Reactions of 3-(polyfluoroacyl)chromones with hydroxylamine: synthesis of novel RF-containing isoxazole and chromone derivatives

Article abstract of DOI:10.1016/j.tet.2008.06.041

Reaction of 3-(polyfluoroacyl)chromones with hydroxylamine free base proceeds via nucleophilic 1,4-addition followed by opening of the pyrone ring and subsequent cyclization to 4-(polyfluoroalkyl)-4H-chromeno[3,4-d]isoxazol-4-ols in good yields. On treatm

Full text of DOI:10.1016/j.tet.2008.06.041

Tetrahedron 64 (2008) 7877–7889
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Reactions of 3-(polyfluoroacyl)chromones with hydroxylamine:
synthesis of novel RF-containing isoxazole and chromone derivatives
,
a
b
Vyacheslav Ya. Sosnovskikh a , Vladimir S. Moshkin , Mikhail I. Kodess
*
a Department of Chemistry, Ural State University, 620083 Ekaterinburg, Russian Federation
b Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 620041 Ekaterinburg, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 April 2008
Received in revised form 27 May 2008
Accepted 12 June 2008
Available online 14 June 2008
Reaction of 3-(polyfluoroacyl)chromones with hydroxylamine free base proceeds via nucleophilic 1,4-
addition followed by opening of the pyrone ring and subsequent cyclization to 4-(polyfluoroalkyl)-4H-
chromeno[3,4-d]isoxazol-4-ols in good yields. On treatment with trifluoroacetic acid, the isoxazole ring
of this annulated heterocyclic system opens to give 3-cyano-2-(polyfluoroalkyl)chromones, which were
successfully hydrolyzed with concentrated H2SO4 to afford 3-carbamoyl-2-(polyfluoroalkyl)chromones.
On the other hand, oximation of 3-(polyfluoroacyl)chromones with hydroxylamine hydrochloride occurs
either at the carbonyl carbon atom connected to the RF group or at the C-2 atom to give 3-RFC(]NOH)-
chromones and 5-RF-4-salicyloylisoxazole oximes, respectively. The former were easily converted to 3-
RF-4-salicyloylisoxazoles by simple heating in dimethyl sulfoxide.
Keywords:
3-(Polyfluoroacyl)chromones
Hydroxylamine
Nucleophilic 1,2- and 1,4-addition
Isoxazoles
Ó 2008 Elsevier Ltd. All rights reserved.
Oximes
3-Cyano- and 3-carbamoyl-2-
(polyfluoroalkyl)chromones
1. Introduction
3-benzoylchromone 1b,4 and 3-acetylchromone 1c5 with hydroxyl-
amine have been shown to give chromone derivatives 2a,b and 3a–
3-Formyl- and 3-acylchromones 1 have attracted attention long
ago as highly reactive compounds, which can serve as the starting
substances in the syntheses of a whole series of heterocycles with
useful properties due to three strong electrophilic centers (C-2 and
C-4 atoms of the chromone system and the carbonyl carbon of 3-
RCO group).1 In the chromone ring, the oxygen atom at the 1-po-
sition diminishes electron density on the adjacent C-2 atom and
two carbonyl groups withdraw electrons through a double bond,
hence the 2-position of 3-acylchromones 1 is highly reactive to-
ward the nucleophiles. That is why the reactions of these com-
pounds with such dinucleophiles as hydroxylamine and hydrazines
start predominantly from the attack of the unsubstituted C-2 atom
(1,4-addition) and are accompanied by pyrone ring-opening to
c and regioisomeric isoxazoles 4a–c and 5a,b, depending on the
reaction conditions. These products can result from the initial nu-
cleophilic 1,2- or 1,4-additions of hydroxylamine to 1a (due to
chemical equivalency of the 3-CHO group and C-2 atom) and 1,4-
addition to 1b,c. In the latter case, no 1,2-addition of hydroxylamine
to the PhC]O and MeC]O double bonds was observed (Fig. 1).
Trifluoromethylated heterocycles continue to be of great aca-
demic and industrial interest, because the replacement of hydrogen
by the fluorine atom sometimes brings about a dramatic change in
the physical properties, chemical reactivity, and biological activity
of the derived fluorinated compounds arising as a result of the high
electronegativity of fluorine and high C–F bond energy.6
However, in contrast to well studied 3-formylchromones 1a7 and
3-acylchromones 1b,c8 no data on the reaction of 3-(poly-
fluoroacyl)chromones 69 with hydroxylamine have been docu-
mented. In connection with this, and as an extension of our studies
on the synthetic potential of 3-(polyfluoroacyl)chromones 6, which
turned out to be highly reactive substrates in the reactions with
mono- and dinucleophiles,10 we decided to investigate their re-
actions with hydroxylamine under basic and acidic conditions in
order to develop a simple synthesis of novel RF-containing iso-
xazole and chromone derivatives (preliminary communication11).
One would expect that the reactions of chromones 6 with 1,2-
nucleophilic reagents, such as hydrazine and hydroxylamine,
form the
b-dicarbonyl intermediate capable of regioselective
intramolecular heterocyclizations.1 Along with this route, the initial
attack can occur at the 3-RCO group as well (1,2-addition), which
does not exclude the variant of recyclization due to the intra-
molecular Michael addition and the subsequent ring-opening
reaction.2 Thus, the reactions of 3-formylchromone 1a,3
* Corresponding author. Fax: þ7 343 261 59 78.
E-mail
addresses:
svy@etel.ru,
vyacheslav.sosnovskikh@usu.ru
(V.Ya.
Sosnovskikh).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.041

7878
V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 7877–7889
O
O
the polyfluoroacyl substituent. It is noteworthy that the structure of
isoxazoles 9 indicates unambiguously the initial attack of hydroxyl-
amine at the electrophilic C-2 atom (1,4-addition) followed by ring-
opening to intermediate A, which then undergoes heterocyclization
to the carbonyl at the benzene ring (only in this case the RFCO group
remains free and can participate in the formation of cyclic semiketal
form 9).
R
O
1a-c
O
O
NOH
R
The alternative cyclization of A involving the oxime hydroxyl
and the carbonyl carbon connected to the RF group to give 5-RF-
isoxazoles 10 occurs only in the case of 3-CF2HCO-chromone 6i.
When 6i was employed, a 10:1 mixture of 5-CF2H-4-salicyloyl-
isoxazole 10i and its oxime 11i was obtained with hydroxylamine
free base (method A). Recrystallization of this mixture from tolu-
ene–hexane (1:3) afforded a pure sample of the major product 10i.
The same result was achieved in the presence of AcONa (method B)
with the only difference that the selectivity of the reaction de-
creases and the ratio of compounds 10i and 11i becomes equal to
4:1, respectively. Thus, in the basic and weakly acidic conditions
compounds 9a–h and 10i are formed, most probably, through
common intermediate A (Scheme 2), which, in the case of starting
chromones 6a–h, undergoes ring closure to the carbonyl carbon
atom at the aromatic ring, whereas for 6i the ring closure proceeds
at the carbonyl connected to the CF2H group. The firmest distinc-
tion between the isomeric 5-CF2H-isoxazole 10i and 3-CF2H-isox-
azole 15i (see below, Scheme 3) was obtained from the mass
spectrum fragments arising from loss of the CF2H group at the 5-
position of the isoxazole ring (m/z 188 [MꢀCF2H]þ (92)).13
CN
R
O
O
2a,b
3a-c
N
O
O
R
O
COR
N
OH
OH
4a-c
5a,b
R = H (a), Ph (b), Me (c)
Figure 1. Products from the reaction of 3-acylchromones with hydroxylamine.
would lead to the possibility of competition between different
initial nucleophilic attacks and then toward different cyclization
patterns. In fact, we have recently shown12 that the main direction
of the reaction of 3-(trifluoroacetyl)chromones 6 with hydrazine
hydrate and methylhydrazine is the 1,4-addition followed by
opening of the pyrone ring and subsequent ring closure to the
CF3CO group (pyrazoles 7) or to the carbonyl at the aromatic ring
(pyrazoles 8) (Scheme 1).
Noticeably, the nature of the substituents on the benzene ring
do not have any major effect on the reaction outcome. At the same
time, 6-nitrochromones 6g,j, readily available from the nitration of
chromones 6c,a, respectively, with 96% HNO3 and H2SO4 at 75 ꢁC
for 1.5 h, reacted with hydroxylamine to give different products,
depending on the length of the polyfluoroalkyl group. Thus, if the
reaction of hydroxylamine is carried out with 6g (RF¼(CF2)2H),
compound 9g was isolated in 24% (method A) and 51% (method B)
yields, whereas chromone 6h (RF¼CF3) reacted with hydroxyl-
amine under the same reaction conditions affording a mixture of
two geometrical isomers of dioxime 12 (syn/anti isomers) and
isoxazoline 13 (ring-chain isomer) in the ratio of 12/13¼(55þ40):5
and in 40% yield, as it was observed earlier in the reaction of the
unsubstituted chromone with hydroxylamine.14 In our case, the
CF3CO group seems to behave like a good leaving group and det-
rifluoroacetylation took place as an unwanted reaction (Scheme 2).
The structures of 9a–h were confirmed with the help of spectral
and analytical data. A characteristic feature of the 1H NMR spectra
of compounds 9 in CDCl3 is the appearance of a broadened singlet
O
O
O
O
R
R
NH2NHR
1,4-AN
CF3
CF3
O
6
OH NNH2
R
R
H
O
R
O
N
N
CF3
R
N
OH
CF3
N
O
8
R
7
R = H, Me
Scheme 1.
In the present paper, we wish to report that treatment of
chromones 6 with hydroxylamine leads to five types of products,
depending on the reaction conditions and the nature of the
substituents.
at
the H-3 proton as a quartet or triplet with JH,F¼0.6–1.1 Hz; in
DMSO-d6 these protons appeared as singlets at 9.2–9.5 and 8.9–
d 3.9–4.7 ppm for the OH group and a signal at d 8.4–8.5 ppm for
5
d
9.0 ppm, respectively. In the cases of compounds 9c,d,g, the at-
tachment of the (CF2)2H group to a chiral center is clearly supported
by the 1H NMR spectra, in which the terminal hydrogen atom of this
2. Results and discussion
2.1. 4-RF-Chromeno[3,4-d]isoxazol-4-ols and 5-RF-4-
group (d 6.20–6.22 ppm) is split into a triplet of doublets of dou-
2
3
salicyloylisoxazoles
blets with JH,F¼52.5–52.7 Hz and JH,F¼7.3–7.7, 4.1–4.3 Hz instead
of the usual triplet of triplets. In the 19F NMR spectra the CF3 group
5
We found that 3-RFCO-chromones 6a–h smoothly reacted with
hydroxylamine to afford chromeno[3,4-d]isoxazoles 9a–h in mod-
erate to good yields (except for 3-CCl3CO-chromone 6h). All the
reactions were carried out in methanol at room temperature using
hydroxylamine (2 equiv) obtained in situ from the corresponding
hydrochloride after reaction with potassium hydroxide (method A).
Furthermore, the same products were obtained in lower yields
when chromones 6 were treated with a combination of NH2OH$HCl
and AcONa in methanol (method B). Compounds 9 represent a cy-
clic form of 5-(20-hydroxyaryl)-4-(polyfluoroacyl)isoxazoles, which
appears due to the addition of phenolic OH to the carbonyl group of
of 9a,f manifests itself as a singlet or doublet with JF,H¼0.9 Hz at
w76.5 ppm (C6F6); the 13C NMR spectrum of 9a exhibits a quartet
(1JC,F¼285.7 Hz) at 121.4 ppm for the carbon of the CF3 group and
a quartet (2JC,F¼36.3 Hz) at 95.6 ppm for the C–CF3. This confirms
that the CF3 group is bonded to the sp3 hybridized carbon atom.
2.2. Chromone 3-RF-oximes, 3-RF-4-salicyloylisoxazoles, and
5-RF-4-salicyloylisoxazole oximes
We found that chromones 6b,c,i,k react in different manner
with hydroxylamine hydrochloride in refluxing methanol or

