Fluorine-containing heterocycles: X. Acetoacetamides in the synthesis of fluorine-containing chromone

Article abstract of DOI:10.1023/B:RUJO.0000045899.90635.62

Fluorine-containing chromone-3-carboxamides were synthesized by reaction of tetra(penta)fluoro-benzoyl chlorides with acetoacetamides in dichloromethane in the presence of triethylamine. Nucleophilic substitution of fluorine atoms by amine rests in compounds synthesized was investigated.

Full text of DOI:10.1023/B:RUJO.0000045899.90635.62

Russian Journal of Organic Chemistry, Vol. 40, No. 8, 2004, pp. 1162 -1166. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 8, 2004,
pp. 1209-1213.
Original Russian Text Copyright Ó 2004 by Lipunova, Nosova, Kodess, Charushin.
Fluorine-containing Heterocycles: X.*
Acetoacetamides in the Synthesis of Fluorine-containing Chromone
G.N. Lipunova1, E.V. Nosova1, M.I. Kodess2, and V.N. Charushin2
1Ural State Technical University, Yekaterinburg, Russia
2Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences, Yekaterinburg, 620219 Russia
Received June 18, 2003
Abstract—Fluorine-containing chromone-3-carboxamides were synthesized by reaction of tetra(penta)fluoro-
benzoyl chlorides with acetoacetamides in dichloromethane in the presence of triethylamine. Nucleophilic
substitution of fluorine atoms by amine rests in compounds synthesized was investigated.
Selectively recorded 19F NMR spectra of compounds
Interest grew recently to polycyclic derivatives of
IIIa, f contained the same number of signals as the
number of fluorine atoms in the compound. The
molecular ion peaks in the mass spectra of compounds
IIIa–d are sufficiently intensive (38–56%) but the most
abundant is the peak of ion with m/z 241 arising on
elimination of the anilide fragment.
fluorine-containing azaheterocycles possessing anti-
bacterial, tuberculocidal, and other types of biological
activity [2–6]. In extension of our research on the
synthesis of fluoroazaheterocycles by reaction of
polyfluorobenzoyl chlorides I with bifunctional
nucleophiles [1, 7, 8] we deemed promising to apply
acetoacetamides (II).As distinct from alkyl acetoacetates
(classic C,O-dinucleophiles) the acetoacetamides can
undergo N-acylation and function as C,N- or C,O-di-
nucleophiles [9–11]. Therefore the condensation of
reagents I and II might afford either N-aryl-substituted
isoquinolones, chromones with an amide moiety in
position 3, or coumarines.
The structure of cyclocondensation products is
supported by the 13C NMR spectrum registered for
compound IIIa where in the coupling with fluorine are
involved atoms C5–C8, nodal carbons C4a and C8a, and
also the C4 atom of the carbonyl group. These data permit
rejection of isoquinolone and coumarine structures and
confirm the choice of the chromone system III.
The reaction of acyl chlorides I with amides IIa–d in
dichloromethane in the presence of triethylamine at room
temperature within 3 h gave rise to chromones III in
63–76% yield, and we failed to isolate under given
conditions the intermediate products of C-acylation
(Scheme 1).
Chromones were formerly synthesized by reaction of
esters of aceto-, benzoyl-, and pentafluorobenzoylacetic
acids with pentafluorobenzoyl chloride in the presence
of magnesium ethoxide [12–14] but the preparation of
chromone-3-carboxylic acid benzylamide from the
corresponding ethyl ester was mentioned in a single
publication [15].
According to 1H NMR spectra the reaction between
pentafluorobenzoyl chloride (Ib) and acetoacetanilide
(IIa) in dichloromethane in the presence of triethylamine
gave rise to a mixture of N-acyl derivative IV and
chromene IIIg in 1:1 ratio. The presence of a broadened
singlet downfield from the signal of NH group proton in
the 1H NMR spectrum of the mixture (see
EXPERIMENTAL) suggests that the resonance belongs
to the hydroxy group of enol IV. The downfield shift
1
The structure of chromones III was derived using H
and 19F NMR and mass spectra (Table 1). In the 1H NMR
spectra of compounds III appear broadened singlets from
protons of NH groups, singlets from methyl groups in
the a-position with respect to oxygen, and also
1
resonances from the aryl substituent. The H NMR
spectra of chromones IIIa–d possess a characteristic
doublet of doublets of doublets signal from H5 proton.
* For communication IX see [1].
1070-4280/04/4008-1162Ó2004 MAIK “Nauka/Interperiodica”

