Synthesis of naphtho[2,3-b]furan-4,9-diones having a trifluoromethyl group under conditions of phase-transfer catalysis

Full text of DOI:10.1023/B:RUJO.0000034925.06446.8a

Russian Journal of Organic Chemistry, Vol. 40, No. 1, 2004, pp. 134-136. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 1, 2004,
pp. 143-145.
Original Russian Text Copyright Ó 2004 by Davydov, Beletskaya.
SHORT
COMMUNICATIONS
Dedicated to Full Member of the Russian Academy of Sciences
A.I. Konovalov on the 70th Anniversary of His Birth
Synthesis of Naphtho[2,3-b]furan-4,9-diones
Having a Trifluoromethyl Group under Conditions
of Phase-Transfer Catalysis
D. V. Davydov and I. P. Beletskaya
Faculty of Chemistry, Lomonosov Moscow State University, Vorob’evy Gory, Moscow, 119992 Russia
e-mail: dvdav@elorg.chem.msu.ru
Received December 17, 2003
4,9-diones ensures formation of the expected condensa-
tion product, Va or VIa. Our attempts to obtain the target
products under conditions of phase-transfer catalysis us-
ing the system benzene–50% NaOH–Bu4NBr [16] or
toluene–K2CO3–Me3(C16H33)NBr on heating were also
unsuccessful. On the other hand, replacement of toluene
in the latter system by o-xylene allowed us to isolate the
condensation products in 15–35% yield.
Naphtho[2,3-b]furan-4,9-diones are fairly widely
spread in nature [1], and they exhibit versatile biological
activity [2–6]. Introduction of fluorine-containing substitu-
ents, e.g., CF3 group, into molecules of a biologically ac-
tive compound usually improves its properties, specifi-
cally enhances its lipophilicity and volatility [7]. A sim-
plest version of the synthesis of naphtho[2,3-b]furan-4,9-
dione having a trifluoromethyl group may be condensa-
tion of a 2,3-disubstituted 1,4-naphthoquinone with a
4,4,4-trifluoro-1,3-dicarbonyl compound. While studying
the reactivity of enolates derived from 1,3-diketones in
nucleophilic substitution at an sp2-hybridized carbon atom,
we examined the possibility of synthesizing 3-aroyl-2-
trifluoromethyl-naphtho[2,3-b]furan-4,9-diones Va–Vg by
reaction of 2,3-dichloronaphthoquinone (I) with the cor-
responding 4,4,4-trifluoro-1-phenyl-1,3-butanediones IIa–
IIg (Scheme 1). It should be noted that we previously
observed formation of benzofurans in analogous processes
with participation of nonfluorinated 1,3-dicarbonyl com-
pounds [8–10] and that strongly acidic 4,4,4-trifluoro-1,3-
dicarbonyl compounds (pKa = 5.4–6.0) [11] failed to re-
act under similar conditions [9].
These findings indicated that, in the initial stage of
the process, substrate I is attacked (at least partially) by
the nucleophilic carbon center of the ambident anion de-
rived from diketone II to give two possible substitution
products, III and IV. We believe that this reaction is the
first example of substitution at an sp2-hybridized carbon
atom involving a soft nucleophilic carbon center in strongly
acidic enolates derived from 1,3-dicarbonyl compounds
[11]. In the second stage of the process, intermediate
enolates III or IV are capable of undergoing intramo-
lecular cyclization to isomeric naphthofurandiones V or
VI with participation of the hard oxygen center [8, 9].
The choice between the isomeric condensation products
(structures V and VI) was made on the basis of the
13C NMR data. The 13C NMR spectra of naphtho-
[2,3-b]furan-4,9-diones V should contain three singlets
from three nonequivalent carbonyl carbon atoms. Isomers
VI should give rise to two singlets from the carbonyl
groups in the naphthoquinone fragment and one quartet
from the trifluoroacetyl group due to coupling with fluo-
rine nuclei. In the 13C NMR spectra of the condensation
products obtained from diketones IIa, IIb, and IId we
observed only three singlets in the dC region from 165 to
200 ppm. These data unambiguously indicated that the
Several general procedures for the synthesis of
naphtho[2,3-b]furan-4,9-diones from 2,3-dichloronaphtho-
quinone (I) and fluorine-free 1,3-dicarbonyl compounds
have been reported [12]. These procedures are based on
condensation of the reactants in alcohol in the presence
of an organic base [13, 14] or in DMF in the presence of
KF [15]. Optimization of the reaction conditions with com-
mercially available 4,4,4-trifluoro-1-phenyl-1,3-butane-
dione (Ia) as an example showed that none of the classi-
cal procedures for the preparation of naphtho[2,3-b]furan-
1070-4280/04/4001-0134Ó2004 MAIK “Nauka/ Interperiodica”

SYNTHESIS OF NAPHTHO[2,3-b]FURAN-4,9-DIONES
135
Scheme 1.
