Interaction of 3-ethoxycarbonyl(carboxy)-substituted 5,6,7,8-tetrafluorochromones with N-nucleophiles: Synthesis of fluorocoumarins

Article abstract of DOI:10.1016/S0022-1139(98)00350-9

Polyfluorobenzopyranopyrazoles(isoxazoles) have been prepared via cyclization of 5-tetrafluorophenyl-4-ethoxycarbonyl(carboxy)pyrazoles(isoxazoles) produced by the reaction of 3-ethoxycarbonyl-2-methyl- and 3-carboxy-substituted 5,6,7,8-tetrafluorochromones with hydrazine(hydroxylamine). It has been found that 3-ethoxycarbonyl-2-methyl-5,6,7,8-tetrafluorochromone forms the corresponding 2-ethylidenamino-substituted 1,3-keto esters with ammonia and benzylamine, from which 3-ethylidenamino-4-oxy-5,6,7,8-tetrafluorocoumarins were readily obtained. In contrast to the non-fluorinated analogues, 3-ethoxycarbonyl-2-methyl-5,6,7,8-tetrafluorocoumarins were found to undergo acyl-lactone transformation into coumarin structures under acidic conditions.

Full text of DOI:10.1016/S0022-1139(98)00350-9

Journal of Fluorine Chemistry 94 (1999) 83±90
Interaction of 3-ethoxycarbonyl(carboxy)-substituted
5,6,7,8-tetra¯uorochromones with N-nucleophiles:
synthesis of ¯uorocoumarins
V.I. Saloutin*, Z.E. Skryabina, I.T. Bazyl', S.P. Kisil'
Institute of Organic Synthesis, Urals Division, Russian Academy of Sciences, Kovalevskoy Str. 20, 620219, Ekaterinburg, GSP-147, Russian Federation
Received 30 July 1998; accepted 24 November 1998
Abstract
Poly¯uorobenzopyranopyrazoles(isoxazoles) have been prepared via cyclization of 5-tetra¯uorophenyl-4-ethoxycarbonyl(carboxy)pyr-
azoles(isoxazoles) produced by the reaction of 3-ethoxycarbonyl-2-methyl- and 3-carboxy-substituted 5,6,7,8-tetra¯uorochromones with
hydrazine(hydroxylamine). It has been found that 3-ethoxycarbonyl-2-methyl-5,6,7,8-tetra¯uorochromone forms the corresponding 2-
ethylidenamino-substituted 1,3-keto esters with ammonia and benzylamine, from which 3-ethylidenamino-4-oxy-5,6,7,8-tetra¯uorocou-
marins were readily obtained. In contrast to the non-¯uorinated analogues, 3-ethoxycarbonyl-2-methyl-5,6,7,8-tetra¯uorocoumarins were
found to undergo acyl-lactone transformation into coumarin structures under acidic conditions. # 1999 Elsevier Science S.A. All rights
reserved.
Keywords: Fluorinated chromones; Fluorinated coumarins; N-nucleophiles
1. Introduction
tion of the heterocycle to give an oxime [8]; treatment of 3-
ethoxycarbonyl-2-methyl-5,6,7,8-tetra¯uorochromone with
benzylamine leads to the formation of N-benzylamide of 2-
methyl-5,6,7,8-tetra¯uorochromone-3-carboxylic acid [8].
The products above are not typical for interaction of non-
¯uorinated analogues with amines [3,4]; moreover, the
structure of these compounds has not been con®rmed by
NMR spectroscopy [8].
In this paper, the interaction of 3-carboxy-5,6,7,8-tetra-
¯uorochromone (1), 3-ethoxycarbonyl-2-methyl-5,6,7,8-
tetra¯uorochromone (2) and 3-carboxy-2-methyl-5,6,7,8-
tetra¯uorochromone (3) with hydroxylamine, hydrazine,
benzylamine, ammonia and also with ortho-phenylenedi-
amine is described.
Our previous investigations have shown the differences in
reactivity with N-nucleophiles between 2-carboxy- and 2-
ethoxycarbonyl-5,6,7,8-tetra¯uorochromones [1,2].
It seems to us that the chemistry of 3-ethoxycarbonyl-and
3-carboxy-substituted ¯uorochromones is also interesting
and may be comparable with that of non-¯uorinated 3-
ethoxycarbonyl(carboxy)chromones, particularly, in acyl-
lactone transformation of their amino-derivatives [3±6].
However, this acyl-lactone transformation would have more
signi®cance for alternative syntheses of ¯uoro-coumarin
structures from tetra¯uorochromones, compared to the
non-¯uorinated compounds, as tetra¯uorosalicylic acid is
not as available as salicylic acid, which is known to be useful
in this area [7].
2. Experimental
Although a great deal of work has been published con-
cerning reactions of 3-ethoxycarbonyl(carboxy)chromones
with N-nucleophiles [3±6], none has been reported on
reactions of ¯uoro-containing 3-carboxychromones, and
little is known about the interaction of 3-ethoxycarbonyl-
substituted tetra¯uorochromone with amines [8], thus it has
been reported that 3-ethoxycarbonyl-2-metyl-5,6,7,8-tetra-
¯uorochromone reacts with hydroxylamine at the C-4 posi-
Melting points were measured in open capillaries and are
reported uncorrected. Infrared spectra were measured on a
Specord 75 IR spectrometer. 1H NMR spectra were recorded
on a Tesla BS-567 A instrument (1H: 100 MHz) using TMS
as an internal standard. 19F NMR spectra were recorded on a
Tesla BS-587 A instrument (19F: 75 MHz) using CFCl3 as an
internal standard. All chemical shifts are reported in ppm
1
*Corresponding author. Fax: +7-3432-745954; e-mail: fc@ios.ural.ru
and wavenumbers in cm
.
