Novel chemical modifications at the 4-position of chromones. Synthesis and reactivity of 4H-chromene-4-spiro-5′-isoxazolines and related compounds

Article abstract of DOI:10.1016/j.tetlet.2004.07.158

Reactions of chromones with dilithiooximes proceed via nucleophilic 1,2-addition to give, on acidification, 4H-chromene-4-spiro-5′-isoxazoline derivatives in high yields. On treatment with concentrated H₂SO ₄ the isoxazoline ring of this novel spiroannulated heterocyclic system opens to give α,β-unsaturated oximes, which undergo nitrosation, bromination, and the Beckmann rearrangement to the corresponding spiroisoxazolines and α,β-unsaturated amides, respectively. The latter can be obtained directly by the Beckmann rearrangement of 4H-chromene-4-spiro-5′-isoxazolines.

Full text of DOI:10.1016/j.tetlet.2004.07.158

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7351–7354
Novel chemical modifications at the 4-position of chromones.
Synthesis and reactivity of
4H-chromene-4-spiro-50-isoxazolines and related compounds
a
a
Vyacheslav Ya. Sosnovskikh,a, Boris I. Usachev, Aleksei Yu. Sizov and
*
Mikhail I. Kodessb
aDepartment of Chemistry, Ural State University, 620083 Ekaterinburg, Russian Federation
bInstitute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 620219 Ekaterinburg, Russian Federation
Received 14 June 2004; revised 22 July 2004; accepted 30 July 2004
Available online 19 August 2004
Abstract—Reactions of chromones with dilithiooximes proceed via nucleophilic 1,2-addition to give, on acidification, 4H-chromene-
4-spiro-50-isoxazoline derivatives in high yields. On treatment with concentrated H2SO4 the isoxazoline ring of this novel spiro-
annulated heterocyclic system opens to give a,b-unsaturated oximes, which undergo nitrosation, bromination, and the Beckmann
rearrangement to the corresponding spiroisoxazolines and a,b-unsaturated amides, respectively. The latter can be obtained directly
by the Beckmann rearrangement of 4H-chromene-4-spiro-50-isoxazolines.
Ó 2004 Elsevier Ltd. All rights reserved.
It is well known that chromones (4H-chromen-4-ones)
are widespread in the plant kingdom in a variety of
forms and are the parent compounds of important
flower and fruit pigments.1 Many natural and synthetic
chromone derivatives have unique biological and
pharmacological activities, including antiviral,2 anti-
allergic,3 and neuroleptic4 activity. Since their reactivity
towards nucleophiles provides a useful route to the
preparation of a variety of rearranged products and
new heterocyclic systems, their versatility as reactive inter-
mediates is well documented in the literature.1,5 Chro-
mones are usually readily ring-opened via nucleophilic
attack at the 2-position.1,5 We have recently shown,5a
however, that the presence of a 2-polyfluoroalkyl group
appreciably increases the reactivity of the pyrone ring
towards N-, S- and C-nucleophiles, and in certain
cases facilitates 1,4-nucleophilic ring addition rather
than ring fission. Thus, interaction of 2-trifluoro-
methylchromones with (trifluoromethyl)trimethylsilane
(RuppertÕs reagent) and lithium enolates derived from
acetophenones gave 2,2-bis(trifluoromethyl)chroman-4-
ones6 and 2-trifluoromethyl-2-phenacylchroman-4-ones,7
respectively. Here, we wish to report that, in contrast
to acetophenone enolates, condensation of 2-trifluoro-
methylchromones with dilithiooximes proceeds via
nucleophilic 1,2-addition and can be employed to obtain
4H-chromene-4-spiro-50-isoxazoline derivatives. These
compounds represent a novel spiroannulated hetero-
cyclic system with some unexpected chemical properties.
1,4-Dianions generated from ketoximes having an a-
hydrogen are useful intermediates in organic synthesis.
The condensation of oxime dianions with various electro-
philic substrates, such as carboxylic esters,8 amides,9
ketones and a,b-unsaturated ketones,10 provides regio-
controlled access to b-keto and b-hydroxy oximes,
which undergo cyclodehydration to form isoxazoles
and 2-isoxazolines. However, the action of dilithio-
oximes on chromones has, to our knowledge, hitherto
not been investigated.
We have found that reaction of acetophenone E-oxime11
with 2.2equiv of lithium diisopropylamide in ether at
0°C followed by the addition of 2-trifluoromethylchro-
mones (À20°C!rt, 2h) and careful treatment of the
resulting mixture with water leads to the formation of
b-hydroxy oximes 1a,b in good yields. Note that oximes
1a,b cyclize to spiroisoxazolines 2a,b so readily that
Keywords: Chromones; Dilithiooximes; 4H-Chromene-4-spiro-50-isox-
azolines; a,b-Unsaturated oximes; Beckmann rearrangement; Nitro-
sation; Bromination.
*
Corresponding author. Fax: +7 343 261 59 78; e-mail: vyacheslav.
sosnovskikh@usu.ru
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.158

