Reactions of 6-(tri- and 6-(difluoromethyl))comanic acids and their ethyl esters with aniline and its 2-substituted derivatives

Article abstract of DOI:10.1016/j.jfluchem.2012.06.003

Reactions of 6-(tri- and 6-(difluoromethyl))comanic acids with aniline, o-phenylenediamine and o-aminophenol were investigated. R^F-containing derivatives of 4-pyridones, benzodiazepines and quinoxalinones were synthesized. Electrophilic propert

Full text of DOI:10.1016/j.jfluchem.2012.06.003

Journal of Fluorine Chemistry 141 (2012) 41–48
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Reactions of 6-(tri- and 6-(difluoromethyl))comanic acids and their ethyl
esters with aniline and its 2-substituted derivatives
*
Dmitrii L. Obydennov, Boris I. Usachev
Department of Chemistry, Ural Federal University, Kuybysheva st., 48, 620026 Ekaterinburg, Russia
A R T I C L E I N F O
A B S T R A C T
Article history:
Reactions of 6-(tri- and 6-(difluoromethyl))comanic acids with aniline, o-phenylenediamine and o-
aminophenol were investigated. RF-containing derivatives of 4-pyridones, benzodiazepines and
quinoxalinones were synthesized. Electrophilic properties of 6-(trifluoromethyl)comanic acid were
evaluated.
Received 30 March 2012
Received in revised form 25 May 2012
Accepted 3 June 2012
Available online 13 June 2012
ß 2012 Elsevier B.V. All rights reserved.
Keywords:
Fluorine-containing comanic acid
derivatives
2-Substituted anilines
Benzodiazepines
Quinoxalinones
Electrophilicity
1. Introduction
2. Results and discussion
Fluorine-containing organic compounds have attracted much
interest because of their unique chemical properties and biological
activities [1]. Among those, trifluoromethylated and other
fluoroalkylated pyrones belong to a peculiar group of fluorinated
compounds. In spite of some representatives of RF-pyrones were
described earlier, their chemical properties till investigated very
poorly [2]. Recently we described regioselective solvent-sensitive
reactions of such CF3-pyrones as 6-(trifluoromethyl)comanic acid
and its derivatives with phenylhydrazine [2f], which lead to
trifluoromethylated 3-(pyrazolyl)indoles [2p]. It is known, that 5-
methyl-2-(trifluoromethyl)-4H-pyran-4-one reacts with methyl-
amine in methanol to give the corresponding pyridone, 1,5-
dimethyl-2-(trifluoromethyl)-4(1H)-pyridin-4-one [2c], however,
there are no data in literature about reactions of 2-RF-4-pyrones
with aromatic amines. With the aim to develop approaches for the
preparation of fluorine-containing heterocycles on the basis of
pyrone compounds, we studied reactions of 6-tri(di)fluoromethyl-
comanic acids and their ethyl esters with such aromatic amines as
aniline, o-phenylenediamine (o-PhDA) and o-aminophenol under
various reaction conditions.
We have found that 2-RF-4-pyrones 1a–d [2g] (derivatives of 4-
pyrone-2-carboxylic (comanic) acid) react with aniline and o-
aminophenol by heating the mixtures in a protic solvent under
acidic conditions (HCl or H2SO4) to give the corresponding 2-RF-1-
arylpyridin-4(1H)-ones 2a–h in 21–65% yield (Scheme 1). Pyr-
idonecarboxylic acids 2a,b were also synthesized in 74–70% yield
by saponification of esters 2e,f with KOH. Pyridones 2 are the first
representatives of 2-tri(di)fluoromethylated N-aryl-4-pyridones
and they are fluorine-containing analogs of pharmaceutically
important pyridone compounds [3a–c], which were prepared
using the reactions of such non-fluorinated 4-pyrones as comanic
[3a] or chelidonic acid (its derivatives) with anilines [3b–g]. In all
cases, described reactions of non-fluorinated 4-pyrones with
aniline and their 2-substituted analogs give 4-pyridones [3a–g]
or their annulated derivatives [3h–j]. In the last case (when o-PhDA
or o-aminophenols were used as nucleophiles), the reactions were
followed by intramolecular cyclization due to the attack of the
second nucleophilic atom on the ester carbonyl group, resulting in
the formation of pyrido[2,1-c]benzoxazine and pyrido[1,2-a]qui-
noxaline derivatives [3h–j].
We have shown, that in contrast to those non-fluorinated 4-
pyrones, 2-CF3(CF2H)-4-pyrones 1a–d react with o-PhDA in the
presence of a strong acid to give RF-bearing benzodiazepines 3a–d
(Scheme 1). Nevertheless, besides the benzodiazepines, quinox-
alin-2(1H)-one derivatives were formed in the reaction of 1 with o-
PhDA, which were precipitated from the reaction mixtures as low
* Corresponding author.
E-mail address: boris.usachev@mail.ru (B.I. Usachev).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.06.003

42
D.L. Obydennov, B.I. Usachev / Journal of Fluorine Chemistry 141 (2012) 41–48
Scheme 2.
with reactions (1) and (2). Theoretically, intermediate A could give
compounds 5 via quinoxalinones 4. However, 4a did not react with
excess o-PhDA (heating the reagents in EtOH with or without HCl).
Vice versa, treatment of 5a with HCl led to hydrolysis of the
diazepine moiety and formation of 4a (46%). This result excludes A
as an intermediate by the formation of 5.
Scheme 1.
soluble red solids. NMR spectra and elemental analysis of these
residues showed that in the case of the carboxylic acids (1a,b) they
are almost pure (Z)-(5,5,5-trifluoro- and (Z)-(5,5-difluoro-2,4-
dioxopentylidene))-1,2,3,4-tetrahydro-2-quinaxolinones
4a,b,
whereas a red residue, prepared from ester 1c, is a mixture of
4a and (Z)-3-[(2-(trifluoromethyl)-1H-benzo[b][1,4]diazepin-4-
yl)methylene]-3,4-dihydroquinoxalin-2(1H)-one 5a (Scheme 1).
In the case of ethyl 6-(difluoromethyl)comanoate 1d the red
residue consisted of only (Z)-3-[(2-(difluoromethyl)-1H-ben-
zo[b][1,4]diazepin-4-yl)methylene]-3,4-dihydroquinoxalin-
2(1H)-one 5b.
We have found that compounds 5 can be prepared more
selectively by treatment of 4-pyrone-2-carboxylic acids 1a,b with
o-PhDA in the absence of a strong acid. According to the 1H NMR
spectra, the crude products are mixtures of 5 and their diimine
The main and common intermediate in the reactions of 1 with
anilines for strongly acidic conditions, most probably, is enam-
inodione A (Scheme 2), which is formed by nucleophilic attack at
the C-2 carbon of the pyrone ring. Intermediates A then could be
transformed either into benzodiazepines 3 through path (1) or into
quinoxalinones 4 through path (2). The reaction (1) is a reversible
process due to facile ring opening of labile seven-membered
diazepine ring. This supposition was confirmed by heating of 3c in
AcOH/HCl, which gave 4a in 31% yield. On the other hand, the
alternative reaction pathway (2) leads to the formation of stable
six-membered pyrazine ring. Thus, benzodiazepines 3 can be
considered as kinetically controlled products, whereas compounds
4 are thermodynamically controlled ones (Scheme 2).
Neither the corresponding 4-pyridone nor pyrido[1,2-a]qui-
noxaline derivatives were detected in crude samples of 3. The
reason which prevents the formation of pyridones and pyrido[2,1-
c]quinoxalines (structures C and D, Scheme 2) from RF-pyrones 1
and o-PhDA can be explained by relatively slow dehydratation of
intermediate RF-hemiaminals B (dehydratation of trifluoromethy-
lated cyclic hemiaminals occurs not so rapidly [4]) in comparison
Scheme 3.

D.L. Obydennov, B.I. Usachev / Journal of Fluorine Chemistry 141 (2012) 41–48
43
Table 1
functions [5f] via expression (4) [5g]:
vþk ¼ fkþvþ
Electroaccepting power (v+) of 1a, 1aH+ and 1aS, and regional electrophilicity (vkþ
)
of atoms C-2 and C-6.
