Structure of diethyl (polyfluorobenzoyl)malonates and their thermal intramolecular cyclization

Article abstract of DOI:10.1007/s11172-011-0145-4

The reaction of the C-ethoxymagnesium derivative of diethyl malonate with polyfluorobenzoyl chlorides affords the corresponding (polyfluorobenzoyl) malonates prone to thermal cyclization into coumarin derivatives. The compounds obtained are inherent in ke

Full text of DOI:10.1007/s11172-011-0145-4

Russian Chemical Bulletin, International Edition, Vol. 60, No. 5, pp. 929—932, May, 2011
929
Structure of diethyl (polyfluorobenzoyl)malonates
and their thermal intramolecular cyclization*
D. N. Bazhin, E. V. Schegol´kov, Yu. S. Kudyakova, Ya. V. Burgart, and V. I. Saloutin
I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22 ul. S. Kovalevskoi, 620990 Ekaterinburg, Russian Federation.
Fax: +7 (343) 362 3105. Eꢀmail: bazhin@ios.uran.ru
The reaction of the Cꢀethoxymagnesium derivative of diethyl malonate with polyfluoꢀ
robenzoyl chlorides affords the corresponding (polyfluorobenzoyl)malonates prone to thermal
cyclization into coumarin derivatives. The compounds obtained are inherent in keto—enol
tautomerism.
Key words: malonates, coumarins, heterocyclization, keto—enol tautomerism, organoꢀ
fluorine compounds.
Scheme 1
Diethyl (polyfluorobenzoyl)malonates are key interꢀ
mediates in the synthesis of polyfluorineꢀcontaining quiꢀ
nolones1—4 and benzothiazines5 exhibiting antiviral,6 anꢀ
tibacterial,7 and antitumor8 activity. Fluoroquinolones
represent a particular group of modern antibiotics, such as
ofloxacin, levofloxacin, and others. Polyfluorobenzoylꢀ
malonates are not often obtained in the pure form and are
generally used in situ for the synthesis of the correspondꢀ
ing 3ꢀoxoesters.9—11 No data were found on other transꢀ
formations of this type of compounds.
The purpose of the present work is to obtain diethyl
(polyfluorobenzoyl)malonates and to study their structures
and further chemical transformations.
The reactions of 2,3,4,5ꢀtetrafluorobenzoyl (1а) and
pentafluorobenzoyl (1b) chlorides with malonic ester unꢀ
der the action of magnesium ethoxide afforded diethyl
(polyfluorobenzoyl)malonates (2a,b) (Scheme 1) similarly
to earlier works.11—13
X = H (a), F (b)
The structures of isolated (polyfluorobenzoyl)malonꢀ
ates 2a,b (Scheme 2) were studied in detail. Their individꢀ
ual character was confirmed by TLC, the quantitative
composition was established using elemental analysis, and
structural features and tautomeric composition were studied
by IR spectroscopy and 1H and 19F NMR spectroscopy.
Compounds 2a,b are prototropic systems and, accordꢀ
ing to the data of NMR spectroscopy, in CDCl3 solutions
they exist as a mixture of tautomeric forms A and B.
The presence of the enol form in the spectra is indicated
by the signal of the proton of the hydroxyl group at
δ 13.82—13.96, and keto form А can easily be identified by
the signal of the methine proton at δ 5.10—5.42. The sigꢀ
i. EtOMgCH(CO2Et)2, toluene, 0 °С; ii. 150—200 °C.
Scheme 2
* Dedicated to Academician of the Russian Academy of Scienꢀ
ces V. N. Charushin on his 60th birthday.
X = H (a), F (b)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 907—910, May, 2011.
1066ꢀ5285/11/6005ꢀ929 © 2011 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
Bazhin et al.
nals of protons of the ethoxy group of form B are observed
as two different signals because of their nonequivalence
caused by the formation of an intramolecular hydrogen
bond between the proton of the hydroxyl group and the
oxygen atom of one of the ester fragments (see Scheme 2).
It should be mentioned that tetrafluorineꢀcontaining
benzoylmalonate 2а is characterized by the difference
in signals of protons of the tetrafluorophenyl groups of
the enol and keto forms detected at δ 7.16 and 7.80,
respectively.