II–VI,Ar = Ph (a), 4-FC6H4 (b), 4-BrC6H4 (c), 4-MeOC6H4 (d), 3,4-(MeO)2C6H3 (e), 3,4,5-(MeO)3C6H2 (f), 2-thienyl (g).
1
mp 192–194°C (from CHCl3). H NMR spectrum
(CDCl3), d, ppm: 7.50–7.86 m (5H, Ph), 7.88–7.93 m
(2H, 6-H, 7-H), 8.08–8.12 m and 8.26–8.30 m (1H each,
5-H, 8-H). 19F NMR spectrum (CDCl3, C6F6): dF:
–64.5 ppm, s (3F, CF3). Mass spectrum, m/z (Irel, %) :
370 (25) M +, 342 (20) [M–CO]+, 322 (30) [M–CO–HF]+,
condensation products have the structure of 3-aroyl-2-
trifluoromethylnaphtho[2,3-b]furan-4,9-dione V.Although
the yields of compounds Va–Vg did not exceed 35%, the
products can readily be detected in the reaction mixture
by TLC on Silufol UV-254 plates (under UV irradiation
at ë 365 nm) and isolated by flash chromatography.
293 (25) [M–Ph]+. IR spectrum: n 1690 cm , br (C=O ).
Found, %: C 64.80; H 2.40; F 15.24. C20H9F3O4. Calcu-
lated, %: C 64.87; H 2.45; F 15.39.
–1
The NMR spectra were recorded on a Varian VXR-
400 spectrometer. The mass spectra were measured on
a Finnigan MAT-113 instrument with direct sample ad-
mission into the ion source. The IR spectra were obtained
on a UR-20 spectrometer from samples dispersed in min-
eral oil.
3-(4-Fluorobenzoyl)-2-trifluoromethyl-naphtho-
[2,3-b]furan-4,9-dione (Vb). Yield 30%. Colorless crys-
tals, mp 160–162°C (from CHCl3). H NMR spectrum
1
Condensation of 2,3-dichloro-1,4-naphtho-
quinone (I) with 4,4,4-trifluoro-1-aryl-1,3-
butanediones IIa–IIh (general procedure). A mixture
of 1.135 g (5 mmol) of naphthoquinone I, 0.14 g (11 mmol)
of K2CO3, and 0.091 g (5 mol %) of cetyltrimethyl-am-
monium bromide in 100 ml of o-xylene was heated to the
boiling point, and 0.01 mol of the corresponding 4,4,4-tri-
fluoro-1-aryl-1,3-butanedione II was added in small por-
tions over a period of 1 h under vigorous stirring. The
mixture was heated with stirring until initial naphthoquinone
disappeared (TLC, eluent CHCl3) and was then passed
through a layer of silica gel which was washed with ex-
cess xylene. The product was washed off with chloro-
form. The solution was evaporated, and the residue was
recrystallized from chloroform.
(CDCl3, TMS), d, ppm: 7.30–7.36 m (2H, Harom), 7.88–
7.98 m (2H, 6-H, 7-H), 8.04–8.08 m and 8.23-8.27 m (1H
each, 5-H, 8-H), 8.11–8.17 m (2H, Harom). 19F NMR spec-
trum (CDCl3, C6F6), dF, ppm: –62.00 s (3F, CF3), –
102.61 s (1F, C6H4F). Mass spectrum, m/z (Irel, %): 388
(35) M +, 360 (10) [M – CO]+, 340 (30) [M–CO–HF]+,
–1
293 (25) [M–C6H4F]+. IR spectrum: n 1690 cm , br
(C=O). Found, %: C 61.77; H 2.00; F 19.45. C20H8F4O4.
Calculated, %: C 61.87; H 2.08; F 19.57.