(4)
where index vþk is the regional electrophilicity condensed to atom
k in a molecule, and fkþ is the condensed Fukui function [5h] at
atom k for a nucleophilic attack, which is given by
fkþ ¼ qkðN þ 1Þ ꢀ qkðNÞ
(5)
1a
1aH+
1aS
where N is the total number of electrons in the reference molecule,
qk(N) and qk(N + 1) denote the atomic population on atom k in the
molecule with N and N + 1 electrons.
Electroaccepting power v+ (eV)
v+
6.832
35.143
0.273
Regional electrophilicity vþk (eV) of atoms C-2 (v2þ) and C-6 (vþ6
)
The results of the calculations of global and regional electro-
philicity of 1a and its protonated, and deprotonated forms are
compiled in Table 1. Protonation of 1a (v+ = 6.832 eV) dramatically
increases electrophilicity of the pyrone system to value 35.143 eV
(protonated form 1aH+). Deprotonation of 1a to anion 1aS
moderately decreases v+ to value 0.273 eV. According to Table
1, atoms C-2 in 1a and 1aH+ possess a higher the regional
electrophilicity (vþ2 ¼ 0:544 eV for 1a and 3.486 eV for 1aH+) than
atoms C-6 in the same structures (vþ6 ¼ 0:327 and 2.520 eV,
respectively). Atoms C-2 and C-6 in anion 1aS possess the lowest
values of the regional electrophilicity (0.0144 and 0.0293 eV,
respectively), and these values show that in contrast to 1a and
1aH+, electrophilicity of carbon C-6 in the anion is about 2.0 times
higher than electrophilicity of carbon C-2. Since the relative
v2þ
v6þ
0.544
0.327
3.486
2.520
0.0144
0.0293
tautomers
6 (5a:6a = 21:79; 5b:6b = 65:35) (Scheme 3). To
transform partially 6 into more conjugated tautomers 5 the
mixtures were heated in DMSO at 80–120 8C. The syntheses of
compounds 5 and 6 confirm that in the absence of a strong acid o-
PhDA attacks carbon C-6 of the pyrone ring rather than carbon C-2
(formation of intermediate E, Scheme 3). This supposition was
proved theoretically and experimentally.
There are three possible reactive forms that can react with o-
PhDA in the case of carboxylic acid 1a: pyrone form 1a, protonated
form 1aH+ and anionic form 1aS (Table 1). The reactivity of the C-2
and C-6 carbons of the pyrone ring can be described using indices
of reactivity calculated with computational methods such as
Density Functional Theory (DFT) [5a]. Parr et al. [5b], promoted by
the work of Maynard et al. [5c] have determined the electrophilic-
ity index that measures the energy changes of an electrophile
when it becomes saturated with electrons, by considering the case
when an electrophile (electrophilic ligand) is immersed in
idealized zero-temperature free electron sea of zero chemical
potential. In this case the electrophile (electrophilic species)
becomes saturated with electrons when its chemical potential
becomes equal to the chemical potential of the sea. The energy
change becomes
electrophilicity
(
v2þ
=
v6þ
)
decreases from 1a to 1aꢀ
(1.66 < 1.38 < 0.49), the formation of intermediates type of E
(attacking at the C-6 carbon) becomes more likely in accordance
with this series. Therefore, treatment of compounds 1a,b with o-
PhDA without adding any strong acid leads to the formation of 5 or
6 (via the carboxylate anions), whereas conducting the reactions of
1 with aromatic amines in a strongly acidified medium gives 2 or 3
(via attacking at the C-2 carbon and the formation of A). The
decrease of the relative electrophilicity from 1a to 1aH+ (1.66
versus 1.38) explains the appearance of some amounts of 5 in
strongly acidified media due to the existence of trace concentra-
tions of the protonated forms of 1.
Heating pyrone 1a with a weaker than o-PhDA nucleophile, o-
aminophenol in water without addition of a strong acid led to the
formation of (Z)-(5,5,5-trifluoro-2,4-dioxopentylidene)-3,4-dihy-
dro-2H-benzo[b][1,4]oxazin-2-one 7 in 40% yield (Scheme 4).
Probably, nucleophilicity of o-aminophenol not enough to attack
effectively the C-6 atom of 1aS with v6þ ¼ 0:0293 eV, and this
nucleophile attacks mainly more electrophilic atom C-2 of more
reactive substrate 1aH+, which must be presented in the reaction
mixture as one of the forms of the equilibrium protonation–
deprotonation process, with v2þ ¼ 3:486 eV, leading to 7 (instead of
m2
D
E ¼ ꢀ
< 0;
2h
and it was suggested as the definition of electrophilicity (
global electrophilicity index) as
v
) (the
(1)
m2
v
¼
;
2h
where
m
is the chemical potential and h is the chemical hardness.
´
Gazquez et al. have proposed the following expression for
electroaccepting power (v+) to describe electrophilic properties
of molecules (chemical systems) [5d]:
2
ðI þ 3AÞ
vþ
¼
(2)
16ðI ꢀ AÞ
where I is the ionization potential, and A is the electron affinity.
Using Koopmans’ theorem [5e] the ionization potential and
electron affinity can be replaced by the HOMO and LUMO energies:
I ¼ ꢀEHOMO and A ¼ ꢀELUMO
(3)
The calculated LUMO energies of 1a (ꢀ3.50 eV), 1aS (0.10 eV)
and 1aH+ (ꢀ8.85 eV) show ability of the forms to accept electrons
from nucleophiles.
Electroaccepting power (v+) is a global reactivity index. This
index can be specified for each atom in a molecule by Fukui
Scheme 4.

44
D.L. Obydennov, B.I. Usachev / Journal of Fluorine Chemistry 141 (2012) 41–48
Scheme 5.
2c, which is formed in acidified media). The low yield (40%) of
compound 7 can be explained by the formation of side products,
which were not isolated, and, therefore, not identified. Quinox-
alinones 4 and their structurally closest analogue, benzoxazinone
7, are fluorine-containing representatives of important groups of
compounds, (Z)-(2-oxoalkylidene)-1,2,3,4-tetrahydro-2-quinaxo-
lones and (Z)-(2-oxoalkylidene)-3,4-dihydro-2H-benzo[b][1,4]ox-
azin-2-ones, many derivatives of which possess antimicrobial
activities [6].
Pyridone 2c, which was isolated in acidified media (Scheme 1),
or the corresponding oxazepine were not detected in crude
compound 7. These facts arise from slow dehydratation of cyclic
tautomer B into pyridone 2c in low-acid media and lower stability
of the oxazepine ring (in comparison with the diazepine ring). 6-
(Difluoromethyl)comanic acid 1b do not give detectible amounts
of the corresponding CF2H-containing benzoxazinone in the
reaction with o-aminophenol.
Scheme 6.
of [(3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl]-1,2,3,4-tetrahy-
dro-2-quinaxolones 9. The more sterically hindered nucleophilic
nitrogen atom of the N-phenylhydrazone intermediates, probably,
unable to attack intramolecularly the diazepine ring. Instead, this
intermediate reacts with excess phenylhydrazine with loss of o-
PhDA to give pyrazole-phenylhydrazones 10 (10a earlier was
prepared rapidly from pyrone 1c and PhNHNH2 [2f]).
