Fluoroaryl containing β,β′-dioxoesters in the synthesis of fluorobenzopyran-4(2)-ones

Article abstract of DOI:10.1016/S0022-1139(01)00346-3

Fluoroaryl containing β,β′-dioxoesters and their copper(II) chelates have been prepared by acylation of ethyl acetoacetate with 2,6-dimethoxy-3,4,5-trifluorobenzoyl, 2-methoxy-3,4,5,6-tetrafluorobenzoyl and pentafluorobenzoyl chlorides. Cyclization of these β,β′-dioxoesters leads to formation of substituted fluorochromones. Depending on conditions, 2-methyl-5-methoxy-6,7,8-trifluoro-3-ethoxycarbonylchromone hydrolyzed to 5-hydroxy-2-methyl-6,7,8-trifluorochromone or 5-hydroxy-2-methyl-6,7,8-trifluorochromone-3-carboxylic acid. The same chromone reacts with morpholine to form a seven-substituted product and ammonium hydroxide to give 3-iminoacetyl-4-hydroxy-5-methoxy-6,7,8-trifluorocoumarin. Hydrolysis of the latter affords 3-acetyl-4-hydroxy-5-methoxy-6,7,8-trifluorocoumarin. Ethyl-2-(2,6-dimethoxy-3,4,5-trifluorobenzoyl)-3-oxobutanoates undergoes ketone-splitting to 1-(2,6-dimethoxy-3,4,5-trifluorophenyl)-1,3-butandione.

Full text of DOI:10.1016/S0022-1139(01)00346-3

Journal of Fluorine Chemistry 108 ꢀ2001) 125±131
Fluoroaryl containing b,b0-dioxoesters in the synthesis of
¯uorobenzopyran-4ꢀ2)-ones
S.P. Kisil', Ya.V. Burgart, V.I. Saloutin*, O.N. Chupakhin
Institute of Organic Synthesis, Urals Division, Russian Academy of Sciences, 620219, GSP-147 Ekaterinburg, Russia
Received 9 October 2000; accepted 8 December 2000
Abstract
Fluoroaryl containingb,b0-dioxoestersandtheircopperꢀII)chelateshave been preparedbyacylationofethyl acetoacetatewith2,6-dimethoxy-
3,4,5-tri¯uorobenzoyl, 2-methoxy-3,4,5,6-tetra¯uorobenzoyl and penta¯uorobenzoyl chlorides. Cyclization of these b,b0-dioxoesters leads to
formation of substituted ¯uorochromones. Depending on conditions, 2-methyl-5-methoxy-6,7,8-tri¯uoro-3-ethoxycarbonylchromone hydro-
lyzed to 5-hydroxy-2-methyl-6,7,8-tri¯uorochromone or 5-hydroxy-2-methyl-6,7,8-tri¯uorochromone-3-carboxylic acid. The same chromone
reacts with morpholine to form a seven-substituted product and ammonium hydroxide to give 3-iminoacetyl-4-hydroxy-5-methoxy-6,7,8-
tri¯uorocoumarin. Hydrolysis of the latter affords 3-acetyl-4-hydroxy-5-methoxy-6,7,8-tri¯uorocoumarin. Ethyl-2-ꢀ2,6-dimethoxy-3,4,5-
tri¯uorobenzoyl)-3-oxobutanoates undergoes ketone-splitting to 1-ꢀ2,6-dimethoxy-3,4,5-tri¯uorophenyl)-1,3-butandione. # 2001 Elsevier
Science B.V. All rights reserved.
Keywords: Acylation; b,b0-Dioxoesters; CopperꢀII) chelate; Tri¯uorochromone; Tri¯uorocoumarin
1. Introduction
by heating the corresponding acids 1a,b with an excess of
phosphorus pentachloride ꢀScheme 1). These ¯uorobenzoyl
chlorides were used for acylation of ethyl acetoacetate.
It is known that acylation of ethyl acetoacetate by penta-
¯uorobenzoyl chloride leads to formation of 3-ethoxycar-
bonyl-2-methyl-5,6,7,8-tetra¯uorochromone instead of
expected b,b0-dioxoester [1,2]. In the present work, it has
been found that interaction of ¯uorobenzoyl chlorides 2a,b
with ethyl acetoacetate in the presence of magnesium eth-
oxide results in b,b0-dioxoesters 3a,b ꢀScheme 1). The
treatment of these b,b0-dioxoesters 3a,b with copperꢀII)
acetate gives copperꢀII) chelates 4a,b. The same chelates
can be obtained directly from the reaction of ethyl acetoa-
cetate with ¯uorobenzoyl chlorides 2a,b without intermedi-
ate isolation of b,b0-dioxoesters 3a,b when the reaction mass
was treated with copperꢀII) acetate. The decomposition of
copper chelates 4a,b with hydrochloric acid affords free
ligands 3a,b.