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
P I I : S 0 0 2 2 - 1 1 3 9 ( 9 8 ) 0 0 3 5 0 - 9

84
V.I. Saloutin et al. / Journal of Fluorine Chemistry 94 (1999) 83±90
2.1. Materials
cooling, the resulting precipitate was collected, washed with
water, dried at 808C and puri®ed by recrystallization from
CCl4 to give 0.7 g (82%) of 5 (m.p. 214±2158C): H NMR
1
Literature methods were used to prepare compound 1 [1]
and compound 2 [8]. Compound 3 was prepared from 3-
ethoxycarbonyl-2-methyl-5,6,7,8-tetra¯uorochromone 2, as
described below.
(CD3COCD3) ꢀ: 2.61 (3H, s, CH3) ppm. 19F NMR
(CD3COCD3) ꢀ: 161.71 (1F, t); 155.70 (1F, d-d);
148.98 (1F, d-t); 140.79 (1F, d-d-d) ppm. IR (cm 1):
1770 (C=O); 1660, 1630, 1600, 1500 (C=N, C=C); 990
(CF). Analysis: Found: C, 48.51; H, 1.06; F, 28.09; N,
5.24%. Calc. for C11H3F4NO3: C, 48.37; H, 1.11; F,
27.82; N, 5.13%.
2.2. Synthesis of the 3-carboxy-2-methyl-5,6,7,8-
tetrafluorochromone (3) (nc)
A mixture of compound 2 (30.1 g, 100.0 mmol) and
concentrated HCl (20 ml) and 150 ml of CH3COOH was
stored at 458C for 4 days. The resulting precipitate was
collected, washed with water and dried at 808C to give
12.7 g (46%) of 3 [m.p. 137±1408C (decomp.)], which
exists in an unseparated mixture with coumarin (21), ratio
2.5. Synthesis of 4-carboxy-5-(20-hydroxy-30,40,50,60-
tetrafluorophenyl)pyrazole (6) (nc)
A mixture of compound 1 (3.0 g, 11.4 mmol) and hydra-
zine hydrate (15.0 g, 300 mmol) in 150 ml of water was
stored at room temperature for 24 h. The reaction mixture
was poured into a solution of concentrated HCl (120 ml) in
200 ml of water, extracted with 150 ml of ether, washed
with 250 ml of water and dried over CaCl2. The organic
layer was concentrated, the resulting precipitate was col-
lected by ®ltration, dried at 808C to give 1.8 g (57%) of 6
(m.p. 210±2208C decomp.). 1H NMR (DMF-d7) ꢀ: 5.5 (3H,
w s, OH, NH, COOH); 8.32 (1H, s, =CH) ppm. 19F NMR
(DMF-d7) ꢀ: 172.65 (1F, d-d-d); 162.77 (1F, d-d-d);
158.48 (1F, t); 141.42 (1F, d-d) ppm. IR (cm 1): 3500±
2350 (NH, OH); 1690 (C=O); 1530, 1500 (C=N, C=C, NH);
990 (CF). Analysis: Found: C, 43.48; H, 1.07; F, 28.00; N,
10.42%. Calc. for C10H4F4N2O3: C, 43.49; H, 1.46; F,
27.52; N, 10.14%.
1
3/21ˆ3:1. H NMR (CD3COCD3) ꢀ: 2.23 (3, 3H, s, CH3);
13.2 (3, 1H, w s, OH); 5.71 (21, 1H, s, =CH); 11.56 (21 1H,
w s, 0H). 19F NMR (CD3COCD3) ꢀ: 159.79 (3, 1F, t);
158.13 (3, 1F, d-d); 145.85 (3, 1F, d-t); 141.07 (3, 1F,
d-d-d); 164.45 (21, 1F, d-t); 159.52 (21, 1F, d-d-d);
152.11 (21, 1F, d-t); 141.32 (21, 1F, d-d-d). IR
(cm 1): 2800±2500 (3, 21, OH); 1730 (3, C=O, acid);
1700 (21, C=O); 1650 (3, C=O); 1600, 1525, 1500 (3,
21, C=C); 1020 (3, CF); 1000 (21, CF). Analysis: Found:
C, 47.65; H, 1.23; F, 27.31%. Calc. for C11H4F4O4: C,
47.84; H, 1.46; F, 27.52%.
2.3. Synthesis of 4-ethoxycarbonyl-3-methyl-5-(20-
hydroxy-30,40,50,60-tetrafluorophenyl) isoxazole (4) (nc)
A mixture of compound 2 (10.1 g, 32.9 mmol), 5.0 g
(77.5 mmol) of hydroxylamine hydrochloride and 7.0 g
(69.3 mmol) triethylamine in 150 ml of MeOH was stored
at room temperature for 2 h. To the reaction mixture, 400 ml
of water was added. The mixture was neutralized with HCl
to pH 2, and then 100 ml of hexane was added. The resulting
precipitate was collected, washed with water and dried to
give crude product, which was heated in re¯uxing hexane
for 1 h, collected by hot ®ltration and dried at 808C to give
2.6. Synthesis of 4-ethoxycarbonyl-3-methyl-5-(20-
hydroxy-30,40,50,60-tetrafluorophenyl)pyrazole (7) (nc)
To a solution of compound 2 (20.0 g, 65.8 mmol) in
250 ml of MeOH, a solution of hydrazine hydrate (8.0 g,
160 mmol) in 20 ml of MeOH was added. The reaction
mixture was stored at room temperature for 0.5 h and then
was poured into a solution of concentrated HCl (25 ml) in
1200 ml of water. The resulting precipitate was collected by
®ltration, washed with water (200 ml), washed with CHCl3
(50 ml),dried at 808C to give 17.6 g (84%) of 7 (m.p. 171±
1738C). 1H NMR (CD3OD) ꢀ: 1.13 (3H, t, Jˆ7.1 Hz, CH3);
2.55 (3H, s, CH3); 4.12 (2H, q, Jˆ7.1 Hz, CH2); 4.80 (1H, w
s, OH) ppm. 19F NMR (CD3OD) ꢀ: 172.26 (1F, d-d-d);
163.69 (1F, d-d-d); 158.33 (1F, t); 141.61 (1F, d-d)
ppm. IR (cm 1): 3270, 2750±2550 (NH, OH); 1690 (C=O);
1560, 1530, 1500 (C=C, C=N, NH); 990 (CF). Analysis:
Found: C, 49.22; H, 3.10; F, 23.60; N, 8.73%. Calc. for
C13H10F4N2O3: C, 49.07; H, 3.17; F, 23.88; N, 8.80%.