V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 7877–7889
7879
R2
R2
O
O
R2
O
O
N
O
R1
R2
R1
R2
R1
R2
RF
RF
NH2OH
i, ii
OH
RF
O
OH N OH
O
A
9a-h
6a-j
6j
6i
H
OH
N
O
RF
O
OH
X
OH
O
N
NHOH
N
OH
+
N
NO2
NO2
10i (X = O);
11i (X = NOH)
13
12
Reaction conditions (i): NH2OH HCl, KOH, MeOH, rt (method A);
(ii): NH2OH HCl, AcONa, MeOH, rt (method B)
Chromone
RF
R1
R2
Product
Yielda
(%)
6a
6b
6c
6d
6e
6f
CF3
H
H
H
H
H
Me
H
H
H
H
H
9a
9b
9c
9d
72b, 48c
65b, 44c
70b
CF3
Me
H
(CF2)2H
(CF2)2H
(CF2)2H
CF3
Me
H
57b
40b,c
54b
24b, 51c
10b
55b, 20c
40b
d
9e
Cl
9f
6g
6h
6i
(CF2)2H
CCl3
NO2
H
9g
9h
e
CF2H
CF3
H
10i
f
6j
NO2
12
a Isolated yields.
b Method A.
c Method B.
d A 3:1 mixture of 9e and 16e.
e A mixture of 10i and 11i.
f A mixture of 12 and 13.
Scheme 2.
ethanol in the presence of a catalytic amount of concentrated HCl
for 5 h (method C).2,3a Under strongly acidic conditions the only
products isolated were the corresponding chromone 3-RF-oximes
14b,c,i,k, formed undoubtedly by nucleophilic 1,2-addition of hy-
droxylamine to the RFCO group (Scheme 3). This result is in marked
contrast to those obtained by Eiden et al.4 and Ghosh et al.,5 in
which they found that the addition of hydroxylamine to 3-ben-
zoylchromone 1b and 3-acetylchromone 1c occurred exclusively at
the 2-position (Fig. 1, compounds 2b–5b, 3c, 4c). Oximes 14 were
obtained in 24–45% yields and no starting material was recovered,
which may suggest that decomposition of the starting chromones 6
under the reaction conditions accounts for the incomplete mass
balance. A similar reaction with chromone 6a gave no isolated
products. All the compounds 14 were identified with 1H, 19F, 13C
NMR and IR spectroscopies, and by elemental analyses.
trifluoromethylated oximes and hydrazones appeared at 97–
99 ppm, whereas for the E-isomers it appeared at 92–96 ppm.
In addition, all signals in the 1H and 13C NMR spectra of com-
pound 14i were assigned on the basis of 2D HSQC and HMBC ex-
periments. Since the C-2 atom is not bonded to the CF2H group and
the HMBC spectrum displayed cross-peaks between the resonances
of the H-2 and the carbon atoms C-3, C-4, C-8a, and C]N, the
structure 140 is excluded. Thus, the regiochemistry was determined
and higher reactivity of a RFCO group than C-2 atom of 6 toward
the amino group of hydroxylamine in acidic conditions was shown.
The 1H NMR spectra of chromone oximes 14 in CDCl3 displayed the
expected singlets at
d 7.96–8.10 and 8.61–8.85 ppm (d 8.47–8.50
and 12.44–12.86 ppm in DMSO-d6) due to H-2 and OH, respectively.
The IR spectra of 14 recorded in KBr showed three distinct ab-
sorption bands at 1620–1630, 1650–1665, and 3200–3250 cmꢀ1
assigned to the C]N, C]O, and OH functions, respectively.
The structure of chromone oxime 14c was established by con-
sideration of the 3JH,F value of 5.3 Hz for the terminal proton of the
(CF2)2H group. This value agrees well with the data for compounds
with a (CF2)2H group at the oxime carbon atom (3JH,F¼5.4 Hz in the
The initial attack of the RFCO group does not exclude the
recyclization of chromone 3-E-oximes 14 to the isomeric 3-RF-iso-
xazoles 15 due to the intramolecular Michael addition (Scheme 3,
intermediate B) and the subsequent ring-opening reaction.2 In this
case, a rearrangement between 14 and 15 may be involved. Oximes
14 were thermally stable enough to be recrystallized from a tolu-
ene–hexane (1:1) mixture, however, the rearrangement was
markedly favored when carried out in DMSO as a solvent even at
room temperature. Indeed, we found that oximes 14 on dissolution
in DMSO-d6 spontaneously rearrange into 3-(polyfluoroalkyl)-4-
3
case of oximes15 and JH,F¼3.0–3.8 Hz in the case of 2-(1,1,2,2-tet-
rafluoroethyl)chromones16). This allowed us to reject the alterna-
tive structure 140, which can result from the initial nucleophilic 1,4-
addition via intermediate A (Scheme 3). The E-configuration of the
C]N bond was suggested from the 19F NMR chemical shift of the
CF3 group in oxime 14b (93.4 ppm, C6F6). According to published
data,17 the signal for this group in the spectra of Z-isomers of

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V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 7877–7889
RF
H
H
O
O
O
O
O
O
O
CF2H
CF2H
R
R
RF
N
OH
NH2OH
5
3
4
3
4
5
i
O
N
O
O
N
O
6b,c,i,k
14b,c,i,k
10i
15i
~H+ DMSO
121.2 (t, C-4, 3
151.4 (C-3),
J
C,F = 4.6 Hz),
C,F = 25.4 Hz)
119.0 (t, C-4, 3
156.0 (t, C-3, 2
166.3 (C-5)
J
C,F = 1.7 Hz),
1,4-A
X
N
JC,F = 24.9 Hz),
162.6 (t, C-5, 2
J
RF
O
O
OH
Figure 2. 13C NMR data for regioisomeric isoxazoles 10i and 15i.
R
R
R
RF
N
O
in nature18 and the higher stability of the formed isoxazole ring,
with respect to the starting chromone 3-oxime, plays an important
role. This reaction is consistent with the E-configuration of the
oxime C]N bond, which was deduced on the basis of the 19F NMR
chemical shift of the CF3 group.
The structures of isoxazoles 15 were confirmed by their ele-
mental and spectral analyses, including 2D HSQC and HMBC ex-
periments for 15i. Regioisomeric isoxazoles 15i and 10i could be
easily distinguished by their 1H and 13C NMR spectra (Fig. 2). The
diagnostic triplet for the isoxazole proton in 3-CF2H-isoxazole 15i,
which appeared at 9.71 ppm with 5JH,F¼1.5 Hz, was shifted upfield
in 5-CF2H-isoxazole 10i (triplet at 9.08 with 5JH,F¼1.7 Hz), that is, in
15i this proton is more deshielded than in 10i due to the neigh-
boring oxygen atom of the isoxazole ring.
In contrast to 6b,c,i,k, refluxing chromones 6g,j bearing the
electron-withdrawing nitro group with hydroxylamine hydro-
chloride in methanol for 5 h (method C) led to the formation of 5-
RF-4-salicyloylisoxazole oximes 11g,j. Only one regioisomer has
been obtained in this reaction in 37 and 70% yields, respectively.
The mass spectrum of 11j exhibited a molecular ion at m/z 317 [M]þ
(83), consistent with the addition of two hydroxylamine molecules
to 6j, and the most intense signal at m/z 248 [MꢀCF3]þ (100) in-
dicating that the major fragmentation pathway involves cleavage of
a trifluoromethyl group. Hence, these compounds belong to the
series of 5-CF3-isoxazoles and the reaction proceeds via the
mechanism of nucleophilic 1,4-addition followed by pyrone ring-
opening with concomitant addition of a second molecule of NH2OH
(intermediate C) and subsequent ring closure involving the oxime
hydroxyl and RFCO group. This fact seems to indicate that the
pyrone ring-opening is facilitated by the presence of an electron-
withdrawing substituent in the para position of the heterocyclic
oxygen (Scheme 4). Non-fluorinated oxime of 4-salicyloylisoxazole
NOH
OH
O
O
A
B
~H+
H
RF
N
NOH
RF
O
O
O
O
R
14'
15b,c,i,k
Reaction conditions (i): NH2OH
HCl, MeOH, reflux (method C)
Chromone
RF
R
Oxime
14b
14c
Yield (%)
6b
6c
6i
CF3
(CF2)
Me
H
28
24
45
35
2H
CF2H
CF2H
H
14i
6k
Cl
14k
Scheme 3.
salicyloylisoxazoles 15 and monitored the reaction progress by 1H
NMR (Table 1). The application of 2D HSQC and HMBC NMR tech-
niques has made it possible to assign all the signals in the mixture.
At 24 ꢁC after only 1 min the spectrum of 14i already showed the
presence of resonances at 10.65 (phenolic OH) and 9.71 ppm (isox-
azolic H-5), while in 3 h isoxazole 15i was the predominant species
in a mixture with starting material. A similar transformation
with different reaction rates was observed in all the chromone
oximes 14. The sensitivity of the reaction rate to electronic effects
can be seen in the behavior of 6-chlorochromone oxime 14k. It
should be emphasized that in CDCl3 only one set of signals attrib-
uted to 14 was observed. The rearrangement of 14 occurs on storing
at room temperature for some months and could be easily achieved
also by heating above their melting point. Note that mass spectra of
14b and 15b are identical.
´
was obtained by Basinski et al. from the reaction of chromone 3-
oxime 2a with hydroxylamine hydrochloride in ethanol.3f,g
O
O
O
NOH O
In a pure form 3-RF-isoxazoles 15 were isolated in 62–70% yields
after heating of 14 in DMSO-d6 at 85 ꢁC for 5 h (the reaction con-
ditions were not optimized). To the best of our knowledge, 3-for-
mylchromone 3-oximes have not been examined in a ring-to-ring
rearrangement, although the reaction of 3-formylchromones with
hydroxylamine without isolation of the intermediate 3-oximes was
used for the preparation of 4-salicyloylisoxazoles 5a.2 The driving
force for the irreversible interconversion 14/15 is thermodynamic
O2N
O2N
RF
RF
NH2OH
i
NOH
OH
6g,j
C
H
OH
O
OH
N
RF
O
N
RF
NOH
O
N
Table 1
Heterocyclic rearrangement of 14i,k to 15i,k in DMSO-d6 at 24 ꢁ
C
NO2
NO2
11'
Reaction time
Ratio of 14i/15i
Reaction time
Ratio of 14k/15k
11g (RF = CF2CF2H, 37%)
11j (RF = CF3, 70%)
1 min
45 min
1.5 h
3 h
20 h
50 h
90:10
70:30
65:35
45:55
25:75
18:82
1 min
2.5 h
6.5 h
27 h
62:38
8:92
2:98
0:100
NH OH HCl, MeOH, reflux (method C)
Reaction conditions (i):
2
Scheme 4.