Based on the assignment of the signals of protons to
two forms and comparison of their integral intensities for
tetrafluorobenzoylmalonate 2a, we observed the predomiꢀ
nation of the keto form (67%) over the enol form (33%),
due to which compound 2a is close to polyfluoroalkyl
analogs.14 Unlike 2a, pentafluorinated analog 2b was enoꢀ
lized by 80%. Evidently, its higher susceptibility to enoꢀ
lization is due to the additive action of the negative inducꢀ
tive effect of two orthoꢀfluorine atoms.
The thermal transformation of diethyl (polyfluoroꢀ
benzoyl)malonates 2a,b found in this work is a convenient
route for the synthesis of fluorineꢀcontaining 4ꢀhydroxyꢀ
polyfluorocoumarins. The chromone—coumarin rearꢀ
rangement of 3ꢀethoxycarbonylꢀ2ꢀmethylꢀ5,6,7,8ꢀtetraꢀ
fluorochromone has earlier21 been used for the synthesis
of 3ꢀsubstituted 4ꢀhydroxyꢀ5,6,7,8ꢀtetrafluorocoumarins.
This chromone was obtained by the oneꢀstep acylation of
acetoacetic ester with pentafluorobenzoyl chloride in the
presence of magnesium ethoxide and without isolation of
intermediately formed β,β´ꢀdioxo ester.22
A distinctive feature of thermal cyclization of comꢀ
pounds 2a,b is the participation of the oxygen atom of the
ester group as a nucleophilic center. The formation of
4ꢀhydroxypolyfluorocoumarins 3a,b proceeds without catꢀ
alysts and in the absence of bases and solvent, while
the intramolecular cyclization of 2ꢀ(2ꢀacetoxybenzoyl)ꢀ
malonate to 4ꢀhydroxyꢀ3ꢀethoxycarbonylcoumarin deꢀ
scribed in the literature23 occurs only under acidic condiꢀ
tions.23
The obtained coumarin derivatives 3a,b can also be
susceptible to keto—enol transformations and, therefore,
it is reasonable to assume for them the existence of three
tautomeric forms С, D, and E (Scheme 3).
The Xꢀray diffraction analysis carried out for a crystal
of compound 3a (Fig. 1) unambiguously showed that this
substance is ethyl 4ꢀhydroxyꢀ2ꢀoxoꢀ6,7,8ꢀtrifluorobenzoꢀ
pyran(2Н)ꢀ3ꢀcarboxylate (form С). The coumarin ring of
the molecule is planar. An intramolecular hydrogen bond
between the atoms O(2) and H(4) has the following charꢀ
acteristics: the intramolecular distance O(2)…H(4) is
1.61(2) Å and the angles C(7)O(4)H(4) and H(4)O(2)C(10)
are 102(1) and 99.0(6)°, respectively.
The IR spectra of benzoylmalonates 2a,b recorded in
thin layer contain two absorption bands of the ethoxycarbꢀ
onyl groups at ν 1741—1739 cm–1 and 1705—1703 cm–1
.
The first of them is close in value to the absorption of the
isolated ester group and is caused by vibrations of two
equivalent ethoxycarbonyl groups of keto form А. The band
at ν 1705—1703 cm–1 corresponds to vibrations of the
unbound ester group of enol form B. The lowꢀfrequency
shift of the band of this group is caused by its conjugation
with the С=С bond. These data indicate the existence of
diesters 2a,b in a mixture of keto and enol forms (А and В)
without a solvent.
We found that the distillation of diesters 2a,b produces
byꢀproducts identified as 4ꢀhydroxypolyfluorocoumarins
(3a,b). Obviously, this heterocyclization is caused by heatꢀ
ing. Heating of neat benzoylmalonates 2a,b to 150—200 °С
results in their complete conversion to products 3a,b in
high yields 82—89% (see Scheme 1).
The substitution of the fluorine atom by the action of
diverse nucleophiles is an important property characterisꢀ
tic of polyfluorinated aromatic compounds.15—19 Transꢀ
formation 2→3 is a particular case of intramolecular subꢀ
stitution of the fluorine atom in the orthoꢀposition under
the action of the nucleophilic center to form the sixꢀmemꢀ
bered cycle.10,20
A comparative analysis of the IR spectra of compounds
3a,b revealed no substantial difference between them.