1
8.9 g (85%) of 4 (m.p. 133±1358C). H NMR (CDCl3) ꢀ:
1.29 (3H, t, CH3, Jˆ7.0 Hz); 2.52 (3H, s, CH3); 4.31 (2H, q,
CH2, Jˆ7.0 Hz); 7.80 (1H, w s, OH) ppm. 19F NMR
(CDCl3) ꢀ: 168.01 (1F, d-d-d); 162.02 (1F, d-d-d);
151.75 (1F, d-t); 139.14 (1F, d-d-d) ppm. IR (cm 1):
3130, 2700±2500 (OH); 1730 (C=O); 1660, 1620, 1535,
1500 (C=C, C=N); 995 (CF). Analysis: Found: C, 49.30; H,
2.78; F, 24.19; N, 4.51%. Calc. for C13H9F4NO4: C, 48.91;
H, 2.84; F, 23.81; N, 4.39%.
2.4. Synthesis of 3-methyl-4H-[1]-6,7,8,9-
tetrafluorobenzopyrano[3,4-d]isoxazole-4-one (5)
(nc)
2.7. Synthesis of 4-carboxy-3-methyl-5-(20-hydroxy-
30,40,50,60-tetrafluorophenyl)pyrazole (8) (nc)
A mixture of compound 4 (1.0 g, 3.13 mmol), 10 ml of
H2SO4 and 10 ml of water was re¯uxed for 1.5 h. After
A mixture of compound 3 (5.0 g, 18.1 mmol) and hydra-
zine hydrate (15.0 g, 300 mmol) in 150 ml of water was

V.I. Saloutin et al. / Journal of Fluorine Chemistry 94 (1999) 83±90
85
stored at room temperature for 24 h. The reaction mixture
was poured into a solution of concentrated HCl (120 ml) in
200 ml of water, extracted with 150 ml of ether and dried
over CaCl2. The organic layer was concentrated, the result-
ing precipitate was collected by ®ltration, dried at 808C to
give 3.8 g (72%) of 8 (m.p. 214±2188C, decomp.). 1H NMR
(CD3COCD3) ꢀ: 2.59 (3H, s, CH3); 9.8 (3H, w s, OH, NH,
COOH) ppm. 19F NMR (CD3COCD3) ꢀ: 171.80 (1F, d-d-
d); 163.42 (1F, d-d-d); 158.35 (1F, t); 140.58 (1F, d-d)
ppm. IR (cm 1): 3570, 3450, 3350±2250 (NH, OH); 1690
(C=O); 1650, 1550, 1520 (C=C, NH, C=N); 970, 980 (CF).
Analysis: Found: C, 45.56; H, 2.07; F, 25.89; N, 9.60%. Calc.
for C11H6F4N2O3: C, 45.53; H, 2.08; F, 26.19; N, 9.65%.
74 mmol) was re¯uxed for 20 min. After cooling at 108C,
the reaction mixture was stored at room temperature for 3 h.
The resulting precipitate was collected by ®ltration, washed
with toluene and dried at 808C to give 1.2 g (86%) of 11
(m.p. 225±2278C). 1H NMR (DMF-d7) ꢀ: 8.87 (1H, s, =CH);
13.5 (1H, w s, NH) ppm. 19F NMR (DMF-d7) ꢀ: 164.01
(1F, t); 157.87 (1F, m); 156.31 (1F, m); 141.23 (1F, d-
d) ppm. IR (cm 1): 3190, 3110 (NH); 1770, 1720 (C=O);
1545, 1515, 1500 (C=C, C=N, NH); 990 (CF). Analysis:
Found: C, 46.36; H, 0.14; F, 29.46; N, 11.17%. Calc. for
C10H2F4N2O2: C, 46.55; H, 0.78; F, 29.44; N, 10.85%.