7352
V. Ya. Sosnovskikh et al. / Tetrahedron Letters 45 (2004) 7351–7354
R2
mixtures of 1 and 2 were obtained on attempted quench-
ing under mildly acidic conditions. Cyclization could be
completed by simple addition of aqueous hydrochloric
acid to the strongly basic mixture after the condensation
step. In the case of aliphatic oximes, the intermediate b-
hydroxy oximes 1c,d were, without isolation, subjected
to acidic hydrolysis to give spiroisoxazolines 2c,d in
64% and 22% yields, respectively. This reaction is a
novel C–C bond forming reaction at the 4-position of
the chromone system to give the 4H-chromene-4-spiro-
50-isoxazolines 212 (Scheme 1).
R2
N
OH
N
OH
R1
R1
O
CF3
O
CF3
A
Scheme 2.
retained9b,15 and is substantiated by the products of the
Beckmann rearrangement, which proceeds by intramole-
cular migration of the group anti to the departing OH
group.16 Indeed, phosphorus pentachloride, in diethyl
ether at room temperature, rearranged oximes 1a,b
and 3a–c in high yield to amides 4a–c, and hence com-
pounds 1 and 3 presumably exist with the R2 group anti
to the N–O bond. This reaction is not limited to 1 and 3,
but occurs readily with spiroisoxazolines 2a–d, which
may be regarded as latent oxime forms. To the best of
our knowledge, this is the first example of the Beckmann
rearrangement with participation of an isoxazoline ring
and without isolation of the corresponding a,b-unsatu-
rated oxime. Note that compound 2d did not convert
into 3d under the action of sulfuric acid, and hence the
Beckmann rearrangement occurs at the benzopyrylium
cation A stage. The stereochemistry and assignment of
the H-3 and @CH protons of amides 4 were determined
with the 2D NOESY and 2D HSQC spectra of 4c.17 The
On treatment of compounds 2a–c with concentrated
sulfuric acid for 20min at room temperature, followed
by aqueous work-up, the isoxazoline ring opens to give
a,b-enoximes 3a–c in 45–85% yields.13 This result is
rather unexpected and represents a specific property of
the chromene-4-spiro-50-isoxazoline system because
only base-induced ring-opening reactions have been re-
ported for 2-isoxazolines.14 Most likely, the initial inter-
mediate in the sulfuric acid ring-opening of 2 is the
aromatic benzopyrylium salt A, which then undergoes
deprotonation to give 3. Apparently, the conversion of
1a,b to 3a,b under the same reaction conditions also pro-
ceeds via the intermediate cation A and its deprotona-
tion to the enoxime moiety (Scheme 2).
The E-configuration of the exo C@C double bond has
been proved by the 2D NOESY spectrum of compound
3a, which displayed cross peaks between the resonances
of the @CH (d 6.79) and the aromatic H-5 (d 7.86) pro-
tons. The configuration with the hydroxyl anti to
the phenyl group was anticipated for oximes 1 and 3
on the basis that the geometry of the starting oxime is
1
characteristic feature of the H NMR spectra of amides
4 is the unusually downfield signal of the H-3 proton (d
8.42–8.49). Such strong deshielding of the H-3 atom,
which is usually manifested at 6–7ppm, is a result of
R2
N
R2
O
HO
HO
N
O
R1
Me
HO
R2
Pri2NLi
R1
R1
H3O+
+
N
O
CF3
O
CF3
O
CF3
2a-d
1a-d
H2SO4
PCl5
R2
N
NHR2
O
Ph
N
O
R1
NOH
CF3
R1
OH
R1
HNO2
PCl5
O
O
CF3
3a-c
O
CF3
5a,b
4a-d
Br2
Ph
N
O
R1 = H, R2 = Ph (a);
R1 = Me, R2 = Ph (b);
R1 = H, R2 = Me (c);
R1 = H, R2 = t-Bu (d)
R1
Br
O
CF3
6a,b
Scheme 1.