The structures of the synthesized compounds were confirmed
by 1H, 19F, 13C NMR and IR spectroscopy, and elemental analysis. In
the 1H NMR spectra of pyridones 2 the pyridone protons (H-3 and
H-5) appeared either as two characteristic doublets at field in a
6.50–6.85 range (4J 2.7 Hz) or as a singlet at about
when the protons H-3 and H-5 have identical chemical shifts). In
the 19F NMR spectra of the pyridones the signal of the
trifluoromethyl group appeared at about
6-RF-4-pyridon-2-carboxylic acids 2a,c,d easily decarboxylate
by melting to give 2-RF-pyridones 8a,c,d in 54–71% yield (Scheme
5), and only N-phenyl-2-(difluoromethyl)-4-pyridone 8b cannot
be synthesized via decarboxylation due to the formation of a
complex mixture of products. Such behavior of 2b can be explained
by relatively high acidity of the hydrogen connected to the –CF2–
C55C–CO moiety. A likely pathway for this facile decarboxylation
involves the formation of intermediate betaines F and G [7]. The
corresponding basic intermediate type of G derived from 2b could
react with this acidic hydrogen leading to side products. The
electron-withdrawing RF group should promote the decarboxyl-
ation due to additional stabilization of the negative charge at the
carbons of the pyridine ring. In the 19F NMR spectrum of pyridone
8d two nonequivalent fluorines appeared as doublets of doublets
d
d
6.6 (in the cases
d 100.0.
The characteristic triplet at d 5.30 (J 1.9 Hz) of the diazepine CH
proton (coupling to two NH protons) in the 1H NMR spectrum of
benzodiazepine 3c confirms the 1H,5H-1,5-benzodiazepinic struc-
ture of compounds 3 [8]. Similar buried triplet at
d 5.24 was
observed in the 1H NMR spectrum of 5a. In the 13C NMR spectrum
of benzodiazepine 3a the trifluoromethyl and carbonyl carbons of
the side chain appeared as quartets at
d
117.1 (1JC,F 289.1 Hz) and
175.7 (2JC,F 32.4 Hz), respectively, confirming that the trifluor-
at
d
41.9 and 46.3 (2JF,F 303.3 Hz, 2JH,F 53.0 Hz), due to a high energy
omethyl substituent is attached to the carbonyl group. In the 13C
barrier for rotation around the C–N bond.
NMR spectrum of 5a three characteristic quartets of the
1
Benzodiazepines 3 are chemically active substrates toward
nucleophiles. Thus, reactions of 3c,d with hydrazine and phenyl-
hydrazine in the presence of HCl occur with destruction of the
diazepine ring to produce different pyrazole derivatives (9a,b and
10a,b) (Scheme 6). It is more likely that these reactions proceed
through intermediate hydrazones H. Recyclization of the N-
unsubstituted intermediate hydrazones leads to the formation
trifluoromethyl (
d
120.9, JC,F 275.7 Hz) and diazepine (
d
133.4,
2JC,F 30.8 Hz;
d
98.1, 3JC,F 5.2 Hz) carbons were observed, confirming
the CF3-diazepine structure of 5. In the 1H NMR spectra of the
diimine tautomers 6a,b the methylene protons appeared as
singlets at
trifluoromethyl group in 5a appeared at
substituent in diimine tautomer 6a appeared at
d
3.67–3.50 [9]. According to the 19F NMR spectra the
d
94.1, whereas the same
90.6.
d

D.L. Obydennov, B.I. Usachev / Journal of Fluorine Chemistry 141 (2012) 41–48
45
Compounds 3–7 and 9 possess near-planar structures due to
4.3. 6-(Difluoromethyl)-1,4-dihydro-4-oxo-1-phenylpyridine-2-
carboxylic acid (2b)
intramolecular hydrogen bond stabilizing effect (in the 1H NMR
spectra the hydrogen bonded NH protons appeared as low-field
signals at about
d
11.2–13.2).
Method A. A mixture of 1b (39 mg, 0.21 mmol), aniline (21 mg,
0.22 mmol) and conc. HCl (0.1 mL) was refluxed in 40% aqueous
EtOH (0.8 mL) for 1.5 days. Then excess EtOH was distilled off, the
resulting mixture was diluted with water, the residue was filtered,
washed with water and dried to give 2b (11 mg, 21%) as gray solid,
mp 187–188 8C. Method B. KOH (47 mg, 0.84 mmol) was added to a
suspension of 2f (68 mg, 0.23 mmol) in H2O (1.5 mL). The mixture
was stirred at ambient temperature for 1 h, filtered, and the cooled
filtrate quenched with 15% HCl until pH ꢁ 1–2. The residue was
filtered, washed with water (2 mL) and dried to give 2b (42 mg, 70%)
3. Conclusion
Thus, we have shown the versatile reactivity of 2-CF3(CF2H)-4-
pyrones toward aromatic amines, synthesized the first represen-
tatives of 2-tri(di)fluoromethylated N-phenyl-4-pyridones, novel
CF3(CF2H)-containing benzodiazepines, quinoxalinones and (Z)-3-
[(1H-benzo[b][1,4]diazepin-4-yl)methylene]-3,4-dihydroquinox-
alin-2(1H)-ones, and explained possible reasons of the regioselec-
tivitiy of the reactions. Electrophilic properties of such 2-RF-4-
pyrones as 6-(tri(di)fluoromethyl)comanic acids and their ethyl
esters were evaluated.
as white solid, mp 187–188 8C;
nmax (ATR) 3547, 1642, 1590, 1459,
1376 cmꢀ1 H (400 MHz, DMSO-d6) 6.55 (1H, t, 2JH,F 52.6 Hz, CF2H),
;
d
6.56 (1H, d, J 2.7 Hz, CH), 6.59 (1H, d, J 2.7 Hz, CH), 7.46–7.55 (5H, m,
Ph), 13.5–15.0 (1H, br s, CO2H); dF (376.5 MHz, DMSO-d6) 45.0 (d,
2JH,F 52.6 Hz, CF2H) [Found: C, 55.06; H, 3.79; N, 4.93.
C13H9F2NO3ꢂH2O requires C, 55.13; H, 3.91; N, 4.95%].
4. Experimental
4.1. General
4.4. 6-(Trifluoromethyl)-1,4-dihydro-4-oxo-1-(2-
1H, 19F and 13C NMR spectra were recorded on Bruker AVANCE
DRX-400 spectrometer. Chemical shifts for 1H NMR spectra are
reported in parts per million (ppm) downfield from TMS, shifts for
19F NMR spectra are reported in ppm downfield from internal C6F6.
Coupling constants (J) are given in hertz (Hz). Infrared spectra (IR)
were recorded on Nicolet 6700 spectrometer, equipped with
attenuated total reflection accessory (ATR), absorbance frequen-
cies are given at maximum of intensity in cmꢀ1. Density Functional
Theory (DFT) calculations of 1a, 1aH+ and 1aS have been
performed using the PRIRODA [10a,b] program. A generalized
gradient approximation (GGA) exchange-correlation density
functional by Perdew, Burke and Ernzerhoff (PBE) [11] was used
with double-zeta-polarized quality. Correlation-consistent Gauss-
ian basis set: (2s,2p,1d)/(10s,7p,3d) for C and O atoms; (2s,1p)/
(6s,2p) for H atoms [12]. The electroaccepting power (v+) was
evaluated using Eq. (2). The Koopmans’ theorem [5e] was utilized
to calculate values of the ionization potential (I) and electron
affinity (A) of the pyrone structures (Eq. (3)). The regional
hydroxyphenyl)pyridine-2-carboxylic acid (2c)
A solution of 1a (200 mg, 2.12 mmol), o-aminophenol (120 mg,
2.29 mmol) and conc. HCl (0.5 mL) in H2O (2 mL) was refluxed for
6 h. The residue was filtered and crystallized from aqueous EtOH to
give 2c (180 mg, 62%) as white powder, mp 177–178 8C.
nmax (ATR)
dH (400 MHz,
2940, 2712, 1751, 1633, 1601, 1556, 1465 cmꢀ1
;
DMSO-d6) 6.59 (1H, d, J 2.7 Hz, H-3), 6.82 (1H, d, J 2.7 Hz, H-5), 6.87
(1H, t, J 7.7 Hz, H-50), 6.94 (1H, d, J 8.1 Hz, H-60), 7.33 (1H, td, J 7.7,
1.4 Hz, H-40), 7.37 (1H, d, J 8.1 Hz, H-30), 10.37 (1H, s, OH); dF
(376.5 MHz, DMSO-d6) 100.1 (s, CF3) [Found: C, 52.64; H, 2.60; N,
4.71. C13H8F3NO4 requires C, 52.19; H, 2.70; N, 4.68%].
4.5. 6-(Difluoromethyl)-1,4-dihydro-4-oxo-1-(2-
hydroxyphenyl)pyridine-2-carboxylic acid (2d)
A solution of acid 1b (150 mg, 0.79 mmol), o-aminophenol
(90 mg, 0.82 mmol) and conc. HCl (0.25 mL) in H2O (2 mL) was
refluxed for 3 h. The residue was filtered and crystallized from
aqueous EtOH to give 2d (92 mg, 48%) as white crystals, mp 179–
electrophilicity indices (vþk ) of atoms C-2 and C-6 (v2þ and v6þ
)
were evaluated using Eq. (4). The condensed Fukui functions were
calculated from the Mulliken population of atoms C-2 and C-6 in
the molecule with N and N + 1 electrons (Eq. (5)).