2.11. Synthesis of 2-amino-4-(20-hydroxy-30,40,50,60-
tetrafluorophenyl)-2-buten-4-one (12) (nc)
2.8. Synthesis of 3-methyl-5-(20-hydroxy-30,40,50,60-
tetrafluorophenyl)pyrazole (9) (nc)
A mixture of compound 3 (3.0 g, 10.87 mmol) and
ammonium hydroxide (9 ml, 25%) in 120 ml of water
was stored at room temperature for 3 days. The resulting
precipitate was collected by ®ltration, washed with water
(100 ml), dried at 808C and recrystallized from n-heptane to
give 1.6 g (59%) of 12 (m.p. 139±1408C). 1H NMR
(CD3COCD3) ꢀ: 2.20 (3H, s, CH3); 5.73 (1H, d, JH±
A mixture of compound 7 (6.9 g, 21.7 mmol) and con-
centrated H2SO4 (55 ml) in 55 ml of water was re¯uxed for
2.5 h. The reaction mixture was poured into 200 ml of water,
the resulting precipitate was collected by ®ltration, washed
with water and dried at 808C to give a crude product (4.65 g,
87%) which was recrystallized from methanol±acetone
mixture (20:1) to give 2.5 g (47%) of 9 (m.p. 236±
ˆ1.0, =CH); 8.1 (1H, w s, NH); 10.11 (2H, w s, OH,
F
NH) ppm. 19F NMR (CD3COCD3) ꢀ: 173.57 (1F, d-d-d);
165.33 (1F, d-d-d); 153.84 (1F, d-t); 137.80 (1F, d-d-d)
ppm. IR (cm 1): 3370, 3320, 2700±2000 (NH2, OH); 1650
(C=O); 1630 sh, 1580, 1520 (C=C, NH); 1000 (CF). Ana-
lysis: Found: C, 48.30; H, 2.85; F, 30.56; N, 5.75%. Calc. for
C10H7F4NO2: C, 48.20; H, 2.83; F, 30.50; N, 5.62%.
1
2378C). H NMR (CD3COCD3) ꢀ: 2.44 (3H, d, Jˆ0.7 Hz,
CH3); 6.57 (1H, d-d, JH±NHˆ0.6, JH±Fˆ5.2 Hz, =CH); 12.5
(2H, w s, NH, OH) ppm. 19F NMR (CD3COCD3) ꢀ:
172.24 (1F, d-t); 164.35 (1F, d-d-d); 159.84 (1F, d-
d-d); 144.17 (1F, d-d-d-d, JF±Hˆ5.5 Hz, F-6) ppm. IR
(cm 1): 3350 (NH); 2600 (OH); 1660, 1570, 1550,1520
(C=C, C=N, NH); 990, 1000 (CF). Analysis: Found: C,
48.82; H, 2.50; F, 30.94; N, 11.55%. Calc. for C10H6F4N2O:
C, 48.79; H, 2.46; F, 30.87; N, 11.38%.
2.12. Synthesis of 2-methyl-7-piperidino-5,6,8-
trifluorochromone (13) (nc)
A mixture of compound 3 (2.76 g, 10 mmol), piperidine
(3.4 g, 40 mmol), methanol (80 ml) in 80 ml of water was
stored at room temperature for 24 h. The resulting precipi-
tate was collected by ®ltration, washed with 5% HCl and
recrystallized from hexane to give 1.4 g (47%) of 13 (m.p.
128±1298C). 1H NMR (CDCl3) ꢀ: 1.67 (6H, w s, CH2±CH2±
CH2); 2.32 (3H, s, CH3); 3.2 (4H, w s, CH2±N±CH2); 5.6
(1H, s, =CH) ppm. 19F NMR (CDCl3) ꢀ: 151.64 (1F, d, J 6-
5ˆ19 Hz, F-6); 150.31 (1F, d, J 8-5ˆ12.2 Hz, F-8);
146.97 (1F, d-d, J5-6ˆ18.6; J5-8ˆ12.2 Hz, F-5) ppm. IR
(cm 1): 1660 (C=O); 990, 1010 (CF). Analysis: Found: C,
60.66; H, 4.78; F, 19.28; N, 4.82%. Calc. for C15H14F3NO2:
C, 60.66; H, 4.75; F 19.17; N, 4.71%.
2.9. Synthesis of 3-methyl-4H-6,7,8,9-
tetrafluorobenzopyrano[3,4-d]pyrazol-4-one (10) (nc)
A mixture of pyrazole 7 (10.0 g, 31.4 mmol), concen-
trated CH3COOH (70 ml) and concentrated HCl (7 ml) was
re¯uxed for 15 h. Then the reaction mixture was concen-
trated to half of its original volume. The resulting precipitate
was collected by ®ltration and dried at 808C to give 4.0 g
1
(47%) of 10 (m.p. 222±2238C). H NMR (CD3COCD3) ꢀ:
2.67 (3H, s, CH3); 13.20 (1H, w s, NH) ppm. 19F NMR
(CD3COCD3) ꢀ: 164.23 (1F, d-t); 157.71 (1F, d-d);
156.10 (1F, t); 140.85 (1F, d-d) ppm. IR (cm 1):
3250 (NH); 1730 (C=O); 1530, 1510 (C=C, C=N, NH);
990, 1000 (CF). Analysis: Found: C, 49.01; H, 1.46; F,
28.20; N, 10.21%. Calc. for C11H4F4N2O2: C, 48.55; H,
1.48; F, 27.92; N, 10.29%.
2.13. Synthesis of 2-methyl-4H-5,6,7,8-
tetrafluorochromone (14) (nc)
Method A. A mixture of compound 12 (0.2 g, 0.8 mmol),
concentrated H2SO4 (3 ml) in 3 ml of water was re¯uxed for
4 h. After cooling, 50 ml of water was added to the reaction
mixture. The mixture was extracted with CHCl3 (20 ml).
The organic layer was concentrated. The residue was col-
lected and recrystallized from heptane to give 0.12 g (64%)
2.10. Synthesis of 4H-6,7,8,9-tetrafluorobenzopyrano[3,4-
d]pyrazole-4-one (11) (nc)
A mixture of compound 6 (1.5 g, 5.43 mmol), toluene
(75 ml), DMF (0.3 g) and thionyl chloride (10.0 g,

86
V.I. Saloutin et al. / Journal of Fluorine Chemistry 94 (1999) 83±90
of 14 (m.p. 105±1078C). 1H NMR (CD3COCD3) ꢀ: 2.45
(3H, d, JH±Hˆ0.8 Hz, CH3); 6.16 (1H, w s, =CH) ppm.