FLUORINE-CONTAINING HETEROCYCLES: X.
1163
Scheme 1.
5
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2
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I, X = H (a), F (b); II, R1 = R2 = H (a); R1 = CH3, R2 = H (b); R1 = H, R2 = CH3 (c); R1 = OCH3, R2 = H (d); III, X = H,
R1 = R2 = H (a); R1 = CH3, R2 = H (b); R1 = H, R2 = CH3 (c); R1 = OCH3, R2 = H (d); X = F, R1 = CH3, R2 = H (e); R1 = Í,
R2 = CH3 (f); R1 = R2 = H (g); V, X = H, R1 = R2 = H (a); R1 = OÑÍ3, R2 = H (b); X = F, R1 = OÑÍ3, R2 = H (c).
may originate from a hydrogen bond formation; the
existence of enol form is confirmed by a singlet from
CH group at 6.0 ppm.
Thus in this study conditions were established for
preparation of fluorine-containing derivatives of
chromone-3-carboxamide (III).
In reaction of pentafluorobenzoyl chloride (Ib) with
p-acetoacetanisidide (IId) a product of transacylation Vc
was isolated. Amides of similar structure Va, b were
obtained by boiling tetrafluorobenzoyl chloride (Ia) with
anilides IIa, d in toluene; their structure was confirmed
by 1H NMR spectra (see EXPERIMENTAL).
EXPERIMENTAL
1H NMR spectra were registered on spectrometers
Bruker WM-250 and Bruker DRX-400 at operating
frequencies 250.14 and 400.13 MHz respectively, 19F
NMR spectra were measured on spectrometer Bruker
DRX-500 at operating frequency 376.45 MHz. As
internal references were used TMS (1H) and hexafluoro-
A heating of chromone IIIa with morpholine, 2,6-
dimethylmorpholine, ethoxycarbonylpiperazine, or
isopropylamine in acetonitrile for 3 h yielded products
1
of atom F7 replacement VIa–d (Scheme 2). In the H
Scheme 2.
NMR spectra of compounds VI characteristic signal of
proton H5 appears as a doublet of doublets, also are
present a broadened singlet of NH group in the 10.6–
11.0 ppm region, a singlet of the a-methyl group at 2.6–
2.7 ppm, and the resonances of the phenyl substituent
and the corresponding amine rest (Table 2). The values
of proton-fluorine coupling constants 3J 11.5–12.0 and
5J 1.5–2.5 Hz for H5 permit an unambiguous conclusion
on substitution of the F7 atom. Mass spectrum of
compound VIa is consistent with its assumed structure.
2
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IV, NR3R4 = morpholinO (a), 4-ethoxycarbonylpiper-
azino (b), 2,6-dimethylmorpholinO (c), NHCH(CH3)2 (d).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 8 2004

1164
LIPUNOVA et al.
Table 1. 1H, 19F NMR, and mass spectra of compounds IIIa–f
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 8 2004