V. Ya. Sosnovskikh et al. / Tetrahedron Letters 45 (2004) 7351–7354
7353
the conformation in which the amide carbonyl is situ-
ated near H-3 and deshields this atom.
Acknowledgements
This work was financially supported by the Russian
Foundation for Basic Research (Grant 02-03-32706)
and by the U.S. Civilian Research and Development
Foundation and Russian Federation Ministry of Educa-
tion (Grants EK-005-X1 and Y1-005-04).
Further transformations are also possible for a,b-enoxi-
mes 3. Nitrosation of these compounds using NaNO2 in
dilute HCl afforded oximinoisoxazolines 5a,b in 78%
and 59% yields, respectively. Formation of 5 from 3
may occur via electrophilic attack at the a-position of
3 by the nitrosonium cation. The resulting cationic spe-
cies then undergoes nucleophilic attack by the hydroxyl
group to give the 4-nitrosoisoxazoline which exists in the
oxime form. Nitrosation of a,b-unsaturated oximes with
nitrous acid has been described previously, however, the
products were 3,5,5-trimethylpyrazolenine 1,2-dioxide
(from mesityl oxide oxime),18 3,4-diazacyclopentadi-
enone 3,4-dioxides (from b-alkyl or aryl a,b-unsaturated
oximes),19 and 1-hydroxypyrazole 2-oxides (from a-substi-
tuted a,b-unsaturated oximes),20 which arise from initial
attack at the oxime nitrogen atom by the nitrosonium
cation. Bromination of oximes 3a,b was accomplished
in CCl4 with bromine at room temperature. The reaction
was rapid and gave 4-bromoisoxazolines 6a,b as a mix-
ture of two diastereomers in 89–92% yields (92:8 for 6a
and 96:4for 6b). The relative ease with which electrophi-
lic attack towards the a-C atom of the exo-double bond
occurs may be due to the intermediate benzopyrylium
cation A and the neighboring-group participation of
the oxime hydroxyl group, which is syn to the C@C
bond.
References and notes
1. Ellis, G. P. Chromenes, Chromanones, and Chromones.
In The Chemistry of Heterocyclic Compounds; Wiley: New
York, 1977; Vol. 31.
2. De Meyer, N.; Haemers, A.; Mishra, L.; Pandey, H.-K.;
Pieters, L. A. C.; Van den Berghe, D. A.; Vlietinck, A. J.
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3. (a) Nohara, A.; Kuriki, H.; Saijo, T.; Ukawa, K.; Murata,
T.; Kanno, M.; Sanno, Y. J. Med. Chem. 1975, 18, 34–37;
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Kanno, M.; Sanno, Y. J. Med. Chem. 1977, 20, 141–145;
(c) Ellis, G. P.; Becket, G. J. P.; Shaw, D.; Wilson, N. K.;
Vardey, C. J.; Skidmore, I. F. J. Med. Chem. 1978, 21,
1120–1126.
4. Bolos, J.; Gubert, S.; Anglada, L.; Planas, J. M.; Burgar-
´
olas, C.; Castello, J. M.; Sacristan, A.; Ortiz, J. A. J. Med.
Chem. 1996, 39, 2962–2970.
5. (a) Sosnovskikh, V. Ya. Uspekhi Khimii 2003, 72, 550–578,
(Russ. Chem. Rev. 2003, 72, 489–516); (b) Ghosh, C. K. J.
Heterocycl. Chem. 1983, 20, 1437–1445; (c) Morin, C.;
Beugelmans, R. Tetrahedron 1977, 33, 3183–3192.
6. (a) Sosnovskikh, V. Ya.; Sevenard, D. V.; Usachev, B. I.;
Ro¨schenthaler, G.-V. Tetrahedron Lett. 2003, 44,
2097–2099; (b) Sosnovskikh, V. Ya.; Usachev, B. I.;
Sevenard, D. V.; Ro¨schenthaler, G.-V. J. Org. Chem.
2003, 68, 7747–7754; (c) Sevenard, D. V.; Sosnovskikh, V.
Ya.; Kolomeitsev, A. A.; Ko¨nigsmann, M. H.; Ro¨schent-
haler, G.-V. Tetrahedron Lett. 2003, 44, 7623–7627.
7. Sosnovskikh, V. Ya.; Usachev, B. I. Izv. Akad. Nauk, Ser.
Khim., in press (Russ. Chem. Bull., Int. Ed., 2004, 53, in press).
8. (a) Beam, C. F.; Dyer, M. C. D.; Schwarz, R. A.; Hauser,
C. R. J. Org. Chem. 1970, 35, 1806–1810; (b) Fulmer, T.
D.; Dasher, L. P.; Bobb, B. L.; Wilson, J. D.; Sides, K. L.;
Beam, C. F. J. Heterocycl. Chem. 1980, 17, 799–800;
(c) Livingston, M. J.; Chick, M. F.; Shealy, E. O.; Beam,
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Lin, N.-H. Synthesis, 1994, 989–992.
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Warner, M. E.; Beam, C. F. Synth. Commun. 2003, 33,
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Finally, in attempting to ascertain if related chromones
can participate in this reaction, we found that 2-methyl-
chromone reacts with acetophenone oxime in the
presence of lithium diisopropylamide to give the corre-
sponding spiroisoxazoline 2e in a remarkable 97% yield,
in spite of the known susceptibility of the 2-methyl
group to deprotonation by basic reagents.21 Flavone
was similarly converted in 65% yield to compound 2f.
However, in the case of chromone, the reaction mix-
ture almost immediately becomes dark-red and resinifies
under the same conditions, since the absence of a
substituent allows the base relatively free access to the
2-position and consequently to nucleophilic attack and
other ring-opening reactions.22 (Scheme 3).
In summary, we have developed a simple and practical
access to 4H-chromene-4-spiro-50-isoxazolines, which
can be easily converted to other chromone derivatives
possessing a variety of functionalities. Further studies
on the synthetic application of spiroannulated isoxazo-
lines are now in progress.
Ph
12. 2-(Trifluoromethyl)-4H-chromene-4-spiro-50-30-phenyl- 40,
50-dihydroisoxazole (2a). Yield 83%, mp 124–125°C,
colorless needles; (Found: C, 65.18; H, 3.43; N, 4.20.
C18H12F3NO2 requires C, 65.26; H, 3.65; N, 4.23%); mmax
(Nujol) 1695 (C@C), 1615, 1595, 1585 (arom.) cmÀ1; d
(400MHz, CDCl3) 3.57 (1H, d, J = 17.5Hz, CHH), 3.78
(1H, d, J = 17.5Hz, CHH), 5.95 (1H, s, @CH), 7.18 (1H,
dd, oJ = 8.4Hz, mJ = 1.1Hz, H-8), 7.24(1H, ddd, oJ = 7.9,
N
O
O
Me
HO
Ph
1) Pri2NLi
2) H3O+
+
N
O
R
O
R
2e,f
R = Me (e), Ph (f)
Scheme 3.
o
7.3Hz, mJ = 1.1Hz, H-6), 7.39 (1H, ddd, J = 8.4, 7.3Hz,