Chromone and coumarin fragments enter into the struc-
tures of both natural and synthetic biologically active com-
pounds, therefore creation of new representatives of this
class of compounds is potentially useful. One of the methods
for synthesis of ¯uorine containing benzopyran-2ꢀ4)-ones is
acylation of various b-oxoesters by penta¯uorobenzoyl
chloride [1±4]. We previously developed a method of selec-
tive o-methoxylation of penta¯uorobenzoic acids allowing
us to obtain 2-methoxy-3,4,5,6-tetra¯uorobenzoic acids and
2,6-dimethoxy-3,4,5-tri¯uorobenzoic acids depending on
the conditions [5].
In this paper, acylation of ethyl acetoacetate by these
¯uorobenzoyl chlorides and synthesis of novel ¯uoroben-
zopyran-2ꢀ4)-ones are described.
2. Results and discussion
We obtained the copperꢀII) chelate of ethyl-2-penta¯uor-
obenzoyl-3-oxobutanoate 4c ꢀScheme 2) from the reaction
of ethyl acetoacetate with penta¯uorobenzoyl chloride 3c
when the reaction mass was treated with copperꢀII) acetate.
Decomposition of the latter by hydrogen chloride gives the
corresponding b,b0-dioxoester 3c. Previous attempts to iso-
late b,b0-dioxoester 3c failed because of instability and
intramolecular cyclization into 3-ethoxycarbonyl-2-methyl-
5,6,7,8-tetra¯uorochromone 5b [1].
2.1. Acylation of ethyl acetoacetate by fluorobenzoyl
chlorides
2,6-Dimethoxy-3,4,5-tri¯uorobenzoyl and 2-methoxy-
3,4,5,6-tetra¯uorobenzoyl chlorides 2a,b were obtained
* Corresponding author. Fax: ‡7-3432-745954.
E-mail address: saloutin@ios.uran.ru ꢀV.I. Saloutin).
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ꢀ 0 1 ) 0 0 3 4 6 - 3

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S.P. Kisil' et al. / Journal of Fluorine Chemistry 108 82001) 125±131
Scheme 1.
b,b0-Dioxoesters 3b,c readily cyclized into chromone
6 can be obtained by heating b-diketone 7 in hydrogen
bromide also.
The dif®culty of cyclization of b,b0-dioxoester 3a into a
chromone is explained by the absence of readily leaving
o-¯uorine atoms unlike its penta¯uorophenyl and tetra¯uor-
ophenylsubstituted analogues 3b,c.
5a,b on heating in the absence of solvents or in DMSO
ꢀSchemes 2 and 3). The same chromones can be obtained
from chelates 4b,c by heating in DMSO. The cyclization
proceeds through intramolecular substitution of the o-¯uor-
ine atom in the ¯uorophenyl substituent.
In contrast, b,b0-dioxoester 3a and its chelate 4a are stable
compounds. Attempts to subject the b,b0-dioxoester to
cyclization failed. Heating b,b0-dioxoester 3a in hydrogen
bromide results in chromone 6 or b-diketone 7 depending on
the reaction time and temperature ꢀScheme 4). Treatment of
the latter with copperꢀII) acetate gives chelate 8. Chromone
2.2. Reactions of 3-ethoxycarbonyl-2-methyl-5-methoxy-
6,7,8-trifluoro-4H-1,4-dihydrobenzopyran-4-one 5a
Reactions of 2-ethoxycarbonyl-5,6,7,8-tetra¯uorochro-
mone and 3-ethoxycarbonyl-2-methyl-5,6,7,8-tetra¯uoro-
Scheme 2.

S.P. Kisil' et al. / Journal of Fluorine Chemistry 108 82001) 125±131
127
Scheme 3.
Scheme 4.
chromone with secondary amines is known to give seven-
substituted heterocycles [6,7]. Chromone 5a acts with mor-
pholine in DMSO to yield seven-substituted chromone 9
also ꢀScheme 5). Thus, the substituent at the position ®ve of
chromone cycle does not change the direction of the reaction
with secondary amines.
Chromone 5a on boiling in aqueous ammonia undergoes
an acyl-lactone rearrangement to form 3-iminoacetyl-4-
hydroxy-5-methoxy-6,7,8-tri¯uorocoumarin 10 ꢀScheme 5)
like chromone 5b described previously [7]. Heating
3-iminoacetylcoumarin 10 in dilute sulfuric acid affords
3-acetylcoumarin. Under these conditions, the methoxy
group does not hydrolyze.
Hydrolysis of chromone 5b in an acid medium at room
temperature is known to afford the corresponding chro-
mone-3-carboxylic acid, moreover the reaction is accom-
panied by partial rearrangement of chromone 5b into
3-acetyl-5,6,7,8-tetra¯uorochromone [7]. In contrast to
transformations of chromone 5b, the 5-methoxysubstituted
analogue 5a is not hydrolyzed under these conditions. Under
Scheme 5.

128
S.P. Kisil' et al. / Journal of Fluorine Chemistry 108 82001) 125±131
Scheme 6.
more severe conditions on boiling in an acid medium,
chromone 5a gives chromone 6 as a result of decarboxyla-
tion and hydrolysis of methyl-phenyl ether ꢀScheme 6).
