Reactions of 3-(polyfluoroacyl)chromones with hydroxylamine. The first synthesis of 3-cyano-2-(polyfluoroalkyl)chromones

Article abstract of DOI:10.1016/j.tetlet.2006.09.136

Reaction of 3-(polyfluoroacyl)chromones with hydroxylamine 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. Reaction of 3-(polyfluoroacyl)chromones with hydroxylamine hydrochloride occurs only at the carbonyl carbon atom connected to the R^F group to give the corresponding oximes in low yields.

Full text of DOI:10.1016/j.tetlet.2006.09.136

Tetrahedron Letters 47 (2006) 8543–8546
Reactions of 3-(polyfluoroacyl)chromones with hydroxylamine.
The first synthesis of 3-cyano-2-(polyfluoroalkyl)chromones
Vyacheslav Ya. Sosnovskikh,* Vladimir S. Moshkin and Roman A. Irgashev
Department of Chemistry, Ural State University, prosp. Lenina 51, 620083 Ekaterinburg, Russia
Received 16 August 2006; revised 12 September 2006; accepted 22 September 2006
Available online 10 October 2006
Abstract—Reaction of 3-(polyfluoroacyl)chromones with hydroxylamine 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-(poly-
fluoroalkyl)chromones. Reaction of 3-(polyfluoroacyl)chromones with hydroxylamine hydrochloride occurs only at the carbonyl
carbon atom connected to the RF group to give the corresponding oximes in low yields.
Ó 2006 Elsevier Ltd. All rights reserved.
The electron-withdrawing acyl group in 2-unsubstituted
3-acylchromones enhances the electrophilicity of the
C(2) atom of the pyrone ring, which is usually attacked
by nucleophilic reagents. This reactivity has been
exploited in both Michael and Diels–Alder reactions of
these useful synthetic intermediates.1 The majority of
the reactions with 3-acylchromones are nucleophilic
additions with concomitant opening of the pyrone ring
leading to various types of heterocyclic products. How-
ever, in contrast to well studied 3-formyl-2 and 3-acyl-
chromones,3 no data on the chemical properties of 3-
(polyfluoroacyl)chromones 1 have been documented.
This is quite surprising, especially as these compounds
should contain three strong electrophilic centers, that
is the C(2) and C(4) atoms of the chromone system
and the carbonyl carbon of 3-polyfluoroacyl group.
and synthetic utility of these chromone derivatives. In
connection with this, we have recently developed an effi-
cient method for the preparation of 3-RFCO-chromones
1 from readily available, inexpensive starting materials
and established their feasibility as novel RF-containing
building blocks for the synthesis of a wide variety of het-
erocycles.6,7 It was found that the reactions of chro-
mones 1 with primary amines and indoles proceeded
via nucleophilic 1,4-addition with subsequent opening
of the pyrone ring and cyclization into 3-(alkyl/arylam-
inomethylene)-6 and 3-(indol-3-ylmethylene)-2-hydroxy-
2-(polyfluoroalkyl)chroman-4-ones7 in good yields. One
would expect that the reaction of chromones 1 with 1,2-
dinucleophilic reagents, such as hydroxylamine, would
lead to the possibility of competition between different
initial nucleophilic attacks and then towards different
cyclization patterns.
In view of the unique biological properties displayed by
many fluorinated heterocyclic compounds4 and as an
extension of our continuing synthetic studies on the
reactivity of RF-containing chromones,5 we have fo-
cussed our attention on the 3-RFCO-chromones 1 as a
new class of polydentate electrophilic substrates. We
reasoned that replacing the hydrogens of the 3-acyl
group with fluorine atoms, which are strongly electro-
negative, would have a positive effect on the reactivity
The reactions of 3-formylchromone 2a,8 3-benzoylchro-
mone 2b,9 and 3-acetylchromone 2c10 with hydroxyl-
amine have been shown to give chromone derivatives
3a,b and 4a–c and regioisomeric isoxazoles 5a–c and
6a,b, depending on the reaction conditions (Fig. 1).
These products can result from the initial nucleophilic
1,2- or 1,4-additions of hydroxylamine to 2a and 1,4-
addition to 2b,c. In the latter case, no 1,2-addition of
hydroxylamine to the PhC@O and MeC@O double
bonds was observed.
Keywords: 3-(Polyfluoroacyl)chromones; Hydroxylamine; 4H-Chro-
meno[3,4-d]isoxazol-4-ols;
Oximes.
3-Cyano-2-(polyfluoroalkyl)chromones;
In this context, we decided to study the interaction of 3-
(polyfluoroacyl)chromones 1 with hydroxylamine with
the emphasis on the synthesis of the hitherto unknown
*
Corresponding author. Tel.: +7 343 261 68 24; fax: +7 343 261 59
78; e-mail addresses: Vyacheslav.Sosnovskikh@usu.ru; svy@etel.ru
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.136