19F NMR (CD3COCD3) ꢀ: 163.04 (1F, t); 158.99 (1F, d-
d-d); 150.45 (1F, d-t); 143.83 (1F, d-d-d) ppm. IR
(cm 1): 1665 (C=O); 1610, 1515 (C=C); 1000 (CF). Ana-
lysis: Found: C, 51.71; H, 1.77; F, 32.71%. Calc. for
C10H4F4O2: C, 51.74; H, 1.74; F, 32.74%.
Method B. By analogy, a mixture of compound 15 (0.2 g,
0.623 mmol), concentrated H2SO4 (3 ml) in 3 ml of water
was re¯uxed for 4 h. After cooling, 50 ml of water was
added to the reaction mixture. The mixture was extracted
with CHCl3 (20 ml). The organic layer was concentrated
and recrystallized from heptane to give 0.1 g (69%) of 14
(m.p. 105±1078C). The physicochemical data were identical
to those listed above.
Method C. A mixture of compound 16 (0.35 g,
1.27 mmol) and a solution of NaOH (10 ml, 5%) was
stored at room temperature overnight. The mixture was
neutralized with HCl to pH 2. The resulting precipitate
was collected and re¯uxed with a mixture of acetic acid
(5 ml) and concentrated HCl (1 ml) for 1 h. The reaction
mixture was poured into water (20 ml), and then the
resulting precipitate was collected and recrystallized
from heptane to give 0.1 g (34%) of 14 (m.p. 105±
1078C). The physicochemical data were identical to those
listed above.
4.40%. Calc. for C13H11F4NO4: C, 48.61; H, 3.45; F,
23.66; N, 4.36%
2.15. Synthesis of 4-hydroxy-2H-3-(20-iminoethyl)-5,6,7,8-
tetrafluorocoumarin (16) (nc)
Method A. The residue from the above reaction was
recrystallized from toluene to give 16 (0.8 g, 18%) (m.p.
171±1738C). 1H NMR (CD3COCD3) ꢀ: 2.68 (3H, d,
JCH NHˆ0.7 Hz, CH3); 9.31 (1H, w s, OH); 12.10 (1H, w
3
s, NH) ppm. 19F NMR (CD3COCD3) ꢀ: 165.67 (1F, d-t);
160.34 (1F, d-d-d); 151.09 (1F, d-t); 144.61 (1F, d-d-d)
ppm. IR (cm 1): 3250, 2600 (NH, OH); 1710 (C=O); 1600,
1500 (C=C, NH); 995 (CF). Analysis: Found: C, 48.00; H,
1.56; F, 27.31; N, 5.11%. Calc. for C11H5F4NO3: C, 48.01;
H, 1.83; F, 27.62; N, 5.09%.
Method B.
A mixture of compound 2 (10.0 g,
329.0 mmol) and NH4OH (150 ml, 25%) was heated under
re¯ux and stirred for 3 h. The resulting precipitate was
collected, washed with water and dried at 808C to give
16 (8.1 g, 90%) (m.p. 171±1738C). The physicochemical
data were identical to those listed above.
Method C. A mixture of compound 15 (2.05 g,
6.38 mmol) and NH4OH (70 ml, 25%) was re¯uxed for
0.5 h. The resulting precipitate was collected and dried at
808C to give 1.5 g (85%) of 16 (m.p. 171±1738C). The
physicochemical data were identical to those listed above.
2.14. Synthesis of ethyl 3-(20-hydroxy-30,40,50,60-
tetrafluorophenyl)-2-(20-amino)ethylidenepropane-
1,3-dionate (15) (nc)
2.16. Synthesis of ethyl 3-(20-hydroxy-30,40,50,60-
tetrafluorophenyl)-2-(20-benzylamino)-
ethylidenepropane-1,3-dionate (17) (nc)
A mixture of compound 2 (5.0 g, 16.4 mmol) and
NH4OH (13 ml, 25%) in 100 ml of MeOH was stored at
room temperature for 1 h. To the reaction mixture, a mixture
of water (500 ml), concentrated HCl (50 ml) and hexane
(50 ml) was added. The reaction mixture was shaken for
5 min and stored overnight. The resulting precipitate was
collected by ®ltration, washed with water and dried to give
4 g of crude product, which was a mixture of two com-
pounds (15 and 16). Compound 15 (2.5 g, 47%) (m.p. 94±
978C) was obtained by recrystallization of the crude product
from hexane. 1H NMR (CDCl3 keto, enol-isomers, ratio
keto/enolˆ70:30%) ꢀ: 1.00 (3H, t, Jˆ7.0 Hz, CH3, keto);
1.02 (3H, t, Jˆ7.0 Hz, CH3, enol); 2.25 (3H, s, CH3, keto);
2.46 (3H, s, CH3, enol); 4.04 (2H, q, Jˆ7.0 Hz, CH2, keto);
4.04 (2H, q, Jˆ7.0 Hz, CH2, enol); 5.6 (1H, w s, NH); 9.5
(1H, w s, NH); 10.9±12.0 (1H, w s, OH) ppm. 19F NMR
(CDCl3) ꢀ: 173.18 (1F, d-d-d, keto); 172.30 (1F,d-d-d,
enol); 164.78 (1F, d-d-d, keto); 164.08 (1F, d-d-d, enol);
150.40 (1F, d-t, keto); 153.86 (1F, d-t, enol); 138.64
(1F, d-d-d, keto); 139.96 (1F, d-d-d, enol) ppm. IR (cm 1):
3380, 3300, 3220 (NH, OH); 1650 (C=O); 1615, 1590,
1530, 1500 (C=C, C=N, NH); 980, 1000 (CF). IR (5%
CHCl3) (cm 1): 3690, 3470 (NH, OH); 1720 sh (C=O,
ester); 1660 (C=O, keto); 1590, 1520 (C=C, NH); 1000
(CF). Analysis: Found: C, 48.77; H, 3.32; F, 23.36; N,
A mixture of compound 2 (5.0 g, 16.4 mmol) and ben-
zylamine (3.75 g, 35.0 mmol) in MeOH (100 ml) was stored
at room temperature for 0.5 h. To the reaction mixture,
500 ml of water was added. The mixture was neutralized
with HCl until the pH value was 2. Hexane (50 ml) was
added to the mixture. The resulting precipitate was col-
lected, washed with water (50 ml), dried and recrystallized
from hexane to give 17 (6.25 g, 93%) (m.p. 106±1088C).
