Reaction of polyfluorinated chalcones with guanidine

Article abstract of DOI:10.1134/S1070428015120143

Reactions of polyfluorinated chalcones with guanidine in the presence of bases are accompanied by elimination of the polyfluorophenyl group. 3-(Pentafluorophenyl)-1-phenylprop-2-en-1-one and its derivatives reacted with guanidine under basic conditions to give 4-phenylpyrimidin-2-amine, polyfluorobenzenes, and Michael adducts, 3-(2-amino-4-phenylpyrimidin-5-yl)-3-(4-R-2,3,5,6-tetrafluorophenyl)-1-phenylpropan-1-ones. 1-(Pentafluorophenyl)-3-phenylprop-2-en-1-one and 1,3-bis(pentafluorophenyl)prop-2-en-1-one were converted into cinnamic acid derivatives whose reaction with guanidine afforded 2-amino-6-aryl-5,6-dihydropyrimidin-4(1H)-ones.

Full text of DOI:10.1134/S1070428015120143

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 12, pp. 1745–1752. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © E.A. Borodina, N.A. Orlova, Yu.V. Gatilov, O.I. Sal’nikova, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51,
No. 12, pp. 1778–1785.
Reaction of Polyfluorinated Chalcones with Guanidine
E. A. Borodinaa, N. A. Orlovaa, Yu. V. Gatilova, b, and O. I. Sal’nikovaa
a Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
e-mail: ona@nioch.nsc.ru
b Novosibirsk State University, ul. Pirogova 2, Novosibirsk, 630090 Russia
Received July 29, 2015
Abstract—Reactions of polyfluorinated chalcones with guanidine in the presence of bases are accompanied by
elimination of the polyfluorophenyl group. 3-(Pentafluorophenyl)-1-phenylprop-2-en-1-one and its derivatives
reacted with guanidine under basic conditions to give 4-phenylpyrimidin-2-amine, polyfluorobenzenes, and
Michael adducts, 3-(2-amino-4-phenylpyrimidin-5-yl)-3-(4-R-2,3,5,6-tetrafluorophenyl)-1-phenylpropan-1-
ones. 1-(Pentafluorophenyl)-3-phenylprop-2-en-1-one and 1,3-bis(pentafluorophenyl)prop-2-en-1-one were
converted into cinnamic acid derivatives whose reaction with guanidine afforded 2-amino-6-aryl-5,6-dihydro-
pyrimidin-4(1H)-ones.
DOI: 10.1134/S1070428015120143
Reactions of α,β-unsaturated carbonyl compounds
(including chalcones) with urea, thiourea, and guani-
dine were reported to produce various pyrimidine
derivatives which exhibited a broad spectrum of bio-
logical activity, in particular antimicrobial [1, 2], anti-
tumor [3], anti-inflammatory, analgesic [4–6], antiviral
[7], anti-HIV [8], antioxidant [9], and other kinds of
activity. Reactions of chalcones with urea derivatives
follow 1,2- and/or 1,4-addition path [10]. The most in-
teresting are products of their reactions with guanidine,
2-amino-4,6-diarylpyrimidines, which can be subjected
to further functionalization via transformations of the
amino group. Polyfluorinated analogs of such com-
pounds have not been reported, though some deriva-
tives with one or two fluorine atoms in the aromatic
rings are known [11–13]. Chalcones generally react
with guanidine hydrochloride in alcohols or DMF in
the presence of strong bases such as aqueous alkali,
sodium ethoxide, or sodium hydride [11, 12, 14, 15].
phenyl rings with guanidine hydrochloride in ethanol
and DMF in the presence of bases.