8544
V. Ya. Sosnovskikh et al. / Tetrahedron Letters 47 (2006) 8543–8546
O
O
O
O
HO
O
O
O
N
N
RF
R
NH2OH
HCl
R
R
R
R
R
R
RF
RF
O
O
-H2O
O
1a-d
O
2a-c
1
9b,c
NH2OH
O
O
NOH
R
HO
O
CN
R
O
O
RF
O
OH
RF
O
OH
N
OH
O
3a,b
4a-c
A
B
-H2O
N
O
O
R
N
O
O
O
O
CN
RF
COR
CF3CO2H
-H2O
N
OH
OH
OH
RF
O
5a-c
6a,b
10a-d
7a-d
R = H (a), Ph (b), Me (c)
-H+
H+
-H2O
Figure 1.
N
N
O
O
R
R
H
3-cyano-2-(polyfluoroalkyl)chromones. We found that
3-RFCO-chromones 1a–d smoothly reacted with
hydroxylamine to afford chromeno[3,4-d]isoxazoles
7a–d in good yields (Table 1).11 All the reactions were
carried out in methanol at room temperature using
hydroxylamine obtained in situ from the corresponding
hydrochloride after reaction with potassium hydroxide.
Furthermore, the same products were obtained in lower
yields when chromones 1 were treated with a combina-
tion of NH2OHÆHCl and AcONa.
O
RF
O
RF
C
Scheme 1.
RF
O
NOH
OH
R
O
OH
O
N
O
(CF2)2H
11
8
A plausible reaction pathway involves an initial attack
of hydroxylamine at the electrophilic C(2) atom fol-
lowed by ring opening to intermediate A, which then
leads to B by cyclization between the phenolic hydroxyl
and the RFCO group. Intermediate B then undergoes
cyclodehydration to give chromeno[3,4-d]isoxazoles 7
(Scheme 1). The alternative cyclization of A involving
the oxime hydroxyl and the carbonyl carbon connected
to the RF group to give isoxazolines 8 does not occur
(Fig. 2). In this case, the RF group hinders the dehydra-
tion and, therefore, the formation of the aromatic isox-
azole ring is prevented.
Figure 2.
et al.,10 in which they found that the addition of hydr-
oxylamine to 3-benzoylchromone and 3-acetylchromone
occurred exclusively at the 2-position (Fig. 1, com-
pounds 3b–6b, 4c, 5c).
The structure of oxime 9c was established by consider-
ation of the JH,F value of 5.3 Hz for the terminal pro-
3
ton 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,F = 5.4 Hz in the case of oxi-
3
When the same reaction was carried out with chromones
1b,c and hydroxylamine hydrochloride in the presence
of a catalytic amount of concentrated HCl in 95% etha-
nol,8a,e the only products obtained were the corre-
sponding oximes 9b,c (yields 19–24%),12 formed
undoubtedly by nucleophilic 1,2-addition of hydroxyl-
amine to the RFCO group. This result is in marked con-
trast to those obtained by Eiden et al.9 and Ghosh
mes13 and JH,F = 3.0–3.8 Hz in the case of 2-(1,1,2,2-
tetrafluoroethyl)chromones14). This allowed us to reject
the alternative structure 11 (Fig. 2), which can result
from intermediate B. The E-configuration of the C@N
bond was suggested from the 19F NMR chemical shift
of the CF3 group in oxime 9b (93.4 ppm, C6F6). Accord-
ing to published data,15 the signal for this group in the
spectra of Z-isomers of trifluoromethylated oximes
Table 1. Isolated yields for compounds 7a–d and 10a–d
Chromone
R
RF
Isoxazole
Yield (%)
Mp (°C)
Nitrile
Yield (%)
Mp (°C)
1a
1b
1c
1d
H
Me
H
CF3
CF3
(CF2)2H
(CF2)2H
7a
7b
7c
7d
72
65
70
57
144–145
143–144
105–106
117–118
10a
10b
10c
10d
83
72
85
71
118–119
149–150
138–139
186–187
Me

