Fluorinated NH-iminophosphonates and iminocarboxylates: Novel synthons for the preparation of biorelevant α-aminophosphonates and carboxylates

Article abstract of DOI:10.1016/j.tet.2014.03.030

A convenient synthetic approach to previously unknown N-H α-iminophosphonates and iminotrifluoropropionates was developed. The synthetic potential of N-H iminophosphonates and iminotrifluoropropionates, existing as an equilibrium mixture of E/Z-isomers, w

Full text of DOI:10.1016/j.tet.2014.03.030

Tetrahedron 70 (2014) 2928e2937
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Fluorinated NH-iminophosphonates and iminocarboxylates: novel
synthons for the preparation of biorelevant
a-aminophosphonates
and carboxylates
,
,
Yuliya V. Rassukana a b, Ivanna P. Yelenich a, Anatoly D. Synytsya a, Petro P. Onys’ko a
*
a Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmans’ka str., Kyiv 02660, Ukraine
b Department of Organic Chemistry, National Technical University of Ukraine ‘Kyiv Polytechnic Institute’, 37, Prospect Peremogy, Kyiv, 03056, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthetic approach to previously unknown NeH
fluoropropionates was developed. The synthetic potential of NeH iminophosphonates and iminotri-
fluoropropionates, existing as an equilibrium mixture of E/Z-isomers, was demonstrated by their easy
a-iminophosphonates and iminotri-
Received 30 December 2013
Received in revised form 23 February 2014
Accepted 11 March 2014
functionalization to afford biorelevant fluorinated
a
-aminophosphonic and
a-aminocarboxylic acid
Available online 18 March 2014
derivatives.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Iminophosphonates
Iminocarboxylates
NeH imines
Fluoroalkyl
Aminophosphonates
Aminocarboxylates
1. Introduction
task. Fluorinated imidoyl phosphonates and carboxylates are at-
tractive and promising building blocks for construction of func-
tionalized aminophosponates and carboxylates for several reasons:
(1) the compounds already contain the ‘oxidized’ fragment of the
aminocarboxylic or aminophosphonic acid; (2) electron-with-
drawing phosphonyl or alkoxycarbonyl groups and fluorinated
substituents additionally activate the C]N bond leading to an in-
crease in reactivity; (3) the compounds with a free NeH group seem
especially promising for this purpose as they can be functionalized
both by nucleophilic addition across the C]N bond, and electro-
philic substitution at the nitrogen atom; (4) functionalization of NH-
iminophosphonates and iminocarboxylates leads directly to N-un-
protected aminophosphonates and aminocarboxylates; note that
the removal of protecting groups in highly functionalized amino-
phosphonates and aminocarboxylates (especially in those, bearing
electron-withdrawing groups) is often accompanied by the cleavage
The chemistry of a-amino acids and their phosphorus analogs
has been extensively developed in recent years, first of all due to the
wide spectrum of biological activity of these compounds. The rap-
idly expanding interest in the field of peptidomimetics has
prompted chemists to develop novel and efficient approaches to
unnatural amino acids. An extremely intriguing class of unnatural
amino acids is represented by those incorporating one or more
fluorine atoms. It is generally accepted that substitution of a hy-
drogen by a fluorine, or introduction of a trifluoromethyl group in
place of a methyl, may improve the pharmacodynamic and the
pharmacokinetic profiles of the compound by concomitant alter-
ation of its electronic, lipohilic, and steric characteristics as well as
its metabolic stability.1,2 As a result, selectively fluorinated ana-
logues of biologically active compounds can be considered to be
valuable candidates for drug discovery. Specifically,
a
-tri-
of CeP bond or decarboxylation. At the same time, N-unprotected
iminophosphonates were unknown until recently.4 On the other
hand, attempts to synthesize -iminotrifluoropyruvate by reaction
a-
fluoromethylated amino acids are known to be potent inhibitors of
pyridoxal phosphate-dependent enzymes, which catalyze trans-
amination and decarboxylation processes.3 Therefore, the de-
velopment of methods for such compounds remains a challenging
a
of methyl trifluoropyruvate with hexamethyldisilazane failed.5 In
the present work, we propose new simple and effective approaches
to fluorinated NH-iminophosphonates and carboxylates and reveal
their synthetic potential as promising building blocks for the
preparation of biorelevant fluorinated aminophosphonic and car-
boxylic acid derivatives.
* Corresponding author. Tel./fax: þ380 44 573 25 94; e-mail address: onysko@
rambler.ru (P.P. Onys’ko).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.030

Y.V. Rassukana et al. / Tetrahedron 70 (2014) 2928e2937
2929
2. Results and discussion
depends on the fluorinated substituent at C]N bond, but it is
practically independent of the nature of the phosphonyl group.
Identification of Z,E-isomers is based mainly on the significant
difference in coupling constants of the NeH proton and phospho-
rus atom (37e39 and 58e60 Hz, respectively). The dynamic equi-
librium between geometrical isomers was substantiated by the fact
that on heating imine 3a in toluene-d8 solutions, the NeH proton
signals of the Z/E-isomers first broaden then coalesce (w100 ꢀC). On
cooling to rt the starting state is recovered.
Less nucleophilic diphenyl phosphite reacts with fluorinated
nitriles in the same manner to afford imidoyl phosphonates 4, as
a dynamic mixture of Z/E-isomers. This reaction, unexpectedly,
proceeds essentially faster than with its dialkyl analogs, and is
completed in less than 1 h at room temperature. Note that in the
three-component KabachnikeFields reaction, diphenyl phosphite
reacted slower than diethyl phosphite.9
It turned out that iminophosphonates 4, on storage at room
temperature, undergo partial dissociation to the starting com-
pounds. Diphenyl phosphite, formed upon dissociation, quickly
adds to the activated C]N bond of starting iminophosphonates
4a,b to form stable geminal bisphosphonates 5a,b, which are the
final products of this reaction (Scheme 3). The reversibility of
iminophosphonate formation was verified experimentally by direct
observation of low intensity NMR signals of the starting nitrile and
phosphite upon dissolution of pure 4a in deuterochloroform, and
also by cross-experiment: addition of diethyl phosphite to imine 4a
results in partial formation of iminophosphonate 3a, detected by
31P NMR spectroscopy.
2.1. Synthesis of fluorinated NH-iminophosphonates
In the last decades, several methods to prepare imidoyl phos-
phonates bearing various substituents at the nitrogen atom were
developed in our laboratory.6 None of them, however, can be used
for synthesis of NH-imidoyl phosphonates. Addition of hydro-
phosphoryl compounds to the triple bond of nitriles represents the
most straightforward route to such compounds. Analysis of the
literature data shows, however that in reactions of nitriles with
dialkyl phosphites, the respective iminophosphonates were never
isolated or even detected as reaction intermediates.7 Thus, sodium
salts of dialkyl phosphites react with nitriles to yield phosphor-
ylamino phosphonates 1.7a In the presence of acids,7b,c or under free
radical conditions7d aminobisphosphonates 2, as the main products,
were reported to form in low to moderate yields (Scheme 1).
O
(AlkO)2P
Ph
O
O
R = Ph
EtONa
(AlkO)2P
P(OEt)2
N
H
NH
RCN
+
Ph
1
O
H
(EtO)2P
O
(AlkO)2P
H3O+ or
Cp2TiCl4, Zn,
O
R
NH2
2
(EtO)2P
Alk= Et, Pr
R=Alk, Ar, cycloalkyl, 2-Py
O
Scheme 1.
Most probably, the reactions in Scheme 1 do involve initial
formation of the iminophosphonate followed by fast addition of
a second molecule of phosphite resulting in aminobisphosphonates
2. Formation of phosphorylamino phosphonates 1 was explained
by C,N-phosphoryl shift in intermediate aminobisphosphonates7a
(cf. Ref. 8). It was claimed that for ordinary nitriles addition of
dialkyl phosphites under conditions of base catalysis is not char-
acteristic.7b We believed that in the case of highly electrophilic
fluorinated acetonitriles the reaction could be stopped at the first
stage due to the higher reactivity of the C^N bond and the mild
reaction conditions.
Indeed, we have found that dialkyl phosphites react with
difluoro- or trifluoroacetonitriles in the presence of a catalytic
amount of nitrogen base at room temperature to form imino-
phosphonates 3 in high yields (Scheme 2). Formation of the PeC
bond is confirmed by 13C NMR spectra of compounds 3 in which the
(PhO)2P
RF
O
(PhO)2P
RF
O
(PhO)2P(O)H
+
H
NH2 80-90%
N
RF
N
O
P(OPh)2
5a,b
4a,b
4a, 5a: RF =CF3
4b, 5b: RF = CHF2
Scheme 3.
Thus, the iminophosphonates 4 are products of kinetic control,
and bisphosphonates 5dthe products of thermodynamic control.
The presented scheme offers an excellent preparative approach
to biorelevant fluorinated aminobisphosphonates 5. It is worth-
while noting that peptidomimetics bearing
a diaryl amino-
phosphonate fragment exhibit high activity as serine protease
inhibitors, due to the possibility of covalent binding with the en-
zyme by means of substitution of an aroxy group at the phosphorus
imine C-atom signal (d 167e171 ppm) with a large direct CeP
coupling constant (JCP 150e164 Hz) was identified. It is worthwhile
noting that the less electrophilic fluoroacetonitrile, CH2FCN, does
not react with hydrophosphoryl compounds under the same
conditions.
atom.10 The diverse biomedical potential of diaryl
a-amino-
phosphonates for the treatment of various pathologies, such as
cancer and metastasis, inflammatory diseases, emphysema, hy-
pertension, type 2 diabetes, infections, immunological and fibro-
genic disorders, has been discussed.10,11a
O
O
(AlkO)2P
RF
(AlkO)2P
RF
H
O
Et3N
(AlkO) P
+
RFCN
+
N
N
2
2.2. Synthesis of a-iminotrifluoropropionates
H
r.t., 7 days
H
(Z)-3
(E)-3
An essentially different methodology, namely the aza-Wittig
reaction of commercially available trifluoropyruvates with triphe-
nylphosphine imide, was used for the synthesis of NeH imines of
trifluoropyruvate.12 It is noteworthy that at rt the reaction leads
initially to a mixture (w1:10) of the respective imine 8 and phos-
phine imide 7 (dF ꢁ80.2 to ꢁ80.4 ppm, dP 4.2e4.6 ppm). The latter
results from nucleophilic addition of the imino NeH function of
triphenylphosphine imide across the highly electrophilic C]O
bond of 6. Imides 7 are stable at rt in ethereal or benzene solutions,
but upon heating or thermal distillation they cleanly convert into
Z/E
3a: RF =CF3; Alk = Et; 10 :1
3b: RF = CF3; Alk= Pr, 10 :1
3c: RF =CHF2; Alk = Et; 5:1
Scheme 2.
In solution, imidoyl phosphonates 3 exist as an equilibrium
mixture of Z/E-isomers, the more sterically hindered Z-configura-
tion being thermodynamically preferable. The Z/E ratio essentially

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Y.V. Rassukana et al. / Tetrahedron 70 (2014) 2928e2937
imines 8. We believe that the transformation 7/8 involves 1,3-
proton transfer followed by elimination of triphenylphosphine
phosphonyl or alkoxycarbonyl groups being in the syn-position
with the ]NH hydrogen atom. At the same time the ]CeP bond in
the iminophosphonates is prone to scission. This peculiarity reveals
itself in partial dissociation of compounds 4 and their subsequent
transformations (Scheme 3). That is why iminophosphonates 4a,b
were not isolated in analytically pure state, and should be used in
synthesis immediately after preparation.
