1F), À132.18 (1F),
3
3H, CH3), 1.34 (t, 3JH,H = 7.1 Hz, 3H, CH3), 4.14 (m, 2H, CH2), 4.30 (m,
2H, CH2), 5.51 (d, 2JP,H = 18.6 Hz, 1H, CCH), 7.13 (br.m, 2=, arom.),
7.34 (t, 3J=,= = 7.6 Hz, 2H, arom.), 7.40–7.47 (m, 4H, arom.), 7.70 (d,
À116.01 (br., 1F); 31P NMR (162 MHz, CDCl3):
d 18.49. Anal. Calcd.
forC28H21F7NO3P:E, 57.56;H, 3.68;N, 2.53. Found: E, 57.64;H, 3.63;
N, 2.40.
3J=,= = 7.9 Hz, 2=, arom.); 13E NMR (101 MHz, CDCl3):
(3JC,E = 5.9 Hz, CH3), 16.37 (3JC,E = 6.0 Hz, CH3), 58.17 (1JC,E
d 16.22
=
4.4. Diethyl amino(2,3,5,6-tetrafluoropyridin-4-
163.8 Hz, CP), 63.36 (2JC,E = 6.9 Hz, CH2), 64.18 (2JC,E = 6.1 Hz,
CH2), 119.38 (EArF), 121.10 (EArF), 122.56 (1JF,E = 264.7 Hz, CF3),
127.41 (2CH arom.), 128.17 (2CH arom.), 128.77 (2CH arom.),
129.04 (2CH arom.), 129.20 (CH arom.), 131.07 (CH arom.), 134.92
(C arom.), 138.65 (C arom.), 143.99 (1JF,E = 258.8 Hz, 2EF), 145.10
(1JF,E = 254.6 Hz, 2EF), 174.03 (3JC,E = 16.9 Hz, E55N); 19F NMR
yl)methanephosphonate hydrochloride (3)
A solution of phosphonate 2a (48.4 mg, 0.1 mmol) in THF (8 mL)
and 1 N hydrochloric acid (1 mL) was stirred at 0 @E for 1 h. THF
was removed on a rotary evaporator. The residue was extracted
with ether (3 Â 3 mL) to remove benzophenone, neutralized with
sodium hydrocarbonate, and extracted with chloroform
(3 Â 3 mL). The extract was dried over magnesium sulfate, and
the solvent was removed on a rotary evaporator. The obtained
diethyl amino(2,3,5,6-tetrafluoropyridin-4-yl)methanephospho-
nate was treated with an excess of HCl solution in ethanol. After
removing of volatile components in vacuo hydrochloride 3 was
(376 MHz, CDCl3):
d
À56.39 (4JF,F = 21.6 Hz, 3F, CF3); À135.76 (2F),
À140.85 (2F); 31P NMR (162 MHz, CDCl3):
d 17.54. Anal. Calcd. for
C
25H21F7NO3P: E, 54.94; H, 4.09; N, 2.54. Found: E, 54.85; H, 3.87;
N, 2.56.
4.3.2. Diethyl (diphenylmethyleneamino)(4-diethoxymethyl-2,3,5,6-
tetrafluorophenyl)methanephosphonate (2F)
Synthesized similarly to 2a in 71% yield from Schiff base 1
(300 mg, 0.91 mmol), potassium hydride (with 65% paraffin oil,
310 mg, 2.71 mmol), and diethoxymethylpentafluorobenzene [22]
(380 mg, 1.40 mmol). Acetic acid (240 mg, 4.00 mmol) was used
obtained in a yield of 25.0 mg (71%). 1H NMR (400 MHz, D2O):
d
3
1.31 (t, JH,H = 7.1 Hz, 6H, CH3), 4.27 (m, 4H, OCH2), 5.52 (d,
2JP,H = 20.4 Hz, 1H, PCH); 31P NMR (162 MHz, D2O):
d 13.40.