7354
V. Ya. Sosnovskikh et al. / Tetrahedron Letters 45 (2004) 7351–7354
mJ = 1.6Hz, H-7), 7.42–7.49 (3H, m, H-30, H-40, H-50),
crystals; (Found: C, 57.76; H, 3.93; N, 5.19. C13H10F3NO2
requires C, 58.00; H, 3.74; N, 5.20%); mmax(KBr) 3280
(NH), 1675 (C@O), 1630, 1595, 1560 (arom.) cmÀ1; dH
(400MHz, DMSO-d6) 2.69 (3H, d, J = 4.7Hz, Me), 6.40
(1H, s, @CH), 7.35–7.42 (2H, m, H-8, H-6), 7.56 (1H, ddd,
oJ = 8.4, 7.2Hz, mJ = 1.4Hz, H-7), 7.75 (1H, dd,
oJ = 8.1Hz, mJ = 1.4Hz, H-5), 8.07 (1H, q, J = 4.7Hz,
NH), 8.48 (1H, s, H-3); dC (100MHz, DMSO-d6) 25.43
7.52 (1H, dd, oJ = 7.9Hz, mJ = 1.6Hz, H-5), 7.68–7.73
(2H, m, H-20, H-60).
13. 1-Phenyl-2-[2-(trifluoromethyl)-4H-chromen-4-ylidene]eth-
an-1-one oxime (3a). Yield 85%, mp 174–175°C, light
yellow needles; (Found: C, 65.38; H, 3.63; N, 4.22.
C18H12F3NO2 requires C, 65.26; H, 3.65; N, 4.23%); mmax
(Nujol) 3200 (OH), 1675 (C@C), 1620, 1595, 1575 (arom.)
cmÀ1; d (400MHz, CDCl3) 6.03 (1H, s, H-3), 6.79 (1H, s,
3
(Me), 105.45 (q, JC,F = 4.2Hz, C-3), 109.67 (@CH),
118.05 (C-8), 119.21 (q, JC,F = 271.5Hz, CF3), 119.25
o
1
@CH), 7.18 (1H, dd, J = 8.3Hz, mJ = 1.2Hz, H-8), 7.27
(1H, ddd, oJ = 8.1, 7.3Hz, mJ = 1.2Hz, H-6), 7.38–7.44
(4H, m, H-7, H-30, H-40, H-50), 7.56–7.59 (2H, m, H-20,
H-60), 7.86 (1H, dd, oJ = 8.1Hz, mJ = 1.6Hz, H-5), 8.0–
9.0 (1H, br s, H).
(C-4a), 122.84 (C-5), 126.10 (C-6), 131.22 (C-4), 131.72
(C-7), 139.93 (q, JC,F = 36.8Hz, C-2), 150.30 (C-8a),
2
166.13 (C@O).
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17. N-Methyl-2-[2-(trifluoromethyl)-4H-chromen-4-ylidene]acet-
amide (4c). Yield 89%, mp 191–192°C, light yellow
21. Costa, A. M. B. S. R. C. S.; Dean, F. M.; Jones, M. A.;
Smith, D. A. J. Chem. Soc., Perkin Trans. 1, 1986,
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