In keeping with the generally accepted mechanism
[10], the reaction of chalcone 1a with guanidine under
conventional conditions (heating with an equimolar
amount of guanidine hydrochloride in ethanol in the
presence of sodium hydroxide) should be expected to
give pyrimidine A (Scheme 1). However, the reaction
mixture contained only decomposition products,
4-phenylpyrimidin-2-amine (2) and ethoxy derivative
3a. In addition, we detected a compound which was
assigned the structure of 3-(2-amino-4-phenylpyrimi-
din-5-yl)-3-(4-ethoxy-2,3,5,6-tetrafluorophenyl)-1-
phenylpropan-1-one (4a) on the basis of X-ray diffrac-
tion data and 1H and 19F NMR spectra (Scheme 1). The
polyfluorophenyl rings in 3a and 4a contained
an ethoxy group as a result of reaction with ethanol in
the presence of alkali. Chalcones 1b and 1c with
a phenoxy or piperidino group in the fluorinated ring
reacted with guanidine in alcohol in a similar way, and
the products were mixtures of amine 2, tetrafluoro-
In this work we studied reactions of polyfluorinated
chalcones 1a–1f containing one or two polyfluoro-
O
F
F
O
F
O
F
F
F
F
F
F
F
F
R
R
F
F
F
F
F
F
F
1a–1c
1d, 1e
1f
R = F (a, d), PhO (b), (CH2)5N (c, e).
1745

BORODINA et al.
1746
Scheme 1.
NH2
N
N
F
F
NH
NaOH, EtOH, ∆
F
1a–1c
+
·HCl
NH2
H2N
F
R
A
NH2
N
N
NH2
F
F
F
F
Ph
F
O
N
N
+
+
F
Ph
R
F
R
F
2
3a–3c
4a–4c
R = EtO (a), PhO (b), (CH2)5N (c).
benzene 3b or 3c, and Michael adduct 4b or 4c. The
fraction of the latter in the product mixture was found
to correlate with the effect of the R substituent on the
stability of polyfluorophenyl anion.
of relatively stable C6F5– anion is well known [16, 17].
Presumably, azomethine derivatives of carbonyl com-
pounds are also prone to behave in this way.
Formalistically, compound 4a is the product of
Michael addition to chalcone 1a of the carbon-centered
nucleophile generated from aminopyrimidine 2 by the
action of alkali. However, compound 1a failed to react
Haloform-type reaction of polyfluoroaromatic
carbonyl compounds, including chalcone derivatives,
by the action of charged nucleophiles with elimination
Scheme 2.
NH
NH
H
NH
O
HN
NH2
F
N
NH
1a
+
Ph
HO
H2N
NH2
F
NH
NH
NH
H
HO–
N
N
N
N
N
N
–H2O
–C6HF5
–H2O
Ph
Ph
Ph
F
H
H
B
C
NH
NH
NH2
N
N
N
N
N
N
H2O
–HO–
1a
O–
Ph
F
O
Ph
F
O
Ph
F
Ph
Ph
Ph
4a
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 12 2015

REACTION OF POLYFLUORINATED CHALCONES WITH GUANIDINE
1747
Scheme 3.
(1) KOH, EtOH, ∆
(2) 30% H2O2
2
+ 3a + 4a
NH
Ph
(1) EtOH, 30% H2O2
(2) KOH
(3) ∆
O
1a
+
·HCl
NH2
H2N
F
N
HN
EtO
NH2
5a
reaction mixture which contained mainly water-soluble
compounds and was not studied in detail.
with pyrimidine 2 in the presence of alkali, and only
the initial compounds were detected in the reaction
mixture. On the other hand, carbon nucleophile can be
formed from the precursor of A, dihydropyrimidine B
possessing an acidic proton, and adduct 4a can result
from the reaction of 1a with carbanion C according to
Scheme 2. In order to verify this assumption we per-
formed experiments with addition of hydrogen perox-
ide, by analogy with the data reported in [18] for non-
fluorinated chalcone. It was found that the product
composition depends on the order of addition of the
reactants (Scheme 3). Heating of the reaction mixture
in boiling ethanol in the presence of KOH for 2 h,
followed by addition of 30% hydrogen peroxide, led to
the formation of the same compounds as in the absence
of oxidant. When hydrogen peroxide was added first,
we obtained dihydroimidazole derivative 5a, as re-
ported for nonfluorinated chalcone. Compound 5a was
isolated in a poor yield from the organic part of the
The mechanism of formation of dihydroimidazo-
lones [18] includes oxidation of chalcone at the double
bond to epoxide, transformation of the latter into
1,2-diketone, and subsequent reaction with guanidine.
Intramolecular cyclization of the resulting Schiff base
is accompanied by migration of the benzyl group to the
neighboring position with closure of five-membered
ring.