These compounds have the characteristic absorption band
at ν 2642—2640 cm–1 corresponding to vibrations of the
hydroxyl group bound by the intramolecular hydrogen
bond, the strong absorption band at ν 1736—1735 cm–1
caused by vibrations of the carbonyl group of the lactone
fragment, and the absorption band at ν 1644—1643 cm–1
due to vibrations of the ester group bound by the intramoꢀ
lecular hydrogen bond. Thus, the data of IR spectroscopy
indicate that compounds 3a,b exist as enol form C.
Scheme 3

(Polyfluorobenzoyl)malonates
O(4)
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
931
retrieving.html (or CCDC No. 811 939, 12 Union Road, Camꢀ
bridge CB2 1EZ, UK; eꢀmail: deposit@ccdc.cam.ac.uk).
The initial 2,3,4,5ꢀtetrafluorobenzoyl (1а) and 2,3,4,5,6ꢀpenꢀ
tafluorobenzoyl (1b) chlorides and diethyl malonate are comꢀ
mercially available synthones.
O(2)
H(4)
C(7)
F(3)
C(5)
C(10)
C(11)
C(12)
C(6)
C(4)
C(8)
C(1)
O(3)
O(5)
C(3)
C(9)
Diethyl (2,3,4,5ꢀtetrafluorobenzoyl)malonate (2а). Anꢀ
hydrous CCl4 (1 mL) and absolute ethanol (>99.9%, 7 mL) and
then a mixture of diethyl malonate (32 g, 0.20 mol) and absolute
toluene (100 mL) were added to iodineꢀactivated magnesium
chips (4.6 g, 0.20 mol). After magnesium was dissolved, the obꢀ
tained homogeneous solution was evacuated until a viscous resiꢀ
due was formed to which absolute ethanol (150 mL) was added.
The reaction mixture was cooled to 0 °С, and a solution of tetraꢀ
fluorobenzoyl chloride 1а (40 g, 0.20 mol) in absolute toluene
(70 mL) was added. The mixture was stored for 3 h. A 10%
solution of H2SO4 (250 mL) was added, and the organic layer
was separated and washed with water. The solvent was distilled
off under reduced pressure, and the residue was distilled in vacuo.
Oily yellow product 2а was obtained in a yield of 59.81 g (89%),
b.p. 140—143 °С (3 Torr). IR, ν/cm–1: 3079, 2987, 2942, 2910
(О—Н, C—H); 1739 (С=О); 1703 (С=О); 1632 (C=О); 1526
(С=С); 1485, 1448, 1407, 1365 (C=CAr); 1277, 1236 (C—F).
1H NMR (CDCl3), δ of mixture of tautomers А—B (67 : 33):
tautomer А, 1.30 (t, 3 Н, Me, J = 7.1 Hz); 4.30 (q, 2 Н, СH2,
J = 7.1 Hz); 5.10 (d, 1 Н, CH, J = 2.6 Hz); 7.80 (dddd, 1 Н, С6F4H,
J = 10.4 Hz, J = 8.4 Hz, J = 6.1 Hz, J = 2.5 Hz); tautomer B,
1.15 and 1.38 (both t, 6 Н, 2 Me, J = 7.1 Hz); 4.12 and 4.37 (both q,
4 Н, 2СH2, J = 7.1 Hz); 7.16 (m, 1 Н, С6F4H), 13.83 (s, 1 Н,
OH). 19F NMR (CDCl3), δ: tautomer А, 8.83 (m, 1 F); 17.00
(m, 1 F); 25.82 (m, 1 F); 26.40 (m, 1 F); tautomer B, 7.46 (m, 1 F);
10.73 (m, 1 F); 23.81 (dddd, 1 F, J = 21.1 Hz, J = 12.7 Hz,
J = 9.9 Hz, J = 3.2 Hz); 24.68 (tdd, 1 F, J = 18.4 Hz, J = 12.0 Hz,
J = 5.9 Hz). Found (%): С, 49.87; Н, 3.47; F, 22.49. C14H12F4O5.
Calculated (%): С, 50.01; Н, 3.60; F, 22.60.
C(2)
O(1)
F(2)
F(1)
Fig. 1. General view of a molecule of compound 3a.
1
The H NMR spectra of 4ꢀhydroxypolyfluorocouꢀ
marins 3a,b detected in DMSOꢀd6 exhibit the single set of
signals corresponding to the enol form. The signal of the
proton of the hydroxyl group is observed in a weak field
(δ 10.36) due to its deshielding because of the formation of
an intramolecular hydrogen bond with the oxygen atom of
the ester substituent.