Heating chromone 5a in hydrogen bromide yields chro-
mone-3-carboxylic acid 12 ꢀScheme 6). The same product
may be obtained from b,b0-dioxoester 3b.
Jꢀ4-3† ˆ Jꢀ4-5† ˆ 19:6 Hz), 5.90 ꢀ2F, dq, F-3, F-5,
Jꢀ3-4† ˆ Jꢀ5-4† ˆ 19:6, JF3ÀH ˆ JF5ÀH ˆ 2:2 Hz) ppm. IR:
2950 ꢀCH); 1790 ꢀCOCl); 1500 ꢀC=C); 1125, 1120, 1040
ꢀC±F) cmÀ1. Analysis: Found: C, 42.30; H, 2.37; F, 22.35.
Calc. for C9H6ClF3O3: C, 42.46; H, 2.38; F, 22.39%.
Thus, for the ®rst time, the ¯uoroaryl containing b,b0-
dioxoesters are obtained and their use for the synthesis of
¯uorobenzopyran-2ꢀ4)-ones is established.
3.2.2. 2-Methoxy-3,4,5,6-tetrafluorobenzoylchloride 82b)
In a similar manner, compound 2b ꢀ26 g, 88%) was
obtained from acid 1b ꢀ27.36 g, 0.12 mol). A bp of
1
À908C ꢀ3 Torr). H NMR ꢀCDCl3) d: 4.13 ꢀ3H, d, OCH3,
JHÀF ˆ 2:4 Hz) ppm. 19F NMR ꢀCDCl3) d: 21.6 ꢀ1F, ddd,
F-6,Jꢀ6-5† ˆ 22:0,Jꢀ6-3† ˆ 9:3,Jꢀ6-4† ˆ 4:9 Hz),13.37ꢀ1F,dt,
F-4, Jꢀ4-6† ˆ 4:9, Jꢀ4-5† ˆ Jꢀ4-3† ˆ 20:0 Hz); 8.99 ꢀ1F, ddq,
F-3, Jꢀ3-6† ˆ 9:3, Jꢀ3-4† ˆ 20:0, Jꢀ3-5† ˆ 0; JF3ÀH ˆ 2:4 Hz);
0.25 ꢀ1F, dd, F-5, Jꢀ5-6† ˆ 22:0, Jꢀ5-4† ˆ 20:0, Jꢀ5-3† ˆ 0 Hz)
ppm. IR: 1770 ꢀCOCl); 1630, 1510, 1490 ꢀC=C); 1020
ꢀC±F) cmÀ1. Analysis: Found: C, 39.81; H, 1.34; F,
30.70. Calc. for C8H3ClF4O2: C, 39.76; H, 1.25; F, 31.45%.
3. Experimental details
Melting points were measured in open capillaries and are
reported uncorrected. Infrared spectra were measured on a
Specord 75 IR spectrometer ꢀusing vaseline oil as solvent).
1H and 19F NMR spectra were recorded on a Tesla BS-587A
instrument ꢀ1H: 80 MHz, using TMS as an internal standard,
19F: 75 MHz, using C6F6 as an internal standard). Micro-
analyses were performed with a Carlo Erba CHNS-O EA
1108 elemental analyzer.
3.2.3. Ethyl-2-82,6-dimethoxy-3,4,5-trifluoro-
benzoyl)-3-oxobutanoate 83a)
Ethyl acetoacetate ꢀ4.7 g, 36.1 mmol) was added to a
solution of MgꢀOEt)2 prepared from Mg chips ꢀ9.36 g,
39.1 mmol). The reaction mixture was stirred for 1 h at
508C. A solution of benzoyl chloride 2a ꢀ7.8 g, 30.6 mmol)
in 10 ml of benzene was added. The reaction mixture was
stirred for 1 h at 208C and 15 min at 508C, cooled to 208C
and poured into a solution of conc. HCl ꢀ7.8 ml) in 12 ml of
water. The benzene layer was separated. The aqueous solu-
tion was extracted with benzene ꢀ2 Â 20 ml). The benzene
layers were combined and dried under MgSO4. After dis-
tillation under reduced pressure, compound 3a ꢀ8.5 g, 80%)
was obtained. A bp of 154±1558C ꢀ3 Torr). 1H NMR
ꢀCDCl3, a mixture of two tautomers in a ratio of 11:1) d:
17.63, 14.59 ꢀ1H, br.s, OH); 4.02, 4.05 ꢀ2H, q, OCH2CH3,
3J ˆ 7:1 Hz); 3.90, 3.86 ꢀ3H, d, OCH3, JHÀF3 ˆ 1:7 Hz);
2.51, 2.48 ꢀ3H, s, CH3); 1.01, 1.08 ꢀ3H, t, OCH2CH3, 3J ˆ
3.1. Materials
Acids 1a,b were prepared by the method described
previously [5].