FLUORINE-CONTAINING HETEROCYCLES: X.
1165
benzene (19F). 13C NMR spectra were obtained on
spectrometer Bruker DRX-400 at operating frequency
100.61 MHz. Mass spectra were measured on Varian
MAT 311A instrument in the following conditions:
accelerating voltage 3kV, catode emission current
300 mA, ionizing electrons energy 70 eV, direct sample
admission into the ion source.
F8) 1.4, 2J(C6, H5) 6.0 Hz], 161.14 C (N–CO), 175.50
d.d.d.d [C4, 4J(C4, F6) 2.6, 5J(C4, F7) 2.6, 6J(C4, F8) 1.2,
3J(C4, H5) 3.7 Hz], 176.10 d [C2, 2J(C2, CH3) 6.7 Hz].
Compounds IIIb–f were prepared in a similar way.
2-Methyl-5,6,7,8-tetrafluoro-4-oxo-4H-chromene-
3-carboxanilide (IIIg) and N-pentafluorobenzoyl-N-
phenylacetamide (IV). To 0.7 g (4.0 mmol) of
acetoacetanilide (IIa) in 6 ml of anhydrous dichloro-
methane was added 1.2 ml (8 mmol) of triethylamine
and then by small portions 1.4 ml (4 mmol) of
pentafluorobenzoyl chloride (Ib) solution in toluene. The
reaction mixture was left standing at room temperature
for 24 h, the separated mixed precipitate of compounds
IIIg and IV was filtered off, washed with water, and
dried. 1H NMR spectrum (DMSO-d6), d, ppm: 1.94 s
[3H, CH3, (IV)], 2.60 s [3H, CH3, (IIIg)], 6.02 s [1H,
CH, (IV)], 7.13 t.t [1H, H4', 3J4',3' 7.5, 4J4',2' 1.2 Hz (IIIg)],
7.21 m [2H, H2', H6' (IV)], 7.35 d.d [2H, H3', H5', 3J3',4'
7.5, 3J3',2' 8.5 Hz (IIIg)], 7.45–7.55 m [3H, H3'–H5' (IV)],
Yields, melting points, and elemental analyses of
compounds synthesized are given in Table 3.
2-Methyl-5-X-6,7,8-trifluoro-4-oxo-4H-chromene-
3-carboxamides (IIIa–f). To a solution of 0.7 g
(4.0 mmol) of acetoacetanilide (IIa) in 6 ml of anhydrous
dichloromethane was added 1.2 ml (8 mmol) of
triethylamine and then dropwise 1.7 ml (4 mmol) of
tetrafluorobenzoyl chloride solution in toluene. The
reaction mixture was left standing at room temperature
for 24 h, the separated precipitate of chromone IIIa was
filtered off, washed with water, and recrystallized from
ethanol. Yield 0.9 g (69%), mp 202–204°C. 13C NMR
spectrum (CDCl3), d, ppm: 22.48 d (CH3, 1J 132.1 Hz),
3
4
7.65 d.d [2H, H2', H6', J2',3' 8.5, J2',4' 1.2 Hz (IIIg)],
10.37 br.s [1H, NH (IIIg)], 15.69 br.s [1H, OH (IV)].
The ratio of compounds IIIg and IV was 1:1.
1
2
107.35 d.d.d [C5, J(C5, H5) 172.9, J(C5, F6) 19.5,
3J(C5, F7) 3.8 Hz], 114.48 d [C3, J(C3, CH3) 2.0 Hz],
4
119.27 d.d.d [C4a, 3J(C4a, F6) 7.4, 3J(C4a, H5) 2.4, 4J(C4a,
2,3,4,5-Tetrafluoro-6-X-benzamides (Va–c). (a) To
a solution of 0.7 g (3.4 mmol) of N-acetoacetyl-p-
anisidine in 6 ml of anhydrous dichloromethane was
added 1.1 ml (7 mmol) of triethylamine and then by small
portions 1.2 ml (3.4 mmol) of pentafluorobenzoyl
chloride (Ib) solution in toluene. The reaction mixture
was left standing at room temperature for 3 h, the
separated precipitate of amide Vc was filtered off, washed
with water, and recrystallized from ethanol. Yield 0.71 g
F7) 2.8 Hz], 120.67 d.d.d.d [C2',6', 1J 162.6, 2J 4.1, 3J 7.3,
4J 3.5 Hz], 124.49 d [C4',1J 160.6 Hz], 128.98 d.d.d [C3',5'
,
1J 157.6, 2J 3.0, 3J 8.5 Hz], 138.01 d.d [C1', 2J 1.7, 3J 9.3
Hz], 140.28 d.d.d.d [C8, 1J(C8, F8) 260.8, 2J(C8, F7) 12.8,
3J(C8, F6) 3.1, 4J(C8, H5) 1.7 Hz], 141.28 d.d.d.d [C8a,
2J(C8a, F8) 8.7, J(C8a, H5) 9.6, J(C8a, F7) 2.8, J(C8a,
3
3
4
F6) 2.8 Hz], 144.01 d.d.d.d [C7, J(C7, F7) 261.8,
1
2J(C7, F6) 17.6, J(C7, F8) 11.6, 3J(C7, H5) 1.9 Hz],
2
149.07 d.d.d.d [C6,1J(C6, F6) 253.7,2J(C6, F7) 11.0, 3J(C6,
1
(66%), mp 188–190°C. H NMR spectrum (DMSO-d6),
Table 3. Yields, melting points, and elemental analyses of compounds synthesized
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 8 2004