V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 7877–7889
7881
The choice between the isomeric 5-RF-isoxazoles 11 and 110 (the
latter arises from initial attack at the RFCO carbonyl by the
hydroxyimino group connected to the aromatic ring) was made in
favor of the former on the basis of analysis of 2D HSQC and HMBC
spectra. In a DMSO-d6 solution of compound 11j, the phenolic and
oximic protons appear as narrow singlets (dOH¼11.56 ppm and
dNOH¼12.58 ppm) due to the absence of an exchange process that
allows to observe cross-peaks between these protons and carbon
atoms. In particular, the HMBC spectrum exhibits the cross-peaks
between the proton of the NOH group and non-protonated C]N
carbon at 141.3 ppm, as well as between the aromatic proton H-60
and carbon of C]N. Hence, structure 110 bearing CH]NOH moiety
is excluded. In addition, the isoxazole proton H-3 is bound due to
the 2JC,H and 3JC,H coupling constants with the carbon atoms C-4 and
C-5, but none with the oxime carbon atom. Similar correlations
were also observed for 3-CF2H-isoxazole 15i. These results show
that the framework of molecules 11 and 15 consists of two non-
planar to each other parts: the isoxazole cycle and the benzene ring
with oxime or keto groups lying in the same plane. Apparently, the
intramolecular O–H/N]C and O–H/O]C hydrogen bonds are
responsible for the planar structure of the second fragment.
Thus, we demonstrated a subtle influence of the remote sub-
stituent on the reactivity of 3-RFCO-chromones 6 with hydroxyl-
amine hydrochloride. The change in the reaction pathway in the
case of 6g,j is probably due to the fact that the attack on the C-2
atom is accompanied by the cleavage of the C–O bond, and the
strong electron-withdrawing NO2 group favors stabilization of the
leaving phenolate anion, thus facilitating the pyrone ring-opening.
It is interesting that chromone 6g reacted with hydroxylamine via
only 1,4-addition to afford isoxazoles 9g or 11g depending on the
reaction conditions. By proper choice of the pH of the medium
these compounds could be selectively obtained in 37–51% yields.
On the whole, the above results show that acidic conditions facil-
itate the addition reaction at the RFCO group. This observation is not
completely unexpected, considering that the RF group complicates
a dehydration stage due to the destabilization of the intermediate
carbocation and, therefore, the formation of the aromatic isoxazole
ring and chromone 3-oxime is hindered under the basic reaction
conditions.
cyano-2-(polyfluoroalkyl)chromones 16a–d in high yields. This
result probably represents a specific property of fused isoxazoles 9
because only base-induced ring-opening reactions have been
reported for non-fluorinated analogues 4 and 5.2,3a,4 A possible
mechanism for the trifluoroacetic acid ring-opening of 9 is outlined
in Scheme 5. We favor the pathway involving the intermediacy of
the aromatic benzopyrylium cation D since its formation via
elimination of water is especially facile under acidic conditions.
Subsequent deprotonation of cation D with concomitant isoxazole
ring-opening leads to 3-cyano-2-RF-chromones 16. However, we
cannot exclude the formation of the intermediate chromone 3-
oxime 140 (Scheme 3), which is readily dehydrated to 16 under
these conditions. The simple and efficient synthesis of 3-cyano-2-
RF-chromones 16 is of doubtless interest, because this class of or-
ganic compounds remained inaccessible and unstudied up to now.
R2
R2
O
N
O
R1
R2
R1
R2
CN
RF
CF3CO2H
OH
RF
O
9a-e
O
16a-e
-H2O H+
R2
-H+
R2
N
N
O
O
O
R1
R2
R1
R2
H
O
RF
RF
D
Nitrile
RF
R1
R2
Yield (%)
16a
16b
16c
16d
16e
CF3
CF3
H
H
83
72
85
71
73
Me
H
H
(CF2)2H
(CF2)2H
(CF2)2H
H
Me
H
H
Me
Scheme 5.
2.3. 3-Cyano-2-RF-chromones
Surprisingly, isoxazoles 9f,g failed to provide the corresponding
carbonitriles 16f,g and only starting materials were recovered un-
der the same reaction conditions. In the case of 9f, besides the
starting material, 5-(5-chloro-2-hydroxyphenyl)isoxazole (18%),
which is likely the result of the detrifluoroacetylation of 9f, and
unidentified product (12%) were detected by 1H NMR spectroscopy.
On the other hand, chromone 6e bearing two electron-donating
methyl groups reacted with hydroxylamine (methods A and B) to
afford a 3:1 mixture of 9e and 16e, which was converted to car-
bonitrile 16e by simple crystallization from toluene (9e was con-
verted to 16e during crystallization). All our attempts to obtain 9e
as the sole product were fruitless. Thus, it appears that electronic
effects play an important role in the ring-opening of isoxazoles 9 to
carbonitriles 16 (the presence of the electron-withdrawing sub-
stituents, such as Cl and NO2, on the benzene ring inhibit and the
electron-donating methyl group facilitates this process). This ob-
servation is consistent with our assumption that the reaction
proceeds via the intermediate benzopyrylium cation D, the
destabilization of which by electron-withdrawing substituents
would increase the energy barrier to dehydration. As a result, 9f,g
are sufficiently stable in CF3CO2H solution. Isoxazole 9b was un-
changed in acetic acid and ethanolic KOH at heating for 15 min,
however, when a solution of 9b in toluene in the presence of pi-
peridine was refluxed for 10 min, the loss of the trifluoroacetyl
group took place cleanly to lead to the formation of 2-amino-6-
methylchromone 17b in 62% yield (Scheme 6). Note that the loss of
3-Cyanochromones are important intermediates in the synthe-
sis of biologically interesting compounds.19 On the other hand, due
to the powerful electron-withdrawing ability of RF groups, the in-
sertion of polyfluoroalkyl substituents into the 2-position of chro-
mones activates these molecules and 2-RF-chromones are highly
reactive substrates in reactions with various N-, S-, and C-nucleo-
philes.20 Although
a number of synthetic methods for the
preparation of 3-cyanochromones,19 including 3-cyano-2-methyl-
chromones5,21 and 3-cyanoflavone,4 have been reported, only
one patent on the synthesis of 3-cyano-7-hydroxy-2-(tri-
fluoromethyl)chromone from 2,4-dihydroxybenzoyl acetonitrile
and trifluoroacetic anhydride have appeared in the literature,19i
despite the possible enhancement of their reactivity due to the
presence of the CF3 group. In connection with this, we examined
the possibility of preparing 3-cyano-2-(polyfluoroalkyl)chromones
16 from compounds 9.
Attempts to obtain 3-cyano-2-RF-chromones 16 from chro-
meno[3,4-d]isoxazoles 9 in the presence of KOH in ethanol, con-
ditions that had previously been used for the preparation of
3-cyanoflavone 3b from 2b, 4b, and 5b,4 proved fruitless. However,
it was found that the required compounds 16 could be easily pre-
pared by refluxing isoxazoles 9 in trifluoroacetic acid for 15 min
(only starting material was recovered from a similar reaction in
acetic acid). Thus, isoxazoles 9a–d are easily ring opened to give 3-

7882
V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 7877–7889
CF3CO moiety in some reactions of trifluoromethyl
compounds is a known phenomenon.10c,22a
b
-dicarbonyl
parameter for structural assignment is the chemical shift for the H-
5 proton, which was shifted downfield to 8.05–8.28 ppm due to
d
the deshielding effect of the carbonyl group in the peri-position as
indicated in the case of chromones.23 The IR spectra of 16 in KBr
N
O
O
showed two intense peaks at 1662–1680 and 1627–1639 cmꢀ1
,
N
H
PhMe
Me
Me
which are ascribed to C]O and C]C absorptions, respectively. The
weak CN absorptions observed at 2237–2245 cmꢀ1 are typical for
CN systems substituted by strong electron-withdrawing groups.24
OH
CF3
O
O
NH2
17b
9b
Scheme 6.
2.4. Some reactions of 3-cyano-2-RF-chromones
It is commonly known22b that isoxazoles having a free 3-posi-
tion are less stable toward bases than those having a substituent in
the 3-position. We found that on reflux in DMSO for 5 min, iso-
xazole 10i undergoes the ring-opening/ring-closure sequence to
form 3-cyano-2-(difluoromethyl)chromone 16i in 57% yield.
According to the 1H NMR spectroscopic data, this irreversible
process is evident immediately on simple dissolution of 10i in
DMSO-d6 (9% of 16i after 1–2 min) and there is subsequent change
in the percentage rearrangement (18% of 16i after 2.5 h). In CDCl3,
reaction does not occur, only the starting material 10i being pres-
ent. It is obvious that 5-CF2H-isoxazole 10i is initially formed as the
kinetically controlled product, which in DMSO-d6 easily undergoes
rearrangement via an intramolecular attack of phenolic hydroxyl
on the electrophilic C-5 atom of the isoxazole ring (intermediate E)
with concomitant opening of the isoxazole ring and subsequent
dehydration of intermediate aldoxime 140 (non-isolable) to the
thermodynamically controlled chromone product 16i. Also,
we cannot exclude the alternative deprotonation of the
isoxazole ring followed by ring-opening with cleavage of the N–O
bond (intermediate F) and dehydration of 160 (non-isolable) to 16i
(Scheme 7).
The high reactivity of 2-RF-chromones and their application as
key intermediates in various transformations for the preparation of
fluorine-containing compounds20 provided the motivation for
further studies dealing with the reactivity of 3-cyano-2-RF-chro-
mones. We anticipated that these compounds, as a result of the
presence of the CN group, might undergo nucleophilic addition
reactions and intramolecular heterocyclizations giving various
heterocycles bearing an RF group more easily than the previously
studied 2-RF-chromones.20
Among the diverse transformations of 3-cyanochromones, one
of the more interesting reactions that has been encountered is the
conversion of these compounds, on heating with morpholine in
aqueous DMF19b or in the presence of NaOH in water,3d to 2-amino-
3-formylchromones in high yields. Thus, 3-cyanochromone is
‘chemically equivalent’ to 2-amino-3-formylchromone under cer-
tain reaction conditions.19g On the other hand, under strongly acidic
conditions this carbonitrile hydrolyzes to chromone-3-carbox-
amide.3c,19c,h (Scheme 8).
O
CONH2
H+
O
OH
O
NOH
O
O
CN
H2O
N
O
O
O
O
CF2H
CHO
NH2
HO-
CF2H
E
14'
O
Scheme 8.
H
O
O
O
O
O
When 3-cyano-2-RF-chromones 16 were treated with concen-
trated H2SO4 at 90 ꢁC for 3 h, 3-carbamoyl-2-RF-chromones 18
were obtained in high yields. It was also found that the carbonitrile
precursors, chromeno[3,4-d]isoxazoles 9, could be employed di-
rectly in this reaction to effect a more practical synthesis of 18
(Scheme 9). Previously, 7-hydroxy-2-(trifluoromethyl)chromone-
3-carboxamide was obtained by the reaction of 7-hydroxy-2-
(trifluoromethyl)chromone-3-carbonitrile with sulfuric acid at
120–135 ꢁC for 1.5 h.19i
CF2H
CN
DMSO
-H2O
O
N
CF2H
16i (57%)
10i
OH
OH
CF2H
OH
O
CN
OH
CF2H
CN
R2
O
F
16'
R1
R2
CONH2
RF
9a,b,f
H2SO4
Scheme 7.
16a,c,e
O
18a-c,e,f
Similar transformation in the series of non-fluorinated 4-
salicyloylisoxazoles has been described previously,2,3a however,
3-cyanochromones were obtained in very low yields (2–3%).2
Apparently, the strong electron-withdrawing nature of the CF2H
group plays an important role in the acceleration of this reaction.
Thus, contrary to 3-RF-isoxazoles 15, isoxazoles 9 and 10 with the 3-
position vacant can be considered as aldoximes in protected form,
having a masked cyano group. However, (20-hydroxy-50-nitro-
phenyl)[5-(trifluoromethyl)isoxazol-4-yl]methanone oxime 11j
failed to produce the chromone ring under the same reaction
conditions.
Amide
18a
18b
18c
18e
18f
RF
R1
R2
H
Yield (%)
80a, 74b
75
CF3
H
CF3
Me
H
H
(CF2)2H
(CF2)2H
CF3
H
75
H
Me
H
68
Cl
77
aFrom 9a.
bFrom 16a.
The 1H, 19F, and 13C NMR spectra of chromones 16 displayed the
expected signals. In the 1H NMR spectra the most diagnostic
Scheme 9.

V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 7877–7889
7883
In the 1H NMR spectra of 18 the signal of the H-5 proton
appeared at 7.90–8.12 ppm and two broadened singlets of the NH2
group appeared at 7.74–7.93 ppm. The IR spectra of 18 exhibited
two or three intense absorption bands at 3190–3410 cmꢀ1 due to
the amino group and three intense bands at 1608–1695 cmꢀ1
were allowed to react with hydrazines and hydroxylamine in
refluxing methanol for 2–3 h. Our preliminary results showed that
16c smoothly reacted with hydrazine and phenylhydrazine to pro-
duce the expected pyrazoles 20 and 21 in 31 and 98% yields,
respectively. Unlike hydrazines, hydroxylamine hydrochloride
(2 equiv) in the presence of AcONa reacted with 16b to give 5-
aminoisoxazole oxime 22 in 47% yield. In conjunction with the
pharmaceutical importance known for fused heterocycles in-
corporating a coumarin moiety,29,30 it should be noted that the
conjugate addition of acetamidine hydrochloride also took place
under weakly acidic conditions (AcONa) in refluxing DMF for
15 min to give a 73:27 mixture of 2,9-dimethyl-4-(trifluoromethyl)-
5H-chromeno[4,3-d]pyrimidin-5-one 23a and imine derivative
23b, indicating that partial hydrolysis of 23b had occurred. When
this mixture was treated with aqueous AcOH, analytically pure
coumarin 23a was obtained (Scheme 11). The structures have been
arrived at by detailed spectroscopic analysis and comparison of
the spectroscopic data with the data reported for related
systems.29,31,32
d
d
,
corresponding to the double bond, the chromone, and amide car-
bonyl groups.
All our attempts to prepare 2-RF-chromone-3-carboxylic acids
from 16 and 18 were fruitless. For instance, attempts to hydrolyze
16a,b with 55% sulfuric acid at 130 ꢁC or with concentrated HCl at
reflux for 2 h, conditions that had previously been used for the
hydrolysis of 3-cyanochromone to chromone-3-carboxylic
acid,3c,19c,h only caused the recovery of unchanged starting mate-
rials. It should be noted that 2-(trifluoromethyl)chromone-3-car-
boxylic acid ethyl ester was obtained previously by the reaction of
o-fluorobenzoyl chloride with ethyl trifluoroacetoacetate in the
presence of sodium hydride25 as well as from salicyloylacetic acid
ester, which was condensed with trifluoroacetic anhydride in the
presence of K2CO3 in refluxing toluene.26 This ester is an important
intermediate to a class of therapeutics for the treatment of
inflammation.26
(CF2)2H
N
NC
OH
In marked contrast to the known 3-cyanochromones, 3-cyano-
2-CF3-chromones 16a,b under the reaction conditions that had
been used for the preparation of 2-amino-3-formylchromone19b,3d
were prone to the facile detrifluoroacetylation to give either 2-
aminochromones 17a,b with morpholine or salicyloylacetonitriles
19a,b with NaOH. The latter readily isomerize on heating into 17.21
The transformation 16/19 also occurs in aqueous DMSO through
intermediate 160, which was detected in the 1H and 13C NMR
spectra of 16b in DMSO-d6. Spectral data and melting points of
17a,b and 19a,b were consistent with previous reports.21,27,28 The
expected products, 2-amino-3-(trifluoroacetyl)chromones 1600,
were not obtained, a result, which reflects the ease with which
chromones 16 undergo detrifluoroacetylation (Scheme 10).
O
R1
CN
RF
NH2NHR
N
R
O
16b,c
R = H (20), Ph (21)
MeC(=NH)NH2
NH2OH
Me
OH NOH
NH2
N
O
N
O
CF3
N
F3C
Me
X
22
23a (X = O),
23b (X = NH)
O
O
O
Scheme 11.
R
CN
R
N
H
We believe that these reactions proceed through common in-
termediate formed by the attack of the NH2 group at the C-2 atom
with pyrone ring-opening. Further, in the case of hydrazines, the
intramolecular heterocyclization occurs between the C]O and
NHR groups to produce pyrazoles 20 and 21. In the case of hy-
droxylamine, additions of the second NH2OH molecule to the aroyl
carbonyl and oxime hydroxyl to the cyano group give 5-amino-
isoxazole 22. Reaction with acetamidine includes two intra-
molecular cyclizations at the keto and cyano groups to form
a tricyclic imino intermediate 23b, which is subsequently followed
by hydrolysis to 23a. Similar non-fluorinated products are reported
by Trimeche et al.31 in the synthesis of 5H-chromeno[4,3-d]pyr-
imidin-5-ones using chromeno[4,3-b][1,5]benzodiazepin-7(8H)-
ones and substituted amidines in the presence of triethylamine.
Thus, the initial Michael addition to 16 leads to three different
types of products, depending on the nature of a bidentate nucleo-
phile. These results clearly indicate that the C-2 atom of chromones
16 is very susceptible to nucleophilic attack and make them an
attractive building block for the synthesis of various heterocycles
containing the RF group. An investigation of the reactivity of 3-
cyano-2-RF-chromones is now in progress.
DMF, H2O
O
CF3
O
NH2
17a,b
16a,b
DMSO
H2O
H
OH
O
O
R
O
R
R
CN
OH
CF3
CN
H2O
-CF3CO2H
16'
19a,b
X
O
COCF3
NH2
O
16''
Scheme 10.
When chromone 16a was treated with an excess of aniline un-
der solvent-free conditions or in ethanol at 80–90 ꢁC for 2–3 h, only
unchanged starting material was recovered; 16a is dissolved in 25%
NH3, but does not react with it at room temperature for 15 min. The
reactions of 16a with benzylamine, pyrrolidine, and piperidine at
reflux in methanol were accompanied by cleavage of the chromone
system and were not examined more closely.
3. Conclusion
In conclusion, we have shown, for the first time, that the re-
action of 3-(polyfluoroacyl)chromones with hydroxylamine occurs
mainly as nucleophilic 1,4-addition and provides a simple and
practical method for the introduction of CN and CONH2 groups at
To demonstrate the ability of compounds 16 to undergo hetero-
cyclization reactions, chromones 16b,c as representative examples