180 8C;
n
max (ATR) 3067, 1630, 1462 cmꢀ1
;
d
H (400 MHz, DMSO-d6)
2
6.47 (1H, t, JH,F 52.8 Hz, CF2H), 6.55 (1H, d, J 2.7 Hz, H-3 (H-5)),
6.58 (1H, d, J 2.7 Hz, H-5 (H-3)), 6.89 (1H, t, J 7.6 Hz, arom.), 6.97
(1H, d, J 8.6 Hz, arom.) 7.30–7.37 (2H, m, arom.), 10.21–10.65 (1H,
4.2. 6-(Trifluoromethyl)-1,4-dihydro-4-oxo-1-phenylpyridine-2-
2
carboxylic acid (2a)
br s, OH); dF (376.5 MHz, DMSO-d6) 44.9 (d, JH,F 52.5 Hz, CF2H)
[Found: C, 54.44; H, 3.34; N, 4.88. C13H9F2NO4ꢂ0.33 H2O requires C,
Method A. Aniline (140 mg, 1.5 mmol) and conc. HCl (0.5 mL)
were added to a solution of 1a [2g] (250 mg, 1.2 mmol) in 40%
aqueous EtOH (4 mL). The mixture was refluxed for 24 h, excess
EtOH was distilled off, and the residue was diluted with H2O
(3 mL). The resulting residue was filtered and crystallized from
aqueous EtOH to give 2a (75 mg, 30%) as white solid, mp 186–
187 8C. Method B. KOH (54 mg, 0.96 mmol) was added to a
suspension of 2e (100 mg, 0.32 mmol) in H2O (2.0 mL). The
mixture was stirred at ambient temperature for 1 h, filtered, and
the cooled filtrate quenched with 15% HCl until pH ꢁ 1–2. The
residue was filtered, washed with water and dried to give 2a
54.36; H, 3.39; N, 4.88%].
4.6. Ethyl 6-(trifluoromethyl)-1,4-dihydro-4-oxo-1-phenylpyridine-
2-carboxylate (2e)
Method A. Aniline (100 mg, 1.1 mmol) and conc. HCl (0.2 mL)
were added to a solution of ethyl 4-oxo-6-(trifluoromethyl)-4H-
pyran-2-carboxylate 1c [2g] (250 mg, 1.06 mmol) in EtOH (3 mL).
The mixture was refluxed for 24 h, the solvent was evaporated, and
the residue was quenched with water (10 mL). The resulting
residue was filtered and crystallized from petroleum ether (10 mL)
to give compound 2e (150 mg, 47%) as white crystals, mp 100–
101 8C. The use H2SO4 instead of HCl as a strong acid (refluxing a
mixture of 1c (400 mg, 1.69 mmol) and H2SO4 (0.8 mL) in EtOH
(67 mg, 74%) as white solid, mp 186–187 8C; dH (400 MHz, DMSO-
d6) 6.61 (1H, d, J 2.7 Hz, CH), 6.83 (1H, d, J 2.7 Hz, CH), 7.48–7.57
(5H, m, Ph), 14.2 (1H, br s, CO2H); nmax (ATR) 1720, 1638,
1484 cmꢀ1
;
d
F (376.5 MHz, DMSO-d6) 102.2 (s, CF3);
d
C (100 MHz,
(4 mL) for 18 h) allows preparation of 2e in 65% yield;
nmax (ATR)
3
1
DMSO-d6) 117.2 (C-3), 117.9 (q, JC,F 4.2 Hz, C-5), 119.6 (q, JC,F
275.1 Hz, CF3), 128.7, 129.4, 130.4, 137.1, 138.4 (q, 2JC,F 32.8 Hz, C-
6), 147.68, 162.6 (CO), 176.6 (CO) [Found: C, 55.14; H, 2.62; N, 4.92.
1736, 1641, 1595, 1586, 1487 cmꢀ1
; d
H (400 MHz, CDCl3) 1.01 (3H,
t, J 7.1 Hz, CH3), 4.00 (2H, q, J 7.1 Hz, CH2), 6.76 (1H, d, J 2.7 Hz, H-3),
6.96 (1H, d, J 2.7 Hz, H-5), 7.37 (2H, d, J 8.0 Hz, H-20, H-60), 7.47 (2H,
dd, J 7.5, 8.0 Hz, H-30, H-50), 7.54 (1H, t, J 7.5 Hz, H-40); dF
C15H12F3NO3 requires C, 55.13; H, 2.85; N, 4.95%].

46
D.L. Obydennov, B.I. Usachev / Journal of Fluorine Chemistry 141 (2012) 41–48
(376.5 MHz, DMSO-d6) 102.2 (s, CF3) [Found: C, 57.66; H, 3.72; N,
[Found: C, 52.24; H, 3.00; N, 9.36. C13H9F3N2O3 requires C, 52.36;
4.41. C15H12F3NO3 requires C, 57.88; H, 3.89; N, 4.50%].
H, 3.04; N, 9.39%]. For data of 4a, please see Section 4.14.
4.7. Ethyl 6-(difluoromethyl)-1,4-dihydro-4-oxo-1-phenylpyridine-
4.11. (Z)-4-(2-Oxo-3,3-difluoropropyliden)-1,5-dihydro-1,5-
benzodiazepin-2-carboxylic acid (3b) and (Z)-3-[(2-(difluoromethyl)-
1H-benzo[b][1,4]diazepin-4-yl)methylene]-3,4-dihydroquinoxalin-
2(1H)-one (4b)
2-carboxylate (2f)
A
mixture of 1d (150 mg, 0.69 mmol), aniline (80 mg,
0.86 mmol) and conc. H2SO4 (0.2 mL) in EtOH (2 mL) was refluxed
for 30 h. After cooling to ambient temperature, the mixture was
diluted with water, the residue was filtered and crystallized from a
mixture of petroleum ether and toluene (1:1) to give 2f (100 mg,
A mixture of 1b (150 mg, 0.79 mmol), o-PhDA (93 mg, 0.86 mmol)
and conc. HCl (0.3 mL) in H2O (1.5 mL) was refluxed for 30 min. The
residue was filtered, washed with water and dried to give a mixture of
3b and 4b (130 mg, 59%, ratio 3b:4b = 28:72), mp ꢃ225 8C; dH
(400 MHz, DMSO-d6) 3b (28%) 5.24 (1H, buried t, CH), 5.37 (1H, s, CH),
50%) as white solid, mp 129–130 8C;
1489, 1404 cmꢀ1
dH (400 MHz, DMSO-d6) 0.88 (3H, t, J 7.1 Hz,
CH3), 3.93 (2H, q, J 7.1 Hz, CH2), 6.58 (1H, t, 2JH,F 52.5 Hz, CF2H), 6.62
(2H, s, H-3, H-5), 7.47–7.58 (5H, m, Ph); F (376.5 MHz, DMSO-d6)
nmax (ATR) 1728, 1637, 1578,
;
2
6.12 (1H, t, JH,F 54.5 Hz, CF2H), 6.49 (1H, m, arom.), 6.79 (2H, m,
d
arom.), 6.93 (1H, m, arom.), 7.88 (1H, d, J0.6 Hz, NH), 11.36 (1H, s, NH);
2
2
44.9 (d, JH,F 52.5 Hz, CF2H) [Found: C, 61.30; H, 4.39; N, 4.80.