1H NMR (C5D5N) ꢀ: 0.85 (3H, t, Jˆ7.0 Hz, CH3, ethyl);
2.25 (3H, s, CH3); 3.99 (2H, q, Jˆ7.0 Hz, CH2, ethyl); 4.42
(2H, d, JCH
ˆ5.6 Hz, CH2, benzyl); 7.13±7.22 (5H, m,
2 NH
C6H5); 13.0 (1H, t, JNHCH ˆ5.5 Hz, NH) ppm. 19F NMR
2
(C5D5N) ꢀ: 172.92 (1F, d-d-d); 162.75 (1F, d-d-d);
160.83 (1F, t); 146.94 (1F, d-d) ppm. IR: 3260(OH);
1670 (C=O); 1575, 1520 (C=C); 1010 (CF). Analysis:
Found: C, 58.47; H, 4.12; F, 18.96; N, 3.30%. Calc. for
C20H17F4NO4: C, 58.40; H, 4.17; F, 18.47; N, 3.41%.
2.17. Synthesis of 4-hydroxy-2H-3-(20-benzyliminoethyl)-
5,6,7,8-tetrafluorocoumarin (18) (nc)
Compound 17 (3.2 g, 7.78 mmol) was heated at 1008C for
2 h, and then recrystallized from toluene to give 1.8 g (63%)
1
of 18 (m.p. 142±1448C). H NMR (CD3COCD3) ꢀ: 2.77

V.I. Saloutin et al. / Journal of Fluorine Chemistry 94 (1999) 83±90
87
(3H, s, CH3); 5.00 (2H, d, JCH
ˆ5.6 Hz, CH2); 7.42±7.49
3. Results and discussion
2 NH
(5H, m, C6H5); 13.9 (1H, w s, OH or NH) ppm. 19F NMR
(CD3COCD3) ꢀ: 165.69 (1F, d-t); 160.55 (1F, d-d-d);
151.16 (1F, d-t); 144.37 (1F, d-d-d) ppm. IR (cm 1):
2500±2700 (OH); 1715 (C=O); 1595, 1575, 1520 (C=C,
C=N); 980, 1000 (CF). Analysis: Found: C, 59.31; H, 3.00;
F, 21.12; N, 3,85%. Calc. for C18H11F4N3: C, 59.19; H, 3.04;
F, 20.08; N, 3.80%.
3.1. Reaction of 3-ethoxycarbonyl-2-methyl-5,6,7,8-
tetrafluorochromone with hydroxylamine
In the present work, it has been found that 3-ethoxycar-
bonyl-2-methyl-5,6,7,8-tetra¯uorochromone (2) does not
react with hydroxylamine hydrochloride under the reaction
conditions (heat at 1008C in the presence of acetic acid)
described previously [8]. However, in the presence of
triethylamine at room temperature, the interaction of chro-
mone 2 with hydroxylamine hydrochloride results in the
formation of isoxazole 4, which could only arise from
addition of the N-nucleophile at the C-2 position of the
heterocycle (Scheme 1).
The same type of product is postulated for the reaction of
non-¯uorinated 3-ethoxycarbonyl-2-methylchromone with
hydroxylamine in pyridine [3]. As is well known, this non-
¯uorinated isoxazole was subjected to cyclization to give
benzopyranoisoxazole via acyl-lactone transformation [3].
In contrast, 3-carboxychromones are not useful for synthesis
of the same benzopyranoisoxazole structure, as decarboxy-
lation takes place easily during the interaction of 3-car-
boxychromones with hydroxylamine [3].
2.18. Synthesis of 2-(20-hydroxy-30,40,50,60-
tetrafluorophenyl)imidazole (19) (nc)
A mixture of 2 (0.5 g, 1.64 mmol), ortho-phenylenedia-
mine (0.21 g, 1.94 mmol) in anhydrous EtOH (10 ml) was
re¯uxed for 6 h. The resulting precipitate was collected by
®ltration, recrystallized from EtOH to give 0.15 g (32%) of
1
19 (m.p.>2708C subl.). H NMR (DMF-d7) ꢀ: 7.33±7.81
(4H, m, C6H4); 13.20 (1H, w s, NH) ppm. 19F NMR (DMF-
d7) ꢀ: 173.17 (1F, d-t); 163.68 (1F, d-d-d); 155.16 (1F,
d-t); 143.23 (1F, d-d-d) ppm. IR (cm 1): 2500±3300 (NH,
OH); 1600, 1550, 1500 (C=N, Cˆ-C, NH); 990, 1000 (CF).
Analysis: Found: C, 55, 37; H, 2, 60; F, 26.66; N, 9.82%.
Calc. for C13H6F4N2O: C, 55, 33; H, 2, 14; F, 26.93; N,
9.93%.
By analogy, the non-¯uorinated isoxazole, compound 5
was derived from 4 on re¯uxing under acidic conditions
(Scheme 1).