V. Ya. Sosnovskikh et al. / Tetrahedron Letters 47 (2006) 8543–8546
8545
R1
O
O
O
3:1 mixture of 7f and 10f, which was converted to carbo-
nitrile 10f by simple crystallization from toluene (7f was
converted to 10f during crystallization). Thus, it appears
that electronic effects play an important role in the ring
opening of isoxazoles 7 (Scheme 2). This observation is
consistent with our assumption that the reaction pro-
ceeds via the intermediate benzopyrylium cation C. An
investigation of the scope and limitations of the trans-
formation 7 ! 10 is now in progress.
N
O
R2
R1
Cl
RF
NH2OH
OH
O
CF3
1e,f
7e
NH2OH
CF3CO2H
X
R1
O
N
Me
O
R2
R1
CN
RF
OH
(CF2)2H
-H2O
Me
O
O
In conclusion, we have shown that the reaction of
3-(polyfluoroacyl)chromones with hydroxylamine is a
simple and practical method for introduction of a
CN group at the 3-position of 2-(polyfluoroalkyl)-
chromones. The resulting 3-cyano-2-(polyfluoroalkyl)-
chromones are of considerable interest as reactive
precursors in the synthesis of other useful organic mate-
rials containing polyfluoroalkyl groups.
7f
10e,f
R1 = H, R2 = Cl, RF = CF3 (e);
1 = Me, R2 = H, RF = (CF2)2H (f)
R
Scheme 2.
and hydrazones appeared at 97–99 ppm, whereas for the
E-isomers it appeared at 92–96 ppm.
Next, we examined the possibility of preparing 3-cyano-
2-(polyfluoroalkyl)chromones from compounds 7. 3-
Cyanochromones are important intermediates in the
synthesis of biologically interesting compounds.16 On
the other hand, due to the powerful electron-withdraw-
ing ability of RF groups, the insertion of polyfluoroalkyl
substituents into the 2-position of chromones activates
these molecules and 2-RF-chromones are highly reactive
substrates in reactions with N-, S-, and C-nucleophiles.5
To the best of our knowledge, there have been no
reports on the preparation of 2-polyfluoroalkyl substi-
tuted 3-cyanochromones, despite the possible enhance-
ment of their reactivity due to the presence of the RF
group, however, 3-cyano-2-methylchromones are
known.10,17
Acknowledgments
This work was financially supported by the Russian
Foundation for Basic Research (Grant 06-03-32388).
References and notes
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Attempts to obtain 3-cyano-2-(polyfluoroalkyl)chro-
mones 10 from chromeno[3,4-d]isoxazoles 7 in the pres-
ence of KOH in ethanol, conditions that had previously
been used for the preparation of carbonitrile 4b from 3b,
5b, and 6b,9 proved fruitless. However, it was found that
the required compounds 10 could be easily prepared by
refluxing isoxazoles 7 in trifluoroacetic acid for 15 min
(only starting material 7b was recovered from a similar
reaction in acetic acid). Thus, isoxazoles 7a–d are easily
ring opened to give 3-cyano-2-(polyfluoroalkyl)chro-
mones 10a–d in high yields (Table 1).18 This result prob-
ably represents a specific property of fused isoxazoles 7
because only base-induced ring-opening reactions have
been reported for non-fluorinated analogues 5 and
6.8a,e,9 The most likely, intermediate in the trifluoroace-
tic acid ring opening of 7 is the aromatic benzopyrylium
cation C, which undergoes deprotonation to give 10
(Scheme 1).
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Borrell, J. I.; Teixido, J.; Schuler, E.; Michelotti, E.
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polskii, L. M., Eds.; Elsevier: Amsterdam, 1993; (b)
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Organofluorine Compounds. Chemistry and Application;
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Surprisingly, isoxazole 7e failed to provide the corre-
sponding carbonitrile 10e under the same reaction con-
ditions. Besides the starting material, a small amount
(ꢀ20%) of 5-(5-chloro-2-hydroxyphenyl)isoxazole was
detected by 1H NMR spectroscopy. This product is
the result of the detrifluoroacetylation of 7e. On the
other hand, chromone 1f bearing two electron-donating
methyl groups reacted with hydroxylamine to afford a
5. Sosnovskikh, V. Ya. Uspekhi Khim. 2003, 72, 550–578
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Barabanov, M. A. Synthesis 2006, 2707–2718; (c)