The feasibility of transforming imines 3, 4, 8 into amino-
phosphonic or aminocarboxylic acid derivatives possessing fluo-
roalkyl group are demonstrated by their reduction, addition
reactions or cyclocondensations with bifunctional reagents.
oxide in the classical aza-Wittig reaction intermediate
A
(Scheme 4). Compounds 8 are quite stable in dry, inert atmospheres
and can be easily purified by distillation. In solution, imino-
carboxylates 8, like their phosphorus analogs 3 and 4, exist as
equilibrium mixture of the E/Z-isomers (E/Zz10:1 at 25 ꢀC). Iden-
tification of E,Z-isomers is based on a comparison of 1H, 19F NMR
spectroscopic characteristics with those of the respective imino-
phosphonates 3, 4.
OH
O
C
O
C
2.3.1. Reduction and addition of XeH nucleophiles. Reduction of the
C]N bond of iminophosphonates 3a,b with BH3$Me2S in toluene
solution quantitatively leads to fluorinated aminophosphonates
9a,b. Compound 9a was hydrolyzed under acidic conditions to af-
F3C
RO
N
PPh3
7a,b
+
Ph3P NH
F3C
OR
O
6a,b
+
O
ford a
-aminotrifluoroethylphosphonic acid 10 (Scheme 5).4 Both
PPh3
F3C
Δ
iminophosphonates 3,4 and iminocarboxylates 8 readily react with
P-, N-, O-, and S-centered XeH nucleophiles to give biorelevant
highly functionalized fluorinated aminophosphonates and amino-
carboxylates 5, 11e16. The unusual stability of aminals 11e16 is
most likely caused by the presence of the electron-withdrawing
phosphonyl or alkoxycarbonyl group and fluorinated substituents.
At the same time, adducts 13 in CDCl3 solutions, according to NMR
spectroscopy, partially (about 5e10%) dissociate into the starting
F3C
RO
N H
N
H
-Ph3PO
ROOC
O
8a,b
A
6a-8a: R =Me
6b-8b: R = Et
Scheme 4.
E
(EtO)2P
O
N H
Me2S*BH3
THF
ArSH
RF
RF
NH2
H
3a,b; 4a,b; 8a,b
9a,b
R'2P(O)H
RO
ArNH2
ROH
HCl
E
HO
HO
F3C
E
P=O
(EtO)2P
O
RO
RF
P
O
RF
RO
13a-d, 14
RF
ArS
F3C
NH2
NH2
O
NH2
NH2
NH2
R'2P
ArNH
H
12a,b
15a,b; 16
5a, 11a,b
10
9: RF = CF3 (a), CHF2 (b); 11: R = Et, RF = CF3, R′ = Ph (a), PhO (b);
12: Ar = 4-MeOC6H4 (a), 4-MeC6H4 (b); 13: E = P(O)(OEt)2, RF = CF3,
R = Me (a), Et (b), 2-PyCH2 (c), RF = CHF2, R = Me (d); 14: E = COOMe, RF =CF3, R =
Me; 15: E = P(O)(OEt)2, RF = CF3, Ar = 4-CH3C6H4 (a), 4-FC6H4 (b); 16: E = COOMe, RF
=CF3, Ar = 4-CH3C6H4 (a), 4-FC6H4 (b)
Scheme 5.
2.3. Chemical reactivity
compounds. Hence, adducts 13 serve as masked sources of the
corresponding imines 3: we have successfully explored this prop-
erty for the improvement of the enantiomeric excess in catalytic
asymmetric reduction by maintaining a beneficial catalyst/imine
ratio during the course of a reaction.14
The simple preparative access to fluorinated heminal diphos-
phorylated derivatives of the type 5, 11, bearing the same or dif-
Iminophosphonates 3,4 and iminocarboxylates 8 contain a po-
larized azomethyne group and are promising building blocks in the
synthesis of aminophosphonic and aminocarboxylic acid de-
rivatives with a fluoroalkyl group. Two electron-withdrawing
groups at the imine carbon atom essentially activate the C]N
bond allowing, addition of nucleophilic reagents under mild and
neutral conditions. As alkoxycarbonyl and phosphonyl groups have
close electronic parameters [sp 0.45 and 0.52 for COOEt and
(EtO)2PO substituents, respectively],13 one would expect similar
reactivity for the respective iminophosphonates and imino-
carboxylates. In addition, the compounds have similar geometry:
preferential Z-configuration for iminophosphonates 3,4 and E-
configuration for iminocarboxylates 8, in both cases the more bulky
ferent phosphorus groups at the
a-carbon atom, is of special
importance when taken into consideration the wide spectrum of
biological activity exhibited by compounds containing a PeCeP
triad, in particular by aminomethylenebisphosphonates. The drugs
on their bases are widely used in the treatment of diseases caused
by a disorder in calcium or phosphate exchange (Paget’s disease,
bone metastasis, myeloma, osteoporosis, steroid-induced osteo-
genesis), inflammations, and so on.11 The pharmacological effect of

Y.V. Rassukana et al. / Tetrahedron 70 (2014) 2928e2937
2931
the drugs essentially depends on the lipophilic and electronic
characteristics of the substituents at the C and N atoms.
It is noteworthy that all these reactions occur at room temper-
ature, almost quantitatively, and do not require base or acid
catalysis.
respectively, whereas the latter under the same conditions affords
only 2-pyrrolylaminocarboxylate 23 (Scheme 7).
We believe that the steric influence of the substituent is
mainly responsible for the change in regioselectivity of pyrrole
aminoalkylation. In the absence of steric shielding (NeH pyrroles)
the reaction proceeds as expected in the
a-position, whereas
2.3.2. Aminoalkylation of electron-rich heterocycles. Reactions of
fluorinated NH-iminocarboxylates and iminophosphonates with
electron-rich heterocycles offers a novel approach to direct CeC
bond formation, and introduction of an aminophosphonic or ami-
nocarboxylic fragment into the heterocyclic nucleus. Amino-
alkylation of indoles 17aec, independently of the R1 and R2
substituents, proceeds regioselectively into the 3-position of the
heterocycle (Scheme 6).
a bulky tert-butyl substituent favors -aminoalkylation. In line
b
with this, differences in regioselectivity for phosphonate 3a and
carboxylate 8a can be accounted for by reduced steric re-
quirements of the less bulky COOMe group in 8a (as compared
with the (EtO)2PO substituent in 3a). Steric control of the regio-
chemistry of electrophilic substitution in pyrroles was observed
earlier in the example of electrophilic phosphorylation with
phosphorus(III) halides.15
2.3.3. Cyclocondensations and dipolar cycloaddition. Cycloconden
sations with bifunctional compoundsdthioglycolic, 3-mercapto
propionic, or 2-mercaptobenzoic aciddallow the preparation of
biologically promising thiazolidone 27, 28, thiazinanone 29, 30 or
benzothiazine derivatives 31 and 32 bearing a polyfluorinated
aminophosphonic or aminocarboxylic acid fragment as part of
a five- or six-membered heterocycle (Scheme 8).
O
P(OEt)2
3a
NH2
CF3
N
R2
18a-c
R1
N
R2
COOMe
Primary adducts A resulting from reactions of 3a with thio-
glycolic (Scheme 8) acid can be detected only spectroscopically.
Even at room temperature, they undergo intramolecular ring clo-
sure to give the previously unknown C-phosphorylated thiazoli-
dones 27. The ease of cyclization is explained by the steric
accessibility of the unsubstituted N-nucleophilic center in adduct A
and beneficial five-membered ring formation.
R1
8a
NH2
CF3
17a-c
R1 = R2 = H
19
N
H
17, 18: R1= R2 = H (a), R1 =H, R2 = Me (b); R1 = Me, R2 = H (c)
Scheme 6.
Synthetic advantages of NeH imines clearly reveal themselves
in the reaction with salicylic aldehyde. In this case, both the elec-
trophilic imine carbon and the nucleophilic NeH function are in-
volved in the process (Scheme 9).
This interesting reaction proceeds via addition of the OeH group
across C]N bond of imines 3, 8. Subsequent creation of a novel C]
N bond by means of the intramolecular condensation of amino
In contrast, regioselectivity of pyrroles aminoalkylation is con-
trolled by the N-substituent in the heterocycle (Scheme 7). Thus,
pyrrole and 2,4-dimethylpyrrole give exclusively
a-substituted
products 20 and 21, whereas N-tert-butyl pyrrole is aminoalkylated
R
R
E
R
N
H
20a,b; 21a,b
R
N
NH2
H
CF3
O
P(OEt)2
E
N
NH2
CF3
E
+
NH2
CF3
N
H
N
N
F3C
3a; 8a,b
24
22; 23
22/24 = 4:1
E
NH2
N
CF3
25, 26
N
20: E = P(O)(OEt)2, R = H (a), Me (b); 21: E = COOEt, R = H (a), E = COOMe, R = Me (b);
22, 25: E = P(O)(OEt)2; 23, 26: E = COOMe
Scheme 7.
at the
b
-position. Different regioselectivity was observed for the
group thus formed, with the carbonyl moiety leads to benzoxazines
33, 34 bearing a fluoroalkyl and phosphonate or methoxycarbonyl
function. Note that the latter reaction is possible only for imines
with a free NeH function.
reaction of iminophosphonate 3a and iminocarboxylate 8a with N-
methylpyrrole: the first reacts non-selectively to give a mixture
(4:1) of 2- and 3-pyrrolylaminophosphonates 22 and 24,

2932
Y.V. Rassukana et al. / Tetrahedron 70 (2014) 2928e2937
transformation 36/37 is completed within 30 min at room tem-
E
HS
COOH
H
E
N
perature. Note that analogs of NH-diazoline 36, bearing a XC6H4
group at the N-4 atom, are quite stable compounds and have close
chemical shifts (dP¼6.7e8.3 ppm).16 The differences in stability of
oxadiazolines 35 and their phosphorus analog 36 can be accounted
for by a higher nucleofugicity of the (EtO)2PO substituent.
O
NH2
RF
r.t., C6H6
S
COOH
RF
S
A
27 a,b; 28
E
S
COOH
E
HS
r.t., C6H6
RF
N
H
N
H
2.3.4. Electrophilic functionalization at nitrogen atom. The presence
of two electron-withdrawing groups results in reduced nucleo-
philicity of the imine nitrogen atom in compounds 3, 8, therefore
they can react only with strong electrophiles. The possibility for
functionalization at the nitrogen atom is exemplified by reaction of
3a with trichloroacetyl isocyanate, leading to a new type of syn-
thetically promising activated C-phosphorylated N-acylimine 37.4
Iminocarboxylate 8a reacts with methyl trifluoropyruvate also
without involvement of the C]N bond to afford highly function-
alized imine 38 resulting from addition of the NeH function across
the highly electrophilic C]O bond (Scheme 11).12
RF
29 a,b; 30
3a,b; 8a
O
SH
E
S
COOH
r.t., C6H6
RF
N
H
O
31 a,b; 32
27a, 29a, 31a: E = P(O)(OEt)2, RF = CF3
27b, 29b, 31b: E= P(O)(OEt)2, RF = CHF2
28, 30, 32: E = COOMe, RF = CF3
Scheme 8.