In the reaction of pentafluorophenyl ketone 1d with
guanidine in ethanol in the presence of NaOH, the
major products resided in the aqueous phase, and they
were not isolated by extraction with different organic
solvents. Obviously, the water-soluble product was
sodium cinnamate resulting from elimination of poly-
fluorophenyl group from 1d under alkaline conditions.
Cinnamic acid (6a) was detected by GC/MS together
with 2,3,5,6-tetrafluorophenol (3d) in the reaction
Scheme 4.
O
NH2
NH
R
F
F
F
F
NH
DMF, NaH, 20°C
OH
N
1d, 1e
+
·HCl
NH2
+
+
H2N
O
F
Ph
6a
7a
3c, 3d
R = (CH2)5N (c), HO (d).
Scheme 5.
O
F
NaOH, EtOH, ∆
OH
EtO
F
NH
F
6b
1f
+
·HCl
NH2
H2N
NH2
DMF, NaH, ~50°C
N
NH
+
C6HF5
O
C6F5
7c
3e
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 12 2015

BORODINA et al.
1H NMR spectrum with those of a sample described in
1748
N3
[19], as well as by X-ray analysis of its hydrochloride
7b (Fig. 1). The formation of 7a may be rationalized
by elimination of polyfluorophenyl residue from initial
chalcone 1d to give cinnamoyl cation and subsequent
Michael addition of guanidine, followed by lactam ring
closure. Likewise, piperidino-substituted chalcone 1e
reacted with guanidine hydrochloride in DMF/NaH to
afford a mixture of 7a and 3c.
C7
Cl1
C1
C8
C6
C5
N1
N2
C9
C4
C2
C10
C3
O1
In the reaction of decafluorochalcone 1f with
guanidine in ethanol in the presence of NaOH we
isolated only 4-ethoxy-2,3,5,6-tetrafluorocinnamic acid
(6b) (Scheme 5, Fig. 2). Chalcone 1f reacted with
guanidine in DMF/NaH in a way similar to compounds
1d and 1e, with formation of cyclic amino ketone 7c
and pentafluorobenzene (3e) (Scheme 5).
Fig. 1. Structure of the molecule of 2-amino-6-phenyl-5,6-
dihydropyrimidin-4(1H)-one hydrochloride (7b) according
to the X-ray diffraction data.
O2
C9
F4
C6
F3
1
19
C5
C7
The melting points and H and F NMR spectra of
2 and 3a were consistent with the data of [20–22]. The
structure of the newly synthesized compounds was
determined on the basis of spectral and analytical data.
The structure of 4a was unambiguously proved by
X-ray analysis (Fig. 3). The bond lengths in the
2-aminopyrimidine fragment of 4a were similar to the
corresponding bond lengths in the crystal structure of
tert-butyl 4-{[2-amino-4-(2-hydroxyphenyl)pyrimidin-
5-yl]methyl}piperazine-1-carboxylate [23]. The di-
hedral angles between the tetrafluorophenyl ring and
phenyl ring in position 4 of the pyrimidine ring in the
two independent molecules of 4a are 23.7 and 20.8°,
which favors C–F · · · π interactions [the shortest
distance between fluorine atoms and the centroid of the
4-phenyl ring is 3.613(3) and 3.482(2) Å]. Molecules
4a are linked to form dimers through hydrogen bonds
N3–H · · · N1A and N3A–H · · · N1 [H · · · N 2.18(4),
2.24(4) Å, ∠NHN 164(3), 157(3)°].
C8
C1
C2
O1
O3
C4
C10A
C11
O3A
C3
F2
F1
C10
C11A
Fig. 2. Structure of the molecule of 3-(4-ethoxy-2,3,5,6-
tetrafluorophenyl)prop-2-enoic acid (6b) according to the
X-ray diffraction data.
C21
C20
O2
F3
C17
C18
C19
F2
F4
C2
C7
C16
C26
C15
F1
C27
C22
C25
C14
C1
O1
C3
C9 C10
The geometric parameters of molecule 6b coincide
with those of (E)-3-(pentafluorophenyl)prop-2-enoic
acid [24]. Molecules 6b in crystal are also linked to
dimers through hydrogen bonds O1–H···O2 [H···O
1.72(5) Å, ∠OHO 176(4)°].