7884
V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 7877–7889
the 3-position of 2-(polyfluoroalkyl)chromones. The resulting 3-
cyano- and 3-carbamoyl-2-(polyfluoroalkyl)chromones are of
considerable interest as reactive precursors in the synthesis of
other useful organic materials containing polyfluoroalkyl groups. In
addition, oximation of 3-(polyfluoroacyl)chromones with hydroxyl-
amine hydrochloride depending on the nature of the substituents
results in the formation of chromone 3-oxime and 4-salicyloyl-
isoxazole derivatives. The observed difference in reactivity between
3-RFCO-chromones and the non-fluorinated 3-RCO-chromones is
undoubtedly due to the presence of the powerful electron-with-
drawing RF group in place of H, Me or Ph on the 3-acyl moiety, by
which the electron density is reduced considerably, thus facilitating
the reactions with nucleophilic reagents.
dried, and recrystallized from a toluene–hexane (1:1) mixture to
give 9 as colorless crystals.
4.2.1. 4-(Trifluoromethyl)-4H-chromeno[3,4-d]isoxazol-4-ol (9a)
Yield 72%, mp 144–145 ꢁC; IR (KBr) 3105, 1651, 1608, 1573, 1515,
1470, 1454 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 4.12 (br s, 1H, OH),
7.17–7.22 (m, 2H, H-6, H-8), 7.47 (ddd, 1H, H-7, J¼8.5, 7.6, 1.6 Hz),
7.77 (dd, 1H, H-9, J¼7.6, 1.6 Hz), 8.40 (s, 1H, H-3); 19F NMR
(376 MHz, CDCl3, HFB)
d
76.47 (d, CF3, J¼0.9 Hz); 13C NMR
(100 MHz, CDCl3)
d
95.6 (q, C–CF3, 2JC,F¼36.3 Hz), 104.2, 110.5, 117.2,
121.4 (q, CF3, 1JC,F¼285.7 Hz), 122.6, 123.3, 133.0, 146.6, 151.3, 163.3.
Anal. Calcd for C11H6F3NO3: C, 51.38; H, 2.35; N, 5.45. Found: C,
51.09; H, 2.12; N, 5.46.
4.2.2. 8-Methyl-4-(trifluoromethyl)-4H-chromeno[3,4-d]isoxazol-
4-ol (9b)
4. Experimental section
4.1. General
Yield 65%, mp 143–144 ꢁC; IR (KBr) 3109, 1652, 1611, 1580, 1509,
1482, 1457 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 2.39 (s, 3H, Me), 3.90
(br s, 1H, OH), 7.07 (d, 1H, H-6, J¼8.5 Hz), 7.27 (ddq, 1H, H-7, J¼8.5,
1H (400 MHz), 13C (100 MHz), and 19F (376 MHz) NMR spectra
were recorded on a Bruker DRX-400 spectrometer in CDCl3 or
DMSO-d6 with TMS and C6F6 as internal standards, respectively.
Assignment of chemical shifts was based on standard 2D NMR
techniques (1H–13C HSQC and HMBC). IR spectra were recorded on
a Perkin–Elmer Spectrum BX-II instrument as KBr discs. Electron
impact mass spectra were obtained on a Perkin–Elmer model GC–
MS instrument. Elemental analyses were performed at the Micro-
analysis Services of the Institute of Organic Synthesis, Ural Branch,
Russian Academy of Sciences. Melting points are uncorrected. All
solvents used were dried and distilled per standard procedures. The
starting chromones 6a–f,h,i,k were prepared according to de-
scribed procedure.9b,10c
2.2 Hz, 4JH,Me¼0.6 Hz), 7.57 (br d, 1H, H-9, J¼2.0 Hz), 8.39 (q, 1H, H-
5
3, JH,F¼0.8 Hz); 1H NMR (400 MHz, DMSO-d6)
d 2.35 (s, 3H, Me),
7.16 (d, 1H, H-6, J¼8.5 Hz), 7.36 (dd, 1H, H-7, J¼8.5, 2.1 Hz), 7.63 (br
d, 1H, H-9, J¼2.0 Hz), 9.00 (s, 1H, H-3), 9.43 (s, 1H, OH). Anal. Calcd
for C12H8F3NO3: C, 53.15; H, 2.97; N, 5.16. Found: C, 53.22; H, 2.85;
N, 5.44.
4.2.3. 4-(1,1,2,2-Tetrafluoroethyl)-4H-chromeno[3,4-d]isoxazol-
4-ol (9c)
Yield 70%, mp 105–106 ꢁC; IR (KBr) 3142, 1643, 1607, 1572, 1513,
1468, 1456 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 4.50 (br s, 1H, OH),
6.22 (tdd, 1H, CF2CF2H, 2JH,F¼52.7 Hz, 3JH,F¼7.7, 4.3 Hz), 7.16 (d, 1H,
H-6, J¼8.3 Hz), 7.20 (td, 1H, H-8, J¼7.6, 1.0 Hz), 7.46 (ddd, 1H, H-7,
J¼8.3, 7.5, 1.6 Hz), 7.74 (dd, 1H, H-9, J¼7.7, 1.6 Hz), 8.36 (d, 1H, H-3,
4.1.1. 6-Nitro-3-(2,2,3,3-tetrafluoropropionyl)chromone (6g)
5JH,F¼1.1 Hz); 19F NMR (376 MHz, CDCl3, HFB)
d 24.34 (dddd, CFFH,
A mixture of concentrated H2SO4 (2 mL), 96% HNO3 (2 mL), and
chromone 6c (1.0 g, 3.65 mmol) was heated at 75 ꢁC for 1.5 h. After
cooling, the reaction mixture was poured with stirring onto
crushed ice (20 g). The precipitate formed was filtered, washed
with water, dried, and recrystallized from a toluene–hexane (1:3)
mixture to give 6g as colorless crystals. Yield 52%, mp 93–95 ꢁC; IR
2JF,F¼306.0 Hz, 2JF,H¼52.7 Hz, 3JF,F¼10.8, 6.0 Hz), 26.80 (dddd, CFFH,
2JF,F¼306.0 Hz, 2JF,H¼52.7 Hz, 3JF,F¼11.5,1.4 Hz), 30.67 (ddd, CFF, 2JF,F
¼
272.5 Hz, 3JF,F¼10.8 Hz, 3JF,H¼4.3 Hz), 32.61 (ddt, CFF, 2JF,F¼272.5 Hz,
3JF,F¼11.5 Hz, 3JF,Hz3JF,Fz6.8 Hz). Anal. Calcd for C12H7F4NO3: C,
49.84; H, 2.44; N, 4.84. Found: C, 49.84; H, 2.45; N, 4.90.
(KBr) 3438, 3100, 3075, 1701, 1680, 1627, 1566, 1534, 1348 cmꢀ1; 1H
4.2.4. 8-Methyl-4-(1,1,2,2-tetrafluoroethyl)-4H-chromeno-
[3,4-d]isoxazol-4-ol (9d)
2
NMR (400 MHz, CDCl3)
d
6.68 (tt, 1H, CF2CF2H, JH,F¼53.0 Hz,
3JH,F¼5.7 Hz), 7.76 (d, 1H, H-8, J¼9.2 Hz), 8.59 (s, 1H, H-2), 8.62 (dd,
Yield 57%, mp 117–118 ꢁC; IR (KBr) 3224, 1650, 1609, 1579, 1508,
1H, H-7, J¼9.2, 2.8 Hz), 9.13 (d, 1H, H-5, J¼2.8 Hz); hydrate form
1509, 1482, 1452 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 2.39 (s, 3H,
2
(25%)
d
6.03 (s, 2H, 2OH), 6.28 (tt, 1H, CF2CF2H, JH,F¼52.9 Hz,
2
Me), 4.08 (br s, 1H, OH), 6.20 (tdd, 1H, CF2CF2H, JH,F¼52.6 Hz,
3JH,F¼6.2 Hz), 7.75 (d, 1H, H-8, J¼9.2 Hz), 8.43 (s, 1H, H-2), 8.61 (dd,
1H, H-7, J¼9.2, 2.8 Hz), 9.10 (d, 1H, H-5, J¼2.8 Hz). The same
nitrating mixture was used for the preparation of chromone 6j9b
from 6a, yield 55%.
3JH,F¼7.7, 4.3 Hz), 7.04 (d, 1H, H-6, J¼8.5 Hz), 7.26 (ddq, 1H, H-7,
4
J¼8.5, 2.2 Hz, JH,Me¼0.6 Hz), 7.57 (br d, 1H, H-9, J¼2.0 Hz), 8.39 (t,
1H, H-3, 5JH,F¼1.1 Hz). Anal. Calcd for C13H9F4NO3: C, 51.50; H, 2.99;
N, 4.62. Found: C, 51.25; H, 3.05; N, 4.71.
4.2. General procedures for the synthesis of 4-
(polyfluoroalkyl)-4H-chromeno[3,4-d]isoxazol-4-ols (9a–h)
4.2.5. 7,9-Dimethyl-4-(1,1,2,2-tetrafluoroethyl)-4H-chromeno-
[3,4-d]isoxazol-4-ol (9e)
This compound was obtained as a mixture with 5,7-dimethyl-4-
oxo-2-(1,1,2,2-tetrafluoroethyl)-4H-chromene-3-carbonitrile (16e),
total yield 40% (methods A and B), mp 135–140 ꢁC (toluene–hex-
Method A. To a solution of hydroxylamine, prepared from
NH2OH$HCl (1.0 mmol) and KOH (0.9 mmol) in MeOH (3 mL), 3-
RFCO-chromone 6 (0.5 mmol) was added. The resulting mixture
was allowed to stand for 18–24 h at room temperature and then
diluted with water (5–8 mL) containing AcOH (1.5 mmol). After
cooling, the precipitate formed was filtered, washed with water,
dried, and recrystallized from a toluene–hexane (1:1) mixture to
give 9 as colorless crystals.
ane, 3:1); 1H NMR (400 MHz, DMSO-d6)
d (9e, 75%) 2.31 (s, 3H, Me-
2
7), 2.62 (s, 3H, Me-9), 6.76 (tt, 1H, CF2CF2H, JH,F¼51.7 Hz,
3JH,F¼6.6 Hz), 6.85 (s, 1H, H-6), 6.88 (s, 1H, H-8), 8.86 (s, 1H, H-3),
9.22 (s, 1H, OH); (16e, 25%) 2.44 (s, 3H, Me-7), 2.72 (s, 3H, Me-5),
2
3
7.05 (tt, 1H, CF2CF2H, JH,F¼51.4 Hz, JH,F¼4.4 Hz), 7.29 (s, 1H, H-6),
7.45 (s, 1H, H-8).
Method B. To a hot solution of NH2OH$HCl (1.0 mmol) and
AcONa (1.0 mmol) in MeOH (3 mL), 3-RFCO-chromone 6 (0.5 mmol)
was added. The resulting mixture was allowed to stand for 3 days at
room temperature and then diluted with water (5–8 mL). After
cooling, the precipitate formed was filtered, washed with water,
4.2.6. 8-Chloro-4-(trifluoromethyl)-4H-chromeno[3,4-d]isoxazol-
4-ol (9f)
Yield 54%, mp 125–126 ꢁC; IR (KBr) 3121, 1648, 1604, 1563, 1510,
1509, 1467 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 4.24 (br s, 1H, OH),