3.2. Acylation of ethyl acetoacetate by fluorobenzoyl
chlorides
3.2.1. 2,6-Dimethoxy-3,4,5-trifluorobenzoylchloride 82a)
Phosphorus pentachloride ꢀ3 g, 14.4 mmol) was added to
acid 1a ꢀ3 g, 12.7 mmol). The mixture was re¯uxed for 1 h
and stored for 12 h at 208C. After distillation in vacuum,
compound 2a ꢀ2.25 g, 70%) was obtained. A bp of 98±
1
1008C ꢀ4 Torr). H NMR ꢀCDCl3) d: 4.04 ꢀ6H, d, 2OCH3,
JHÀF ˆ 2:2 Hz) ppm. 19F NMR ꢀCDCl3) d: 9.98 ꢀ1F, t, F-4,

S.P. Kisil' et al. / Journal of Fluorine Chemistry 108 82001) 125±131
129
7:1 Hz) ppm. 19F NMR ꢀCDCl3, a mixture of two tautomers
cipitate was ®ltered off and dried at 1008C to give compound
4a ꢀ0.23 g, 80%) as a blue powder, mp of 198±2008C ꢀfrom
ethanol). IR: 1680 ꢀC=O), 1560 ꢀC=O); 1480 ꢀC=C); 1030
ꢀC±F) cmÀ1. Analysis: Found: C, 47.44; H, 3.79; F, 14.96.
Calc. for C30H28F6O12Cu: C, 47.53; H, 3.72; F, 15.04%.
in a ratio of 11:1) d: 5.91 ꢀ1F, t, F-4, Jꢀ4-3† ˆ Jꢀ4-5†
ˆ
19:7 Hz), 4.42 ꢀ2F, dq, F-3, F-5, Jꢀ3-4† ˆ Jꢀ5-4† ˆ 19:7,
JF3ÀH ˆ JF5ÀH ˆ 1:7 Hz) ppm. IR: 3450 ꢀOH); 1720
ꢀC=O); 1625 ꢀC=O); 1485 ꢀC=C); 1035 ꢀC±F) cmÀ1. Ana-
lysis: Found: C, 51.93; H, 4.35; F, 16.83. Calc. for
C15H15F3O6: C, 51.73; H, 4.34; F, 16.36%.
3.2.7. Bis8ethyl-2-82-methoxy-3,4,5,6-tetrafluoro-
benzoyl)-3-hydroxy-2-butenoate)copper8II) 84b)
3.2.4. Ethyl-2-82-methoxy-3,4,5,6-tetrafluoro-
benzoyl)-3-oxobutanoate 83b)
In a similar manner, compound 4b ꢀ0.23 g, 78%) was
obtained from compound 3b ꢀ0.27 g, 0.8 mmol) as a blue
powder, mp 135±1398C ꢀfrom ethanol). IR: 1700 ꢀC=O);
1615, 1590 ꢀC=O, C=C); 1490, 1450, 1400 ꢀC=C); 1025
ꢀC±F) cmÀ1. Analysis: Found: C, 46.06; H, 3.15; F, 20.56.
Calc. for C28H22F8O10Cu: C, 45.81; H, 3.02; F, 20.71%.
Ethyl acetoacetate ꢀ23.4 g, 0.18 mol) was added to solu-
tion of MgꢀOEt)2 prepared from Mg chips ꢀ3.51 g,
0.15 mol). The reaction mixture was stirred for 1 h at
508C. A solution of benzoyl chloride 2b ꢀ25 g, 0.1 mol)
in 45 ml of benzene was added. The reaction mixture was
stirred for 1 h at 208C and 15 min at 508C. After cooling, a
solution of copperꢀII) acetate ꢀ12.95 g) and acetic acid
ꢀ5.9 g) in 40 ml of water was added. The organic layer
was separated. The aqueous layer was extracted with ether
ꢀ3 Â 30 ml). The organic layer was dried over MgSO4. The
solvent was removed in vacuum at 208C. The residue was
reprecipitated from MeOH by water to give compound 4b
ꢀ33.5 g, 89%). The physical data were identical to those
listed above.