O
O
O
(EtO)2P
~100%
CCl3C(O)NCO
3a,b +
N
N
N
H
CCl3
F3C
37a,b
E
E
OH
F3C
O
O
OH
COOMe
CF3
CF3C(O)COOMe
+
8a
3a,c, 8a
~100%
RF
RF
N
-H2O
MeOOC
NH2
CHO
38
O
33a,b, 34
B
Scheme 11.
33a: E = P(O)(OEt)2, RF = CF3
3. Conclusions
33b: E = P(O)(OEt)2, RF = CHF2
34: E = COOMe, RF = CF3
In summary, we have developed a simple and efficient synthesis
of previously unknown fluorinated NeH -iminophosphonates 3,4
a
Scheme 9.
and iminotrifluoropropionates 8, and demonstrated their consid-
erable potential as novel convenient building blocks in the design
In reactions with dipolar compounds, NH-iminocarboxylates
and iminophosphonates behave as dipolarophiles. Thus, reaction
of 8a with nitrile oxides, generated from the respective hydrox-
ymoyl chlorides, affords oxadiazolines 35, bearing a fragment of
trifluoroalanine. Reaction with iminophosphonate 3a also leads
initially to the unstable [3þ2]-cycloaddition product 36, which
even at room temperature undergoes fast elimination of diethyl
phosphite to form trifluoromethylated oxadiazole 37 (Scheme 10).
Intermediate oxadiazoline 36 was detected by 31P and 19F NMR
spectroscopy within 10 min after the onset of the reaction
and synthesis of biorelevant
a-aminophosphonates, a-aminobi-
sphosphonates, and -aminocarboxylates bearing a trifluoromethyl
a
or difluoromethyl group. The electron-deficient nature of the im-
ines makes them promising substrates for the preparation of vari-
ous functionalized acyclic and heterocyclic derivatives with an
aminophosphonic or aminocarboxylic fragment by the use of re-
ductive nucleophilic addition reactions, direct aminoalkylation of
electron-rich heterocycles, cyclocondensations, and dipolar cyclo-
addition reactions. The presence of an unprotected imine nitrogen
atom in the imines 3, 4, and 8 allows the direct synthesis of N-
unprotected aminophosphonates and aminocarboxylates.
[
dP¼7 ppm, dF¼ꢁ64.7 (3F, ArCF3) and ꢁ81.6 (3F, 5-CF3) ppm]. The
Ar
N
4. Experimental section
4.1. General
8a,b
O
N
H
35a,b
F3C
COOR
N+
O
IR spectra were obtained on an UR-20 instrument. NMR spectra
were recorded on a Varian VXR-300 spectrometer (operating fre-
quency 299.95 MHz), 19F NMR and 31P NMR spectradon Gemini 200
Varian (188.14 and 80.95 MHz, respectively) and Varian VXR-300
instrument (282.2 and 121.42 MHz, respectively). 13C NMR spectra
were obtained on Bruker Avance DRX 500 spectrometer operating at
125.76 MHz. Chemicalshifts arereported relative to internal TMS (1H)
or CFCl3 (19F) and external 85%-H3PO4 (31P) standards. Melting points
are uncorrected. Solvents were dried before use according to stan-
dard methods. Compounds 3a,b, 9a,10,11a,13aec, 27a, 37a,b,4 7a, 8a,
19, 28, 30, 32, 34, 35a, and 3812 were described in our preliminary
communications. Elemental analysis was carried out in the analytical
laboratory of Institute of Organic Chemistry, NAS of Ukraine.
Ar
Ar
Ar
N
N
-(EtO)2P(O)H
3a
O
N
H
O
N
F3C
P(OEt)2
CF3
O
37
36
35a: Ar = 4-ClC6H4, R= Me
35b: Ar = 4-CF3C6H4, R= Et
36, 37: Ar = 4-CF3C6H4
Scheme 10.

Y.V. Rassukana et al. / Tetrahedron 70 (2014) 2928e2937
2933
4.2. Iminophosphonates
ꢁ127.5 (d, 2JFH¼50.6 Hz) ppm (E). 31P NMR (121 MHz, Et2O)
d
: ꢁ8.4
3
3
(m, JPH¼40.1 Hz, JPF¼15.3 Hz) ppm (Z) and ꢁ5.2 (m,
3JPH¼70.0 Hz) ppm (E). The reaction mixture was left overnight at
rt. The precipitated product 5b was isolated by filtration. Tetra-
phenyl 1-amino-2,2-difluoroethylidenebisphosphonate 5b. White
4.2.1. Diethyl (2,2-difluoroethanimidoyl)phosphonate 3c. A mixture
of difluoroacetonitrile (1.91 g, 24.8 mmol), Et3N (0.45 mL, 0.33 g,
3.3 mmol), and diethyl phosphite (2.28 g, 16.5 mmol) was kept in
ampoule at 15 ꢀC for 5 days and evaporated in vacuo, keeping
temperature below 20 ꢀC, to give iminophosphonate 3c of 90%
purity, which was used in synthesis without further purification.
Yield w100%, light yellow oil. The compound can be kept at 5 ꢀC
under inert atmosphere for about 5 days.
solid, yield 0.70 g (88%), mp: 113e115ꢀC. IR (KBr)
n: 1168 (POC),
1275 (P]O), 3315, 3370 (NH2) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d:
2.46 (t, 3JHP¼14.8 Hz, 2H, NH2), 6.46 (tt, 2JHF¼55.2 Hz, 3JHP¼8.8 Hz,
1H, CHF2), 7.16e7.21 (m, 12H, Ar), 7.26e7.31 (m, 8H, Ar) ppm. 19F
NMR (188 MHz, CDCl3)
d
:
ꢁ122.8 (dt, 2JFH¼55.2 Hz,
IR (neat)
n
: 1080 (POC), 1260 (P]O), 1720 (C]N), 3200, 3230
3JFP¼8.5 Hz) ppm. 31P NMR (81 MHz, CDCl3)
d: 8.1 (m,
(NH) cmꢁ1
.
1H NMR (299.95 MHz, C6D6)
d
: 0.95 (m, 6H, CH3CH2),
3JPCNH¼14.8 Hz, JPCCH¼8.8 Hz, JPF¼8.5 Hz) ppm. Anal. Calcd for
3
3
2
3
3.69e4.18 (m, 4H, OCH2), 5.90 (td, JHF¼55.0 Hz, JHP¼6.5 Hz, 1H,
C26H23F2NO6P2 (545.4): C, 57.26; H, 4.25; N, 2.57; P, 11.36. Found: C,
2
3
CHF2, E-isomer), 6.08 (td, JHF¼54.5 Hz, JHP¼11.3 Hz, 1H, CHF2, Z-
57.34; H, 4.15; N, 2.51; P, 11.25.
3
isomer), 12.00 (br d, JHP¼59.5 Hz, 1H, NH, E-isomer), 12.52 (br d,
3JHP¼39.0 Hz, 1H, NH, Z-isomer) ppm. 13C NMR for major isomer
4.3. Iminotrifluoropropionates
3
(125.76 MHz, C6D6)
d
:
15.7 (d, JCP¼5.5 Hz, CH3), 63.3 (d,
2JCP¼5.8 Hz, OCH2), 113.7 (td, JCF¼246 Hz, JCP¼34.7 Hz, CHF2),
1
2
4.3.1. Ethyl 3,3,3-trifluoro-2-iminoropropionate 8b. Ethyl 3,3,3-
trifluoro-2-iminoropropionate 8b (E/Zz10:1 at 25 ꢀC) was pre-
pared by the same procedure as 8a,12 yellow liquid, yield 84%, bp:
118e120 ꢀC. IR (neat): 1725, 1755 (C]N, C]O), 3250, 3280
171.0 (dt, 1JCP¼150 Hz, 2JCF¼30 Hz, C]N) ppm. 19F NMR (188 MHz,
C6D6)
d
: ꢁ121.5 ppm (d, 2JFH¼55 Hz) (Z-isomer) and ꢁ127.2 ppm (d,
2JFH¼55 Hz) (E-isomer, Z/E 5:1). 31P NMR (81 MHz, C6D6)
d: 0.5 ppm
3
3
(NH) cmꢁ1. (E)-8b: 1H NMR (300 MHz, CDCl3)
d
: 1.32 (t, 3JHH¼7.2 Hz,
(m, JPH¼39 Hz) (Z-isomer) and 3.3 ppm (m, JPH¼59.5 Hz) (E-iso-
mer, Z/E 5:1).
3
3H, CH3), 4.34 (q, JHH¼7.2 Hz, 2H, CH2), 12.13 (br s, 1H, NH). 19F
NMR (188 MHz, CDCl3):
d
ꢁ71.2 ppm. (Z)-8b: 1H NMR (300 MHz,
4.2.2. Diphenyl (2,2,2-trifluoroethanimidoyl)phosphonate 4a. Tri
fluoroacetonitrile (Caution! CF3CN is a highly toxic gas and should
be handled with care) was bubbled for 15 min through a cooled to
ꢁ55 ꢀC solution of diphenyl phosphite (1.00 g, 0.82 mL, 4.27 mmol)
and triethylamine (0.09 g, 0.12 mL, 0.85 mmol) in diethyl ether
(7.5 mL). The mixture was stirred for 0.5 h and allowed to warm to
rt, the solvent was evaporated under reduced pressure to give
phosphonate 4a as a colorless oil, yield 1.4 g (w100%), Z/Ew10:1.
The compound is unstable (see Scheme 3) and should be used in
3
3
CDCl3)
d
: 1.32 (t, JHH¼7.2 Hz, 3H, CH3), 4.35 (q, JHH¼7.2 Hz, 2H,
CH2), 11.70 (br s, 1H, NH). 19F NMR (188 MHz, CDCl3)
d: ꢁ73 ppm.
Anal. Calcd for C5H6F3NO2 (169.1): C, 35.51; H, 3.58; N, 8.28. Found:
C, 35.67; H, 3.52; N, 8.31.
4.4. General procedure for the preparation of amino-
phosphonates 9a,b
BH3$Me2S (2 M solution in toluene, 0.65 mL, 1.3 mmol) was
added at ꢁ20 ꢀC to a stirred solution of the respective imidoyl
phosphonate 3 (1 mmol) in THF (10 mL). The reaction mixture was
stirred at ꢁ20 ꢀC for 1 h then allowed to warm to rt, quenched with
aq NH4Cl (10 mL), and extracted with CH2Cl2 (3ꢂ10 mL). The or-
ganic phase was dried (MgSO4) and concentrated under reduced
pressure to give aminophosphonate 9a4 or 9b, yields 95 and 84%,
respectively. Diethyl 1-amino-2,2-difluoroethylphosphonate 9b, col-
synthesis immediately after preparation. IR (neat)
1280 (P]O), 1720 (C]N), 3220, 3240 (NH) cmꢁ1
(300 MHz, CDCl3) : 7.12e7.26 (m, 6H, Ar), 7.32e7.36 (m, 4H, Ar),
n
: 1170 (POC),
.