V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 7877–7889
7885
7.13 (d, 1H, H-6, J¼8.9 Hz), 7.42 (dd, 1H, H-7, J¼8.9, 2.5 Hz), 7.74 (br
207 ꢁC; IR (KBr) 3316, 1655, 1630, 1609, 1580, 1514, 1485 cmꢀ1
;
1H
5
2
d, 1H, H-9, J¼2.5 Hz), 8.41 (q, 1H, H-3, JH,F¼0.6 Hz); 19F NMR
NMR (400 MHz, DMSO-d6)
d
6.88 (tt, 1H, HCF2CF2, JH,F¼51.6 Hz,
(376 MHz, CDCl3, HFB)
d
76.52 (s, CF3). Anal. Calcd for
3JH,F¼4.1 Hz), 7.02 (d, 1H, H-30, J¼9.0 Hz), 8.16 (d, 1H, H-60,
J¼2.9 Hz), 8.20 (dd, 1H, H-40, J¼9.0, 2.9 Hz), 9.10 (t, 1H, H-3,
5JH,F¼1.1 Hz), 11.54 (s, 1H, OH), 12.49 (s, 1H, NOH); MS (EI): m/z
(%) 331 [MꢀH2O]þ (100), 301 [MꢀH2OꢀNO]þ (55), 280
[MꢀH2OꢀCHF2]þ (44), 257 (32), 230 [MꢀH2OꢀC2HF4]þ (28), 202
(50), 156 (27), 101 (44), 76 (55), 63 (52), 51 (68), 30 (47). Anal. Calcd
for C12H7F4N3O5: C, 41.27; H, 2.02; N, 12.03. Found: C, 41.57; H, 1.90;
N, 11.94.
C
11H5ClF3NO3: C, 45.31; H, 1.73; N, 4.80. Found: C, 45.56; H, 1.68; N,
4.89.
4.2.7. 8-Nitro-4-(1,1,2,2-tetrafluoroethyl)-4H-chromeno-
[3,4-d]isoxazol-4-ol (9g)
Yield 51% (method B), 24% (method A), mp 124–125 ꢁC; IR (KBr)
3123, 1660, 1621, 1578, 1528, 1510, 1471 cmꢀ1
;
1H NMR (400 MHz,
2
CDCl3)
d
4.65 (br s, 1H, OH), 6.22 (tdd, 1H, CF2CF2H, JH,F¼52.5 Hz,
3JH,F¼7.3, 4.1 Hz), 7.30 (d,1H, H-6, J¼9.0 Hz), 8.35 (dd,1H, H-7, J¼9.1,
4.2.12. (20-Hydroxy-50-nitrophenyl)[5-(trifluoromethyl)isoxazol-
4-yl]methanone oxime (11j)
5
2.7 Hz), 8.48 (t, 1H, H-3, JH,F¼1.0 Hz), 8.68 (d, 1H, H-9, J¼2.7 Hz);
MS (EI): m/z (%) 316 [MꢀH2O]þ (57), 286 [MꢀH2OꢀNO]þ (23), 270
[MꢀH2OꢀNO2]þ (28), 191 (42), 107 (31), 75 (100), 63 (44), 51 (36).
Anal. Calcd for C12H6F4N2O5: C, 43.13; H, 1.81; N, 8.38. Found: C,
43.10; H, 1.68; N, 8.47.
This compound was obtained from chromone 6j as described for
11g. Yield 70%, mp 228–230 ꢁC (decomp.); IR (KBr) 3324, 1632,
1609, 1579, 1512, 1483 cmꢀ1 1H NMR (400 MHz, DMSO-d6)
; d 7.03
(d, 1H, H-30, J¼9.0 Hz), 8.22 (dd, 1H, H-40, J¼9.0, 2.9 Hz), 8.25 (d, 1H,
5
H-60, J¼2.9 Hz), 9.11 (q, 1H, H-3, JH,F¼0.9 Hz), 11.56 (s, 1H, OH),
4.2.8. 4-(Trichloromethyl)-4H-chromeno[3,4-d]isoxazol-4-ol (9h)
Yield 10%, mp 156–157 ꢁC (toluene–heptane); IR (KBr) 3107,
1649, 1606, 1574, 1514, 1468, 1451 cmꢀ1; 1H NMR (400 MHz, DMSO-
12.58 (s, 1H, NOH); 19F NMR (376 MHz, DMSO-d6, HFB)
d
99.63 (d,
5
CF3, JF,H¼0.9 Hz); 13C NMR (100 MHz, DMSO-d6)
d 113.5 (q, C-4,
3JC,F¼2.2 Hz), 116.9 (C-30), 118.0 (q, CF3, 1JC,F¼270.5 Hz), 121.6 (C-10),
125.3 (C-60), 126.9 (C-40), 139.6 (C-50), 141.3 (C]N), 152.1 (C-3),
152.4 (q, C-5, 2JC,F¼41.1 Hz), 161.8 (C-20); MS (EI): m/z (%) 317 [M]þ
(83), 299 [MꢀH2O]þ (49), 269 [MꢀH2OꢀNO]þ (28), 248 [MꢀCF3]þ
(100), 202 (29), 108 (57), 79 (56), 69 [CF3]þ (88), 63 (72), 53 (44).
Anal. Calcd for C11H6F3N3O5: C, 41.65; H, 1.91; N, 13.25. Found: C,
41.33; H, 1.87; N, 13.05.
d6)
d
7.18–7.23 (m, 2H, H-6, H-8), 7.53 (ddd, 1H, H-7, J¼8.4, 7.4,
1.7 Hz), 7.80 (dd, 1H, H-9, J¼7.9, 1.7 Hz), 9.05 (s, 1H, H-3), 9.53 (s, 1H,
OH). Anal. Calcd for C11H6Cl3NO3: C, 43.10; H,1.97; N, 4.57. Found: C,
43.34; H, 2.12; N, 4.42.
4.2.9. 5-(Difluoromethyl)-4-salicyloylisoxazole (10i)
Yield 55% (method A), 20% (method B), mp 94–95 ꢁC, pale yel-
low crystals; IR (KBr) 1627, 1601, 1488, 1450 cmꢀ1
;
1H NMR
4.2.13. 3-(20-Hydroxy-50-nitrophenyl)-3-oxopropanal dioxime (12)
Yield 34% (method A), 40% (method B), mp 217–218 ꢁC, yellow
crystals; IR (KBr) 3317, 3216, 3097, 2930, 1628, 1609, 1579, 1509,
(400 MHz, CDCl3)
d
7.00 (ddd, 1H, H-50, J¼8.2, 7.2,1.1 Hz), 7.03 (t,1H,
2
CF2H, JH,F¼52.2 Hz), 7.11 (dd, 1H, H-30, J¼8.4, 1.1 Hz), 7.57 (dd, 1H,
H-60, J¼8.1, 1.6 Hz), 7.61 (ddd, 1H, H-40, J¼8.4, 7.2, 1.6 Hz), 8.62 (t, 1H,
H-3, 5JH,F¼1.5 Hz), 11.49 (s, 1H, OH); 1H NMR (400 MHz, DMSO-d6)
1485, 1388, 1324 cmꢀ1
(55%)
;
1H NMR (400 MHz, DMSO-d6) syn-isomer
d
3.76 (d, 2H, CH2, J¼5.1 Hz), 6.71 (t, 1H, CH]N, J¼5.1 Hz),
d
6.98 (td, 1H, H-50, J¼7.5, 1.0 Hz), 7.02 (dd, 1H, H-30, J¼7.8, 1.0 Hz),
7.07 (d, 1H, H-30, J¼9.0 Hz), 8.16 (dd, 1H, H-40, J¼9.0, 2.8 Hz), 8.27 (d,
7.41 (t,1H, CF2H, 2JH,F¼51.5 Hz), 7.52 (td,1H, H-40, J¼7.6, 1.6 Hz), 7.54
1H, H-60, J¼2.8 Hz), 11.16 (br s, 1H, OH), 11.7–12.5 (br s, 2H, 2NOH);
5
(dd, 1H, H-60, J¼7.7, 1.6 Hz), 9.08 (t, 1H, H-3, JH,F¼1.7 Hz), 10.72 (s,
anti-isomer (40%)
d
3.73 (d, 2H, CH2, J¼5.1 Hz), 7.08 (d, 1H, H-30,
1H, OH); 19F NMR (376 MHz, DMSO-d6, HFB)
d
43.66 (dd, CF2H,
J¼9.0 Hz), 7.39 (t, 1H, CH]N, J¼5.1 Hz), 8.15 (dd, 1H, H-40, J¼9.0,
2.8 Hz), 8.25 (d,1H, H-60, J¼2.8 Hz),10.69 (s,1H, OH),11.7–12.5 (br s,
2H, 2NOH). 3-(20-Hydroxy-50-nitrophenyl)-5-(hydroxyamino)-4,5-
2JF,H¼51.5 Hz, JF,H¼1.7 Hz); 13C NMR (100 MHz, DMSO-d6)
d 106.9
5
1
(t, CF2H, JC,F¼238.1 Hz), 117.3 (C-30), 119.5 (C-50), 121.2 (t, C-4,
3JC,F¼4.6 Hz),123.9 (C-10),130.7 (C-60),135.3 (C-40),151.4 (C-3),157.7
dihydroisoxazole 13 (5%)
d
3.25 (dd, 1H, CHH, J¼18.0, 4.7 Hz), 3.57
2
(C-20), 162.6 (t, C-5, JC,F¼25.4 Hz), 186.9 (C]O); MS (EI): m/z (%)
(dd, 1H, CHH, J¼18.0, 9.8 Hz), 5.55 (br dd, 1H, CH, Jz10.0, 5.0 Hz),
6.55 (br s, 1H, NH), 7.13 (d, 1H, H-30, J¼9.1 Hz), 7.51 (br s, 1H, OH),
8.19 (dd, 1H, H-40, J¼9.1, 2.9 Hz), 8.36 (d, 1H, H-60, J¼2.9 Hz), 11.7–
12.5 (br s, 2H, 2OH). Anal. Calcd for C9H9N3O5: C, 45.19; H, 3.79; N,
17.57. Found: C, 45.06; H, 3.52; N, 17.39.
239 [M]þ (12), 188 [MꢀCF2H]þ (92), 121 [HOC6H4CO]þ (100), 93
[HOC6H4]þ (24), 77 [C6H5]þ (17), 65 [C5H5]þ (46), 51 [CF2H]þ (34).
Anal. Calcd for C11H7F2NO3: C, 55.24; H, 2.95; N, 5.86. Found: C,
55.10; H, 2.89; N, 6.08.
4.2.10. [5-(Difluoromethyl)isoxazol-4-yl](20-hydroxyphenyl)-
methanone oxime (11i)
4.3. General procedure for chromone 3-oximes 14b,c,i,k
This compound was detected in a mixture with 10i and was not
Method C. To a heterogeneous mixture of 3-RFCO-chromone 6
(1.0 mmol) and NH2OH$HCl (84 mg, 1.2 mmol) in methanol or
ethanol (4 mL) was added one drop of concentrated HCl. The
mixture was refluxed for 5 h, concentrated to dryness, diluted with
hot water, and then extracted with benzene. The solvent was
evaporated and the crude solid was recrystallized from a toluene–
hexane (1:1) mixture to give 14 as colorless crystals.
obtained in a pure form. 1H NMR (400 MHz, DMSO-d6)
d 6.88 (td,
1H, H-50, J¼7.5, 1.0 Hz), 6.91 (dd, 1H, H-30, J¼7.7, 1.0 Hz), 7.13 (t, 1H,
CF2H, 2JH,F¼52.0 Hz), 7.18 (dd, 1H, H-60, J¼7.7, 1.6 Hz), 7.30 (ddd, 1H,
5
H-40, J¼7.7, 7.3, 1.6 Hz), 8.88 (t, 1H, H-3, JH,F¼1.5 Hz), 10.28 (s,
1H, OH), 12.24 (s, 1H, NOH); 1H NMR (400 MHz, CDCl3)
d 6.77 (t, 1H,
CF2H, 2JH,F¼52.9 Hz), 6.88 (ddd, 1H, H-50, J¼7.9, 7.2, 1.1 Hz), 6.96 (dd,
1H, H-60, J¼7.9, 1.7 Hz), 7.05 (dd, 1H, H-30, J¼8.3, 1.1 Hz), 7.34 (ddd,
1H, H-40, J¼8.3, 7.2, 1.7 Hz), 8.00 (s, 1H, OH), 8.36 (t, 1H, H-3,
5JH,F¼1.4 Hz), 10.31 (s, 1H, NOH).
4.3.1. 1-(6-Methyl-4-oxo-4H-chromen-3-yl)-2,2,2-trifluoroethan-
1-one oxime (14b)
Yield 28%, mp 202–203 ꢁC; IR (KBr) 3223, 1650, 1628, 1574,
4.2.11. (20-Hydroxy-50-nitrophenyl)[5-(1,1,2,2-tetrafluoroethyl)-
isoxazol-4-yl]methanone oxime (11g)
A mixture of chromone 6g (150 mg, 0.47 mmol) and NH2OH$HCl
(130 mg, 1.9 mmol) in MeOH (5 mL) was refluxed for 5 h. After
cooling, the resulting mixture was diluted with water (15 mL). The
solid product was collected by filtration, dried, and recrystallized
from toluene to give 11g as pale yellow crystals. Yield 37%, mp 206–
1487 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 2.47 (s, 3H, Me), 7.41 (d,1H,
H-8, J¼8.6 Hz), 7.55 (ddq, 1H, H-7, J¼8.6, 2.2 Hz, 4JH,Me¼0.6 Hz), 7.97
(s, 1H, H-2), 8.05 (br d, 1H, H-5, J¼2.0 Hz), 8.69 (s, 1H, OH); 19F NMR
(376 MHz, CDCl3, HFB)
d
93.42 (d, CF3, J¼0.5 Hz); MS (EI): m/z (%)
271 [M]þ (100), 221 (41), 135 [HO(Me)C6H3CO]þ (75), 134
[O(Me)C6H3CO]þ (100), 107 [MeC6H3OH]þ (48), 106 [MeC6H3O]þ
(80), 77 [C6H5]þ (100), 69 [CF3]þ (100), 51 [C4H3]þ (87), 39 (62), 29