Generalizing the data obtained in this work, note that
diethyl (polyfluorobenzoyl)malonates are convenient synꢀ
thones for the synthesis of fluoroaromatic βꢀoxo esters
and also fluorineꢀcontaining heterocycles. In addition, our
work showed that the desired purity and high yield of
(polyfluorobenzoyl)malonates used as key intermediates
in the synthesis of antibiotics of the fluoroquinolone series
can be achieved by a decrease in the distillation temperaꢀ
ture due to the pressure drop.
Experimental
IR spectra were recorded on a Perkin—Elmer Spectrum One
B FTꢀIR spectrometer in the range from 4000 to 400 cm–1 in
thin layer on KBr plates (compounds 2a,b) or with a DRA difꢀ
Diethyl (2,3,4,5,6ꢀpentafluorobenzoyl)malonate (2b). Yellow
oil. The yield was 87%, b.p. 125—127 °С (3 Torr). IR, ν/cm–1
:
3078, 2988, 2942, 2911 (О—Н, C—H); 1741 (С=О); 1705
(С=О); 1631 (C=О); 1524 (С=С); 1485, 1448, 1408, 1365
(C=CAr); 1276, 1237 (C—F). 1H NMR (CDCl3), δ of mixture of
tautomers А—B (20 : 80): tautomer А, 1.28 (m, 3 Н, Me); 4.29
(q, 2 Н, СH2, J = 7.1 Hz); 5.42 (s, 1 Н, CH); tautomer B, 1.14
and 1.39 (both t, 6 Н, 2 Me, J = 7.1 Hz); 4.11 and 4.40 (both q,
4 Н, 2 СH2, J = 7.1 Hz); 13.96 (s, 1 Н, OH). 19F NMR (CDCl3),
δ: tautomer А, 1.53 (m, 2 F); 14.39 (m, 1 F); 24.79 (m, 2 F);
26.40 (m, 1 F); tautomer B, 0.75 (m, 2 F); 11.03 (m, 1 F); 22.79
(m, 2 F). Found (%): С, 47.31; Н, 3.01; F, 26.69. C14H11F5O5.
Calculated (%): С, 47.47; Н, 3.13; F, 26.82.
1
fuse reflectance attachment (products 3a,b). H and 19F NMR
spectra were measured on a Bruker DRX 400 spectrometer with
working frequencies of 400.1 MHz (1Н) and 376.5 MHz (19F)
using Me4Si and C6F6 as internal standard, respectively. Eleꢀ
mental analysis was carried out on a Perkin—Elmer CHN РЕ
2400 automated analyzer. Melting points were measured in open
capillaries on a Stuart SMP30 instrument.
Single crystals of compounds 3а were obtained by crystalliꢀ
zation from toluene. The Xꢀray diffraction experiment was carried
out on an Xcalibur 3 diffractometer with a CCD detector (graphite
monochromator, λ(MoꢀKα) 0.71073 Å, temperature 295(2) K,
ω scan mode). An absorption correction was applied analyticalꢀ
ly by the multifacet crystal model using the CrysAlis RED
1.171.29.9 program. The crystal structure was solved and refined
using the SHELXSꢀ97 and SHELXLꢀ97 program packages.24
Selected crystallographic data for compound 3а: C12H7F3O5;
M 288.18; monoclinic crystal system with the following unit cell
parameters: a = 5.2114(3), b = 24.991(2), c = 8.8377(10) Å;
Ethyl 4ꢀhydroxyꢀ6,7,8ꢀtrifluoroꢀ2ꢀoxoꢀ2Нꢀbenzopyranꢀ3ꢀ
carboxylate (3a). Diester 2a (20 g, 0.06 mmol) was heated to
150—…200 °С, and the solid product was washed with ethanol.
Product 3a was obtained as a yellow powder in a yield of 12.1 g
(89%), m.p. 169—170 °С. IR, ν/cm–1: 3060, 2991, 2946, 2911
(C—H); 2642 (O—H); 1736 (С=Оlactone); 1644 (С=O); 1575,
1
1519, 1478, 1418, 1379 (C=CAr); 1046, 1024, 995 (C—F). H
NMR (DMSOꢀd6), δ: 1.30 (t, 3 Н, Me, J = 7.1 Hz); 4.31 (q, 2 Н,
CH2, J = 7.1 Hz); 7.81 (ddd, 1 Н, С6F4H, J = 10.3 Hz, J = 8.1 Hz,
J = 2.3 Hz); 10.36 (s, 1 Н, OH). 19F NMR (DMSOꢀd6), δ: 9.30
(td, 1 F, J = 20.4 Hz, J = 2.2 Hz); 11.54 (ddd, 1 F, J = 22.3 Hz,
J = 20.4 Hz, J = 8.1 Hz); 22.91 (ddd, 1 F, J = 22.7 Hz, J = 10.4 Hz,
J = 2.1 Hz). Found (%): С, 49.89; Н, 2.26; F, 19.58. C12H7F3O5.