C5 C8
N1
C11
C23
C4
C6
C24
N2
N3
C12
C13
The tetrahydropyrimidine ring in the cation of salt
7b adopts a distorted boat conformation with the N1
and C4 atoms deviating by 0.318 and 0.770 Å toward
one side of the plane formed by the other ring atoms
and axial orientation of the phenyl substituent. Analo-
gous conformation and bond lengths were found in the
crystal structure of 5-cyano-8-methyl-4-oxo-1,3-diaza-
spiro[5.5]undecan-2-iminium chloride [25]. Molecules
7b in crystal are linked through intermolecular hydro-
gen bonds N–H···Cl [2.21(2), 2.28(3) Å, ∠177(2),
Fig. 3. Structure of the molecule of 3-(2-amino-4-phenyl-
pyrimidin-5-yl)-3-(4-ethoxy-2,3,5,6-tetrafluorophenyl)-1-
phenylpropan-1-one (4a) according to the X-ray diffraction
data (one of the two independent molecules is shown).
mixture obtained from 1d and guanidine hydrochloride
in DMF in the presence of sodium hydride (Scheme 4).
In addition, we isolated from that mixture 2-amino-6-
phenyl-5,6-dihydropyrimidin-4(1H)-one (7a) which
was identified by comparing its melting point and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 12 2015

REACTION OF POLYFLUORINATED CHALCONES WITH GUANIDINE
1749
176(2)°] and N–H···O [2.21(2) Å, 139(2)°] to form
bands parallel to the crystallographic a axis.
gramming from 50°C (2 min) to 280°C at a rate of
10 deg/min and 30 min at 280°C; injector temperature
280°C]. The high-resolution mass spectra were record-
ed on a DFS instrument with direct sample admission
into the ion source (electron impact, 70 eV).
The 19F NMR spectrum of 4a displayed two signals
with equal intensities at δF 4.38 and 18.52 ppm,
corresponding to 2,3,5,6-tetrafluoro substitution. The
1H NMR spectrum of 4a contained signals typical of
ethoxy protons and ABX spin system of the CH2CH
fragment, a two-proton singlet from the amino group,
multiplets from aromatic protons in two phenyl rings,
and a broadened singlet belonging to 6-H of the py-
Single crystals of 4a, 6b, and 7b were obtained by
crystallization from ethanol. The X-ray diffraction ex-
periments were performed at 200 K on a Bruker Kappa
Apex II diffractometer (MoKα radiation, graphite
monochromator). Corrections for absorption were
applied empirically using SADABS program. The
structures were solved by the direct method and were
refined in anisotropic approximation for non-hydrogen
atoms using SHELX97 package. The positions of
amino and hydroxy hydrogen atoms were refined in
isotropic approximation, and of the other hydrogens,
according to the riding model. The crystallographic
data for compounds 4a, 6b, and 7b were deposited to
the Cambridge Crystallographic Data Centre.
1
rimidine ring. The H and 19F NMR spectra of 4b and
4c were similar to those of 4a.
In summary, we have found that polyfluorinated
chalcones react with guanidine hydrochloride in etha-
nol or DMF in the presence of strong bases (NaOH or
NaH). The reactions of 3-(polyfluorophenyl)-1-phenyl-
prop-2-en-1-ones are accompanied by elimination of
the polyfluorophenyl fragment from the initially
formed unstable 2-amino-4,6-diarylpyrimidines or
their dihydropyrimidine precursors to afford a mixture
of 4-phenylpyrimidin-2-amine, the corresponding
polyfluorobenzene, and Michael adduct. Under analo-
gous conditions, 1-(polyfluorophenyl)-3-phenylprop-2-
en-1-ones and 1,3-bis(pentafluorophenyl)prop-2-en-1-
one are likely to lose the polyfluorophenyl group
even in the first step to give cinnamic acid derivatives,
and addition of guanidine to the latter and subsequent
intramolecular cyclization of the adduct yield 2-amino-
6-aryl-5,6-dihydropyrimidin-4(1H)-ones 7. Compound
7a can also be formed through the corresponding
diaryl-substituted pyrimidine and dihydropyrimidine as
shown in Scheme 2.