7886
V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 7877–7889
(44). Anal. Calcd for C12H8F3NO3: C, 53.15; H, 2.97; N, 5.16. Found: C,
52.77; H, 3.07; N, 4.99.
39 (58), 29 (39). Anal. Calcd for C12H8F3NO3: C, 53.15; H, 2.97; N,
5.16. Found: C, 52.98; H, 3.13; N, 5.04.
4.3.2. 1-(4-Oxo-4H-chromen-3-yl)-2,2,3,3-tetrafluoropropan-1-
one oxime (14c)
4.4.2. 4-Salicyloyl-3-(1,1,2,2-tetrafluoroethyl)isoxazole (15c)
Yield 65%, mp 56–57 ꢁC; IR (KBr) 1630, 1599, 1572, 1488,
Yield 24%, mp 186–187 ꢁC; IR (KBr) 3225, 1649, 1622, 1602, 1570,
1449 cmꢀ1 1H NMR (400 MHz, DMSO-d6) 6.97 (ddd, 1H, H-50,
; d
1465 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
6.30 (tt, 1H, CF2CF2H,
J¼7.8, 7.3, 1.0 Hz), 7.01 (dd, 1H, H-30, J¼8.3, 0.8 Hz), 7.05 (tt, 1H,
CF2CF2H, 2JH,F¼51.9 Hz, 3JH,F¼5.4 Hz), 7.52 (ddd, 1H, H-40, J¼8.3, 7.3,
1.7 Hz), 7.58 (dd, 1H, H-60, J¼7.8, 1.7 Hz), 9.78 (t, 1H, H-5,
5JH,F¼1.2 Hz), 10.62 (s, 1H, OH). Anal. Calcd for C12H7F4NO3: C,
49.84; H, 2.44; N, 4.84. Found: C, 49.98; H, 2.56; N, 4.88.
2JH,F¼52.8 Hz, JH,F¼5.3 Hz), 7.48 (ddd, 1H, H-6, J¼7.9, 7.3, 0.9 Hz),
7.53 (d, 1H, H-8, J¼8.4 Hz), 7.75 (ddd, 1H, H-7, J¼8.6, 7.2, 1.7 Hz),
8.01 (s, 1H, H-2), 8.26 (dd, 1H, H-5, J¼8.0, 1.6 Hz), 8.78 (s, 1H, OH);
3
1H NMR (400 MHz, DMSO-d6)
d
6.85 (t, 1H, CF2CF2H, 2JH,F¼51.6 Hz,
3JH,F¼5.8 Hz), 7.57 (ddd, 1H, H-6, J¼8.0, 7.1, 1.1 Hz), 7.73 (dd, 1H, H-8,
J¼8.5,1.1 Hz), 7.89 (ddd,1H, H-7, J¼8.5, 7.1,1.7 Hz), 8.08 (dd,1H, H-5,
J¼8.0, 1.7 Hz), 8.50 (s, 1H, H-2), 12.86 (s, 1H, OH). Anal. Calcd for
4.4.3. 3-(Difluoromethyl)-4-salicyloylisoxazole (15i)
Yield 70%, mp 84–85 ꢁC; IR (KBr) 3100, 1630, 1605, 1575, 1568,
C
12H7F4NO3: C, 49.84; H, 2.44; N, 4.84. Found: C, 49.73; H, 2.46; N,
1493, 1445 cmꢀ1; 1H NMR (400 MHz, DMSO-d6)
d 6.98 (ddd, 1H, H-
4.74.
50, J¼7.8, 7.3, 0.8 Hz), 7.03 (dd, 1H, H-30, J¼8.2, 0.8 Hz), 7.46 (t, 1H,
CF2H, 2JH,F¼52.3 Hz), 7.51 (ddd, 1H, H-40, J¼8.2, 7.3, 1.7 Hz), 7.58 (dd,
5
4.3.3. 1-(4-Oxo-4H-chromen-3-yl)-2,2-difluoroethan-1-
one oxime (14i)
1H, H-60, J¼7.8, 1.7 Hz), 9.71 (t, 1H, H-5, JH,F¼1.5 Hz), 10.65 (s, 1H,
OH); 19F NMR (376 MHz, DMSO-d6, HFB)
d 43.59 (dd, CF2H,
5
Yield 45%, mp 166–167 ꢁC; IR (KBr) 3203, 1665, 1620, 1603, 1568,
2JF,H¼52.3, JF,H¼1.5 Hz); 13C NMR (100 MHz, DMSO-d6)
d 109.0 (t,
1468 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
6.47 (t, 1H, CF2H,
CF2H, 1JC,F¼238.6 Hz), 117.3 (C-30), 119.0 (t, C-4, JC,F¼1.7 Hz), 119.4
(C-50), 124.1 (C-10), 130.6 (C-60), 134.8 (C-40), 156.0 (t, C-3,
2JC,F¼24.9 Hz), 157.6 (C-20), 166.3 (C-5), 187.2 (C]O). Anal. Calcd for
3
2JH,F¼54.7 Hz), 7.47 (ddd, 1H, H-6, J¼8.0, 7.2, 1.1 Hz), 7.52 (dd, 1H, H-
8, J¼8.5, 1.0 Hz), 7.74 (ddd, 1H, H-7, J¼8.6, 7.2, 1.7 Hz), 8.10 (s, 1H, H-
2), 8.27 (dd, 1H, H-5, J¼8.0, 1.6 Hz), 8.85 (br s, 1H, OH); 1H NMR
C11H7F2NO3: C, 55.24; H, 2.95; N, 5.86. Found: C, 55.59; H, 3.16; N,
2
(400 MHz, DMSO-d6)
d
6.74 (t, 1H, CF2H, JH,F¼54.2 Hz), 7.57 (ddd,
5.56.
1H, H-6, J¼8.0, 7.1, 1.1 Hz), 7.72 (ddd, 1H, H-8, J¼8.5, 1.1, 0.5 Hz), 7.88
(ddd, 1H, H-7, J¼8.5, 7.1, 1.7 Hz), 8.09 (ddd, 1H, H-5, J¼8.0, 1.7,
0.5 Hz), 8.47 (s, 1H, H-2), 12.44 (s, 1H, OH); 19F NMR (376 MHz,
DMSO-d6, HFB)
DMSO-d6)
4.4.4. 4-(50-Chloro-20-hydroxybenzoyl)-3-(difluoromethyl)-
isoxazole (15k)
d
45.02 (d, CF2H, 2JF,H¼54.2 Hz); 13C NMR (100 MHz,
Yield 65%, mp 107–108 ꢁC; IR (KBr) 3122, 3089, 1633,1605, 1568,
d
113.2 (t, CF2H, 1JC,F¼235.8 Hz), 114.0 (C-3), 118.6 (C-8),
1492,1468 cmꢀ1; 1H NMR (400 MHz, DMSO-d6) 7.02 (m,1H, H-30),
d
123.3 (C-4a), 125.2 (C-5), 126.1 (C-6), 134.8 (C-7), 143.3 (t, C]N,
2JC,F¼27.6 Hz), 155.6 (C-8a), 155.8 (C-2), 172.9 (C-4). Anal. Calcd for
7.44 (t, 1H, CF2H, 2JH,F¼52.2 Hz), 7.48–7.52 (m, 2H, H-40, H-60), 9.72
5
(t, 1H, H-5, JH,F¼1.5 Hz), 10.68 (s, 1H, OH); 19F NMR (376 MHz,
2
5
C
11H7F2NO3: C, 55.24; H, 2.95; N, 5.86. Found: C, 55.48; H, 2.89; N,
DMSO-d6, HFB)
d
43.45 (dd, CF2H, JF,H¼52.2, JF,H¼1.5 Hz). Anal.
5.75.
Calcd for C11H6ClF2NO3: C, 48.29; H, 2.21; N, 5.12. Found: C, 48.07;
H, 2.23; N, 4.90.
4.3.4. 1-(6-Chloro-4-oxo-4H-chromen-3-yl)-2,2-difluoroethan-1-
one oxime (14k)
4.5. General procedure for the preparation of 4-oxo-2-
(polyfluoroalkyl)-4H-chromene-3-carbonitriles (16a–e)
Yield 35%, mp 181–182 ꢁC; IR (KBr) 3246, 1662, 1632, 1613, 1566,
1466 cmꢀ1
; d 6.45 (t, 1H, CF2H,
1H NMR (400 MHz, CDCl3)
2JH,F¼54.7 Hz), 7.49 (d, 1H, H-8, J¼8.9 Hz), 7.68 (dd, 1H, H-7, J¼8.9,
2.6 Hz), 8.07 (s, 1H, H-2), 8.22 (d, 1H, H-5, J¼2.6 Hz), 8.74 (br s, 1H,
A solution of chromeno[3,4-d]isoxazol-4-ol 9 (1.0 mmol) in
CF3CO2H (0.7 mL) was refluxed for 15 min. After cooling, the
resulting mixture was diluted with water (4 mL). The precipitate
formed was filtered, dried, and recrystallized from a toluene–hex-
ane (1:1) mixture to give 16 as colorless crystals.
OH); 1H NMR (400 MHz, DMSO-d6)
d 6.72 (t, 1H, CF2H,
2JH,F¼54.1 Hz), 7.80 (dd, 1H, H-8, J¼9.0, 0.3 Hz), 7.93 (dd, 1H, H-7,
J¼9.0, 2.6 Hz), 8.01 (dd, 1H, H-5, J¼2.7, 0.3 Hz), 8.50 (s, 1H, H-2),
12.47 (s, 1H, OH); 19F NMR (376 MHz, DMSO-d6, HFB)
d 46.40 (d,
2
CF2H, JF,H¼54.0 Hz). Anal. Calcd for C11H6ClF2NO3: C, 48.29; H,
4.5.1. 4-Oxo-2-(trifluoromethyl)-4H-chromene-3-carbonitrile (16a)
2.21; N, 5.12. Found: C, 48.43; H, 2.12; N, 5.13.
Yield 84%, mp 119–120 ꢁC; IR (KBr) 2245, 1667, 1637, 1610, 1580,
1468 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.62 (ddd, 1H, H-6, J¼8.0,
7.3, 1.0 Hz), 7.64 (d, 1H, H-8, J¼8.6 Hz), 7.89 (ddd, 1H, H-7, J¼8.7, 7.2,
4.4. General procedure for 3-(polyfluoroalkyl)isoxazole
15b,c,i,k
1.7 Hz), 8.28 (dd, 1H, H-5, J¼8.0, 1.5 Hz); 19F NMR (376 MHz, CDCl3,
HFB) d d 100.8, 108.8, 117.6
93.67 (s, CF3); 13C NMR (100 MHz, CDCl3)
(q, CF3, 1JC,F¼278.0 Hz), 118.7, 122.1, 126.4, 128.2, 136.5, 154.5, 158.0
(q, C-2, 2JC,F¼39.3 Hz),171.8 (C]O); MS (EI): m/z (%) 239 [M]þ (100),
170 [MꢀCF3]þ (60), 120 [OC6H4CO]þ (100), 92 [C6H4O]þ (100), 69
[CF3]þ (38), 64 [C5H4]þ (73), 63 (76), 50 (72), 38 (39). Anal. Calcd for
A solution of oxime 14 (1.0 mmol) in DMSO (5 mL) was heated at
85 ꢁC for 5 h. After cooling, the resulting mixture was diluted with
water (15 mL) and the solid obtained was filtered and dried to give
15 as pink or pale yellow crystals.
C11H4F3NO2: C, 55.24; H, 1.69; N, 5.86. Found: C, 55.20; H, 1.46; N,
5.87.
4.4.1. 4-(2-Hydroxy-5-methylbenzoyl)-3-(trifluoromethyl)-
isoxazole (15b)
4.5.2. 6-Methyl-4-oxo-2-(trifluoromethyl)-4H-chromene-3-
carbonitrile (16b)
Yield 62%, mp 106–107 ꢁC; IR (KBr) 1636, 1613, 1592, 1573,
1489 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6)
d
2.26 (s, 3H, Me), 6.92
Yield 72%, mp 149–150 ꢁC; IR (KBr) 2239, 1680, 1631, 1484 cmꢀ1
;
(d, 1H, H-30, J¼8.4 Hz), 7.34 (dd, 1H, H-40, J¼8.3, 2.3 Hz), 7.39 (d, 1H,
H-60, J¼2.3 Hz), 9.82 (q, 1H, H-5, 5JH,F¼1.1 Hz), 10.38 (s, 1H, OH); MS
(EI): m/z (%) 271 [M]þ (100), 221 (38), 135 [HO(Me)C6H3CO]þ (69),
134 [O(Me)C6H3CO]þ (100), 107 [MeC6H3OH]þ (46), 106
[MeC6H3O]þ (77), 77 [C6H5]þ (100), 69 [CF3]þ (97), 51 [C4H3]þ (81),
1H NMR (400 MHz, CDCl3)
d 2.52 (s, 3H, Me), 7.53 (d, 1H, H-8,
J¼8.6 Hz), 7.68 (dd, 1H, H-7, J¼8.6, 2.2 Hz), 8.05 (br d, 1H, H-5,
J¼1.5 Hz); 19F NMR (376 MHz, CDCl3, HFB)
d
93.72 (s, CF3); 1H NMR
(400 MHz, DMSO-d6) (16b, 78%) d 2.48 (s, 3H, Me), 7.79 (d, 1H, H-8,
J¼8.6 Hz), 7.83 (dd, 1H, H-7, J¼8.6, 1.9 Hz), 7.92 (br s, 1H, H-5). 2,4-