2.19. Synthesis of 4-hydroxy-2H-3-acetyl-5,6,7,8-
tetrafluorocoumarin (21) (nc)
3.2. Reaction of 3-carboxy-(2-methyl)-5,6,7,8-
tetrafluorochromones and 3-ethoxycarbonyl-2-methyl-
5,6,7,8-tetrafluorochromone with hydrazine
A mixture of 16 (8.0 g, 29.07 mmol), concentrated
H2SO4 (160 ml) in 160 ml of water was heated at 808C
for 2.5 h. The resulting precipitate was collected, washed
with water and dried at 808C to give 5.0 g (62%) of 21 (m.p.
There is no difference between the reactivities of 3-
carboxy- (1), 3-carboxy-2-methyl- (3) and 3-ethoxycarbo-
nyl-2-methyl- (2) 5,6,7,8-tetra¯uorochromones with hydra-
zine hydrate. Under mild conditions, compounds 1±3 form
the corresponding pyrazoles 6±8 (Scheme 2).
Treatment of 4-ethoxycarbonylpyrazole 7 with boiling
dilute H2SO4 (such conditions were used for preparation of
5) causes hydrolysis, then decarboxylation of the intermedi-
ate, thereby leading to the formation of pyrazole 9 (Scheme
2).
When pyrazole 7 was heated with a boiling mixture of
concentrated acetic and hydrochloric acids, benzopyranpyr-
azole 10 was obtained (Scheme 2). 3-Carboxypyrazole 6
undergoes the same type of cyclization to give 11 only in the
presence of thionyl chloride.
1
163±1778C subl.). H NMR (CD3COCD3) ꢀ: 2.74 (3H, s
CH3); 9.6 (1H, w s, OH) ppm. 19F NMR (CD3COCD3) ꢀ:
163.18 (1F, d-t); 158.95 (1F, d-d-d); 145.67 (1F, d-t);
138.82 (1F, d-d-d) ppm. IR (cm 1): 2700±2500 (OH);
1700, 1650 (C=O); 1500, 1520 (C=C); 1000 (CF). Analysis:
Found: C, 47.77; H, 1.40; F, 27.61%. Calc. for C11H4F4O4:
C, 47.84; H, 1.46; F, 27.52%.
2.20. Synthesis of 4-hydroxy-2H-5,6,7,8-
tetrafluorocoumarin (22) (nc)
A mixture of 21 (3.05 g, 11.0 mmol) and concentrated
H2SO4 (20 ml) was heated at 1008C for 4 h. To the mixture,
200 ml of water was added. The resulting precipitate was
collected by ®ltration, washed with water, dried and recrys-
tallized from toluene to give 1.8 g (70%) of 22 (m.p. 222±
2258C subl.). 1H NMR (CD3COCD3) ꢀ: 5.71 (1H, s, =CH);
11.56 (1H, w s, OH) ppm. 19F NMR (CD3COCD3) ꢀ:
164.45 (1F, d-t); 159.52 (1F, d-d-d); 152.11 (1F, d-
t); 141.32 (1F, d-d-d) ppm. IR (cm 1): 2800±2500 (OH);
1700 (C=O); 1600 (C=C); 1000 (CF). Analysis: Found: C,
46.44; H, 0.80; F, 32.55%. Calc. for C9H2F4O3: C, 46.17; H,
0.86; F, 32.46%.
3.3. Interaction of 3-carboxy-2-methyl- and 3-
ethoxycarbonyl-2-methyl-5,6,7,8-
tetrafluorochromones with ammonia and benzylamine
3-Carboxy-2-methyl-5,6,7,8-tetra¯uorochromone
3
reacts with ammonium hydroxide at the C-2 position of
the chromone to cause opening of the heterocycle and
formation of aminovinyl ketone 12 (Scheme 3), as found

88
V.I. Saloutin et al. / Journal of Fluorine Chemistry 94 (1999) 83±90
Scheme 1.
Scheme 2.
Scheme 3.
for the reaction of non-substituted non-¯uorinated chro-
mones [5,6] and also 2-carboxy-5,6,7,8-tetra¯uorochro-
mone [1] with ammonia. In contrast to 2-carboxy-5,6,7,8-
tetra¯uorochromone [1], decarboxylation of compound 3
takes place under the reaction conditions. This decarboxy-
lation has been shown to be a speci®c feature of 3 in the
presence of some amines. Thus, compound 13 was obtained
by reaction of 3 with piperidine (Scheme 3). The same type
of regiospeci®c nucleophilic displacement of the ¯uorine
atom at the C-7-position of the heterocycle is well known for
the interaction of 5,6,7,8-tetra¯uorochromones with sec-
ondary amines [1,2].
Although,
2-ethoxycarbonyl-5,6,7,8-tetra¯uorochro-
mone is known to be stable in reactions with primary amines
[1], 3-ethoxycarbonyl-substituted ¯uorochromone (2) reacts
with ammonium hydroxide even at room temperature to
give the substituted 1,3-keto ester 15 and the cyclic deri-
vative of the latter ± coumarin 16 (Scheme 4). Compound 16
can be derived from 15 by re¯uxing with ammonium
hydroxide. When chromone 2 was heated with ammonium
hydroxide, only coumarin 16 was obtained.
When K2CO3 or triethylamine or tributylamine were used
for synthesis of 16, this compound was obtained in a small
yield in a mixture with non-separated compounds.
Under acidic conditions, compound 15 was hydrolysed to
give 2-methyl-5,6,7,8-tetra¯uorochromone 14, which was
described above.