1H NMR
d
3
12.38 (br d, JHP¼63.8 Hz, 1H, NH, E-isomer) and 12.83 (br d,
3JHP¼40 Hz,1H, NH, Z-isomer) ppm (Z/E w10:1). 19F NMR (188 MHz,
CDCl3)
(81 MHz, CDCl3)
ꢁ8.9 ppm (m, JPH¼63.8 Hz) (E-isomer, Z/E w10:1).
d
: ꢁ69.9 (Z) and ꢁ72.8 (E-isomer, Z/E w10:1). 31P NMR
3
d
: ꢁ10.5 ppm (m, JPH¼40 Hz) (Z-isomer) and
3
orless oil. IR (neat)
NMR (300 MHz, CDCl3)
n
: 1080 (POC), 1265 (P]O), 2970 (NH2) cmꢁ1. 1H
3
d
: 1.30 (t, JHH¼7.2 Hz, 6H, CH3CH2),
4.2.3. Tetraphenyl 1-amino-2,2,2-trifluoroethylidenebis(phosphonate)
5a. Iminophosphonate 4a (0.63 g, 1.9 mmol) was dissolved in
ether. After 3 days the precipitated solid was collected by filtra-
tion to afford bisphosphonate 5a. White solid, yield 0.54 g (96%),
3.39e3.51 (m, 1H, CHP), 3.48 (br s, 2H, NH2), 4.13e4.20 (m, 4H,
2
OCH2), 6.01 (t, JHF¼56 Hz, 1H, CHF2) ppm. 19F NMR (188 MHz,
2
CDCl3): AB system, dA ꢁ124.6 ppm, dB ꢁ128.5 ppm, JAB¼285 Hz,
2JFH¼56 Hz. 31P NMR (81 MHz, CDCl3)
d: 18.6 ppm. Anal. Calcd for
mp: 123e125 ꢀC. IR (KBr)
n: 1165 (POC), 1290 (P]O), 3305, 3355
(NH2) cmꢁ1 1H NMR (300 MHz, CDCl3)
. d: 2.60 (br s, 2H, NH2),
C6H14F2NO3P (217.1): C, 33.19; H, 6.50; N, 6.45; P, 14.26. Found: C,
33.23; H, 6.42; N, 6.33; P, 14.21.
7.07e7.15 (m, 12H, Ar), 7.19e7.30 (m, 8H, Ar) ppm. 13C NMR
2
(125.8 MHz, CDCl3)
d
: 62.9 (tq, 1JCP¼145.6 Hz, JCF¼29.4 Hz, CP),
120.2 (br, C2Ph), 123.3 (q, JCF¼286.5 Hz, CF3), 125.40 and 125.46
4.5. O,O-Diethyl-O0,O0-diphenyl 1-amino-2,2,2-trifluoroethyli
denebis(phosphonate) 11b
1
ðC4PhÞ, 129.44 and 129.50 ðCP3hÞ, 149.8 and 149.9 (two doublets,
2JCP¼8.8 Hz, POC) ppm. 19F NMR (282.2 MHz, CDCl3)
d
: ꢁ68.2 (t,
: 5.5 (q,
3JFP¼4.5 Hz) ppm. 31P{H} NMR (121.42 MHz, CDCl3)
d
A mixture of imidoyl phosphonate 3a (0.23g, 1.00 mmol) and
diphenyl phosphite (0.23 g, 0.20 mL, 1.00 mmol) was maintained at
rt for 5 days and triturated with hexane to give compound 11b as
3JPF¼4.5 Hz) ppm. Anal. Calcd for C26H22F3NO6P2 (563.4): C 55.43;
H 3.94; N 2.49; P 11.00. Found: C 55.25; H 3.88; N 2.45; P 11.08.
colorless viscous oil, yield 0.45 g (96%). IR (neat) n: 1040,1180 (POC),
4.2.4. Reaction of difluoroacetonitrile with diphenyl phosphi-
te. Diphenyl phosphite (0.69 g, 0.56 mL, 2.94 mmol) was added to
a cooled to ꢁ5 ꢀC solution of difluoroacetonitrile (0.11 g, 1.47 mmol)
and triethylamine (0.03 g, 0.04 mL, 0.29 mmol) in diethyl ether
(2 mL), then the reaction mixture was allowed to warm to room
temperature. 31P and 19F NMR spectra show the formation of 4b
and unreacted starting compounds [4b/(PhO)2POH/CHF2CN 2:1:1].
1280 (P]O), 3220, 3310 (NH2) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d:
1.30 (t, 3JHH¼7.2 Hz, 3H, CH3CH2), 1.35 (t, 3JHH¼7.2 Hz, 3H, CH3CH2),
2.46 (br s, 2H, NH2), 4.13e4.38 (m, 4H, OCH2), 7.14e7.22 (m, 6H, Ar),
7.27e7.34 (m, 4H, Ar) ppm. 19F NMR (188 MHz, CDCl3)
d
: ꢁ67.9 (t,
3JFCPOEtz3JFCPOPhz4.8 Hz) ppm. 31P{H} NMR (121.42 MHz, CDCl3)
d
:
3
2
3
5.9 (qd, JPF¼4.8 Hz, JPP¼2.3, 1P, POPh), 12.1 (qd, JPF¼4.8 Hz,
2JPP¼2.3, 1P, POEt) ppm. Anal. Calcd for C18H22F3NO6P2 (467.3): C,
46.26; H, 4.75; N, 3.00; P, 13.26. Found: C, 46.10; H, 4.64; N, 2.93; P,
13.20.
Diphenyl (2,2-difluoroethanimidoyl)phosphonate 4b, Z/E w4:1. 19F
2
NMR (188 MHz, Et2O)
d
: ꢁ121.9 (d, JFH¼50.8 Hz) ppm (Z) and

2934
Y.V. Rassukana et al. / Tetrahedron 70 (2014) 2928e2937
4.6. General procedure for the synthesis of compounds 12a,b
under reduced pressure and the residue was washed with petro-
leum ether.
The solution of imine 3a (0.60 mmol) and respective aniline
(0.60 mmol) in Et2O (2 mL) was left to react at room temperature
for 3 days. The solvent was evaporated under reduced pressure and
the residue was washed with petroleum ether.
4.8.1. Diethyl 1-amino-2,2,2-trifluoro-1-(4-methylphenylthio)ethyl-
phosphonate 15a. Colorless oil, yield 0.35 g (98%). IR (neat) n: 1070
(POC), 1265 (P]O), 3400 (NH2) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d:
1.37 (t, 3JHH¼7.2 Hz, 3H, CH3CH2), 1.42 (t, 3JHH¼7.2 Hz, 3H, CH3CH2),
1.76 (br, 2H, NH2), 2.38 (s, 3H, ArCH3), 4.25e4.35 (m, 2H, OCH2),
4.6.1. Diethyl
1-amino-2,2,2-trifluoro-1-(4-methoxyphenylamino)
3
ethylphosphonate 12a. Yellow oil, yield 0.14 g (67%). IR (neat)
n
:
4.36e4.43 (m, 2H, OCH2), 7.20 (d, JHH¼8 Hz, 2H, Ar), 7.48 (d,
1070 (POC), 1265 (P]O), 3330, 3380, 3420 (NH, NH2) cmꢁ1. 1H NMR
3JHH¼8 Hz, 2H, Ar) ppm. 19F NMR (188 MHz, CDCl3)
: ꢁ72.9 ppm.
d
3
(300 MHz, CDCl3)
d
: 1.33 (t, JHH¼7.2 Hz, 3H, CH3CH2), 1.36 (t,
31P NMR (81 MHz, CDCl3)
d: 14.2 ppm. Anal. Calcd for
3JHH¼7.2 Hz, 3H, CH3CH2), 2.00 (br, 2H, NH2), 3.50 (br, 1H, NH), 3.76
C13H19F3NO3PS (357.3): C, 43.70; H, 5.36; N, 3.92; P, 8.67; S, 8.97.
Found: C, 43.63; H, 5.32; N, 3.88; P, 8.59; S, 8.93.
3
(s, 3H, OCH3), 4.19e4.33 (m, 4H, OCH2), 6.80 (d, JHH¼8.7 Hz, 2H,
Ar), 7.02 (d, 3JHH¼8.7 Hz, 2H, Ar) ppm. 13C NMR (125.7 MHz, CDCl3)
3
d:
15.9 (d, JCP¼6.3 Hz, OCH2CH3), 55.0 (s, OCH3), 63.8 (d,
4.8.2. Diethyl 1-amino-2,2,2-trifluoro-1-(4-fluorophenylthio)ethyl-
phosphonate 15b. White crystals, yield 0.35 g (97%), mp: 36e38 ꢀC.
2JCP¼7.2 Hz, OCH2CH3), 64.1 (d, JCP¼7.2 Hz, OCH2CH3), 71.8 (dq,
1JCP¼172.9 Hz, 2JCF¼29.2 Hz, CP), 113.7, 114.4, 116.0, 126.2 (Ar), 123.9
(qd, 1JCF¼287 Hz, 2JCP¼12.1 Hz, CF3) ppm. 19F NMR (188 MHz, CDCl3)
2
IR (KBr)
(300 MHz, CDCl3)
n
: 1070 (POC),1265 (P]O), 3235, 3420 (NH2) cmꢁ1. 1H NMR
3
d: 1.37 (t, JHH¼7.1 Hz, 3H, CH3CH2), 1.42 (t,
d
: ꢁ76.2 ppm. 31P NMR (81 MHz, CDCl3)
d
: 15 ppm. Anal. Calcd for
3JHH¼7.1 Hz, 3H, CH3CH2), 1.76 (br, 2H, NH2), 4.25e4.34 (m, 2H,
OCH2), 4.35e4.43 (m, 2H, OCH2), 7.10 (dd, 3JHH¼8.7 Hz, 3JHF¼8.7 Hz,
C
13H20F3N2O4P (356.3): C, 43.83; H, 5.66; N, 7.86; P, 8.69. Found: C,
3
4
43.64; H, 5.60; N, 7.77; P, 8.58.
2H, Ar), 7.61 (dd, JHH¼8.7 Hz, JHF¼5.4 Hz, 2H, Ar) ppm. 19F NMR
(188 MHz, CDCl3)
d
: ꢁ74.2 (3F, CF3), ꢁ111.2 (1F, ArF) ppm. 31P NMR
4.6.2. Diethyl 1-amino-2,2,2-trifluoro-1-(4-methylphenylamino)eth-
ylphosphonate 12b. Yellow oil, yield 0.14 g (70%). IR (neat) : 1070
(POC), 1275 (P]O), 3230, 3390, 3425 (NH, NH2) cmꢁ1 1H NMR
(81 MHz, CDCl3) d: 13.5 ppm. Anal. Calcd for C12H16F4NO3PS (361.3):
n
C, 39.89; H, 4.46; N, 3.88; P, 8.57; S, 8.87. Found: C, 39.78; H, 4.32; N,
3.83; P, 8.49; S, 8.90.
.