In a similar manner, compound 3b ꢀ8.5 g, 79%) was
obtained from benzoylchloride 2b ꢀ7.8 g, 31 mmol) as an
oil. 1H NMR ꢀCDCl3, a mixture of two tautomers in a ratio
of 7:1) d: 17.55, 14.61 ꢀ1H, br.s, OH); 4.05, 4.10 ꢀ2H, q,
OCH2CH3, 3J ˆ 7:1 Hz); 3.94, 3.89 ꢀ3H, d, OCH3,
JHÀF3 ˆ 2:0 Hz); 2.54, 2.46 ꢀ3H, s, CH3); 1.05, 1.10 ꢀ3H,
t, OCH2CH3, 3J ˆ 7:1 Hz) ppm. 19F NMR ꢀCDCl3, a mix-
ture of two tautomers in a ratio of 7:1) d: 18.82, 17.18 ꢀ1F,
ddd, F-6, Jꢀ6-5† ˆ 23:0, Jꢀ6-3† ˆ 8:8; Jꢀ6-4† ˆ 2:0 Hz); 7.87,
6.78 ꢀ1F, td, F-4, Jꢀ4-6† ˆ 2:0, Jꢀ4-5† ˆ Jꢀ4-3† ˆ 20:0 Hz);
5.77 ꢀ1F, ddq, F-3, Jꢀ3-6† ˆ 8:8, Jꢀ3-4† ˆ 20:0, Jꢀ3-5† ˆ 0,
JF3ÀH ˆ 2:0 Hz); À1.42 ꢀ1F, ddd, F-5, Jꢀ5-4† ˆ 20:0,
Jꢀ5-3† ˆ 0 Hz) ppm. IR: 2970, 2930 ꢀOH); 1715 ꢀC=O);
1640, 1570 ꢀC=O, C=C); 1510, 1485 ꢀC=C); 1020 ꢀC±
F) cmÀ1. Analysis: Found: C, 50.16; H, 3.86; F, 22.71. Calc.
for C14H12F4O5: C, 50.01; H, 3.60; F, 22.60%.
To a solution of chelate 4b ꢀ19 g, 52 mmol) in 100 ml of
ether, 7 ml of HCl and 15 ml of water were added. The
mixture was stirred at 208C for 15 min. The ether layer was
separated. The aqueous layer was extracted by ether
ꢀ3 Â 15 ml). The combined extracts were washed with water
and dried over MgSO4. The solvent was removed in vacuum
to give compound 3b ꢀ16.55 g, 95%). The physical data were
identical to those listed above.
3.2.8. Bis8ethyl-2-pentafluorobenzoyl-3-
hydroxy-2-butenoato)copper8II) 84c)
Ethyl acetoacetate ꢀ11.7 g, 0.09 mol) was added to solu-
tion of MgꢀOEt)2 prepared from Mg chips ꢀ1.87 g,
0.08 mol). The reaction mixture was stirred for 1 h at
508C.
A solution of benzoyl chloride 2c ꢀ18.4 g,
3.2.5. Ethyl-2-pentafluorobenzoyl-3-oxobutanoate 83c)
Anhydrous gaseous hydrogen chloride was passed
through a solution of chelate 4c ꢀ0.3 g, 0.845 mmol) in
50 ml of dry ether. The resulting precipitate was ®ltered
off. The ether was removed in vacuum at 208C to give
0.08 mol) in 30 ml of benzene was added. The reaction
mixture was stirred for 1 h at 208C and 15 min at 508C. After
cooling, a solution of copperꢀII) acetate ꢀ6.7 g) and acetic
acid ꢀ2.9 g) in 30 ml of water was added. The organic layer
was separated. The aqueous layer was extracted with ether
ꢀ3 Â 20 ml). The organic layer was dried over MgSO4. The
solvent was removed in vacuum at 208C. The residue was
reprecipitated from MeOH by water to give compound 4c
ꢀ8.3 g, 29%) as a green powder, mp 162±1648C ꢀfrom
ethanol). IR: 1680 ꢀC=O); 1630, 1580 ꢀC=O C=C); 1495,
1450, 1430 ꢀC=C); 980 ꢀC±F) cmÀ1. Analysis: Found: C,
43.89; H, 2.22; F, 26.70. Calc. for C26H16F10O8Cu: C, 43.99;
H, 2.27; F, 26.76%.
1
compound 3c ꢀ0.27 g, 99%) as an oil. H NMR ꢀCDCl3, a
mixture of two tautomers in a ratio of 4:1) d: 17.44, 14.65
ꢀ1H, br.s, OH); 4.10, 4.40 ꢀ2H, q, OCH2CH3, 3J ˆ 7:1 Hz);
1.12, 1.39 ꢀ3H, t, OCH2CH3, 3J ˆ 7:1 Hz); 2.57, 2.47 ꢀ3H,
s, CH3) ppm. 19F NMR ꢀCDCl3, a mixture of two tautomers
in a ratio of 4:1) d: 20.21, 18.42 ꢀ2F, m); 9.95 ꢀ1F, m); 1.11,
À2.93 ꢀ2F, m) ppm. IR: 2930 ꢀOH), 1710 ꢀC=O), 1650, 1570
ꢀC=O, C=C), 1520, 1500 ꢀC=C), 985 ꢀC±F) cmÀ1. Analysis:
Found: C, 47.93; H, 2.73; F, 29.15. Calc. for C13H9F5O4: C,
48.16; H, 2.80; F, 29.30%.