V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 7877–7889
7887
Dihydroxy-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carbo-
nitrile 160b (22%)
2.30 (s, 3H, Me), 6.98 (d, 1H, H-8, J¼8.3 Hz), 7.31
4.5.8. 2-Amino-6-methyl-4H-chromen-4-one (17b)
d
A
solution of chromeno[3,4-d]isoxazol-4-ol 9b (100 mg,
(dd, 1H, H-7, J¼8.3, 1.6 Hz), 7.56 (br s, 1H, H-5), 9.27 (br s, 1H, OH),
0.37 mmol) and piperidine (130 mg, 1.53 mmol) in toluene (3 mL)
was refluxed for 10 min, after which the solvent was partially
evaporated. After cooling, the crystalline product was filtered and
dried to give 17b as yellow crystals. Yield 62%, mp>300 ꢁC (lit.21 mp
11.8–13.2 (br s, 1H, OH); 13C NMR (100 MHz, DMSO-d6) (16b)
d
20.4,
1
99.9, 110.3, 117.7 (q, CF3, JC,F¼277.0 Hz), 118.7, 121.6, 124.5, 137.6,
138.2, 152.6, 157.1 (q, C-2, 2JC,F¼38.3 Hz), 172.6 (C]O); (160b)
d 20.1,
2
77.0, 95.5 (q, C-2, JC,F¼33.2 Hz), 114.5, 115.1, 116.1, 122.1 (q, CF3,
323–325 ꢁC, lit.28b mp 320 ꢁC); 1H NMR (400 MHz, DMSO-d6)
d 2.37
1JC,F¼290.0 Hz), 123.9, 131.5, 134.5, 150.1, 162.7. Anal. Calcd for
(s, 3H, Me), 5.14 (s, 1H, H-3), 7.26 (d, 1H, H-8, J¼8.4 Hz), 7.40 (dd, 1H,
C
12H6F3NO2: C, 56.93; H, 2.39; N, 5.53. Found: C, 56.84; H, 2.21;
H-7, J¼8.4, 2.0 Hz), 7.44 (br s, 2H, NH2), 7.69 (d, 1H, H-5, J¼2.0 Hz).
N, 5.54.
4.5.3. 4-Oxo-2-(1,1,2,2-tetrafluoroethyl)-4H-chromene-3-
carbonitrile (16c)
4.6. General procedure for the preparation of 4-oxo-2-
(polyfluoroalkyl)-4H-chromene-3-carboxamides (18a–c,e,f)
Yield 85%, mp 139–140 ꢁC; IR (KBr) 2244, 1664, 1630, 1578,
1463 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
6.24 (tt, 1H, CF2CF2H,
Chromeno[3,4-d]isoxazol-4-ol
9
or 3-cyanochromone 16
2JH,F¼52.7 Hz, JH,F¼2.9 Hz), 7.61 (ddd, 1H, H-6, J¼8.0, 7.3, 1.0 Hz),
7.62 (d, 1H, H-8, J¼8.5 Hz), 7.88 (ddd, 1H, H-7, J¼8.5, 7.2, 1.7 Hz),
8.28 (dd, 1H, H-5, J¼8.0, 1.7 Hz); 19F NMR (376 MHz, CDCl3, HFB)
(0.5 mmol) was added to concentrated H2SO4 (0.5 mL) and the
mixture was left for 3 h at 90 ꢁC. After cooling, the reaction mixture
was diluted with water (5 mL) and the resulting crystalline product
was filtered, washed with water, and dried to give 18 as a colorless
powder.
3
2
3
d
27.32 (dt, CF2H, JF,H¼52.7 Hz, JF,F¼4.6 Hz), 43.78 (td, CF2,
3
3JF,F¼4.6 Hz, JF,H¼3.0 Hz). Anal. Calcd for C12H5F4NO2: C, 53.15; H,
1.86; N, 5.17. Found: C, 53.16; H, 1.87; N, 5.21.
4.6.1. 4-Oxo-2-(trifluoromethyl)-4H-chromene-3-
carboxamide (18a)
4.5.4. 6-Methyl-4-oxo-2-(1,1,2,2-tetrafluoroethyl)-4H-chromene-3-
carbonitrile (16d)
Yield 80% from 9a and 74% from 16a, mp>250 ꢁC (decomp.); IR
Yield 71%, mp 187–188 ꢁC; IR (KBr) 2243, 1665, 1627, 1484 cmꢀ1
;
(KBr) 3410, 3296, 1692, 1661, 1646, 1611, 1580, 1467 cmꢀ1; 1H NMR
1H NMR (400 MHz, DMSO-d6)
d
2.48 (s, 3H, Me), 7.07 (tt, 1H,
(400 MHz, DMSO-d6)
d
7.62 (ddd, 1H, H-6, J¼8.0, 7.2, 1.0 Hz), 7.80 (d,
2
3
CF2CF2H, JH,F¼51.3 Hz, JH,F¼4.5 Hz), 7.73 (d, 1H, H-8, J¼8.6 Hz),
7.82 (ddq, 1H, H-7, J¼8.6, 2.2 Hz, 4JH,Me¼0.5 Hz), 7.94 (br d, 1H, H-5,
J¼1.5 Hz). Anal. Calcd for C13H7F4NO2: C, 54.75; H, 2.47; N, 4.91.
Found: C, 54.44; H, 2.29; N, 4.77.
1H, H-8, J¼8.5 Hz), 7.85 (br s, 1H, NH), 7.92 (br s, 1H, NH), 7.95 (ddd,
1H, H-7, J¼8.5, 7.2, 1.7 Hz), 8.12 (dd, 1H, H-5, J¼8.0, 1.6 Hz); 19F NMR
(376 MHz, DMSO-d6, HFB)
d
95.61 (s, CF3); 13C NMR (100 MHz,
DMSO-d6)
d
118.6, 118.8 (q, CF3, 1JC,F¼275.8 Hz), 122.7, 122.8 (q, C-3,
3JC,F¼1.7 Hz), 125.4, 126.9, 136.0, 146.2 (q, C-2, 2JC,F¼38.0 Hz), 154.5,
161.7, 174.4; MS (EI): m/z (%) 257 [M]þ (88), 241 [MꢀNH2]þ (100),
214 [Mþ1ꢀCONH2]þ (85), 166 (27), 121 [HOC6H4CO]þ (41), 120
[OC6H4CO]þ (34), 104 [C6H4CO]þ (56), 92 [C6H4O]þ (69), 69 [CF3]þ
(24), 64 [C5H4]þ (30), 63 (46), 50 (36), 44 [CONH2]þ (69). Anal. Calcd
for C11H6F3NO3: C, 51.37; H, 2.35; N, 5.45. Found: C, 51.28; H, 2.34;
N, 5.25.
4.5.5. 5,7-Dimethyl-4-oxo-2-(1,1,2,2-tetrafluoroethyl)-4H-
chromene-3-carbonitrile (16e)
Yield 73%, mp 167–168 ꢁC; IR (KBr) 2238, 1662, 1639, 1615, 1562,
1481 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 2.47 (s, 3H, Me-7), 2.81 (s,
3H, Me-5), 6.19 (tt, 1H, CF2CF2H, 2JH,F¼52.8 Hz, 3JH,F¼3.0 Hz), 7.14 (s,
1H, H-6), 7.22 (s, 1H, H-8). Anal. Calcd for C14H9F4NO2: C, 56.20; H,
3.03; N, 4.68. Found: C, 56.21; H, 2.98; N, 4.79.
4.6.2. 6-Methyl-4-oxo-2-(trifluoromethyl)-4H-chromene-3-
carboxamide (18b)
4.5.6. 4-Oxo-2-(difluoromethyl)-4H-chromene-3-carbonitrile (16i)
A solution of isoxazole 10i (100 mg, 0.42 mmol) in DMSO
(2.0 mL) was refluxed for 5 min. After cooling, the resulting mixture
was diluted with water (10 mL). The precipitate formed was fil-
tered, dried, and recrystallized from a toluene–hexane (1:4) mix-
ture to give 16i as colorless crystals. Yield 57%, mp 129–131 ꢁC; IR
Yield 75% from 9b, mp 245–247 ꢁC (decomp.); IR (KBr) 3387,
3285, 3189, 1693, 1656, 1618, 1599, 1484 cmꢀ1; 1H NMR (400 MHz,
DMSO-d6)
d
2.46 (s, 3H, Me), 7.70 (d, 1H, H-8, J¼8.6 Hz), 7.77 (br d,
1H, H-7, J¼8.6 Hz), 7.83 (br s, 1H, NH), 7.90 (br s, 1H, H-5), 7.93 (br s,
1H, NH). Anal. Calcd for C12H8F3NO3$0.25H2O: C, 52.28; H, 3.11; N,
5.08. Found: C, 52.38; H, 2.96; N, 4.87.
(KBr) 2237, 1663, 1630, 1608, 1577, 1465 cmꢀ1
;
1H NMR (400 MHz,
2
DMSO-d6)
d
7.31 (t, 1H, CF2H, JH,F¼51.4 Hz), 7.67 (ddd, 1H, H-6,
J¼8.0, 7.2, 1.0 Hz), 7.86 (dd, 1H, H-8, J¼8.6, 1.0 Hz), 7.99 (ddd, 1H, H-
4.6.3. 4-Oxo-2-(1,1,2,2-tetrafluoroethyl)-4H-chromene-3-
7, J¼8.6, 7.2, 1.7 Hz), 8.13 (dd, 1H, H-5, J¼8.0, 1.7 Hz); 19F NMR
carboxamide (18c)
2
(376 MHz, DMSO-d6, HFB)
d
39.74 (d, CF2H, JF,H¼51.4 Hz). Anal.
Yield 75% from 16c, mp 180–181 ꢁC; IR (KBr)
n 3391, 3305, 3190,
Calcd for C11H5F2NO2: C, 59.74; H, 2.28; N, 6.33. Found: C, 59.47; H,
2.34; N, 6.20.
1694, 1658, 1614, 1574, 1467 cmꢀ1 1H NMR (400 MHz, DMSO-d6)
;
d
6.97 (tt, 1H, CF2CF2H, 2JH,F¼51.7 Hz, 3JH,F¼5.5 Hz), 7.61 (ddd, 1H, H-
6, J¼8.0, 7.2, 1.0 Hz), 7.74 (d, 1H, H-8, J¼8.5 Hz), 7.81 (br s, 1H, NH),
7.88 (br s, 1H, NH), 7.94 (ddd, 1H, H-7, J¼8.5, 7.2, 1.7 Hz), 8.12 (dd,
1H, H-5, J¼8.0, 1.6 Hz). Anal. Calcd for C12H7F4NO3: C, 49.84; H,
2.44; N, 4.84. Found: C, 49.47; H, 2.57; N, 4.87.
4.5.7. 2-Amino-4H-chromen-4-one (17a)
This compound was prepared according to the procedure de-
scribed previously.19b 3-Cyanochromone 16a (100 mg, 0.42 mmol)
was added to a mixture of morpholine (0.1 mL), DMF (0.14 mL), and
water (0.5 mL) over a period of 5 min at 60 ꢁC, and the mixture was
stirred for 2 h at the same temperature. After the reaction mixture
had been cooled with ice, the separated crystals were collected by
filtration, washed with water, and dried to give 17a as a yellow
powder. Yield 60%, mp 270–272 ꢁC (decomp.) (lit.27 mp 268–270 ꢁC
(decomp.), lit.28a mp 275 ꢁC (decomp.), lit.28b mp 274 ꢁC); 1H NMR
4.6.4. 5,7-Dimethyl-4-oxo-2-(1,1,2,2-tetrafluoroethyl)-4H-
chromene-3-carboxamide (18e)
Yield 68% from 16e, mp 200–203 ꢁC (decomp.); IR (KBr) 3395,
3287, 3199, 1695, 1664, 1647, 1619, 1568, 1484 cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6)
d 2.42 (s, 3H, 7-Me), 2.71 (s, 3H, 5-Me), 6.93
2
3
(tt, 1H, CF2CF2H, JH,F¼51.7 Hz, JH,F¼5.4 Hz), 7.19 (s, 1H, H-6), 7.35
(400 MHz, DMSO-d6)
d
5.18 (s, 1H, H-3), 7.35 (t, 1H, H-6, J¼7.6 Hz),
(s, 1H, H-8), 7.74 (br s, 1H, NH), 7.84 (br s, 1H, NH). Anal. Calcd for
7.37 (d, 1H, H-8, J¼8.3 Hz), 7.51 (br s, 2H, NH2), 7.60 (ddd, 1H, H-7,
J¼8.5, 7.3, 1.7 Hz), 7.90 (dd, 1H, H-5, J¼7.8, 1.7 Hz).
C14H11F4NO3: C, 53.00; H, 3.49; N, 4.42. Found: C, 52.80; H, 3.41;
N, 4.25.