4b (72%) 6.04 (1H, s, CH), 6.06 (1H, s, CH), 6.13 (1H, t, JH,F 53.4 Hz,
C15H13F2NO3 requires C, 61.43; H, 4.47; N, 4.78%].
CF2H), 7.10–7.18 (3H, m, arom.), 7.58 (1H, d, J 7.5 Hz, arom.), 12.08
(1H, s, NH), 12.58 (1H, s, NH); dF (376.5 MHz, DMSO-d6) 3b (28%) 36.8
4.8. Ethyl 6-(trifluoromethyl)-1,4-dihydro-4-oxo-1-(2-
(d, 2JH,F 54.5 Hz, CF2H); 4b (72%) 37.1 (d, 2JH,F 53.4 Hz, CF2H).
hydroxyphenyl)pyridine-2-carboxylate (2g)
4.12. Ethyl (Z)-4-(2-oxo-3,3,3-trifluoropropyliden)-1,5-dihydro-1,5-
A solution of 1c (500 mg, 2.1 mmol), o-aminophenol (250 mg,
2.29 mmol) and H2SO4 (1 mL) in EtOH (6 mL) was refluxed for 24 h.
Then the reaction mixture was diluted with H2O (20 mL), the
residue was filtered, washed with H2O and crystallized from
aqueous EtOH to give 2g (450 mg, 65%) as white crystals, mp 188–
benzodiazepin-2-carboxylate (3F)
A mixture of 1c (1.0 g, 4.2 mmol), o-PhDA (500 mg, 4.62 mmol)
and conc. HCl (1.0 mL) was stirred in EtOH (10 mL) at 50 8C for 3 h.
After cooling the reaction mixture to ambient temperature, the
residue was filtered, washed with water and dried. Benzodiazepine
3cwasextractedfromthisresiduebyhot CCl4 (25 mL)andseparated
from insoluble in this solvent a mixture of compounds 4a and 5a
(ꢃ200 mg) by hot filtration. After evaporation of CCl4 from the
extract, the residue was crystallized from EtOH to give 3c (830 mg,
189 8C; nmax (ATR) 1751, 1631, 1601, 1555, 1509 cmꢀ1
; dH
(400 MHz, DMSO-d6) 0.92 (3H, t, J 7.1 Hz, CH3), 3.95 (2H, qd, J
7.1, 1.6 Hz, CH2), 6.65 (1H, d, J 2.7 Hz, H-3), 6.85 (1H, d, J 2.7 Hz, H-
5), 6.88 (1H, t, J 7.5 Hz, arom.), 6.95 (1H, d, J 8.2 Hz, arom.), 7.33–
7.40 (2H, m, arom.), 10.45 (1H, s, OH); dF (376.5 MHz, DMSO-d6)
100.0 (d, J 1.0 Hz, CF3) [Found: C, 54.74; H, 3.84; N, 4.31.
60%) as black crystals, mp 157–158;
nmax (ATR) 3329, 1708, 1624,
C
15H12F3NO3 requires C, 55.05; H, 3.70; N, 4.28%].
1606, 1559, 1491 cmꢀ1
; dH (400 MHz, DMSO-d6) 1.28 (3H, t, J 7.1 Hz,
CH3), 4.25 (2H, q, J 7.1 Hz, CH2), 5.29 (1H, t, J 1.9 Hz, H-3), 5.54 (1H, s,
CH), 6.52 (1H, dd, J 7.4, 1.9 Hz, H-6), 6.83 (2H, qn d, J 7.4, 1.8 Hz, H-7,
H-8), 6.92 (1H, dd, J 7.5, 1.9 Hz, H-9), 8.06 (1H, d, J 1.6 Hz, NH), 11.22
4.9. Ethyl 6-(difluoromethyl)-1,4-dihydro-4-oxo-1-(2-
hydroxyphenyl)pyridine-2-carboxylate (2h)
(1H, s, NH); dF (376.5 MHz, DMSO-d6) 86.9 (s, CF3) [Found: C, 55.24;
A mixture of 1d (200 mg, 0.92 mmol), o-aminophenol (110 mg,
1.0 mmol) and H2SO4 (0.4 mL) was refluxed in EtOH (3 mL) for 48 h.
Then the mixture was diluted with H2O (10 mL), the residue was
filtered and crystallized fromaqueous EtOHtogive2h(108 mg, 40%)
as white crystals, mp 210–211 8C; nmax (ATR) 3010, 1741, 1624,
H, 3.77; N, 8.52. C15H13F3N2O3 requires C, 55.22; H, 4.02; N, 8.59%].
4.13. Ethyl (Z)-2-(2-oxo-3,3-difluoropropyliden)-1,5-dihydro-1,5-
benzodiazepin-4-carboxylate (3d)
1602, 1541 cmꢀ1
;
d
H (400 MHz, DMSO-d6) 0.92 (3H, t, J 7.1 Hz, CH3),
A mixture of 1d (150 mg, 0.69 mmol), o-PhDA (82 mg,
3.96 (2H, q, J 7.1 Hz, CH2), 6.51 (1H, t, 2JH,F 52.8 Hz, CF2H), 6.60 (2H, s,
H-3, H-5), 6.91 (1H, t, J 7.6 Hz, arom.), 6.99 (1H, d, J 8.1 Hz, arom.),
0.76 mmol) and conc. HCl (0.3 mL) was stirred in EtOH (1.5 mL)
for 6 h at 50 8C. After cooling, the reaction mixture was diluted
with H2O (5 mL), the residue was filtered, washed with H2O and
dried to give a crude sample of 3d containing traces of 5b. To
separate 3d from 5b by extraction the crude product was treated
with CCl4 (15 mL), the mixture was filtered to give the extract of 3d
and the residue of 5b (15 mg, 5%). The solvent was evaporated from
the extract and the residue was crystallized from EtOH to give
analytically pure 3d (85 mg, 40%) as black crystals, mp 150–151 8C;
7.33–7.38 (2H, m, arom.), 10.49 (1H, s, OH);
d6) 44.89 (d, 2JH,F 52.5 Hz, CF2H) [Found: C, 58.26; H, 4.14; N, 4.47.
15H13F2NO4 requires C, 58.25; H, 4.24; N, 4.53%].
dF (376.5 MHz, DMSO-
C
4.10. (Z)-4-(2-Oxo-3,3,3-trifluoropropyliden)-1,5-dihydro-1,5-
benzodiazepin-2-carboxylic acid (3a) and (Z)-(5,5,5-trifluoro-2,4-
dioxopentylidene)-1,2,3,4-tetrahydro-2-quinaxolone (4a)
n
max (ATR) 3326, 1708, 1637, 1619, 1559, 1488 cmꢀ1
; dH (400 MHz,
A
mixture of 1a (250 mg, 1.20 mmol), o-PhDA (140 mg,
CDCl3) 1.28 (3H, t, J 7.1 Hz, CH3), 4.25 (2H, q, J 7.1 Hz, CH2), 5.28
(1H, s, CH), 5.44 (1H, s, CH), 6.14 (1H, t, JH,F 54.5 Hz, CF2H), 6.52
(1H, m, arom.), 6.80–6.84 (2H, m, arom.), 6.95 (1H, m, arom.), 7.98
(1H, s, NH), 11.35 (1H, s, NH); dF (376.5 MHz, DMSO-d6) 36.7 (d, J
54.5 Hz, CF2H) [Found: C, 58.07; H, 4.53; N, 8.81. C15H14F2N2O3
requires C, 58.44; H, 4.58; N, 9.09%].