8546
V. Ya. Sosnovskikh et al. / Tetrahedron Letters 47 (2006) 8543–8546
Sosnovskikh, V. Ya.; Irgashev, R. A. Heteroat. Chem.
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crystals; IR (KBr) 3225, 1649, 1622, 1602, 1570,
1465 cmꢁ1 1H NMR (400 MHz, CDCl3) d 6.30 (tt, 1H,
;
2
3
7. Sosnovskikh, V. Ya.; Irgashev, R. A. Izv. Akad. Nauk,
Ser. Khim., in press (Russ. Chem. Bull., Int. Ed. 2006, 55).
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von Strandtmann, M. J. Heterocycl. Chem. 1974, 11, 183–
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Zehnder, L. R.; Park, F.; Kim, M.; Tran, T.-T. T. J. Org.
Chem. 1999, 64, 8736–8740; (f) Reddy, G. J.; Latha, D.;
Thirupathaiah, C.; Rao, K. S. Tetrahedron Lett. 2004, 45,
CF2CF2H, JH,F = 52.8 Hz, JH,F = 5.3 Hz), 7.48 (ddd,
o
1H, H-6, J = 7.9, 7.3 Hz, mJ = 0.9 Hz), 7.53 (d, 1H, H-8,
oJ = 8.3 Hz), 7.75 (ddd, 1H, H-7, oJ = 8.6, 7.2 Hz,
mJ = 1.7 Hz), 8.01 (s, 1H, H-2), 8.26 (dd, 1H, H-5,
oJ = 8.0 Hz, mJ = 1.6 Hz), 8.78 (s, 1H, OH). Anal. Calcd
for C12H7F4NO3: C, 49.84; H, 2.44; N, 4.84. Found: C,
49.73; H, 2.46; N, 4.74.
13. Sosnovskikh, V. Ya.; Usachev, B. I.; Sizov, A. Yu. Izv.
Akad. Nauk, Ser. Khim. 2003, 932–936 (Russ. Chem. Bull.,
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1166–1170 (Russ. Chem. Bull., Int. Ed. 2001, 50, 1223–
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51, 1270–1279).
11. Preparation of 7. To
prepared from NH2OHÆHCl (1.0 mmol) and KOH
(0.9 mmol) in MeOH (3 mL), 3-RFCO-chromone
a solution of hydroxylamine,
1
(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 mL) containing AcOH (1.5 mmol). After
cooling, the precipitate that formed was filtered off,
washed with water, dried and recrystallized from tolu-
ene–hexane (1:7) to give 7 as colorless crystals.
16. (a) Nohara, A.; Kuriki, H.; Saijo, T.; Sugihara, H.;
Kanno, M.; Sanno, Y. J. Med. Chem. 1977, 20, 141–145;
(b) Nohara, A.; Ishiguro, T.; Ukawa, K.; Sugihara, H.;
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Tetrahedron Lett. 2003, 44, 1461–1464.
4-(Trifluoromethyl)-4H-chromeno[3,4-d]isoxazol-4-ol 7a.
IR (KBr) 3105, 1651, 1608, 1573, 1515, 1470, 1454 cmꢁ1
;
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, oJ = 8.5, 7.6 Hz,
mJ = 1.6 Hz), 7.77 (dd, 1H, H-9, oJ = 7.6 Hz, mJ = 1.6 Hz),
8.40 (s, 1H, H-3); 19F NMR (376 MHz, CDCl3, HFB) d
76.47 (d, CF3, J = 0.9 Hz); 13C NMR (100 MHz, CDCl3) d
95.58 (q, C–CF31, 2JC,F = 36.3 Hz), 104.17, 110.49, 117.24,
121.38 (q, CF3, JC,F = 285.7 Hz), 122.58, 123.29, 133.04,
146.61, 151.25, 163.26. Anal. Calcd for C11H6F3NO3: C,
51.38; H, 2.35; N, 5.45. Found: C, 51.09; H, 2.12; N, 5.46.
12. 1-(4-Oxo-4H-chromen-3-yl)-2,2,3,3-tetrafluoropropan-1-
one oxime 9c. Yield 24%, mp 186–187 °C, colorless
´
17. Basinski, W. Polish J. Chem. 1995, 69, 376–384.
18. 4-Oxo-2-(trifluoromethyl)-4H-chromene-3-carbonitrile 10a.
IR (KBr) 2245, 1667, 1637, 1610, 1580, 1468 cmꢁ1 1H
;
o
NMR (400 MHz, CDCl3) d 7.62 (ddd, 1H, H-6, J = 8.0,
o
7.3 Hz, mJ = 1.0 Hz), 7.64 (d, 1H, H-8, J = 8.6 Hz), 7.89
(ddd, 1H, H-7, oJ = 8.7, 7.2 Hz, mJ = 1.7 Hz), 8.28 (dd,
o
1H, H-5, J = 8.0 Hz, mJ = 1.5 Hz); 19F NMR (376 MHz,
CDCl3, HFB)
d 93.67 (s, CF3). Anal. Calcd for
C11H4F3NO2: C, 55.24; H, 1.69; N, 5.86. Found: C,
55.20; H, 1.46; N, 5.87.