3.2.9. 3-Ethoxycarbonyl-2-methyl-5-methoxy-
6,7,8-trifluoro-4H-1,4-dihydrobenzopyrane-4-one 85a)
Compound 3b ꢀ16.5 g, 49 mmol) was distilled at 225±
2268C in vacuum. After cooling, the distillate was crystal-
lized ꢀmp ˆ 50±608C). Recrystallization from hexane gave
3.2.6. Bis8ethyl-2-82,5-dimethoxy-3,4,5-trifluoro-
benzoyl)-3-hydroxy-2-butenoate)copper8II) 84a)
A solution of copperꢀII) acetate ꢀ0.3 g, 1.6 mmol) in
10 ml of water was added to a solution of compound 3a
ꢀ0.27 g, 0.78 mmol) in 1 ml of MeOH. The resulting pre-
1
product 5a ꢀ6 g, 39%) as white crystals ꢀmp 66±688C). H
NMR ꢀCD3COCD3) d: 4.35 ꢀ2H, q, OCH2CH3,

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S.P. Kisil' et al. / Journal of Fluorine Chemistry 108 82001) 125±131
3J ˆ 7:1 Hz); 3.96 ꢀ3H, d, OCH3, JHÀF6 ˆ 0:8 Hz); 2.47
give product 6 ꢀ0.18 g, 71%). The physical data were
identical to those listed above.
ꢀ3H, s, CH3); 1.35 ꢀ3H, t, OCH2CH3, 3J ˆ 7:1 Hz) ppm. 19
F
NMR ꢀCD3COCD3) d: 12.51 ꢀ1F, dd, F-7, Jꢀ7-6† ˆ 21:0;
Jꢀ7-8† ˆ 20:0 Hz), 6.64 ꢀ1F, d, F-6, Jꢀ6-7† ˆ 21:0, Jꢀ6-8†
ˆ
3.2.12. 1-82,6-Dimethoxy-3,4,5-trifluorophenyl)-
butan-1,3-dione 87)
0 Hz), 3.42 ꢀ1F, d, F-8, Jꢀ8-7† ˆ 20:0, Jꢀ8-6† ˆ 0 Hz) ppm.
IR: 1735 ꢀCO2Et); 1660 ꢀC=O); 1630 ꢀC=C); 1485, 1115
ꢀC=C); 1020 ꢀC±F) cmÀ1. Analysis: Found: C, 53.11; H,
3.49; F, 17.99. Calc. for C14H11F3O5: C, 53.17; H, 3.51; F,
18.02%.
To compound 3a ꢀ4.9 g, 19.4 mmol) was added 10 ml of
40% HBr. The reaction mixture was heated at 1008C for 2 h,
cooled to 208C and stored for 3 days. The resulting pre-
cipitate was ®ltered off to give product 7 ꢀ1.4 g, 22%) as a
1
A solution of chelate 4b ꢀ4.1 g, 11.1 mmol) in 15 ml of
DMSO was heated at 808C for 3 h. After cooling, a mixture
of conc. HCl ꢀ15 ml) and water ꢀ30 ml) was added. The
resulting precipitate was collected by ®ltration and recrys-
tallized from hexane to give product 5a ꢀ0.6 g, 18%). The
physical data were identical to those listed above.
white powder, mp 42.5±43.58C ꢀfrom hexane). H NMR
ꢀCDCl3) d: 15.23 ꢀ1H, s, OH), 5.67 ꢀ1H, s, CH), 3.91 ꢀ6H, d,
OCH3, JHÀF3 ˆ JHÀF5 ˆ 1:4 Hz), 2.14 ꢀ1H, s, CH3) ppm.
19F NMR ꢀCDCl3) d: 6.96 ꢀ1F, d, F-4, Jꢀ4-5† ˆ Jꢀ4-3†
ˆ
20:0 Hz), 5.38 ꢀ2F, dd, F-3, F-5, Jꢀ5-3† ˆ Jꢀ3-4† ˆ 20:0,
Jꢀ3-5† ˆ 0, JF3ÀH ˆ JF5ÀH ˆ 1:4 Hz) ppm. IR: 1620
ꢀC=O); 1485 ꢀC=C); 1025 ꢀC±F) cmÀ1. Analysis: Found:
C, 52.07; H, 3.93; F, 20.82. Calc. for C12H11F3O4: C, 52.18;
H, 4.01; F, 20.63%.
3.2.10. 3-Ethoxycarbonyl-2-methyl-5,6,7,8-tetra-
fluoro-4H-1,4-dihydrobenzopyrane-4-one 85b)
Compound 3c ꢀ6.48 g, 0.02 mol) was heated at 100±
1108C for 1 h. The resulting solid was recrystallized from
a mixture of CCl4±hexane ꢀ1:2) to give product 5b ꢀ5.6 g,
92%) as a light yellow crystals ꢀmp 91±928C ꢀlit. mp 908C
[1]). The physical data were identical to those listed [1].
A solution of chelate 4c ꢀ0.5 g, 1.41 mmol) in 12 ml of
DMSO was heated at 808C for 3 h and stored at 208C for
24 h. A mixture of conc. HCl ꢀ12 ml) and water ꢀ12 ml) was
added. The mixture was extracted with ether ꢀ3 Â 15 ml).
The extract was washed with water and dried under
MgSO4. The solvent was removed in vacuum. The residue
was recrystallized from a mixture of CCl4±hexane ꢀ1:2)
to give product 5b ꢀ0.2 g, 47%) as light yellow crystals,
mp 91±928C. The physical data were identical to those
listed [1].