2
1.29 mmol) and conc. HCl (0.5 mL) was refluxed in H2O (4 mL)
for 30 min. The residue was filtered, dried, treated with hot EtOH
(15 mL). Hot filtration gave 4a (100 mg, 28%) as red solid, mp 272–
273 8C. After evaporation of excess the solvent from the filtrate, 3a
was isolated by filtration (105 mg, 29%) as black solid, mp 243–
244 8C; 3a: nmax (ATR) 3320, 1710, 1638, 1616, 1572 cmꢀ1
; dH
(400 MHz, DMSO-d6) 5.26 (1H, buried t, CH), 5.48 (1H, s, CH), 6.50
(1H, dd, J 7.3, 1.7 Hz, arom.), 6.77–6.86 (2H, m, arom.), 6.92 (1H, dd,
J 7.5, 1.8 Hz, arom.), 7.97 (1H, s, NH), 11.22 (1H, s, NH); dF
4.14. (Z)-(5,5,5-Trifluoro-2,4-dioxopentylidene)-1,2,3,4-tetrahydro-
2-quinaxolone (4a)
(376.5 MHz, DMSO-d6) 86.9 (s, CF3);
(CH), 98.8 (CH), 117.1 (q, JC,F 289.1 Hz, CF3), 122.6, 122.7, 125.3,
126.2, 130.4, 135.1, 144.8, 163.3, 164.2, 175.7 (q, 2JC,F 32.4 Hz, CO)
d
C (100 MHz, DMSO-d6) 92.8
Method A. The residue isolated by hot filtration (Method 4.10)
of the extract of 3a was analytically pure compound 4a (100 mg,
28%), red solid, mp 272–273 8C. Method B. Benzodiazepine 3c
1

D.L. Obydennov, B.I. Usachev / Journal of Fluorine Chemistry 141 (2012) 41–48
47
(150 mg, 0.46 mmol) was refluxed in a mixture of AcOH (1 mL) and
conc. HCl (1 mL) for 30 min. Then the reaction mixture was diluted
with water (3 mL), the residue was filtered and crystallized from
AcOH to give 4a (42 mg, 31%) as red solid. Method C. Alternatively,
4a was prepared by refluxing a mixture of 1c (250 mg, 1.06 mmol),
o-PhDA (125 mg, 1.15 mmol) and H2SO4 (0.5 mL) in EtOH (3 mL)
for 4 h. After cooling the reaction mixture was diluted with H2O
(5 mL), the residue was filtered and crystallized from AcOH
(12 mL) to give 4a (140 mg, 36%) as red solid. Method D.
Alternatively 4a was prepared by hydrolysis of the mixture 5a–
6a (21:79) with aqueous HCl. A mixture of 5a–6a (80 mg,
0.22 mmol) and aqueous HCl (20%, 2 mL) was refluxed for
30 min. The residue was filtered and crystallized from AcOH to
give 4a (31 mg, 46%). Hydrolysis of pure 5a in the same conditions
gives 4a in 60% yield as red solid; nmax (ATR) 2860, 1678, 1605,
J 7.5 Hz, arom.), 12.13 (1H, s, NH), 13.11 (1H, s, NH);
d
F (376.5 MHz,
DMSO-d6)5b(65%)41.8(d, 2JH,F 54.4 Hz, CF2H);6b(35%)44.5(d,2JH,F
54.0 Hz, CF2H);Totransform6binto5bthemixtureofthetautomers
(40 mg) was heated in DMSO (1.6 mL) at 80 8C for 4 h. Then the
mixture was diluted with water (10 mL), the residue was filtered,
dried and crystallized from acetone to give analytically pure 5b
(22 mg, 55%) as red solid, mp 317–319 8C.
4.17. (Z)-(5,5,5-Trifluoro-2,4-dioxopentylidene)-3,4-dihydro-2H-
benzo[b][1,4]oxazin-2-one (7)
A mixture of 1a (250 mg, 1.2 mmol) and aminophenol (145 mg,
1.3 mmol) was refluxed in EtOH (3 mL) for 1 h. After cooling the
mixture to ambient temperature the residue was filtered and
crystallized from EtOH to give 7 (145 mg, 40%) as yellow powder,
mp 206–208 8C; n ; dH
max (ATR) 3116, 1749, 1668, 1622, 1614 cmꢀ1
1542 cmꢀ1
CH), 7.13–7.20 (3H, m, arom.), 7.64 (1H, d, J 7.7 Hz, arom.), 12.15
(1H, br s, NH), 12.50 (1H, br s, OH); F (376.5 MHz, DMSO-d6) 89.0
(s, CF3); C (100 MHz, DMSO-d6) 92.4 (CH), 99.5 (CH), 115.4, 117.1,
;
dH (400 MHz, DMSO-d6) 6.15 (1H, s, CH), 6.32 (1H, s,
(400 MHz, DMSO-d6) 5.11 (1H, s, CH), 6.66 (1H, s, CH), 6.80 (1H, d, J
7.7 Hz, arom.), 6.94 (1H, td, J 7.5, 0.8 Hz, arom.), 7.08 (1H, d, J 7.5 Hz,
arom.), 7.21 (1H, tt, J 7.7, 0.9 Hz, arom.), 10.64 (1H, s, NH) [Found: C,
52.07;H,2.56;N,4.64.C13H8F3NO4requiresC,52.19;H,2.70;N,4.68%].
d
d
1
118.5 (q, JC,F 277.4 Hz, CF3), 123.6, 123.7, 124.8, 126.8, 145.7,
154.9 (CONH), 160.4 (buried q, C-CF3), 188.5 (CO) [Found: C, 52.28;
H, 2.91; N, 9.40. C13H9F3N2O3 requires C, 52.36; H, 3.04; N, 9.39%].
4.18. 2-(Trifluoromethyl)-1-phenylpyridin-4(1H)-one (8a)
Acid 2a (50 mg, 0.18 mmol) was molten and kept at its mp.
After CO2 evolution had ceased, the residue was collected by
hexane and crystallized from a mixture of hexane and toluene to
give 8a (24 mg, 57%) as white solid, mp 114–115 8C; nmax (ATR)
1639, 1590, 1571, 1492 cmꢀ1 dH (400 MHz, DMSO-d6) 6.33 (1H, d, J
7.5 Hz, H-5), 6.75 (1H, s, H-3), 7.57 (5H, s, Ph), 7.80 (1H, d, J 7.5 Hz,
H-6), dF (376.5 MHz, DMSO-d6) 101.7 (s, CF3) [Found: C, 60.09; H,
3.26; N, 5.71. C12H8F3NO requires C, 60.26; H, 3.37; N, 5.86%].
4.15. (Z)-3-[(2-(Trifluoromethyl)-1H-benzo[b][1,4]diazepin-4-
yl)methylene]-3,4-dihydroquinoxalin-2(1H)-one (5a) and its diimine
tautomer (6a)
A mixture of 1a (250 mg, 1.2 mmol) and o-PhDA (290 mg,
2.7 mmol) was refluxed in EtOH (4 mL) for 30 min, the residue was
filtered and washed with EtOH to give a mixture of 6a and 5a
(280 mg, 63%) as red solid, mp 325–327 8C;
nmax (ATR) 2845, 1666,
1620, 1604, 1589 cmꢀ1
;
d
H (400 MHz, DMSO-d6) 5a (21%) 5.24 (1H,
4.19. 2-(Trifluoromethyl)-1-(2-hydroxyphenyl)pyridin-4(1H)-one
buried t, CH), 6.03 (1H, s, CH), 6.76–6.89 (3H, m, arom.), 7.00 (1H,
dd, J 7.8, 1.2 Hz, arom.), 7.19–7.28 (2H, m, arom.), 7.36 (1H, td, J 7.8,
1.2 Hz, arom.), 7.71 (1H, dd, J 7.9, 1.0 Hz, arom.), 8.36 (1H, s, NH),
12.20 (1H, s, NH); 6a (79%) 3.67 (2H, s, CH2), 5.98 (1H, s, CH), 7.22
(2H, t, J 7.8 Hz, arom.), 7.28–7.33 (2H, m, arom.), 7.43–7.48 (3H, m,
arom.), 7.70 (1H, d, J 7.8 Hz, arom.), 12.16 (1H, s, NH), 13.11 (1H, s,
(8c)
Acid 2c (100 mg, 0.33 mmol) was molten and kept at its mp.