3
(300 MHz, CDCl3)
d
: 1.32 (t, JHH¼7.2 Hz, 3H, CH3CH2), 1.35 (t,
3JHH¼7.2 Hz, 3H, CH3CH2), 2.05 (br, 2H, NH2), 2.28 (s, 3H, ArCH3),
4.8.3. Methyl
3,3,3-trifluoro-2-(4-methylphenylthio)propionate
3.55 (br, 1H, NH), 4.16e4.31 (m, 4H, OCH2), 6.96 (d, 3JHH¼8.2 Hz, 2H,
16a. Yellow crystals, yield 0.27 g (97%), mp: 38e40 ꢀC. IR (KBr)
n
:
:
Ar), 7.05 (d, 3JHH¼8.2 Hz, 2H, Ar) ppm. 19F NMR (188 MHz, CDCl3)
d:
1765 (C]O), 3420, 3440 (NH2) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d
ꢁ76.3 ppm. 31P NMR (81 MHz, CDCl3)
d
: 15.3 ppm. Anal. Calcd for
2.01 (br, 2H, NH2), 2.38 (s, 3H, ArCH3), 3.84 (s, 3H, OCH3), 7.21 (d,
3
C
13H20F3N2O3P (340.3): C, 45.89; H, 5.92; N, 8.23; P, 9.10. Found: C,
3JHH¼8 Hz, 2H, Ar), 7.36 (d, JHH¼8 Hz, 2H, Ar) ppm. 19F NMR
45.58; H, 5.86; N, 8.15; P, 9.00.
(188 MHz, CDCl3)
(279.3): C, 47.31; H, 4.33; N, 5.02; S, 11.48. Found: C, 47.11; H, 4.28;
N, 4.88; S, 11.34.
d
: ꢁ74.8 ppm. Anal. Calcd for C11H12F3NO2S
4.7. General procedure for the preparation of compounds 13,
14
4.8.4. Methyl
3,3,3-trifluoro-2-(4-fluorophenylthio)propionate
16b. Yellow oil, yield 0.27 g (96%). IR (neat) n: 1770 (C]O), 3370,
A solution of respective imine 3 or 8b (1.0 mmol) in anhydrous
methanol (4 mL) was left at rt for 10 h. The solvent was evaporated
and the residue was washed with hexane.
3450 (NH2) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d: 2.04 (br, 2H, NH2),
3.83 (s, 3H, OCH3), 7.10 (dd, 3JHH¼8.7 Hz, 3JHF¼8.7 Hz, 2H, Ar), 7.48
3
4
(dd, JHH¼8.7 Hz, JHF¼5.4 Hz, 2H, Ar) ppm. 19F NMR (188 MHz,
CDCl3)
d
: ꢁ74.7 (3F, CF3), ꢁ109.3 (1F, ArF) ppm. Anal. Calcd for
4.7.1. Diethyl 1-amino-2,2-difluoro-1-methoxyethylphosphonate
C
10H9F4NO2S (283.3): C, 42.41; H, 3.20; N, 4.95; S, 11.32. Found: C,
13d. Pale yellow oil, yield 0.21 g (84%). IR (neat)
n: 1075 (POC),
42.32; H, 3.14; N, 5.03; S, 11.24.
1250 (P]O), 3235, 3320 (NH2) cmꢁ1. 1H NMR (400 MHz, CDCl3)
d:
1.25e1.31 (m, 6H, CH3CH2), 2.27 (br, 2H, NH2), 3.38 (s, 3H, OCH3),
4.9. General procedure for the synthesis of compounds 18,
22e26
2
4.12e4.20 (m, 4H, OCH2), 5.78 (t, JHF¼56.4 Hz, 1H, CHF2) ppm. 19
F
2
NMR (188 MHz, CDCl3): AB system, dA ꢁ131.4 (dd, JAB¼286.5 Hz,
2JAH¼56.4 Hz), dB ꢁ135.9 (ddd, JAB¼286.5 Hz, JBH¼56.4 Hz,
2
2
A mixture of iminophosphonate 3a (1.00 mmol) and respective
indole or pyrrole (1.00 mmol) was heated at 80 ꢀC for 4 h, cooled,
and triturated with hexane.
3JBP¼13.1 Hz) ppm. 31P NMR (81 MHz, CDCl3)
d: 14.5 ppm. Anal.
Calcd for C7H16F2NO4P (247.2): C, 34.01; H, 6.52; N, 5.67; P, 12.53.
Found: C, 34.12; H, 6.48; N, 5.57; P, 12.37.
4.9.1. Diethyl
1-amino-2,2,2-trifluoro-1-(indol-3-yl)ethyl-
4.7.2. Ethyl 2-amino-2-methoxy-3,3,3-trifluoropropionate
phosphonate 18a. Colorless viscous oil, yield 0.34 g (97%). IR (neat)
14. Colorless oil, yield 0.20 g (99%). IR (neat)
n
: 1760 (C]O),
n
: 1060 (POC), 1260 (P]O), 3270 (NH), 3390 (NH2) cmꢁ1. 1H NMR
3390, 3460 (NH2) cmꢁ1 1H NMR (300 MHz, CDCl3)
. d: 1.35 (t,
3
(300 MHz, CDCl3)
d
: 1.05 (t, JHH¼7.2 Hz, 3H, CH3CH2), 1.30 (t,
3JHH¼7.2 Hz, 3H, CH3CH2), 2.42 (br, 2H, NH2), 3.34 (s, 3H, OCH3),
3JHH¼7.2 Hz, 3H, CH3CH2), 2.32 (br, 2H, NH2), 3.58e3.72 (m, 1H,
OCH2), 3.89e4.02 (m, 1H, OCH2), 4.11e4.24 (m, 2H, OCH2), 7.10 (t,
4.30e4.41 (m, 2H, OCH2) ppm. 19F (188 MHz, CDCl3)
d
: ꢁ81 ppm.
Anal. Calcd for C6H10F3NO3 (201.2): C, 35.83; H, 5.01; N, 6.96. Found:
C, 35.48; H, 4.97; N, 6.78.
3JHH¼7.5 Hz, 1H, Het), 7.16 (t, JHH¼7.5 Hz, 1H, Het), 7.34 (d,
3
3JHH¼7.5 Hz, 1H, Het), 7.44 (s, 1H, Het), 8.23 (d, JHH¼7.5 Hz, 1H,
3
Het), 9.49 (br s, 1H, NH) ppm. 19F NMR (188 MHz, CDCl3)
d:
4.8. General procedure for the preparation of compounds 15,
16
ꢁ74 ppm. 31P NMR (121 MHz, CDCl3)
d: 16.7 ppm. Anal. Calcd for
C14H18F3N2O3P (350.3): C, 48.01; H, 5.18; N, 8.00; P, 8.84. Found: C,
47.78; H, 5.12; N, 7.86; P, 8.73.
To a stirred solution of imine 3a or 8a (1.00 mmol) in Et2O (2 mL)
was added respective thiophenol (1.00 mmol), the mixture was
kept at room temperature for 10 h, the solvent was evaporated
4.9.2. Diethyl 1-amino-2,2,2-trifluoro-1-(2-methylindol-3-yl)ethyl-
phosphonate 18b. Orange crystals, yield 0.35
g (96%), mp:

Y.V. Rassukana et al. / Tetrahedron 70 (2014) 2928e2937
2935
ꢀ
49e51 C. IR (KBr)
n
: 1050 (POC), 1240 (P]O), 3260 (NH), 3300
Het), 6.85e6.87 (m, 1H, Het) ppm. 19F NMR (188 MHz, CDCl3)
d:
d: 17.4 ppm. Anal. Calcd for
C11H18F3N2O3P (314.2): C, 42.04; H, 5.77; N, 8.91; P 9.86. Found: C,
(NH2) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d
: 1.10 (t, 3JHH¼7.2 Hz, 3H,
ꢁ75.6 ppm. 31P NMR (81 MHz, CDCl3)
3
CH3CH2), 1.28 (t, JHH¼7.2 Hz, 3H, CH3CH2), 2.38 (br s, 2H, NH2),
2.67 (s, 3H, CH3), 3.71e3.85 (m, 1H, OCH2), 3.93e4.04 (m, 1H,
41.83; H, 5.68; N, 9.08; P, 9.99.
3
OCH2), 4.10e4.24 (m, 2H, OCH2), 7.06 (t, JHH¼7.8 Hz, 1H, Het),
3
3
7.11 (t, JHH¼7.8 Hz, 1H, Het), 7.25 (d, JHH¼7.8 Hz, 1H, Het), 8.23
4.9.7. Diethyl 1-amino-1-(1-tert-butylpyrrol-3-yl)-2,2,2-
(br s, 1H, NH), 8.30 (d, JHH¼7.8 Hz, 1H, Het) ppm. 13C NMR
trifluoroethylphosphonate 25. Orange viscous oil, yield 0.35
g
3
(125 MHz, CDCl3)
d
: 15.4 (s, CH3), 16.2 (d, 3JCP¼5.5 Hz, OCH2CH3),
(98%). IR (neat)
n
: 1060 (POC), 1250 (P]O), 3400 (NH2) cmꢁ1
.
1H
3
1
16.3 (d, JCP¼5.5 Hz, OCH2CH3), 63.0 (dq, JCP¼154.8 Hz,
NMR (300 MHz, CDCl3)
d
: 1.14 (t, 3JHH¼7.2 Hz, 3H, CH3CH2), 1.30 (t,
2JCF¼29.7 Hz, CP), 63.8 (d, JCP¼7.8 Hz, OCH2CH3), 64.1 (d,
3JHH¼7.2 Hz, 3H, CH3CH2), 1.51 (s, 9H, t-Bu), 2.93 (br, 2H, NH2),
2
2JCP¼7.8 Hz, OCH2CH3), 101.8 (d, JCP¼5.2 Hz, Het), 110.4, 119.5,
3.62e3.75 (m, 1H, OCH2), 3.93e4.03 (m, 1H, OCH2), 4.08e4.18 (m,
2
1
2
3
121.0, 122.3 (Het), 125.8 (qd, JCF¼285 Hz, JCP¼13.8 Hz,
2H, OCH2), 6.34e6.36 (m, 1H, Het), 6.81 (dd, JHH¼2.7 Hz,
CF3),135.0, 135.4 (Het) ppm. 19F NMR (188 MHz, CDCl3)
d
:
3JHH¼2.7 Hz, 1H, Het), 7.05 (dd, JHH 4.5 and 2.7 Hz, 1H, Het) ppm.
4
ꢁ72.2 ppm. 31P NMR (81 MHz, CDCl3)
d
: 17.9 ppm. Anal. Calcd for
19F NMR (188 MHz, CDCl3)
d
: ꢁ76.2 ppm. 31P NMR (81 MHz, CDCl3)
C
15H20F3N2O3P (364.3): C, 49.45; H, 5.53; N, 7.69; P, 8.50. Found:
d: 17.8 ppm. Anal. Calcd for C14H24F3N2O3P (356.3): C, 47.19; H, 6.79;
C, 49.52; H, 5.44; N, 7.54; P, 8.67.
N, 7.86; P, 8.69. Found: C, 47.32; H, 6.67; N, 7.72; P, 8.53.
4.9.3. Diethyl 1-amino-2,2,2-trifluoro-1-(1-methylindol-3-yl)ethyl-
phosphonate 18c. Orange crystals, yield 0.35 g (96%), mp: 55e57 ꢀC.
4.9.8. Methyl 2-(1-tert-butylpyrrol-3-yl)-3,3,3-trifluoropropionate
26. Yellow viscous oil, yield 0.27 g (97%). IR (neat)
n: 1760 (C]
IR (neat)
(300 MHz, CDCl3)
n
: 1050 (POC), 1250 (P]O), 3200 (NH2) cmꢁ1
.