Compound 4a. Orthorhombic crystals system,
space group Pna21; C27H21F4N3O2, M 495.47; a =
12.7084(6), b = 13.5958(7), c = 27.745(2) Å; V =
4793.9(4) Å3; Z = 8; dcalc = 1.373 g/cm3. Number of
independent reflections 9114 (θmax = 25.7°), including
5938 reflections with I > 2σ(I). Final divergence factor
R = 0.0460 (for Fo), S = 1.006. CCDC entry
no. 1442487.
Compound 6b. Triclinic crystal system, space
group P-1; C11H8F4O3, M 264.17; a = 7.9786(4), b =
8.4651(4), c = 9.1297(4) Å; α = 95.434(2), β =
108.876(2), γ = 109.826(2)°; V = 534.20(4) Å3; Z = 2;
d
calc = 1.642 g/cm3. Number of independent reflections
3230 (θmax = 30°), including 2424 reflections with I >
2σ(I). Final divergence factor R = 0.0686 (for Fo), S =
0.992. The ethoxy group is disordered by two positions
with a population ratio of 0.637(9):0.363(9). CCDC
entry no. 1442488.
EXPERIMENTAL
The analytical and spectral studies were performed
at the Joint Chemical Service Center, Siberian Branch,
Russian Academy of Sciences. The H and 19F NMR
1
spectra were recorded on Bruker AV-300 (300.13 MHz
Compound 7b (7a hydrochloride). Monoclinic
crystal system, space group P21/n; C10H12ClN3O,
M 225.68; a = 6.6615(1), b = 23.5775(6), c =
6.8587(2) Å; β = 102.635(1)°; V = 1051.15(4) Å3; Z =
4; dcalc = 1.426 g/cm3. Number of independent reflec-
tions 2827 (θmax = 29°), including 2563 reflections
with I > 2σ(I). Final divergence factor R = 0.0346 (for
Fo), S = 1.137. CCDC entry no. 1442489.
for H and 282.37 MHz for 19F) and Bruker AV-400
1
1
1
instruments (400.13 MHz for H). The H chemical
shifts were determined relative to the residual proton
signals of deuterated solvents (CHCl3, δ 7.24 ppm;
DMSO-d5, δ 2.50 ppm; acetone-d5, δ 2.04 ppm). The
19F chemical shifts were measured relative to C6F6 as
internal standard. GC/MS analyses were obtained on
an Agilent Technologies 6890N gas chromatograph
coupled with an Agilent 5973N mass-selective detector
[electron impact, 70 eV; ion source temperature 230°C;
HP-5MS capillary column, 30 m×0.25 mm×0.25 μm;
carrier gas helium, 1 mL/min; oven temperature pro-
Initial polyfluorinated chalcones 1a, 1d, 1f [26] and
1b, 1c, 1e [17] were synthesized according to known
1
methods. The reaction mixtures were analyzed by H
and 19F NMR.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 12 2015

BORODINA et al.
1750
Reaction of 3-(pentafluorophenyl)-1-phenyl-
mixture was heated for 2 h under reflux with stirring,
cooled, and treated as described in a. The residue,
0.29 g (a multicomponent mixture, according to the
1H and 19F NMR data), was washed with 5 mL of
chloroform–hexane (1:1) to isolate 0.13 g (18%) of
2-amino-5-(4-ethoxy-2,3,5,6-tetrafluoro-benzyl)-5-
phenyl-1H-imidazol-4(5H)-one (5a) as colorless crys-
prop-2-en-1-one (1a) with guanidine. a. Chalcone
1a, 0.3 g (1.0 mmol), was added to a solution of
0.095 g (1.0 mmol) of guanidine hydrochloride and
0.12 g (3.0 mmol) of sodium hydroxide in 7 mL of
ethanol, and the mixture was heated for 2.5 h under
reflux with stirring. The mixture was cooled to room
temperature, poured onto ice, and extracted with ethyl
acetate. The extract was washed with water, dried over
CaCl2, and evaporated under reduced pressure on a ro-
tary evaporator. The product was 0.16 g of a mixture of
compounds 2, 3a, and 4a at a ratio of 60:16:24.