After CO2 evolution had ceased, the residue was collected by
toluene and crystallized from this solvent to give 8c (46 mg, 54%)
as white crystals, mp 193–194 8C; nmax (ATR) 3081, 1632, 1554,
NH); dF (376.5 MHz, DMSO-d6) 5a (21%) 94.1 (s, CF3); 6a (79%) 90.6
1545, 1512, 1461, 1398 cmꢀ1
; dH (400 MHz, DMSO-d6) 6.31 (1H,
(s, CF3) [Found: C, 61.44; H, 3.51; N, 15.09. C19H13F3N4O requires C,
61.62; H, 3.54; N, 15.13%]. To transform 6a into 5a the mixture of
the tautomers (100 mg) was heated in DMSO (4 mL) at 120 8C for
30 min. Then the mixture was diluted with water (10 mL), the
residue was filtered, dried and crystallized from acetone (25 mL) to
give 5a (65 mg, 65%) as red crystals, mp 334–336 8C; (ATR) 3433,
dd, J 7.7, 2.7 Hz, H-5), 6.72 (1H, d, 2,7 Hz, H-3), 6.92 (1H, td, J 7.7,
0.8 Hz, arom.), 7.03 (1H, dd, J 8.2, 0.8 Hz, arom.), 7.34–7.44 (2H, m,
arom.), 7.67 (1H, d, J 7.7 Hz, H-6), 10.42 (1H, s, OH);
DMSO-d6) 99.5 (s, CF3) [Found: C, 56.39; H, 3.13; N, 5.49.
12H8F3NO2 requires C, 56.48; H, 3.16; N, 5.49%].
dF (376.5 MHz,
C
1714, 1656, 1632 cmꢀ1
; dC (100 MHz, DMSO-d6) 97.4 (CH), 98.1 (q,
1
3JC,F 5.2 Hz, CH), 115.0, 120.9 (q, JC,F 275.7 Hz, CF3), 121.2, 121.3,
4.20. 2-(Difluoromethyl)-1-(2-hydroxyphenyl)pyridin-4(1H)-one
(8d)
122.9, 123.4, 123.9, 126.1, 127.7, 130.1, 130.6, 131.6, 132.3, 133.4
(q, JC,F 30.8 Hz, C-CF3), 147.9, 154.6, 155.0. The use ratio 1a:o-
2
Acid 2d (86 mg, 0.30 mmol) was molten and kept at its mp. After
CO2 evolution had ceased, the residue was collected by toluene and
crystallized from this solvent to give 8d (52 mg, 71%) as gray powder,
PhDA = 1:1 gives 38% yield of the mixture of tautomers 5a and 6a.
4.16. (Z)-3-[(2-(Difluoromethyl)-1H-benzo[b][1,4]diazepin-4-
yl)methylene]-3,4-dihydroquinoxalin-2(1H)-ones (5b) and its diimine
tautomer (6b)
mp 207–209 8C; n ; dH
max (ATR) 1635, 1599, 1541, 1514, 1455 cmꢀ1
(400 MHz, DMSO-d6) 6.24 (1H, dd, J 7.4, 1.9 Hz, H-5), 6.49 (1H, buried
d, H-3), 6.53 (1H, t, 2JH,F 52.9 Hz, CF2H); 6.95 (1H, t, J 7.5 Hz, H-50), 7.06
(1H, d, J 8.0 Hz, H-60), 7.34–7.42 (2H, m, H-30, H-40), 7.61 (1H, d, J
A mixture of 1b (70 mg, 0.37 mmol) and o-PhDA (80 mg,
0.74 mmol) was refluxed in EtOH (2.5 mL) for 30 min. After heating
the residue was filtered and washed with EtOH to give a mixture of
7.6 Hz, H-6), 10.50 (1H, s, OH); dF (376.5 MHz, DMSO-d6) 41.9 (1F, dd,
2
2
2
2JF,F 303.3 Hz, JH,F 53.0 Hz, CFFH), 46.3 (1F, dd, JF,F 303.3 Hz, JH,F
53.0 Hz, CFFH) [Found: C, 60.88; H, 3.78; N, 5.75. C12H9F2NO2 requires
C, 60.76; H, 3.82; N, 5.90%].
5b and 6b (57 mg, 44%) as red powder, mp 317–319 8C;
nmax (ATR)
2994, 2895, 1710, 1668, 1619, 1601, 1503, 1474 cmꢀ1
;
dH (400 MHz,
DMSO-d6) 5b (65%) 4.96 (1H, buried t, CH), 5.86 (1H, s, CH), 6.35 (1H,
t, JH,F 54.1, CF2H), 6.72–6.86 (3H, m, arom.), 6.93 (1H, dd, J 7.9,
4.21. General procedure for 3-{[3-(RF)-1H-pyrazol-5-
2
yl]methyl}quinoxalin-2(1H)-ones (9a,b)
1.6 Hz, arom.), 7.19–7.26 (2H, m, arom.), 7.33 (1H, td, J 7.6, 1.4 Hz,
arom.), 7.68 (1H, dd, J 8.0, 1.2 Hz, arom.), 8.19 (1H, buried d, NH),
12.15 (1H, buried d, NH); 6b (35%) 3.50 (2H, s, CH2), 5.92 (1H, s, CH),
6.62 (1H, t, 2JH,F 54.5 Hz, CF2H), 7.18–7.45 (7H, m, arom.), 7.68 (1H, d,
A mixture of benzodiazepine 3c or 3d (0.32 mmol) and
N2H4ꢂ2HCl (50 mg, 0.48 mmol) was refluxed in EtOH (2 mL) for

48
D.L. Obydennov, B.I. Usachev / Journal of Fluorine Chemistry 141 (2012) 41–48
[2] (a) V.I. Tyvorskii, D.N. Bobrov, Chemistry of Heterocyclic Compounds: A Series of
Monographs 33 (1997) 995–996;
1 h. Then the mixture was diluted with water, and the residue was
crystallized from AcOH to give 9.
(b) V.I. Tyvorskii, D.N. Bobrov, O.G. Kulinkovich, N. De Kimpe, K.A. Tehrani,
Tetrahedron 54 (1998) 2819–2826;
(c) V.I. Tyvorskii, D.N. Bobrov, Chemistry of Heterocyclic Compounds: A Series of
Monographs 34 (1998) 679–682;
(d) V.I. Tyvorskii, D.N. Bobrov, O.G. Kulinkovich, K.A. Tehrani, N. De Kimpe,
Tetrahedron 57 (2001) 2051–2055;
(e) V.I. Tyvorskii, D.N. Bobrov, O.G. Kulinkovich, W. Aelterman, N. De Kimpe,
Tetrahedron 56 (2000) 7313–7318;
(f) B.I. Usachev, D.L. Obydennov, V.Y. Sosnovskikh, M.I. Kodess, Tetrahedron
Letters 50 (2009) 4446–4448;
(g) B.I. Usachev, I.A. Bizenkov, V.Y. Sosnovskikh, Russian Chemical Bulletin 56
(2007) 558–559;
(h) S. Babu, M.J. Pozzo, Journal of Heterocyclic Chemistry 28 (1991) 819–821;
(i) R.N. Serdyuk, A.Y. Sizov, A.F. Ermolov, Russian Chemical Bulletin 52 (2003)
1854–1858;
4.21.1. 3-{[3-(Trifluoromethyl)-1H-pyrazol-5-yl]methyl}quinoxalin-
2(1H)-one (9a)
Yield 25%, white solid, mp >300 8C (subl.); nmax (ATR) 3237,
1663, 1612, 1572, 1555, 1487, 1464 cmꢀ1
; dH (400 MHz, DMSO-d6)
4.21 (2H, s, CH2), 6.35 (1H, s, CH), 7.27–7.32 (2H, m, arom.), 7.52
(1H, td, J 7.7, 1.0 Hz, arom.), 7.72 (1H, d, J 8.0 Hz, arom.), 12.48 (1H,
s, NH), 13.15 (1H, s, NH); dF (376.5 MHz, DMSO-d6) 102.3 (s, CF3)
[Found: C, 52.68; H, 3.08; N, 18.82. C13H9F3N4O requires C, 53.07;
H, 3.08; N, 19.04%].