Calculated (%): С, 50.01; Н, 2.45; F, 19.78.
α = γ = 90°, β = 96.036(8)°; V = 1114.64(18) Å3; Z = 4; dcalc
=
= 1.672 g cm–3; μ = 0.161 mm–1; space group P21/c. The total
number of reflections was 7182, the number of independent reꢀ
flections was 3215, the R1 factor was 0.040, and the number of
refined parameters was 185. The full crystallographic parameꢀ
ters for product 3а are available at www.ccdc.cam.ac.uk/conts/

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Bazhin et al.
Ethyl 4ꢀhydroxyꢀ5,6,7,8ꢀtetrafluoroꢀ2ꢀoxoꢀ2Нꢀbenzopyranꢀ
10. V. I. Saloutin, Z. E. Skryabina, I. T. Bazyl´, O. N. Chupaꢀ
khin, J. Fluor. Chem., 1993, 65, 37.
11. R. Filler, Y. S. Rao, A. Biezais, F. N. Miller, V. D. Beaucaire,
J. Org. Chem., 1970, 35, 930.
3ꢀcarboxylate (3b). Yellow powder. The yield was 82%, m.p.
139—140 °С. IR, ν/cm–1: 3062, 2992, 2946, 2912 (C—H); 2640
(O—H); 1735 (С=Оlactone); 1643 (С=O); 1575, 1521, 1478, 1419,
1383 (C=CAr); 1052, 1026, 1002 (C—F). 1H NMR (DMSOꢀd6),
δ: 1.25 (t, 3 Н, Me, J = 7.1 Hz); 4.22 (q, 2 Н, CH2, J = 7.1 Hz);
10.36 (s, 1 Н, OH). 19F NMR (DMSOꢀd6), δ: –2.95 (t, 1 F,
J = 22.2 Hz); 2.00 (ddd, 1 F, J = 22.1 Hz, J = 11.0 Hz, J = 1.9 Hz);
10.82 (t, 1 F, J = 22.3 Hz); 18.44 (br.s, 1 F). Found (%): С, 46.92;
Н, 1.83; F, 24.69. C12H6F4O5. Calculated (%): С, 47.08; Н, 1.98;
F, 24.82.
12. A. T. Prudchenko, G. S. Shchegoleva, V. A. Barkhash, N. N.
Vorozhtsov, Jr., Zh. Obshch. Khim., 1967, 37, 2487 [J. Gen.
Chem. USSR (Engl. Transl.), 1967, 37].
13. A. T. Prudchenko, V. A. Barkhash, N. N. Vorozhtsov, Jr.,
Izv. Akad. Nauk SSSR, Ser. Khim., 1965, 1798 [Bull. Acad.
Sci. USSR, Div. Chem. Sci. (Engl. Transl.), 1965, 14, 1762].
14. V. M. Krokhalev, V. I. Saloutin, A. D. Romas´, B. A. Erꢀ
shov, K. I. Pashkevich, Izv. Akad. Nauk SSSR, Ser. Khim.,
1990, 376 [Bull. Acad. Sci. USSR, Div. Chem. Sci.
(Engl. Transl.), 1990, 39, 316].
15. K. Burger, E. Brunner, Adv. Heterocycl. Chem., 1994, 60, 1.
16. H. Amii, K. Uneyama, Chem. Rev., 2009, 109, 2119.
17. E. V. Nosova, G. N. Lipunova, V. N. Charushin, O. N.
Chupakhin, J. Fluor. Chem., 2010, 131, 1267.
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2010, 131, 1327.
This work was financially supported by the Ural Branch
of the Russian Academy of Sciences (Program No. 09ꢀPꢀ
3ꢀ2001) and the Ministry of Education and Science of the
Russian Federation (State Contract No. 02.522.12.2011).
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Received January 27, 2011