1
tals with mp 272–274°C. H NMR spectrum
(DMSO-d6), δ, ppm: 1.30 t (3H, OCH2CH3, J =
7.0 Hz), 3.34 and 3.40 (1H each, CH2, AB, J =
14.1 Hz), 4.25 q (2H, OCH2, J = 7.0 Hz), 6.91 br.s
(1H, NH2), 7.27–7.30 m (1H, Harom), 7.23–7.37 m (2H,
H
arom), 7.49–7.52 m (2H, Harom), 7.64 br.s (1H, NH2),
3-Ethoxy-1,2,4,5-tetrafluorobenzene (3a) was
8.42 s (1H, NH). 13C NMR spectrum (DMSO-d6), δC,
ppm: 15.17, 31.78, 68.92, 70.79, 108.59, 125.36,
127.38, 128.05, 135.93, 139.44, 139.62, 141.07,
144.42, 146.04, 170.66, 186.94. 19F NMR spectrum
(DMSO-d6), δF, ppm: 4.33 m (3-F, 5-F), 22.22 m (2-F,
6-F). Found: m/z 381.1103 [M]+. C18H15F4N3O2. Cal-
culated: M 381.1109.
1
identified by H and 19F NMR spectroscopy [22].
Mixture 2/3a/4a was subjected to alumina column
chromatography to isolate 0.13 g of a ~1:1 mixture of
4-phenylpyrimidin-2-amine (2) and 3-(2-amino-4-
phenylpyrimidin-5-yl)-3-(4-ethoxy-2,3,5,6-tetrafluoro-
phenyl)-1-phenylpropan-1-one (4a). Recrystallization
of that mixture from benzene gave 0.05 g (29%) of 2
which was identified by the melting point, mp 164–
Reaction of 3-(pentafluorophenyl)-1-phenyl-
prop-2-en-1-one (1a) with 4-phenylpyrimidin-2-
amine (2). Chalcone 1a, 0.09 g (0.3 mmol), was added
to a solution of 0.05 g (0.3 mmol) of pyrimidine 2 and
0.036 g (0.9 mmol) of sodium hydroxide in 3 mL of
ethanol. The mixture was heated for 2.5 h under reflux
with stirring, cooled, and poured onto ice, the precip-
itate was treated with ethyl acetate, the extract was
washed with water, dried over CaCl2, and evaporated
under reduced pressure on a rotary evaporator, and the
1
166°C (mp 165–166°C [20]) and H NMR spectrum
[21]. The mother liquor obtained after separation of 2
was evaporated. The residue, 0.08 g, was a mixture of
2 and 4a at a ratio of 1:1.2. When benzene was
allowed to slowly evaporate from the mother liquor,
crystals of 4a suitable for X-ray analysis separated.
Yield 18% (1H NMR), the product was identified in the
mixture by the NMR data. 1H NMR spectrum (CDCl3),
δ, ppm: 1.34 t (3H, OCH2CH3, J = 7.0 Hz); 3.66, 3.76,
and 5.12 (1H each, CH2CH, ABX, J = 17.5, 8.5, 7.2 Hz);
4.19 q (2H, OCH2, J = 7.0 Hz), 5.44 br.s (2H, NH2),
7.28–7.35 m (2H, Harom), 7.37–7.48 m (5H, Harom),
7.52–7.59 m (1H, Harom), 7.83–7.90 m (2H, Harom),
8.34 br.s (1H, Harom). 19F NMR spectrum (CDCl3), δF,
ppm: 4.38 m (3-F, 5-F), 18.55 m (2-F, 6-F).
residue was analyzed by H and 19F NMR. No com-
pound 4a was detected in the product mixture.