7888
V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 7877–7889
4.6.5. 6-Chloro-4-oxo-2-(trifluoromethyl)-4H-chromene-3-
carboxamide (18f)
resulting mixture was refluxed for 2.5 h and, after cooling, diluted
with water (10 mL). The precipitate formed was isolated by filtra-
tion, washed with water, dried, and recrystallized from toluene–
hexane (3:1) to afford 22 as colorless crystals. Yield 56 mg (47%),
mp 163–164 ꢁC; IR (KBr) 3340, 1672, 1624, 1600, 1580, 1514,
Yield 77% from 9f, mp 265–267 ꢁC (decomp.); IR (KBr) 3370,
3277, 3196, 1692, 1660, 1608, 1599, 1470 cmꢀ1; 1H NMR (400 MHz,
DMSO-d6)
d
7.88 (br s, 1H, NH), 7.89 (d, 1H, H-8, J¼9.0 Hz), 7.92 (br s,
1H, NH), 8.00 (dd,1H, H-7, J¼9.0, 2.6 Hz), 8.06 (d,1H, H-5, J¼2.6 Hz).
Anal. Calcd for C11H5ClF3NO3: C, 45.31; H, 1.73; N, 4.80. Found: C,
45.66; H, 1.54; N, 4.67.
1473 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 2.32 (s, 3H, Me), 5.12 (br s,
2H, NH2), 5.20–6.80 (br s, 2H, 2OH), 6.94 (d, 1H, H-30, J¼8.4 Hz), 7.19
(br d, 1H, H-60, J¼2.0 Hz), 7.24 (ddq, 1H, H-40, J¼8.4, 2.3, 0.6 Hz); 1H
NMR (400 MHz, DMSO-d6) d 2.22 (s, 3H, Me), 5.89 (s, 2H, NH2), 6.90
4.6.6. Salicyloylacetonitrile (19a)
(d, 1H, H-30, J¼8.4 Hz), 7.20 (ddq, 1H, H-40, J¼8.4, 2.3, 0.6 Hz), 7.31
This compound was prepared according to the procedure de-
scribed previously.3d 3-Cyanochromone 16a (150 mg, 0.63 mmol)
was added to a solution of NaOH (0.13 mg, 0.32 mmol) in water
(0.6 mL) and the mixture was stirred for 2 h at 70 ꢁC. After the re-
action mixture had been cooled with ice, the separated crystals
were collected by filtration, washed with water, and dried to give
19a as yellow crystals. Yield 79%, mp 108–110 ꢁC (lit.27 mp 108–
(br d, 1H, H-60, J¼2.0 Hz), 9.72 (s, 1H, OH), 10.20 (s, 1H, NOH); 13C
NMR (100 MHz, DMSO-d6)
d 19.9, 109.7, 112.5, 116.5, 119.6 (q, CF3,
1JC,F¼271.8 Hz), 127.6, 130.4, 133.4, 142.1, 153.2 (q, C–CF3,
2JC,F¼36.2 Hz), 153.7, 170.0; MS (EI): m/z (%) 301 [M]þ (21), 284
[MꢀNH3]þ (67), 269 (100), 135 (54), 107 (21), 91 (19), 77 (55), 69
[CF3]þ (16), 51 (21). Anal. Calcd for C12H10F3N3O3: C, 47.85; H, 3.35;
N, 13.95. Found: C, 48.19; H, 3.41; N, 13.85.
110 ꢁC); 1H NMR (400 MHz, CDCl3)
d 4.14 (s, 2H, CH2), 6.97 (t, 1H, H-
5, J¼7.7 Hz), 7.06 (d, 1H, H-3, J¼8.2 Hz), 7.57 (d, 1H, H-6, J¼7.8 Hz),
4.6.11. 2-Methyl-4-(trifluoromethyl)-5H-chromeno[4,3-d]-
pyrimidin-5-one (23a) and 2-methyl-4-(trifluoromethyl)-5H-
chromeno[4,3-d]pyrimidin-5-imine (23b)
7.58 (t, 1H, H-4, J¼7.5 Hz), 11.41 (s, 1H, OH).
4.6.7. (2-Hydroxy-5-methylbenzoyl)acetonitrile (19b)
A mixture of acetamidine hydrochloride (60 mg, 0.63 mmol)
and AcONa (50 mg, 0.63 mmol) in DMF (2 mL) was stirred at 100–
110 ꢁC for 5 min. After cooling, 3-cyanochromone 16a (100 mg,
0.42 mmol) was added. The resulting mixture was refluxed for
15 min and diluted with water (6 mL). The precipitate formed was
isolated by filtration, washed with water, dried, and recrystallized
from methanol to afford a mixture of 23a and 23b as yellow crys-
tals. Combined yield 27%, mp 160–163 ꢁC; 1H NMR (400 MHz,
A solution of chromone 16b (100 mg, 0.4 mmol) in DMSO (2 mL)
and water (1 mL) was allowed to stand for 4 days at room tem-
perature and then diluted with water (6 mL). The solid obtained
was filtered and dried to give 19b as colorless crystals. Yield 65 mg
(94%), mp 134–136 ꢁC (lit.21 mp 136–140 ꢁC); 1H NMR (400 MHz,
DMSO-d6)
d 2.24 (s, 3H, Me), 4.62 (s, 2H, CH2), 6.90 (d, 1H, H-3,
J¼8.4 Hz), 7.34 (dd, 1H, H-4, J¼8.4, 2.2 Hz), 7.54 (d, 1H, H-6,
J¼2.0 Hz), 10.91 (s, 1H, OH).
CDCl3) 23a (73%)
7.29 (ddd, 1H, H-9, J¼8.0, 7.3, 1.1 Hz), 7.59 (ddd, 1H, H-8, J¼8.4, 7.3,
2.95 (s, 3H,
d
2.91 (s, 3H, Me), 7.16 (dd, 1H, H-7, J¼8.3, 0.9 Hz),
4.6.8. 5-(20-Hydroxyphenyl)-3-(1,1,2,2-tetrafluoroethyl)-1H-
pyrazole-4-carbonitrile (20)
1.7 Hz), 8.50 (dd, 1H, H-10, J¼8.0, 1.6 Hz); 23b (27%)
d
Me), 7.07 (ddd, 1H, H-9, J¼8.2, 7.3, 1.2 Hz), 7.12 (dd, 1H, H-7, J¼8.3,
1.2 Hz), 7.54 (ddd, 1H, H-8, J¼8.4, 7.2, 1.6 Hz), 8.38 (dd, 1H, H-10,
J¼8.2, 1.6 Hz), 11.81 (br s, 1H, NH). Treatment of this mixture with
aqueous AcOH at 85 ꢁC for 3 h gave analytically pure coumarin 23a
as yellow needles, mp 182–183 ꢁC; 1H NMR (400 MHz, DMSO-d6)
A mixture of N2H4$2HCl (80 mg, 0.76 mmol) and KOH (60 mg,
1.1 mmol) in methanol (3 mL) was heated to reflux for 5 min and
then 3-cyanochromone 16c (100 mg, 0.37 mmol) was added. The
resulting mixture was refluxed for 2 h and, after cooling, diluted
with water (5 mL). The precipitate formed was isolated by filtration,
washed with water, and drꢁied to give 20 as a colorless powder. Yield
32 mg (31%), mp 203–204 C; IR (KBr) 3412, 3304, 2242, 2228,1615,
d
2.92 (s, 3H, Me), 7.52 (ddd, 1H, H-9, J¼8.0, 7.3, 1.1 Hz), 7.53 (dd, 1H,
H-7, J¼8.4, 1.1 Hz), 7.84 (ddd, 1H, H-8, J¼8.4, 7.3, 1.7 Hz), 8.55 (dd,
1H, H-10, J¼8.0, 1.7 Hz). Anal. Calcd for C13H7F3N2O2: C, 55.72; H,
2.52; N, 10.00. Found: C, 55.85; H, 2.44; N, 10.12.
1598, 1548, 1491, 1473 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6)
d
6.95
2
3
(tt, 1H, CF2CF2H, JH,F¼51.9 Hz, JH,F¼4.5 Hz), 7.00 (td, 1H, H-50,
J¼7.5, 1.0 Hz), 7.06 (dd, 1H, H-30, J¼8.3, 1.0 Hz), 7.41 (ddd, 1H, H-40,
J¼8.3, 7.4, 1.7 Hz), 7.54 (dd, 1H, H-60, J¼7.7, 1.7 Hz), 10.62 (br s, 1H,
OH), 14.47 (br s, 1H, NH). Anal. Calcd for C12H7F4N3O: C, 50.54; H,
2.47; N, 14.73. Found: C, 50.46; H, 2.23; N, 14.51.
Acknowledgements
This work was financially supported by the RFBR (Grant 06-03-
32388) and CRDF (Grant BP2M05).
4.6.9. 5-(20-Hydroxyphenyl)-1-phenyl-3-(1,1,2,2-tetrafluoroethyl)-
1H-pyrazole-4-carbonitrile (21)
References and notes
A mixture of 3-cyanochromone 16c (100 mg, 0.37 mmol) and
phenylhydrazine (54 mg, 0.5 mmol) in methanol (3 mL) was heated
to reflux for 3 h. After cooling, the resulting solution was diluted
with water (5 mL) containing some drops of AcOH, the precipitate
was filtered, washed with water, and dried to give 21 as a pale
yellow powder. Yield 130 mg (98%), mp 192–193 ꢁC; IR (KBr) 3336,
1. (a) Ghosh, C. K. J. Heterocycl. Chem. 1983, 20, 1437–1445; (b) Sabitha, G. Al-
drichimica Acta 1996, 29, 15–25; (c) Ghosh, C. K. Heterocycles 2004, 63, 2875–
ˇ
´
´
´
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