3-(4-Bromobenzoyl)-2-trifluoromethylnaphtho-
[2,3-b]furan-4,9-dione (Vc). Yield 30%. Colorless crys-
1
tals, mp 164–166°C (from CHCl3). H NMR spectrum
(CDCl3, TMS), d, ppm: 7.75–7.7.79 m (2H, Harom), 7.89–
7.96 m (2H, 6-H, 7-H), 7.96–7.80 (2H, Harom), 8.04–8.07 m
and 8.23–8.26 m (1H each, 5-H, 8-H). 19F NMR spec-
trum (CDCl3, C6F6): dF –62.05 ppm, s (3F, CF3). Mass
3-Benzoyl-2-trifluoromethylnaphtho[2,3-
b]furan-4,9-dione (Va). Yield 35%. Colorless crystals,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

DAVYDOV, BELETSKAYA
136
spectrum, m/z (Irel, %): 450 (40) and 448 (40) [M+ H]+,
422 (10) and 420 (10) [M +H–CO]+, 402 (30) and 400
(30) [M+ H–CO–HF]+, 293 (25) [M +H–C6H4Br]+. IR
spectrum: n 1690 cm , br (C=O). Found, %: C 53.35;
H 1.65; F 12.60. C20H8F3O4. Calculated, %: C 53.48;
3-(2-Thenoyl)-2-(trifluoromethyl)naphtho[2,3-
b]furan-4,9-dione (Vg). Yield 35%. Colorless crystals,
1
mp 208–210°C (from CHCl3). H NMR spectrum
–1
(CDCl3, TMS), d, ppm: 7.24 d.d (1H, thienyl, J1 = 4.91, J2 =
3.95 Hz), 7.84 d.d (1H, thienyl, J1 = 1.12, J2 = 2.75 Hz),
7.90–7.8 m (2H, 6-H, 7-H), 8.08–8.12 m and 8.22–8.25 m
(1H each, 5-H, 8-H), 8.18 d.d (1H, thienyl, J1 = 1.12, J2 =
2.75 Hz). 19F NMR spectrum (CDCl3, C6F6): dF
–64.5 ppm, s (3F, CF3). Mass spectrum, m/z (Irel, %) : 376
(30) M+, 348 (5) [M–CO]+, 322 (5) [M–CO HF]+, 293
H 1.80; F 12.69.
3-(4-Methoxybenzoyl)-2-trifluoromethyl-
naphtho[2,3-b]furan-4,9-dione (Vd). Yield 30%. Col-
orless crystals, mp 153–155°C (from CHCl3). 1H NMR
spectrum (CDCl3, TMS), d, ppm: 3.45 s (3H, CH3O),
6.58 d (2H, Harom, J= 9.00 Hz), 7.42–7.50 m (2H, 6-H, 7-H),
7.52 d (2H, Harom, J = 9.00 Hz), 7.57–7.60 m and 7.76–
7.79 m (1H each, 5-H, 8-H). 19F NMR spectrum (CDCl3,
C6F6): dF –61.90 ppm, s (3F, CF3). Mass spectrum, m/z
(Irel, %): 400 (75) M +, 372 (5) [M–CO]+, 352 (20) [M–
CO–HF]+, 293 (8) [M–C6H4OCH3]+. IR spectrum: n
–1
(10) [M–C4H3S]+. IR spectrum: 1680 cm , br (C=O).
Found, %: C 57.40; H 1.80; F 15.09. C18H7F3O4. Calcu-
lated, %: C 57.45; H 1.87; F 15.15.
REFERENCES
1. Thomson, R.H., Naturally Occurring Quinones, NewYork:
Chapman and Hall, 1997, p. 195.
2. Hagiwara, H., Sato, K., Nishino, D., Hoshi, T., Suzuki, T., and
Ando, M., J. Chem. Soc., Perkin Trans. 1, 2001,
p. 2946.
–1
1680 cm , br (C=O). Found, %: C 62.90; H 2.70; F 14.19.
C21H11F3O5. Calculated, %: C 63.01; H 2.77; F 14.24.