1
Reaction of 1-phenyl-3-(2,3,5,6-tetrafluoro-4-
phenoxyphenyl)prop-2-en-1-one (1b) with guani-
dine. Chalcone 1b, 0.3 g (0.8 mmol), was added to
a solution of 0.08 g (0.8 mmol) of guanidine hydro-
chloride and 0.1 g (2.4 mmol) of sodium hydroxide in
7 mL of ethanol. The mixture was heated for 3.5 h
under reflux with stirring, cooled to room temperature,
and poured onto ice. The precipitate was treated with
ethyl acetate, the extract was washed with water and
dried over CaCl2, the solvent was removed on a rotary
evaporator, and the residue, 0.25 g (a mixture of com-
pounds 2, 3b, and 4b at a ratio of 7:29:64), was
b. Chalcone 1a, 0.3 g (1.0 mmol), was added to
a solution of 0.14 g (1.5 mmol) of guanidine hydro-
chloride and 2 mL of 50% aqueous potassium hydrox-
ide in 10 mL of ethanol. The mixture was heated for
2 h under reflux with stirring, 0.34 mL of 30% hydro-
gen peroxide was added, and the mixture was heated
for 1 h under reflux, cooled, and treated as described in
a. The product was 0.18 g of a mixture containing
compounds 2, 3a, and 4a at a ratio of 33:47:20.
analyzed by H and 19F NMR. The product mixture
1
was washed with hexane–chloroform (2:1) to isolate
0.07 g (32%) of 3-(2-amino-4-phenylpyrimidin-5-yl)-
1-phenyl-3-(2,3,5,6-tetrafluoro-4-phenoxyphenyl)-
propan-1-one (4b) as colorless crystals with mp 156–
c. A solution of 0.6 g (2.0 mmol) of chalcone 1a,
0.28 g (3.0 mmol) of guanidine hydrochloride, and
0.68 mL of 30% hydrogen peroxide in 20 mL of
ethanol was heated to the boiling point, 4 mL of 50%
aqueous potassium hydroxide was added, and the
1
158°C. H NMR spectrum (CDCl3), δ, ppm: 3.67–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 12 2015

REACTION OF POLYFLUORINATED CHALCONES WITH GUANIDINE
1751
3.87 m (2H, CH2), 5.15–5.31 m (3H, CH, NH2), 6.83–
6.91 m (2H, Harom), 7.08 m (1H, Harom), 7.26–7.36 m
(4H, Harom), 7.38–7.48 m (5H, Harom), 7.57 m (1H,
Harom), 7.86–7.94 m (2H, Harom), 8.37 br.s (1H, Harom).
19F NMR spectrum (CDCl3), δF, ppm: 7.29 m (3-F,
5-F), 19.99 m (2-F, 6-F). Found: m/z 543.1559 [M]+.
C31H21F4N3O2. Calculated: M 543.1564.
chloride. The extracts were combined, washed with
water, and dried over CaCl2, and the solvent was re-
moved under reduced pressure on a rotary evaporator.
According to the H NMR data, the residue, 0.03 g,
contained mainly cinnamic acid (6a).
1
Reaction of 3-phenyl-1-[2,3,5,6-tetrafluoro-4-
(piperidin-1-yl)phenyl]prop-2-en-1-one (1e) with
guanidine. Chalcone 1e, 0.6 g (3.4 mmol), was added
to a solution of 0.32 g (6.7 mmol) of guanidine hydro-
chloride and 0.16 g (13.4 mmol) of sodium hydride in
6 mL of DMF. The mixture was stirred for 1 h at 50°C,
cooled, and poured onto ice, and the precipitate was
treated with ethyl acetate. The extract was washed with
water and dried over CaCl2, and the solvent was
removed under reduced pressure on a rotary evaporator
to leave 0.18 g (34%) of compound 3c. A solid
separated from the aqueous phase and was filtered off,
washed with a small amount of water, and dried in air.
We thus isolated 0.07 g (11%) of compound 7a.
Reaction of 1-phenyl-3-[2,3,5,6-tetrafluoro-4-
(piperidin-1-yl)phenyl]prop-2-en-1-one (1c) with
guanidine. Chalcone 1c, 0.3 g (0.8 mmol), was added
to a solution of 0.08 g (0.8 mmol) of guanidine hydro-
chloride and 0.1 g (2.4 mmol) of sodium hydroxide in
7 mL of ethanol. The mixture was heated for 3.5 h
under reflux with stirring, cooled, and treated as
described above for the reaction with 1b. The product,
0.24 g of a mixture of 2, 3c, and 4c at a ratio of
37:46:17, was subjected to alumina column chroma-
tography. Elution with hexane–chloroform (1:1) gave
0.03 g (16%) of 1-(2,3,5,6-tetrafluorophenyl)piperidine
19
(3c) whose F NMR spectrum was identical to that of
Reaction of 1,3-bis(pentafluorophenyl)prop-2-
en-1-one (1f) with guanidine. a. Chalcone 1f, 0.3 g
(0.8 mmol), was added to a solution of 0.07 g
(0.8 mmol) of guanidine hydrochloride and 0.09 g
(2.3 mmol) of sodium hydroxide in 6 mL of ethanol.