4.5. Diethyl (pentafluorophenyl)amidophosphate (4)
for neutralization. Yellow crystals. IR (Nujol):
n 1265, 1070, 1030,
960, 795 cmÀ1; 1H NMR (400 MHz, CDCl3): 1.21 (t, 3JH,H = 7.1 Hz,
d
Obtained in 72% yield similarly to 2a from Schiff base 1 (300 mg,
0.91 mmol), potassium hydride (with 65% paraffin oil, 310 mg,
2.71 mmol), and N-benzylidenepentafluoroaniline [23] (380 mg,
1.40 mmol), which was added to the reaction mixture from a retort
connected with the reaction flask. Acetic acid (240 mg, 4.00 mmol)
was used for neutralization. White crystals. 1H NMR (400 MHz,
3H, CH3), 1.24 (t, 3JH,H = 7.0 Hz, 3H, CH3), 1.25 (t, 3JH,H = 7.0 Hz, 3H,
CH3), 1.32 (t, 3JH,H = 7.1 Hz, 3H, CH3), 3.57 (m, 2H, CH2), 3.75 (m, 2H,
CH2), 4.11 (m, 2H, CH2), 4.28 (m, 2H, CH2), 5.47 (d, 2JP,H = 18.1 Hz,
1H, CCH), 5.69 (s, 1=, CH(OEt)2), 7.13 (br.m, 2=, arom.), 7.31 (t,
3JH,H = 7.6 Hz, 2H, arom.), 7.37–7.44 (m, 4H, arom.), 7.69 (d,
3JH,H = 7.9 Hz, 2=, arom.); 13E NMR (101 MHz, CDCl3):
d
14.96
CDCl3): d
1.34 (t, 3JH,H = 7.1 Hz, 6H, CH3), 4.15–4.23 (m, 4H, OCH2),
(2CH3), 16.19 (3JC,E = 5.9 Hz, CH3), 16.34 (3JC,E = 6.0 Hz, CH3), 57.97
(1JC,E = 165.2 Hz, CP), 63.10 (2JC,E = 6.9 Hz, CH2), 63.53 (CH2), 63.62
(CH2), 64.92 (2JC,E = 6.2 Hz, CH2), 96.56 (CH(OEt)2), 116.42 (EArF),
117.06 (EArF), 127.49 (2CH arom.), 128.04 (2CH arom.), 128.61
(2CH arom.), 128.96 (3CH arom.), 130.79 (CH arom.), 135.01 (C
arom.), 138.86 (C arom.), 144.37 (1JF,E = 251.2 Hz, 2EF), 144.83
(1JF,E = 255.4 Hz, 2EF), 173.26 (3JC,E = 17.7 Hz, E55N); 19F NMR
4.80 (s, 1H, NH); 13E NMR (101 MHz, CDCl3): 15.98 (3JC,E = 6.7 Hz,
d
CH3), 63.61 (2JC,E = 5.1 Hz, CH2), 114.70 (EArF), 137.81
(1JF,E = 249.6 Hz, 2EF), 138.15 (1JF,E = 252.9 Hz, EF), 142.16
(1JF,E = 256.3 Hz, 2EF); 19F NMR (376 MHz, CDCl3):
d
À149.36
(2F), À160.98 (3JF,F = 21.7 Hz, 1F), À126.99 (2F); 31P NMR
(162 MHz, CDCl3):
d 1.01. Anal. Calcd. for C10H11F5NO3P: E,
37.81; H, 3.55; N, 4.43. Found: E, 37.63; H, 3.47; N, 4.39.
(376 MHz, CDCl3):
d
À138.32 (2F), À143.60 (J = 21.7 Hz and
12.1 Hz, 2F); 31P NMR (162 MHz, CDCl3):
d
18.54. Anal. Calcd.
Acknowledgments
for C28H32F4NO5P: E, 59.75; H, 5.77; N, 2.55. Found: E, 59.89; H,
5.55; N, 2.41.
This work was performed in the framework of CNRS French-
Russian Associated Laboratory ‘‘LAMREM’’ supported by the
Russian Foundation for Basic Researches (Grant No. 09-03-
01128-a), CNRS, and by a doctoral fellowship of the French
Ministry of Foreign Affairs awarded to A. Mirofanov. The authors
are also grateful to Dr P.K. Sazonov (Chemistry Department of
Moscow State University) for valuable practical help.
4.3.3. Diethyl (diphenylmethyleneamino)(1,3,4,5,6,7,8-heptafluoro-
2-naphthyl)methanephosphonate (2d)
Synthesized similarly to 2a in 75% yield from Schiff base 1
(300 mg, 0.91 mmol), potassium hydride (with 65% paraffin oil,
310 mg, 2.71 mmol), and octafluoronaphthalene (380 mg,
1.40 mmol). All reactants, including octafluoronaphthalene, were
loaded into the flask before THF was added. Acetic acid (240 mg,
4.00 mmol) was used for neutralization. Yellow-brown crystals. IR
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