Compound 12 was hydrolysed under acidic cond-
itions to give 2-methyl-5,6,7,8-tetra¯uorochromone 14
(Scheme 3).

V.I. Saloutin et al. / Journal of Fluorine Chemistry 94 (1999) 83±90
89
Scheme 4.
Scheme 5.
In contrast to published data [8], compound 2 reacts with
benzylamine at the C-2 position of chromone 2 to form
substituted 1,3-keto ester 17, which was then subjected to
cyclization to give the coumarin 18 without any catalyst or
solvent (Scheme 5). The same coumarin might have been
obtained in [8], as the melting point of 18 is very close to
that described by authors of Ref. [8]. However, the structure
of this compound was not con®rmed by spectral data.
Both keto-enamino and imino-enol isomers are possible
in structures 15, 17. In fact, the observation of two multiple
resonance signals for each aromatic ¯uorine in the 19F NMR
spectrum and two signals for ethyl and methyl groups in the
1H NMR spectrum of 15 seems to support the presence of
two isomers in solution of CDCl3. The 1H NMR spectrum of
compound 17 in CDCl3 exhibited a similar doubling of
signals. However, keto-enamino isomers predominate in the
structure of 17 in a solution of pyridine. The IR spectrum of
15, 17 in vaseline oil con®rmed the existence of the imino-
enol form in their structures in the solid state: one typical
C=O stretching absorption at 1650±1660 cm 1. On the
other hand, the IR spectrum of 15 in solution of CHCl3
displayed two C=O stretching bands at 1660 and
1720 cm 1, attributed to the keto-enamino isomer.
Scheme 6.
The preparation of a coumarin structure from 3-ethoxy-
carbonyl-2-methyl-5,6,7,8-tetra¯uorochromone (2) is also
possible under acidic conditions, which are not typical for
non-¯uorinated analogue [9]. Thus, when 2 was hydrolysed
under acidic conditions to give 3-carboxy-2-methyl-5,6,7,8-
tetra¯uorochromone (3) (Scheme 7), 3-acyl-4-hydroxy-
5,6,7,8-tetra¯uorocoumarine (21) was also obtained as a
non-separated mixture, obviously through the formation of
the intermediate 20. In our view, chromone 3 and coumarin
21 are the products from different processes and cannot be
converted into each other. Thus, transformation of 3 into
coumarin 21 under acidic conditions was unsuccessful,
since compound 3 is highly stable to acid; treatment of 3
with amines causes decarboxylation.
Interestingly, when compound 2 was treated with ortho-
phenylenediamine benzimidazole (19) (Scheme 6) was
obtained instead of expected benzodiazepine. This may
result from the formation of the intermediate, similar to
15, 17, which undergo acid splitting of the ketoester frag-
ment.
In our view, intermolecular trans-esteri®cation, but not
hydrolysis of the COOEt group, is the ®rst step that causes
transformation of compounds 4, 7, 15, 17 derived from 2
into coumarins 5, 10, 16, 18. As a proof, carboxypyrazole 6
forms the corresponding coumarin 11 only in the presence

90
V.I. Saloutin et al. / Journal of Fluorine Chemistry 94 (1999) 83±90
Scheme 7.
Scheme 8.
of thionyl chloride; acids or amines were used for formation
of coumarins 5, 10, 16, 18 from ethoxycarbonyl-sustituted
4, 7, 15, 17, respectively.
References
[1] V.I. Saloutin, I.T. Bazyl', Z.E. Skryabina, S.N. Shurov, S.G.
Perevalov, Zh. Org. Khim. 31 (1995) 718.
Reverse transformation of coumarin into a chromone is
also possible; decarboxylation takes place in this reaction.
Thus, chromone 14 (Scheme 8) was independently prepared
from coumarin 16 by alkaline and subsequent acidic treat-
ment, obviously through the formation of intermediate 12,
which was not isolated. When coumarin 16 was treated with
diluted H2SO4, compound 21 (Scheme 8) was obtained. The
latter was treated with concentrated H2SO4 to give 4-
hydroxy-5,6,7,8-tetra¯uorocoumarine (22) (Scheme 8).
In conclusion, the reactions described demonstrate the
ready preparation of tetra¯uorocoumarin derivatives from 3-
ethoxycarbonyl-2-methyl-5,6,7,8-tetra¯uorochromone.
Decarboxylation of 3-carboxy-(2-methyl)-5,6,7,8-tetra-
¯uorochromones takes place in some of these reactions
inhibiting the formation of a coumarin product.
[2] V.I. Saloutin, I.T. Bazyl', Z.E. Skryabina, O.N. Chupakhin, Izv.
Akad. Nauk. Otd. Khim. Nauk (1994) 904.
[3] B. Chantegrel, A.I. Nadi, S. Gelin, J. Org. Chem. 49 (1984)
4419.
[4] B. Chantegrel, A.I. Nadi, S. Gelin, Tetrahedron Lett. 24 (1983)
381.
[5] M.A.-F. Elkaschev, F.M.E. Abdel-Megeid, K.E.M. Mokhtar, M.F.
Elbarnashawi, Indian J. Chem. 11 (1973) 860.
[6] D.H.R. Barton, W.D. Ollis (Eds.), Obshaya organicheskaya khimiya,
vol. 9, Khimiya, Moscow, 1985, p. 93.
[7] N. Numamoto, T. Yamamoto, A. Yamashita, Japan Patent 0 236 178
[9 036 178] (1988).
[8] N.N. Vorojtzov, V.A. Barkhash, A.T. Prudchenko, T.I. Homenko,
Dokl. Akad. Nauk SSSR 164 (1965) 1046.
[9] S. Klishko, J. Shavel, J.M. Standtmann, J. Org. Chem. 39 (1974)
2436.