The mixture was heated for 1 h under reflux with
stirring, cooled, and treated as described above. We
isolated 0.15 g (75%) of 3-(4-ethoxy-2,3,5,6-tetra-
fluorophenyl)prop-2-enoic acid (6b) as colorless
1
a sample described in [27]. H NMR spectrum
(CDCl3), δ, ppm: 1.66 m (6H, CH2), 3.18 m (4H, CH2),
6.61 m (1H, Harom). 19F NMR spectrum (CDCl3), δF,
ppm: 10.54 m (2-F, 6-F), 20.66 m (3-F, 5-F). Found:
m/z 232.0747 [M – H]+. C11H11F4N. Calculated:
M 233.0822.
We failed to separate compounds 2 and 4c by
chromatography.
1
crystals with mp 129–131°C. H NMR spectrum
Reaction of 1-(pentafluorophenyl)-3-phenyl-
prop-2-en-1-one (1d) with guanidine. a. Chalcone
1d, 1.0 g (3.4 mmol), was added to a solution of 0.64 g
(6.7 mmol) of guanidine hydrochloride and 0.32 g
(13.4 mmol) of sodium hydride in 10 mL of DMF. The
mixture was stirred for 1.5 h at 50°C, cooled, poured
onto ice, and treated with ethyl acetate. The undis-
solved material at the phase boundary was filtered off.
We thus isolated 0.1 g (16%) of 2-amino-6-phenyl-5,6-
dihydropyrimidin-4(1H)-one (7a) which was identical
(acetone-d6), δ, ppm: 1.40 t (3H, OCH2CH3, J =
7.0 Hz), 4.41 q (2H, OCH2, J = 7.0 Hz), 6.63 and
7.58 (1H each, CH=CH, AB, J = 16.3 Hz), 7.92 br.s
(1H, OH). 19F NMR spectrum (acetone-d6), δF, ppm:
5.38 m (3-F, 5-F), 20.87 m (2-F, 6-F).
b. Chalcone 1f, 0.5 g (1.3 mmol), was added to
a solution of 0.25 g (2.6 mmol) of guanidine hydro-
chloride and 0.12 g (5.2 mmol) of sodium hydride in
10 mL of DMF. The mixture was stirred for 10 min at
50°C, cooled, and poured onto ice, and the oily mate-
rial was extracted into ethyl acetate. The extract was
washed with water and dried over CaCl2, and the sol-
vent was removed under reduced pressure on a rotary
evaporator. The residue was 0.20 g of 2-amino-6-
(pentafluorophenyl)-5,6-dihydropyrimidin-4(1H)-one
1
to a sample described in [19] in H NMR data and
melting point (mp 255–257°C; 257.3°C [19]). The
extract was washed with water and dried over CaCl2,
the solvent was removed under reduced pressure on
a rotary evaporator, and the residue, 0.29 g, was ana-
lyzed by NMR and GC/MS.
1
(7c) which was identified by NMR data. H NMR
b. Chalcone 1d, 0.3 g (1.0 mmol), was added to
a solution of 0.095 g (1.0 mmol) of guanidine hydro-
chloride and 0.12 g (3.0 mmol) of sodium hydroxide in
6 mL of ethanol. The mixture was heated for 5 h under
reflux with stirring, cooled, poured onto ice, and
treated first with diethyl ether and then with methylene
spectrum (DMSO-d6), δ, ppm: 2.50, 2.65, and 5.10
(1H each, ABX, CH2CH, J = 6.7, 9.5, 16.4 Hz),
5.77 br.s (2H, NH2), 6.95 br.s (1H, NH). 19F NMR
spectrum (DMSO-d6), δF, ppm: –0.13 m (2F), 6.71 m
(1F), 19.94 m (2F).
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BORODINA et al.
14. Tyagi, V., Khan, S., Shivahare, R., Srivastava, K.,
1752
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