3-(3,4-Dimethoxybenzoyl)-2-trifluoromethyl-
naphtho[2,3-b]furan-4,9-dione (Ve). Yield 30%. Col-
orless crystals, mp 210–212°C (from CHCl3). 1H NMR
spectrum (CDCl3, TMS), d, ppm: 3.85 s (3H, CH3O),
3.90 s (3H, CH3O), 6.83 d (1H, Harom, J = 8.25 Hz),
7.25 d.d (1H, Harom, J1 = 8.25, J2 = 2.05 Hz), 7.63 d (1H,
Harom, J = 2.05 Hz), 7.74–7.82 m (2H, 6-H, 7-H), 8.06–
8.08 m and 8.20–8.22 m (1H each, 5-H, 8-H). 19F NMR
spectrum (CDCl3, C6F6): dF –61.90 ppm, s (3F, CF3).
Mass spectrum, m/z (Irel, %): 430 (100) M+, 412 (5)
[M–CO]+, 392 (5) [M–CO–HF]+, 293 (40) [M–
3. Nagata, H., Hirai, K.-I., Koyama, J., Wada, Y., and Tamu-
ra, T., Antimicrob. Agents Chemother., 1998, vol. 42,
p. 700.
4. Takegami, T., Simamura, E., Hirai, K.-I., and Koyama, J., An-
tiviral Res., 1998, p. 37.
5. Chang, H., Chou, T.-C., Savaraj, N., Liu, L.., Yu, C., and
Cheng, C.C., J. Med. Chem., 1999, vol. 42, p. 405.
6. Cheng, C.C., Dong, Q., Liu, D.-F., Luo, Y.-L., Liu, L.-F.,
Chen, A.-Y., Yu, C., Savaraj, N., and Chou, T.-C., J. Med.
Chem., 1993, vol. 36, p. 4108.
7. Welch, J.T., Tetrahedron, 1987, vol. 43, p. 3123.
8. Davydov, D.V., Kurts,A.L., and Bundel’, Yu.G., Vestn. Mosk.
Gos. Univ., Ser. 2: Khim., 1984, vol. 25, p. 68.
9. Davydov, D.V., Kurts,A.L., and Bundel’,Yu.G., Vestn. Mosk.
Gos. Univ., Ser. 2: Khim., 1984, vol. 25, p. 292.
10. Davydov, D.V. and Beletskaya, I.P., Izv. Ross. Akad. Nauk,
Ser. Khim., 1995, p. 1393.
11. Inaba, K., Itoh, N., Matsuno, Y., and Sekine, T., Bull. Chem.
Soc. Jpn., 1985, vol. 58, p. 2176.
12. Satori, M.F., Chem. Rev., 1963, vol. 63, p. 279.
13. Prata, E.R. and Rice, R.G., J. Am. Chem. Soc., 1957, vol. 79,
p. 5489.
14. Reynolds, G.A., VanAllan, J.A., andAdel, R.E., J. Org. Chem.,
1965, vol. 30, p. 3819.
15. Kuo, H.-S., Hotta, K., Yogo, M., and Yoshina, S., Synthesis,
1979, p. 188.
–1
C6H3(OCH3)2]+. IR spectrum, n, cm : 1670 br (C=O),
1690 br (C=O). Found, %: C 61.35; H 3.00; F 13.20.
C22H13F3O6. Calculated, %: C 61.40; H 3.04; F 13.24.
2-Trifluoromethyl-3-(3,4,5-trimethoxybenzoyl)-
naphtho[2,3-b]furan-4,9-dione (Vf). Yield 30%, color-
1
less crystals, mp 178–180°C (from CHCl3). H NMR
spectrum (CDCl3, TMS), d, ppm: 3.85 s (6H, CH3O),
3.96 s (3H, CH3O), 7.16 s (2H, Harom), 7.80–7.88 m (2H,
6-H, 7-H), 8.12–8.16 m and 8.28–8.32 m (1H each, 5-H,
8-H). 19F NMR spectrum (CDCl3, C6F6): dF –61.70 ppm,
s (3F, CF3). Mass spectrum, m/z (Irel, %) : 460 (100) M+,
432 (5) [M–CO]+, 422 (5) [M–CO–HF]+, 293 (60) [M–
–1
C6H2(OCH3)3]+. IR spectrum, n, cm : 1680 br (C=O),
16. El-Shafei,A.K., Sultan,A., andVernin, G., Heterocycles, 1982,
vol. 19, p. 333.
1690 br (C=O). Found, %: C 61.00; H 3.25; F 12.29.
C23H15F3O7. Calculated, %: C 61.01; H 3.28; F 12.38.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004