3.2.13. Bis81-82,6-dimethoxy-3,4,5-trifluoro-
phenyl)-1-hydroxy-3-oxo-1-butenoate)cooper8II) 88)
A solution of copperꢀII) acetate ꢀ0.15 g, 0.8 mmol) in
10 ml of water was added to a solution of compound 7
ꢀ0.25 g, 0.78 mmol) in 1 ml of MeOH. The resulting pre-
cipitate was ®ltered off and dried at 1008C to give compound
8 ꢀ0.24 g, 85%) as a blue powder, mp 194±1958C ꢀfrom
ethanol). IR: 1640 ꢀC=O); 1485 ꢀC=C); 1035 ꢀC±F) cmÀ1
.
Analysis: Found: C, 46.53; H, 3.30; F, 18.54. Calc. for
C24H20F6O8Cu: C, 46.95; H, 3.28; F, 18.57%.
3.3. Reactions of 3-ethoxycarbonyl-2-methyl-5-
methoxy-6,7,8-trifluoro-4H-1,4-dihydrobenzopyran-4-one
3.3.1. 6,8-Difluoro-3-ethoxycarbonyl-2-methyl-5-methoxy-
7-morpholino-4H-1,4-dihydrobenzopyran-4-one 89)
3.2.11. 5-Hydroxy-2-methyl-6,7,8-trifluoro-
4H-1,4-dihydrobenzopyrane-4-one 86)
A mixture of compound 5a ꢀ0.3 g, 0.95 mmol) and mor-
pholine ꢀ0.33 g, 3.79 mmol) in 3 ml of DMSO was stored at
208C for 24 h. A mixture of conc. HCl ꢀ5 ml) and water
ꢀ5 ml) was added. The precipitated oil was separated,
washed with boiling hexane and dried to give product 9
A mixture of compound 3a ꢀ0.1 g, 0.286 mmol) and 40%
HBr ꢀ0.1 ml) was heated for 6 h at 1208C, then cooled to
208C. The resulting precipitate was ®ltered off and recrys-
tallized from hexane to give product 6 ꢀ0.05 g, 76%) as a
1
1
white powder ꢀmp 125±1278C). H NMR ꢀCD3COCD3) d:
2.46 ꢀ3H, s, CH3), 6.13 ꢀ1H, s, CH), 12.42 ꢀ1H, s, OH) ppm.
ꢀ0.25 g, 68%) as yellow crystals ꢀmp 90±928C). H NMR
ꢀCDCl3) d: 4.32 ꢀ2H, q, OCH2CH3, 3J ˆ 7:1 Hz); 3.87 ꢀ3H,
s, OCH3); 3.84±3.79 ꢀ4H, m, 2 CH2); 3.44±3.38 ꢀ4H, m, 2
CH2); 2.42 ꢀ3H, s, CH3); 1.35 ꢀ3H, t, OCH2CH3,
3J ˆ 7:1 Hz) ppm. 19F NMR ꢀCDCl3) d: 19.92 ꢀ1F, d,
F-6, Jꢀ6-8† ˆ 4:1 Hz), 14.83 ꢀ1F, d, F-8, Jꢀ8-6† ˆ 4:1 Hz)
IR: 1700 ꢀCO2Et); IR: 1650 ꢀC=O); 1600, 1550 ꢀC=C);
1010 ꢀC±F) cmÀ1. Analysis: Found: C, 56.41; H, 5.15; F,
9.83; N, 3.64. Calc. for C18H19F2NO6: C, 56.40; H, 5.00; F,
9.91; N, 3.65%.
19F NMR ꢀCD3COCD3) d: À5.88 ꢀ1F, dd, F-6, Jꢀ6-7† ˆ 20:5,
Jꢀ6-8† ˆ 4:6 Hz), À1.48 ꢀ1F, dd, F-8, Jꢀ8-7† ˆ 20:5, Jꢀ8-6†
ˆ
4:6 Hz), 14.34 ꢀ1F, t, F-7, Jꢀ7-6† ˆ Jꢀ7-8† ˆ 20:5 Hz) ppm.
IR: 3340 ꢀOH); 1670 ꢀC=O); 1645 ꢀC=O); 1610, 1520
ꢀC=C); 990 ꢀC±F) cmÀ1. Analysis: Found: C, 52.12; H,
2.08; F, 24.78. Calc. for C10H5F3O3: C, 52.19; H, 2.19; F,
24.76%.
By analogy, product 6 ꢀ0.05 g, 40%) was obtained from
compound 7 ꢀ0.15 g, 0.543 mmol) for 3 h. The physical data
were identical to those listed above.