(j) C.L. Yeates, J.F. Batchelor, E.C. Capon, N.J. Cheesman, M. Fry, A.T. Hudson, M.
4.21.2. 3-{[3-(Difluoromethyl)-1H-pyrazol-5-yl]methyl}quinoxalin-
´
Pudney, H. Trimming, J. Woolven, J.M. Bueno, J. Chicharro, E. Fernandez, J.M.
2(1H)-one (9b)
Fiandor, D. Gargallo-Viola, F.G. Heras, E. Herreros, M.L. Leo´n, Journal of Medicinal
Chemistry 51 (2008) 2845–2852;
(k) J. Boivin, L. El Kaim, S.Z. Zard, Tetrahedron 51 (1995) 2585–2592;
(l) A. Bunescu, S. Reimann, M. Lubbe, P. Langer, A. Spannenberg, Journal of
Organic Chemistry 74 (2009) 5002–5010;
(m) V.Y. Sosnovskikh, V.Y. Korotaev, D.L. Chizhov, I.B. Kutyashev, D.S. Yachevskii,
O.N. Kazheva, O.A. Dyachenko, V.N. Charushin, Journal of Organic Chemistry 71
(2006) 4538–4543;
(n) D.S. Yachevskii, D.L. Chizhov, V.N. Charushin, Russian Journal of Organic
Chemistry 42 (2006) 142–144;
Yield 41%, white solid, mp 289–290 8C;
nmax (ATR) 3230, 1664,
1612, 1553, 1483, 1399 cmꢀ1
;
d
H (400 MHz, DMSO-d6) 4.21 (2H, s,
CH2), 6.35 (1H, s, CH), 6.92 (1H, t, 2JH,F 54.6 Hz), 7.29 (1H, t, J 7.8 Hz,
arom.), 7.31 (1H, d, J 7.8 Hz, arom.), 7.52 (1H, tt, J 7.7, 1.0 Hz, arom.),
7.72 (1H, d, J 8.0 Hz, arom.), 12.48 (1H, br s, NH), 13.15 (1H, br s,
NH); d
F (376.5 MHz, DMSO-d6) 52.6 (d, 2JH,F 52.6 Hz, CF2H) [Found:
C, 56.55; H, 3.63; N, 20.14. C13H10F2N4O requires C, 56.52; H, 3.65;
N, 20.28%].
(o) D.C. England, Journal of Organic Chemistry 46 (1981) 147–153;
(p) B.I. Usachev, D.L. Obydennov, V.Ya Sosnovskikh, Journal of Fluorine Chemistry
135 (2012) 278–284.
4.22. General procedure for ethyl 5-[3,3,3-tri(2,2-di)fluoro-2-
(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole-3-carboxylates
(10)
[3] (a) F. Eiden, P. Peter, Archiv der Pharmazie 297 (1964) 1–9;
(b) A.R. Katritzky, R. Murugan, K. Sakizadeh, J. Heterocycl, Chemistry 21 (1984)
1465–1467;
(c) F. Arndt, A. Kalischek, Chemische Berichte 63 (1930) 587–596;
(d) A.P. Smirnoff, Helvetica Chimica Acta 4 (1921) 599–612;
(e) H. El-Subbagh, F.A. Badria, Scientia Pharmaceutica 62 (1994) 237–245;
(f) G.N. Tyurenkova, N.V. Serebryakova, I.I. Mudretsova, Russian Journal of Or-
ganic Chemistry 11 (1975) 1669–1672;
A mixture of 3c or 3d (0.32 mmol) and PhNHNH2ꢂHCl (170 mg,
0.70 mmol) was refluxed in a solvent (2 mL) for 1 h. After cooling,
the reaction mixture was diluted with H2O, the residue was filtered
and crystallized.
(g) L. Neelakantan, B.H. Iyer, P.C. Guha, Journal of the Indian Institute of Science
Section A: Engineering & Technology 31 (1949) 51–55;
(h) M.M. El-Kerdawy, M.Y. Yousif, Indian Journal of Chemistry Section A: Inor-
ganic Bio-inorganic Physical Theoretical & Analytical Chemistry 24 (1985) 182–
187;
4.22.1. Ethyl 5-[3,3,3-trifluoro-2-(phenylhydrazono)propyl]-1-
phenyl-1H-pyrazole-3-carboxylate [2f] (10a)
The reaction mixture was refluxed in AcOH. Crude product was
crystallized from toluene to give 10a (49%) as white powder, mp
198–200 8C. For spectral data see Ref. [2f].
(i) D.H. Kim, Journal of Heterocyclic Chemistry 18 (1981) 1393–1397;
(j) D.G. Markees, Journal of Heterocyclic Chemistry 27 (1990) 1837–1838.
[4] N.A. Tolmachova, V.G. Dolovanyuk, I.I. Gerus, I.S. Kondratov, V.V. Polovinko, K.
Bergander, G. Haufe, Synthesis 7 (2011) 1149–1156.
[5] (a) R.G. Parr, W. Yang, Density Functional Theory of Atoms and Molecules, Oxford
University Press, New York, 1989;
(b) R.G. Parr, L. von Szentpa´ly, S.B. Liu, Journal of the American Chemical Society
121 (1999) 1922–1924;
(c) A.T. Maynard, M. Huang, W.G. Rice, D.G. Covell, Proceedings of the National
Academy of Sciences of the United States of America 95 (1998) 11578–11583;
4.22.2. Ethyl 5-[3,3-difluoro-2-(phenylhydrazono)propyl]-1-phenyl-
1H-pyrazole-3-carboxylate (10b)
The reaction mixture was refluxed in EtOH. Crude product was
crystallized from toluene to give 10b (37%) as white powder, mp
186–187 8C; nmax (ATR) 3243, 1718, 1616, 1600, 1498 cmꢀ1
; dH
(d) J.L. Ga´zquez, A. Cedillo, A. Vela, Journal of Physical Chemistry
(2007) 9066–9070;
A 111
(e) T.A. Koopmans, Physica 1 (1933) 104;
(f) K. Fukui, Theory of Orientation and Stereoselection, Springer-Verlag, New
York, 1975;
(g) L.R. Domingo, M.J. Aurell, P. Pe´rez, R. Contreras, Journal of Physical Chemistry
A 106 (2002) 6871–6875;
(h) W. Yang, W.J. Mortier, Journal of the American Chemical Society 108 (1986)
5708.
(400 MHz, DMSO-d6) 1.26 (3H, t, J 7.1 Hz, CH3), 3.93 (2H, s, CH2),
4.26 (2H, q, J 7.1 Hz, CH2), 6.47 (1H, s, CH), 6.48 (1H, t, 2JH,F 54.8 Hz,
CF2H), 6.88 (1H, t, J 7.3 Hz, arom.), 7.16 (2H, d, J 7.6 Hz, arom.), 7.27
(2H, t, J 7.9 Hz, arom.), 7.54 (1H, tt, J 7.0, 2.0 Hz, arom.), 7.59–7.66
(4H, m, arom.), 10.05 (1H, s, NH);
2JH,F 54.8 Hz, CF2H) [Found: C, 63.07; H, 4.83; N, 13.96.
21H20F2N4O2 requires C, 63.31; H, 5.06; N, 14.06%].
dF (376.5 MHz, DMSO-d6) 48.2 (d,
[6] (a) A.V. Babenysheva, N.A. Lisovskaya, I.O. Belevich, N.Y. Lisovenko, Pharmaceu-
tical Chemistry Journal 40 (2006) 611;
(b) X. Li, N. Liu, H. Zhang, S.E. Knudson, R.A. Slayden, P.J. Tonge, Bioorganic and
Medicinal Chemistry Letters 20 (2010) 6306–6309.
[7] (a) N.H. Cantwell, E.V. Brown, Journal of the American Chemical Society 75
(1952) 4466–4468;
C
References
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