1H NMR
O), 3430 (NH2) cmꢁ1 1H NMR (300 MHz, CDCl3)
.
d
: 1.51 (s, 9H, t-
3
d
: 1.09 (t, JHH¼7.2 Hz, 3H, CH3CH2), 1.30 (t,
Bu), 2.24 (br, 2H, NH2), 3.84 (s, 3H, OCH3), 6.25e6.26 (m, 1H, Het),
6.78 (dd, JHH 3.0 and 2.3 Hz, 1H, Het), 6.97e6.99 (m, 1H, Het) ppm.
3JHH¼7.2 Hz, 3H, CH3CH2), 2.31 (br s, 2H, NH2), 3.62e3.75 (m, 1H,
OCH2), 3.77 (s, 3H, NCH3), 3.91e4.04 (m, 1H, OCH2), 4.11e4.24 (m,
19F NMR (188 MHz, CDCl3)
C
d
:
ꢁ76.7 ppm. Anal. Calcd for
12H17F3N2O2 (278.3): C, 51.80; H, 6.16; N, 10.07. Found: C, 52.06;
H, 6.13; N, 10.15.
3
3
2H, OCH2), 7.13 (t, JHH¼7.8 Hz, 1H, Het), 7.24 (t, JHH¼7.8 Hz, 1H,
3
4
Het), 7.31 (d, JHH¼7.8 Hz, 1H, Het), 7.43 (d, JHP¼2.7 Hz, 1H, Het),
3
8.24 (d, JHH¼7.8 Hz, 1H, Het) ppm. 19F NMR (188 MHz, CDCl3)
d:
ꢁ74.1 ppm. 31P NMR (81 MHz, CDCl3)
d
: 17.2 ppm. Anal. Calcd for
4.10. General procedure for the synthesis of compounds 20,
21
C
15H20F3N2O3P (364.3): C, 49.45; H, 5.53; N, 7.69; P, 8.50. Found: C,
49.74; H, 5.47; N, 7.81; P, 8.36.
A mixture of pyrrole or 2,4-dimethylpyrrole (1.00 mmol) and
respective imine 3a or 8 (1.00 mmol) was left at room temperature
overnight and triturated with hexane to afford aminoalkylation
product 20 or 21.
4.9.4. Diethyl 1-amino-2,2,2-trifluoro-1-(1-methylpyrrol-2-yl)ethyl-
phosphonate 22. Diethyl 1-amino-2,2,2-trifluoro-1-(1-methyl
pyrrol-2-yl)ethylphosphonate 22 was isolated from the mixture
with isomer 24 by TLC (silica gel, EtOAc/hexane, 10:1, Rf¼0.74).
Orange crystals, yield 0.21 g (70%), mp: 53e55 ꢀC. IR (neat)
n
: 1060
4.10.1. Diethyl
1-amino-2,2,2-trifluoro-1-(pyrrol-2-yl)ethyl-
(POC), 1270 (P]O), 3400, 3460 (NH2) cmꢁ1
.
1H NMR (300 MHz,
phosphonate 20a. White crystals, yield 0.29 g (97%), mp: 62e64 ꢀC.
CDCl3)
d
: 1.25 (t, 3JHH¼7.2 Hz, 3H, CH3CH2), 1.29 (t, 3JHH¼7.2 Hz, 3H,
IR (KBr)
n
: 1040 (POC), 1260 (P]O), 3320, 3420 (NH, NH2) cmꢁ1. 1H
3
CH3CH2), 1.91 (br s, 2H, NH2), 3.87e3.99 (m, 1H, OCH2), 3.96 (s,
3H, NCH3), 4.00e4.18 (m, 3H, OCH2), 6.08 (dd, JHH 3.9 and
(300 MHz, CDCl3)
d
: 1.16 (t, JHH¼6.9 Hz, 3H, CH3CH2), 1.34 (t,
3JHH¼6.9 Hz, 3H, CH3CH2), 2.12 (br s, 2H, NH2), 3.60e3.73 (m, 1H,
OCH2), 3.93e4.05 (m, 1H, OCH2), 4.12e4.22 (m, 2H, OCH2), 6.22 (dd,
3
3.3 Hz, 1H, Het), 6.52e6.54 (m, 1H, Het), 6.62e6.64 (m, 1H,
4
Het) ppm. 19F NMR (188 MHz, CDCl3)
d
: ꢁ73.7 ppm. 31P NMR
3JHH¼6.2 Hz, JHH¼2.9 Hz, 1H, Het), 6.42 (m, 1H, Het), 6.85 (m, 1H,
(81 MHz, CDCl3)
d
: 16.6 ppm. Anal. Calcd for C11H18F3N2O3P
Het), 9.16 (br s, 1H, NH) ppm. 13C NMR (125 MHz, CDCl3)
d: 16.1 (d,
3
(314.2): C, 42.04; H, 5.77; N, 8.91; P, 9.86. Found: C, 41.57; H, 5.61;
N, 9.11; P, 10.01.
3JCP¼5.5 Hz, OCH2CH3), 16.2 (d, JCP¼5.5 Hz, OCH2CH3), 59.5 (dq,
1JCP¼153.2 Hz, JCF¼29.7 Hz, CP), 63.9 (d, JCP¼7.3 Hz, OCH2CH3),
2
2
64.3 (d, 2JCP¼7.3 Hz, OCH2CH3), 108.6 (s, CHet), 108.7 (d, JCP¼1.8 Hz,
4.9.5. Methyl
3,3,3-trifluoro-2-(1-methylpyrrol-2-yl)propionate
: 1770 (C]O),
: 2.16 (br s, 2H,
C
Het), 119.2 (d, JCP¼1.5 Hz, CHet), 121.9 (d, JCP¼6 Hz, C2Het), 124.5 (qd,
23. Brown viscous oil, yield 0.23 g (97%). IR (neat)
n
1JCF¼284.3 Hz, 2JCP¼10.1 Hz, CF3) ppm. 19F NMR (188 MHz, CDCl3)
d:
3350, 3440 (NH2) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d
ꢁ74.2 ppm. 31P NMR (81 MHz, CDCl3)
d: 16.3 ppm. Anal. Calcd for
NH2), 3.61 (s, 3H, NCH3), 3.83 (s, 3H, OCH3), 6.08 (t, 3JHH¼3.3 Hz, 1H,
C10H16F3N2O3P (300.2): C, 40.01; H, 5.37; N, 9.33; P, 10.32. Found: C,
Het), 6.30 (m, 1H, Het), 6.62 (m, 1H, Het) ppm. 13C NMR (125 MHz,
39.73; H, 5.28; N, 9.44; P, 10.25.
2
CDCl3)
d
: 35.0 (NCH3), 53.8 (OCH3), 64.7 (q, JCF¼29.1 Hz, CCF3),
106.7 (Het), 110.0 (q, JCF¼2.5 Hz, Het), 124.5 (d, 1JCF¼286.9 Hz, CF3),
4.10.2. Diethyl 1-amino-1-(3,5-dimethylpyrrol-2-yl)-2,2,2-
124.6, 125.1 (Het), 168.7 (C]O) ppm. 19F NMR (188 MHz, CDCl3)
d:
trifluoroethylphosphonate 20b. Brown oil, yield 0.32 g (98%). IR
ꢁ74.9 ppm. Anal. Calcd for C9H11F3N2O2 (236.2): C, 45.77; H, 4.69;
(neat): 1070 (POC), 1260 (P]O), 3220 (NH), 3340, 3390 (NH2) cmꢁ1
.
N, 11.86. Found: C, 45.52; H, 4.64; N, 11.72.
1H NMR (300 MHz, CDCl3)
d
: 1.16 (t, 3JHH¼7.2 Hz, 3H, CH3CH2), 1.36
(t, 3JHH¼7.2 Hz, 3H, CH3CH2), 2.09 (br d, 3JHP¼13.2 Hz, 2H, NH2), 2.19
(s, 3H, CH3), 2.32 (s, 3H, CH3), 3.66e3.79 (m, 1H, OCH2), 3.96e4.09
(m, 1H, OCH2), 4.16e4.26 (m, 2H, OCH2), 5.67 (s, 1H, H4), 8.82 (br s,
4.9.6. Diethyl 1-amino-2,2,2-trifluoro-1-(1-methylpyrrol-3-yl)ethyl-
phosphonate
24. Diethyl 1-amino-2,2,2-trifluoro-1-(1-methyl
pyrrol-3-yl)ethylphosphonate 24 was isolated from the mixture
with isomer 22 by preparative TLC (silica gel, EtOAc/hexane, 10:1,
Rf¼0.43). Orange crystals, yield 0.05 g (16%), mp: 61e63 ꢀC. IR
1H, NH) ppm. 13C NMR (125.8 MHz, CDCl3)
d
: 12.9 (]CCH3), 13.0 (]
3
3
CCH3), 16.2 (d, JCP¼5.2 Hz, OCH2CH3), 16.3 (d, JCP¼5.2 Hz,
1
2
OCH2CH3), 61.1 (dq, JCP¼149.1 Hz, JCF¼29.5 Hz, CP), 63.8 (d,
2
(neat)
(300 MHz, CDCl3)
n
: 1060 (POC), 1270 (P]O), 3390, 3410 (NH2) cmꢁ1. 1H NMR
2JCP¼7.2 Hz, OCH2CH3), 64.2 (d, JCP¼7.2 Hz, OCH2CH3), 110.8 (d,
3
d
: 1.20 (t, JHH¼7.2 Hz, 3H, CH3CH2), 1.32 (t,
JCP¼1.4 Hz, CHet), 113.7 (d, JCP¼6.4 Hz, CHet), 120.2 (d, JCP¼8.2 Hz,
1
2
3JHH¼7.2 Hz, 3H, CH3CH2), 2.32 (br, 2H, NH2), 3.66 (s, 3H, NCH3),
3.75e3.88 (m, 1H, OCH2), 3.99e4.09 (m, 1H, OCH2), 4.09e4.24 (m,
C
Het), 124.8 (qd, JCF¼284.8 Hz, JCP¼13.5 Hz, CF3), 127.5 (d,
JCP¼1.8 Hz, CHet) ppm. 19F NMR (188 MHz, CDCl3)
d
: ꢁ74.8 ppm. 31
P
2H, OCH2), 6.32e6.34 (m, 1H, Het), 6.59 (t, JHH¼4JHH¼2.3 Hz, 1H,
NMR (81 MHz, CDCl3) d: 16.9 ppm. Anal. Calcd for C12H20F3N2O3P
3

2936
Y.V. Rassukana et al. / Tetrahedron 70 (2014) 2928e2937
(328.3): C, 43.91; H, 6.14; N, 8.53; P, 9.44. Found: C, 43.53; H, 6.22;
N, 8.40; P, 9.29.
(303.3): C, 35.65; H, 5.32; N, 4.62; P, 10.21; S, 10.57. Found: C, 35.34;
H, 5.29; N, 4.53; P, 10.25; S, 10.43.
4.10.3. Ethyl 3,3,3-trifluoro-2-(pyrrol-2-yl)propionate 21a. Yellow
4.12. General procedure for the synthesis of compounds 31
oil, yield 0.23 g (97%). IR (neat)
n: 1755 (C]O), 3280 (NH), 3360,
3430 (NH2) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d
: 1.34 (t, 3JHH¼7.2 Hz,
Thiosalicylic acid (1.00 mmol) was added to a stirred solution of
respective iminophosphonate 3 (1.0 mmol for 3a and 1.1 mmol for
3b) in THF (2 mL) and was allowed to react for 24 h. The solvent was
evaporated in vacuum and the residue was triturated with hexane.