1166
LIPUNOVA et al.
d, ppm: 3.76 s (3H, OCH3), 6.88 d (2H, H3', H5',
2. Organofluorine Compounds in Medicinal, Chemistry and
Biomedical Applications, Filler, R., Kobayashi, Y., and
Yagupolskii, L.M., Eds., Amsterdam: Elsevier, 1993, 480 p.
3. Mokrushina, G.A., Nosova, E.V., Lipunova, G.N., and
Charushin, V.N., Zh. Org. Khim., 1999, vol. 35, p. 1447.
4. Deetz, M.J., Malerich, J.P., Beatty,A.M., and Smith, B.D.,
Tetrahedron Lett., 2001, vol. 42, p. 1851.
5. Lipunova, G.N., Nosova, E.V., Mokrushina, G.A.,
Sidorova, L.P., and Charushin, V.N., Khim.-Farm. Zh.,
2000, vol. 34, p. 20.
3
3J 8.8 Hz), 7.54 d (2H, H2', H6', J 8.8 Hz), 10.59 br.s
(1H, NH).
(b) To a dispersion of 0.7 g (4 mmol) of acetoacet-
anilide in 10 ml of anhydrous toluene was added 1.6 ml
(11 mmol) of tetrafluorobenzoyl chloride solution in
toluene. The reaction mixture was heated at reflux for
1.5 h, and then evaporated. The residue was washed with
ethanol and recrystallized from ethanol to obtain
1
compound Va. Yield 0.97 g (82%), mp 125–127°C. H
NMR spectrum (DMSO-d6), d, ppm: 7.15 m (1H, H4'),
7.38 m (2H, H2', H6'), 7.69 m (2H, H3', H5'), 7.78 m (1H,
H6), 10.60 br.s (1H, NH).
6. Nosova, E.V., Kravchenko, M.A., Lipunova, G.N.,
Chasovskikh, O.M., Sokolov, V.A., and Charushin, V.N.,
Khim.-Farm. Zh., 2002, vol. 36, p. 12.
7. Lipunova, G.N., Nosova, E.V., Vasil’eva, P.V., and Cha-
rushin, V.N., Izv. Akad. Nauk, Ser. Khim., 2003, p. 436.
8. Nosova, E.V., Lipunova, G.N., Kodess, M.I., Vasil’e-
va, P.V., and Charushin, V.N., Izv. Akad. Nauk, Ser. Khim.,
2004, no. 8.
9. Alekseev, S.G., Charushin, V. N., Chupakhin, O.N.,
Aleksandrov,G.G.,Shorshnev,S.V.,andChernyshev,A.I.,
Izv. Akad. Nauk, Ser. khim., 1989, p.1637.
10. Kazantseva, I.V., Baklykov, V.G., Charushin, V.N., and
Chupakhin, O.N., Khim. Geterotsikl. Soed., 1986, p. 420.
11. Albert, A. and Miruno, N.J., J. Chem. Soc., Perkin Trans.
I, 1973, p. 1615.
12. Vorozhtsov, N.N., Barkhash, V.A., Prudchenko, A.T., and
Khomenko, T.I., Zh. Obshch. Khim., 1965, vol. 35, p. 1501.
13. Saloutin, V.I., Burgart, Ya.V., and Chupakhin, O.N.,
Ftorsoderzhashchie trikarbonil’nye soedineniya (Fluoro-
contaning Three Carbonyl Compounds), Ekaterinburg:
Ural. Russian Akad. Nauk, 2002, 242 p.
Likewise was prepared compound Vb. 1H NMR
spectrum (DMSO-d6), d, ppm: 3.76 C (3H, OCH3),
6.87 d (2H, H3', H5', 3J 8.9 Hz), 7.57 d (2H, H2', H6',
3J 8.9 Hz), 7.57 m (1H, H6), 10.21 br.s (1H, NH).
2-Methyl-6,8-difluoro-7-NR3R4-4-oxo-4H-
chromene-3-carboxanilides (VIa–f). To a dispersion of
0.4 g (1.2 mmol) of compound IIIa in 8 ml of acetonitrile
was added 0.5 ml (6 mmol) of morpholine. The reaction
mixture was heated to 80°C for 3 h. On cooling the
precipitate of derivative VIa was filtered off and
recrystallized from acetonitrile. Yield 0.39 g (81%), mp
200–202°C.
Compounds VIb–d were prepared in a similar way.
The study was carried out under financial support of
the Russian Foundation for Basic Research (grants nos.
03-03-32254, 00-03-40139, and no. 04-03-96107-Ural)
and of Ministry of Education (grant PD 02-1.3-81).
14. Kisil, S.P., Burgart, Y.V., Saloutin, V.I., and Chupa-
khin, O.N., J. Fluor. Chem., 2001, vol. 108, p. 125.
15. Vorozhtsov, N.N., Barkhash, V.A., Prudchenko, A.T., and
Khomenko, T.I., Dokl. Akad. Nauk SSSR, 1965, vol. 164,
p. 1046.
REFERENCES
1. Lipunova, G.N., Nosova, E.V., Mokrushina, G.A.,
Ogloblina,E.G.,Aleksandrov, G.G., and Charushin, V.N.,
Zh. Org. Khim., 2003, vol. 39, p. 270.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 8 2004