A mixture of compound 5b ꢀ0.3 g, 0.95 mmol), conc. HCl
ꢀ0.4 ml) and acetic acid ꢀ1.5 ml) was heated for 48 h. The
reaction mass was poured into 10 ml of water. The resulting
precipitate was ®ltered off, washed with water and dried to
3.3.2. 3-Iminoacetyl-4-hydroxy-5-methoxy-6,7,8-
trifluoro-4H-1,2-dihydrobenzopyran-2-one 810)
A mixture of compound 5a ꢀ0.3 g, 0.95 mmol) and
ammonium hydroxide ꢀ6 ml) was heated for 15 min. The
resulting precipitate was ®ltered off, washed with water,

S.P. Kisil' et al. / Journal of Fluorine Chemistry 108 82001) 125±131
131
1
dried at 808C to give compound 10 ꢀ0.225 g, 83%) as a
white powder ꢀmp 217±2228C). 1H NMR ꢀCD3COCD3)
d: 12.81 ꢀ1H, br.s, OH); 6.70 ꢀ1H, br.s NH); 4.0 ꢀ3H, d,
OCH3, JHÀF ˆ 1:2 Hz); 2.71 ꢀ3H, s, CH3) ppm. 19F NMR
ꢀCD3COCD3) d: 12.69 ꢀ1F, t, F-7, Jꢀ7-6† ˆ Jꢀ7-8† ˆ 21 Hz),
3.96 ꢀ1F, d, F-8, Jꢀ8-7† ˆ 21, Jꢀ8-6† ˆ 0 Hz), 2.96 ꢀ1F, d, F-6,
Jꢀ6-7† ˆ 21, Jꢀ6-8† ˆ 0 Hz) ppm. IR: 3160, 2940 ꢀNH, OH);
158±1608C). H NMR ꢀCDCl3) d: 12.88 ꢀ1H, br.s, OH);
11.29 ꢀ1H, s, OH); 3.1 ꢀ3H, s, CH3) ppm. 19F NMR ꢀCDCl3)
d: 20.05 ꢀ1F, t, F-7, Jꢀ7-6† ˆ Jꢀ7-8† ˆ 20:7 Hz), 3.18 ꢀ1F, dd,
F-6, Jꢀ6-7† ˆ 20:7, Jꢀ6-8† ˆ 3:0 Hz), À2.92 ꢀ1F, dd, F-8,
Jꢀ8-7† ˆ 20:7, Jꢀ8-6† ˆ 3:0 Hz) ppm. IR: 3100, 2720 ꢀOH);
1750 ꢀCO2H); 1665 ꢀC=O); 1575, 1510 ꢀC=C); 1010
ꢀC±F) cmÀ1. Analysis: Found: C, 48.23; H, 1.85; F,
20.52. Calc. for C11H5F3O5: C, 48.19; H, 1.84; F, 20.79%.
By analogy, product 12 ꢀ0.12 g, 48%) was obtained from
compound 3b ꢀ0.3 g, 0.89 mmol) for 3 h. The physical data
were identical to those listed above.
1650 ꢀC=O); 1610, 1515, 1480 ꢀC=C); 1040 ꢀC±F) cmÀ1
.
Analysis: Found: C, 50.22; H, 2.72; F, 19.85; N, 4.93. Calc.
for C12H8F3NO4: C, 50.19; H, 2.81; F, 19.85; N, 4.88%.
3.3.3. 3-Acetyl-4-hydroxy-5-methoxy-6,7,8-
trifluoro-2H-1,2-dihydrobenzopyran-2-one 811)
A mixture of compound 10 ꢀ0.4 g, 1.39 mmol), conc.
H2SO4 ꢀ2 ml) and water ꢀ2 ml) was heated at 808C for
2 h. The resulting precipitate was ®ltered off and dissolved
in 20 ml of boiling benzene. The solution was ®ltered from
non-dissolved impurity. Benzene was removed in vacuum to
give product 11 ꢀ0.19 g, 50%) as a white powder ꢀmp 101±
1028C). 1H NMR ꢀCDCl3) d: 18.65 ꢀ1H, br.s, OH); 4.04 ꢀ3H,
d, OCH3, JHÀF6 ˆ 1:5 Hz); 2.78 ꢀ3H, s, CH3) ppm. 19F
Acknowledgements
The authors wish to thank the Russian Foundation of
Fundamental Researches for ®nancial support of this work
ꢀGrant no. 00-03-32767a).
References
NMR ꢀCDCl3) d: 17.3 ꢀ1F, t, F-7, Jꢀ7-6† ˆ 21:5, Jꢀ7-8†
ˆ
21:1 Hz), 6.08 ꢀ1F, dd, F-6, Jꢀ6-7† ˆ 21:5, Jꢀ6-8† ˆ 0;
JF6ÀH ˆ 1:5 Hz), 3.82 ꢀ1F, d, F-8, Jꢀ8-7† ˆ 21:1,
Jꢀ8-6† ˆ 0 Hz) ppm. IR: 3100, 2720 ꢀOH); 1750 ꢀCO2H);
1665 ꢀC=O); 1575, 1510 ꢀC=C); 1010 ꢀC±F) cmÀ1. Analy-
sis: Found: C, 50.23; H, 2.54; F, 19.56. Calc. for C12H7F3O5:
C, 50.01; H, 2.45; F, 19.78%.
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