3H, CH3CH2), 2.33 (br s, 2H, NH2), 4.25e4.40 (m, 2H, OCH2), 6.22
(dd, 3JHH 6.0 and 2.7 Hz, 1H, Het), 6.41e6.43 (m, 1H, Het), 6.81e6.83
(m, 1H, Het), 9.1 (br, 1H, NH) ppm. 19F NMR (188 MHz, CDCl3)
d:
ꢁ77.3 ppm. Anal. Calcd for C9H11F3N2O2 (236.2): C, 45.77; H, 4.69;
N, 11.86. Found: C, 45.59; H, 4.63; N, 11.74.
4.12.1. Diethyl (4-oxo-2-trifluoromethyl-3,4-dihydro-2H-1,3-
benzothiazin-2-yl)phosphonate 31a. Yellow crystals, yield 0.32 g
ꢀ
4.10.4. Methyl 2-(3,5-dimethylpyrrol-2-yl)-3,3,3-trifluoropropionate
21b. Methyl 2-(3,5-dimethylpyrrol-2-yl)-3,3,3-trifluoropropionate
21b was purified by column chromatography (hexane/
EtOAc¼5:1). Brown crystals, yield 0.24 g (96%), mp: 59e62 ꢀC. IR
(87%), mp: 104e105 C. IR (KBr)
n
: 1050 (POC), 1280 (P]O), 1680
(C]O), 3190 (NH) cmꢁ1
.
1H NMR (400 MHz, CDCl3)
d
: 1.36 (t,
3JHH¼7.2 Hz, 3H, CH3CH2), 1.38 (t, JHH¼7.2 Hz, 3H, CH3CH2), 4.34
3
(m, 4H, OCH2), 6.65 (br,1H, NH), 7.22 (d, 3JHH¼7.6 Hz,1H, Ar), 7.27 (t,
3
(KBr)
CDCl3)
3.86 (s, 3H, OCH3), 5.70 (s, 1H, Het), 8.45 (br, 1H, NH) ppm. 13C NMR
n
: 1765 (C]O), 3330, 3420 (NH, NH2) cmꢁ1
.
1H (300 MHz,
3JHH¼7.6 Hz, 1H, Ar), 7.43 (t, JHH¼7.6 Hz, 1H, Ar), 8.14 (d,
d
: 2.02 (s, 3H, CCH3), 2.10 (br, 2H, NH2), 2.21 (s, 3H, CCH3),
3JHH¼7.6 Hz, 1H, Ar) ppm. 19F NMR (188 MHz, CDCl3)
: ꢁ74.4 ppm.
d
31P NMR (81 MHz, CDCl3)
d: 8.7 ppm. Anal. Calcd for C13H15F3NO4PS
(125 MHz, CDCl3)
d
: 11.7 (CCH3), 12.8 (CCH3), 53.4 (OCH3), 63.7 (q,
(369.3): C, 42.28; H, 4.09; N, 3.79; P, 8.39; S, 8.68. Found: C, 42.12; H,
4.01; N, 3.84; P, 8.44; S, 8.57.
2JCF¼29.1 Hz, CCF3), 110.5, 116.5, 118.8 (Het), 124.4 (d, 1JCF¼285.1 Hz,
CF3), 127.2 (Het), 169.5 (C]O) ppm. 19F NMR (188 MHz, CDCl3)
d:
ꢁ76.5 ppm. Anal. Calcd for C10H13F3N2O2 (250.2): C, 48.00; H, 5.24;
4.12.2. Diethyl [2-(difluoromethyl)-4-oxo-3,4-dihydro-2H-1,3-
benzothiazin-2-yl]phosphonate 31b. Yellow crystals, yield 0.29 g
N, 11.20. Found: C, 47.45; H, 5.18; N, 11.10.
(83%), mp: 103e105 ꢀC. IR (KBr)
n: 1080 (POC),1260 (P]O),1660 (C]
4.11. General procedure for the synthesis of compounds 27, 29
O), 3190 (NH) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d
: 1.34 (t, 3JHH¼7.2 Hz,
3
3H, CH3CH2), 1.39 (t, JHH¼7.2 Hz, 3H, CH3CH2), 4.21e4.37 (m, 4H,
2
3
Mercaptoacetic or 3-mercaptopropionic acid (1.00 mmol) was
added to a stirred solution of the iminophosphonate 3 (1.0 mmol
for 3a and 1.10 mmol for 3b) in benzene (2 mL). The mixture was
refluxed for 4 h, the solvent was evaporated in vacuum and the
residue was triturated with hexane.
OCH2), 6.07 (td, JHF¼55.2 Hz, JHP¼3.3 Hz, 1H, CHF2), 6.73 (br, 1H,
NH), 7.24 (d, 3JHH¼7.8 Hz,1H, Ar), 7.28 (t, 3JHH¼7.8 Hz,1H, Ar), 7.43 (t,
3
3JHH¼7.8 Hz, 1H, Ar), 8.16 (d, JHH¼7.8 Hz, 1H, Ar) ppm. 19F NMR
2
(188 MHz, CDCl3): AB system, dA ꢁ120.9 (dd, JAB¼278 Hz,
2
2
2JAH¼55.5 Hz), dB ꢁ127.8 (ddd, JBA¼278 Hz, JBH¼55.5 Hz,
3JBP¼14.1 Hz) ppm. 31P NMR (81 MHz, CDCl3)
d: 11.9 ppm. Anal. Calcd
4.11.1. Diethyl [2-(difluoromethyl)-4-oxo-1,3-thiazolidin-2-yl]phos-
phonate 27b. White crystals, yield 0.27 g (93%), mp: 54e56 ꢀC. IR
for C13H16F2NO4PS (351.3): C, 44.45; H, 4.59; N, 3.99; P, 8.82; S, 9.13.
Found: C, 44.24; H, 4.50; N, 3.91; P, 8.79; S, 9.06.
(KBr)
n: 1090 (POC), 1240 (P]O), 1700 (C]O), 3190, 3220
3
(NH) cmꢁ1
.
1H NMR (400 MHz, CDCl3)
d: 1.35 (t, JHH¼7 Hz, 6H,
4.13. General procedure for the synthesis of compounds 33
2
CH3CH2), 3.52 (d, JHAHB¼15.2 Hz, 1H, SCHAHB), 3.61 (dd,
2JHBHA¼15.2 Hz, JHBP¼5.4 Hz, 1H, SCHAHB), 4.21e4.32 (m, 4H,
A mixture of salicylaldehyde (2.50 mmol) and iminophospho-
nate 3 (2.50 mmol for 3a and 2.75 mmol for 3b) was left at room
temperature for 24 h. After addition of benzene (5 mL) and
TsOH$H2O (20 mg), the mixture was refluxed for 3 h, the solvent
was evaporated in vacuum, and the residue was purified by
chromatography.
4
2
3
OCH2), 5.97 (td, JHF¼55.5 Hz, JHP¼4 Hz, 1H, CHF2), 7.62 (br, 1H,
NH) ppm. 19F NMR (188 MHz, CDCl3): AB system, dA ꢁ125.8 (dd,
2JAB¼280.1 Hz, JAH¼55.5 Hz, 1F), dB ꢁ128.5 (dd, JAB¼280.1 Hz,
2
2
2JBH¼55.5 Hz, 1F) ppm. 31P NMR (81 MHz, CDCl3)
d: 13.4 ppm. Anal.
Calcd for C8H14F2NO4PS (289.2): C, 33.22; H, 4.88; N, 4.84; P, 10.71;
S, 11.09. Found: C, 33.13; H, 4.78; N, 4.79; P, 10.75; S, 11.01.
4.13.1. Diethyl
[2-(trifluoromethyl)-2H-1,3-benzoxazin-2-yl]phos-
4.11.2. Diethyl [4-oxo-2-(trifluoromethyl)-1,3-thiazinan-2-yl]phos-
phonate 29a. White crystals, yield 0.28 g (88%), mp: 97e99 ꢀC. IR
phonate 33a. Diethyl [2-(trifluoromethyl)-2H-1,3-benzoxazin-2-yl]
phosphonate 33a was purified by column chromatography (silica
(KBr)
n
: 1045 (POC), 1265 (P]O), 1680 (C]O), 3100, 3200
gel, CH2Cl2). Yellow oil, yield 0.57 g (68%). IR (neat) n: 1040 (POC),
3
(NH) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d: 1.32 (t, JHH¼6.6 Hz, 6H,
1270 (P]O), 1650 (C]N) cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
: 1.25 (t,
3
CH3CH2), 2.66e2.74 (m, 2H, SCH2CH2), 2.95e3.09 (m, 2H, SCH2CH2),
3JHH¼7.2 Hz, 3H, CH3CH2), 1.31 (t, JHH¼7.2 Hz, 3H, CH3CH2),
4.17e4.30 (m, 4H, OCH2), 6.50 (br, 1H, NH) ppm. 19F NMR (188 MHz,
4.14e4.29 (m, 4H, OCH2), 6.80 (d, JHH¼7.8 Hz, 1H, Ar), 6.95 (t,
3
3
CDCl3)
d
: ꢁ74.5 ppm. 31P NMR (81 MHz, CDCl3)
d
: 10.2 ppm. Anal.
3JHH¼7.8 Hz, 1H, Ar), 7.14 (d, JHH¼7.8 Hz, 1H, Ar), 7.34 (t,
Calcd for C9H15F3NO4PS (321.3): C, 33.65; H, 4.71; N, 4.36; P, 9.64; S,
9.98. Found: C, 33.26; H, 4.68; N, 4.25; P, 9.48; S, 9.85.
3JHH¼7.8 Hz, 1H, Ar), 8.22 (d, 3JHP¼4.4 Hz, 1H, CH]N) ppm. 19F NMR
(188 MHz, CDCl3)
d
: ꢁ79.2 ppm. 31P NMR (81 MHz, CDCl3)
d:
6.1 ppm. Anal. Calcd for C13H15F3NO4P (337.2): C, 46.30; H, 4.48; N,
4.15; P, 9.18. Found: C, 46.20; H, 4.39; N, 4.07; P, 9.11.
4.11.3. Diethyl
phonate 29b. Yellow viscous oil, yield 0.25 g (83%). IR (neat)
(POC), 1250 (P]O), 1680 (C]O), 3200 (NH) cmꢁ1 1H NMR
[2-(difluoromethyl)-4-oxo-1,3-thiazinan-2-yl]phos-
n: 1080
.
4.13.2. Diethyl
[2-(difluoromethyl)-2H-1,3-benzoxazin-2-yl]phos-
3
(300 MHz, CDCl3)
d
: 1.34 (t, JHH¼6.8 Hz, 3H, CH3CH2), 1.35 (t,
phonate 33. Diethyl [2-(difluoromethyl)-2H-1,3-benzoxazin-2-yl]
phosphonate 33 was purified by column chromatography (silica
3JHH¼6.8 Hz, 3H, CH3CH2), 2.70e2.75 (m, 2H, SCH2CH2), 3.05e3.10
(m, 2H, SCH2CH2), 4.19e4.33 (m, 4H, OCH2), 5.94 (td, 2JHF¼55.5 Hz,
3JHP¼2.4 Hz, 1H, CHF2), 6.74 (br s, 1H, NH) ppm. 19F NMR (188 MHz,
CDCl3): AB system, dA ꢁ121.5 (dd, 2JAB¼278 Hz, 2JAH¼55.5 Hz, 1F), dB
gel, EtOAc). Yellow oil, yield 0.57 g (72%). IR (neat) n: 1040 (POC),
1270 (P]O), 1650 (C]N) cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
: 1.26 (t,
3
3JHH¼6.8 Hz, 3H, CH3CH2), 1.32 (t, JHH¼6.8 Hz, 3H, CH3CH2),
ꢁ127.8 (ddd, 2JAB¼278 Hz, 2JBH¼55.5 Hz, 3JBP¼14.1 Hz, 1F) ppm. 31
P
4.16e4.29 (m, 4H, OCH2), 6.10 (t, JHF¼54.2 Hz, 1H, CHF2), 6.81 (d,
2
3
NMR (81 MHz, CDCl3)
d: 13.3 ppm. Anal. Calcd for C9H16F2NO4PS
3JHH¼7.6 Hz, 1H, Ar), 6.94 (t, JHH¼7.6 Hz, 1H, Ar), 7.13 (d,

Y.V. Rassukana et al. / Tetrahedron 70 (2014) 2928e2937
2937
3JHH¼7.6 Hz, 1H, Ar), 7.34 (t, 3JHH¼7.6 Hz, 1H, Ar), 8.21 (d, 3JHP¼4 Hz,
References and notes
1H, CH]N) ppm. 19F NMR (188 MHz, CDCl3)
d
: ꢁ133.4 (d,
2JFH¼54.2 Hz) ppm. 31P NMR (81 MHz, CDCl3)
d: 10.6 ppm. Anal.
1. Smart, B. E. J. Fluorine Chem. 2001, 109, 3.
2. Ismail, F. M. D. J. Fluorine Chem. 2002, 118, 27 and references therein.
3. Sewald, N.; Riede, J.; Burger, K. J. Chem. Soc., Perkin Trans. 1 1992, 267.
4. Rassukana, Yu. V.; Kolotylo, M. V.; Sinitsa, O. A.; Pirozhenko, V. V.; Onys’ko, P. P.
Synthesis 2007, 2627.
Calcd for C13H16F2NO4P (319.2): C, 48.91; H, 5.05; N, 4.39; P, 9.70.
Found: C, 48.66; H, 4.98; N, 4.30; P, 9.54.
5. Osipov, S. N.; Kolomiets, A. F.; Fokin, A. V. Usp. Khim. 1992, 61, 1457.
6. (a) Sinitsa, O. A.; Kolotilo, N. V.; Onys’ko, P. P. Ukr. Khim. Zh. 1998, 64, 47; [ Ukr.
Chem. J. 1998, 64, 43 (Engl. Transl.)]; (b) Onys’ko, P. P.; Rassukana, Yu. V.; Sinitsa,
O. A. Phosphorus, Sulfur Silicon Relat. Elem. 2008, 183, 399; (c) Onys’ko, P. P.;
Rassukana, Yu. V.; Sinitsa, A. D. Curr. Org. Chem. 2008, 12, 2; (d) Onys’ko, P. P.;
Rassukana, Yu. V.; Sinitsa, A. D. J. Org. Pharm. Chem. 2009, 7, 37; (e) Rassukana,
Yu. V.; Onys’ko, P. P.; Grechukha, A. G.; Sinitsa, A. D. Eur. J. Org. Chem. 2003,
4181; (f) Onys’ko, P. P.; Kim, T. V.; Kiseleva, E. I.; Sinitsa, A. D. Zh. Obshch. Khim.
2004, 74, 1981; (g) Onys’ko, P. P.; Kim, T. V.; Rassukana, Yu. V.; Kiseleva, E. I.;
Sinitsa, A. D. Zh. Obshch. Khim. 2004, 74, 1455; (h) Rassukana, Yu. V.; Davydova,
K. O.; Onys’ko, P. P.; Sinitsa, A. D. J. Fluorine Chem. 2002, 117, 107e113; (i)
Onys’ko, P. P. Zh. Obshch. Khim. 1999, 69, 158; (j) Onys’ko, P. P.; Kim, T. V.; Ki-
seleva, E. I.; Sinitsa, A. D. Zh. Obshch. Khim. 1995, 65, 1961.
7. (a) Zimin, M. G.; Dvoinishnikova, T. A.; Konovalova, I. V.; Pudovik, A. N. Russ.
Chem. Bull. 1978, 436; (b) Nifant’ev, E. Ye Chemistry of Hydrophosphoryl Com-
pounds [in Russian]; Nauka: Moscow, 1983; pp 84e87; (c) Orlovskii, V. V.; Vovsi,
B. A. Zh. Obshch. Khim. 1976, 46, 297; (d) Midrier, C.; Lantsoght, M.; Volle, J.-N.;
Pirat, J.-L.; Virieux, D.; Stevens, C. V. Tetrahedron Lett. 2011, 52, 6693.
8. Rassukana, Yu. V.; Onys’ko, P. P.; Davydova, K. O.; Sinitsa, A. D. Tetrahedron Lett.
2004, 45, 3899.
4.14. Ethyl 5-trifluoromethyl-3-(4-trifluoromethylphenyl)-
4,5-dihydro-1,2,4-oxadiazole-5-carboxylate 35b
4-Trifluoromethylbenzenecarbohydroxymoyl chloride (0.33g,
1.5 mmol) was added to a stirred at ꢁ30 ꢀC solution of the imino-
carboxylate 8b (0.21 g, 1.24 mmol) and triethylamine (0.15 g,
0.21 mL, 1.5 mmol) in diethyl ether (5 mL). After stirring at room
temperature for 3 h, the precipitated solid was separated by fil-
tration, the solvent was evaporated in vacuum, and the residue was
crystallized from hexane. Yield 0.38 g (86%), white crystals, mp:
96e98 ꢀC. IR (KBr)
n
: 1765 (C]O, C]N), 3240, 3270 (NH) cmꢁ1. 1H
3
NMR (300 MHz, CDCl3)
d
: 1.40 (t, JHH¼7.2 Hz, 3H, CH3CH2),
4.35e4.52 (m, 2H, OCH2), 5.92 (br, 1H, NH), 7.73 (d, 3JHH¼8.1 Hz, 2H,
Ar), 7.88 (d, 3JHH¼8.1 Hz, 2H, Ar) ppm. 19F NMR (188 MHz, CDCl3)
d:
ꢁ63.6 (3F, ArCF3), ꢁ82.3 (3F, CF3) ppm. Anal. Calcd for C13H10F6N2O3
9. Sharghi, H.; Ebrahimpourmoghaddam, S.; Doroodmand, M. M. Tetrahedron
2013, 69, 4708.
(356.2): C, 43.83; H, 2.83; N, 7.86. Found: C, 43.69; H, 2.80; N, 7.75.
10. Mucha, A.; Kafarski, P.; Berlicki, L. J. Med. Chem. 2011, 54, 5955.
11. (a) Kukhar, V. P.; Romanenko, V. D. Arkivoc 2012, 127; (b) Ghosh, S.; Chan, J. M.
W.; Lea, C. R.; Meints, G. A.; Lewis, J. C.; Tovian, Z. S.; Flessner, R. M.; Loftus, T. C.;
Bruchhaus, I.; Kendrick, H.; Croft, S. L.; Kemp, R. G.; Kobayashi, S.; Nozaki, T.;
4.15. 5-Trifluoromethyl-3-(4-trifluoromethylphenyl)-1,2,4-
oxadiazole 37
ꢀ
Oldfield, E. J. Med. Chem. 2004, 47, 175; (c) Sanders, J. M.; Gomez, A. O.; Mao, J.;
4-Trifluoromethylbenzenecarbohydroxymoyl chloride (0.29g,
1.3 mmol) was added to a stirred solution of the imine 3a (0.25 g,
1.1 mmol) and triethylamine (0.13 g, 0.18 mL, 1.3 mmol) in diethyl
ether (10 mL) at ꢁ30 ꢀC. The reaction mixture was stirred at rt for
30 min, washed with water (5 mL), and 2 N NaOH (5 mL). The or-
ganic phase was dried (MgSO4) and concentrated under reduced
Meints, G. A.; Van Brussel, E. M.; Burzynska, A.; Kafarski, P.; Gonza’lez-Paca-
nowska, D.; Oldfield, E. J. Med. Chem. 2003, 46, 5171; (d) Russel, G. Phosphorus,
Sulfur, and Silicon 1999, 144e146, 793; (e) Ebetino, F. H. Phosphorus, Sulfur, and
Silicon 1999, 144e146, 9; (f) Widler, L.; Jaeggi, K. A.; Green, J. R. Phosphorus,
€
€
Sulfur, and Silicon 1999, 144e146, 5; (g) Monkkonen, J.; Makkonen, N.; Rogers,
M. J.; Frith, J. C.; Auriola, S. Phosphorus, Sulfur, and Silicon 1999, 144e146, 321; (h)
Chem. Pharm. Bull. 1993, 41, 688; Rassukana, Yu. V. Synthesis 2011, 3426.
12. Rassukana, Yu. V. Synthesis 2011, 3426.
13. (a) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165; (b) Tsvetkov, E. N.;
Lobanov, D. I.; Izosenkova, L. A.; Kabachnik, M. I. Zh. Obshch. Khim. 1969, 39,
2177.
pressure to give compound 37 as colorless viscous oil, yield 0.19 g
3
(61%). 1H NMR (300 MHz, CDCl3)
d
: 7.78 (d, JHH¼8.1 Hz, 2H, Ar),
8.23 (d, JHH¼8.1 Hz, 2H, Ar) ppm. 19F NMR (188 MHz, CDCl3)
d:
3
14. Rassukana, Yu. V.; Onys’ko, P. P.; Kolotylo, M. V.; Sinitsa, A. D.; Lyzwa, P.; Mi-
kolajczyk, M. Tetrahedron Lett. 2009, 50, 288.
ꢁ64.5 (3F, ArCF3), ꢁ66.7 (3F, CF3) ppm. Anal. Calcd for C10H4F6N2O
(282.2): C, 42.57; H, 1.43; N, 9.93. Found: C, 42.21; H, 1.41; N, 9.75.
15. (a) Chaikovskaya, A. A.; Dmitriv, Y. V.; Ivonin, S. P.; Pinchuk, A. M.; Tolmachev,
A. A. Heteroat. Chem. 2005, 16, 599; (b) Chaikovskaya, A. A.; Dmitriv, Y. V.;
Ivonin, S. P.; Pinchuk, A. M.; Tolmachev, A. A. Heteroat. Chem. 2008, 19, 93; (c)
Tolmachev, A. A.; Ivonin, S. P.; Pinchuk, A. M. Heteroat. Chem. 1995, 6, 407.
16. Khomutnik, Ya. Ya; Onys’ko, P. P.; Rassukanaya, Yu. V.; Pirozhenko, V. V.; Sinitsa,
A. D. Zh. Obshch. Khim. 2013, 83, 391.
Acknowledgements
This work was supported by the State Fund of Basic Researches
of Ukraine (Project No.
F53.3/028).