Adamantyl-containing fluorinated 1,3-diketones

Article abstract of DOI:10.1134/S1070428008080083

A convenient one-step procedure has been developed for the synthesis of fluorine-containing 2-(adamant-l-yl)-1,3-diketones by reaction of fluorinated 1,3-diketones with 1,3-dehydroadamantane. The products can be used as starting compounds for the preparation of new fluorinated adamantyl-containing heterocyclic compounds.

Full text of DOI:10.1134/S1070428008080083

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 8, pp. 1157–1160. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © G.M. Butov, V.M. Mokhov, G.Yu. Parshin, R.U. Kunaev, S.A. Shevelev, I.L. Dalinger, I.A. Vatsadze, 2008, published in Zhurnal
Organicheskoi Khimii, 2008, Vol. 44, No. 8, pp. 1171–1174.
Adamantyl-Containing Fluorinated 1,3-Diketones
G. M. Butova, V. M. Mokhovb, G. Yu. Parshina, R. U. Kunaeva, S. A. Shevelevc,
I. L. Dalingerc, and I. A. Vatsadzec
a Volga Polytechnical Institute (a Division of Volgograd State Technical University),
ul. Engel’sa 42a, Volzhskii, 404121 Russia
e-mail: butov@volpi.ru
b Volgograd State Technical Universitety, Volgograd, Russia
с Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia
Received April 18, 2007
Abstract—A convenient one-step procedure has been developed for the synthesis of fluorine-containing
2-(adamant-1-yl)-1,3-diketones by reaction of fluorinated 1,3-diketones with 1,3-dehydroadamantane. The
products can be used as starting compounds for the preparation of new fluorinated adamantyl-containing
heterocyclic compounds.
DOI: 10.1134/S1070428008080083
Introduction of fluorine atoms into molecules of
organic compounds essentially changes their biological
activity and in many cases enhances their efficiency as
medical agents and agrochemicals [1–3]. The effect is
fairly strong in the case of such modification of hetero-
cyclic compounds [4]. On the other hand, molecules of
many effective drugs possessing various pharmacolog-
ical activities contain an adamantane moiety as key
pharmacophoric fragment [5].
multipurpose synthons for the preparation of various
fluorinated heterocyclic compounds which are also ex-
tensively studied as drugs and pesticides [4].
Introduction of an adamantyl fragment into fluor-
inated β-diketone molecules via commonly used
C-alkylation at the activated methylene group is feasi-
ble only in rare cases [6], while their C-adamantylation
has not been reported. We have found that C-ada-
mantylation of fluorinated β-diketones at the methyl-
ene carbon atom can be successfully accomplished
with the use of tetracyclo[3.3.1.13,7.01,3]decane (I,
1,3-dehydroadamantane) as alkylating agent. We pre-
viously synthesized the corresponding adamantyl-con-
taining β-dicarbonyl compounds by reaction of com-
pound I with keto esters and cyclic β-diketones [7, 8].
Development of a general method for the synthesis
of acyclic and heterocyclic compounds containing both
fluorine atoms and an adamantane fragment attracts
strong interest from the viewpoint of design of new
biologically active substances. The goal of the present
work was to synthesize adamantyl-containing fluor-
inated β-diketones in which the adamantanyl substit-
uent is attached to the carbon atom located between the
carbonyl groups. Fluorinated 1,3-diketones per se ex-
hibit biological activity [6]; on the other hand, they are
In fact, 1,3-dehydroadamantane (I) smoothly and
quickly (in 1.5–2 h) reacted with various fluorine-
containing 1,3-diketones of the general formula
RFC(O)CH2C(O)R (IIa–IIj) in boiling diethyl ether
Scheme 1.
O
RF
R
RF
+
O
O
R
O
I
IIa–IIj
IIIa–IIIj
RF = CF3, R = CF3 (a), Ph (b), 4-ClC6H4 (c), 3,4-(MeO)2C6H3 (d), 1,3-benzodioxol-5-yl (e), 2-furyl (f), 2-thienyl (g),
4-(1H-pyrrol-1-yl)phenyl (h), t-Bu (i); RF = CHF2, R = Ph (j).
1157

BUTOV et al.
1158
Scheme 2.
H
H
RF
R
O
O
O
O
O
O
H+
+
O
O
RF
R
RF
O
R
RF
R
O
O
RF
RF
R
+ H+
R
O
under dry oxygen-free nitrogen (Scheme 1). The corre-
sponding fluorine-containing 2-(1-adamantanyl)-1,3-
diketones IIIa–IIIj were formed in 83–98% yield. The
reaction is accompanied by appreciable heat evolution,
and no any catalyst is necessary. The optimal molar
ratio I:II was 1:(1.5–2); in the reactions with lesser
amounts of 1,3-diketones II the conversion of I was
incomplete. Lowering the temperature from 35 to 20°C
almost does not affect the yield of the target products.
nucleophilic center of ambident anion; such center in
anions derived from 1,3-dicarbonyl compounds is
located on the carbon atom between the carbonyl
groups [10, 11].
Thus we were the first to synthesize fluorinated
1,3-diketones having an adamantyl group at the meth-
ylene carbon atom by reaction of 1,3-dehydroadaman-
tane with fluorinated 1,3-diketones RFC(O)CH2C(O)R.
EXPERIMENTAL
The structure of compounds IIIa–IIIj was proved
by the IR, 1H NMR, and mass spectra. Their IR spectra
contained absorption bands in the region 1748–
1780 cm–1 due to stretching vibrations of the carbonyl
group in the diketone tautomer. The fact that the
adamantane fragment in molecules III is linked to the
carbon rather than oxygen atom follows from the
1H NMR spectra: the chemical shift of the CH proton
indicates sp3 hybridization of the corresponding carbon
atom (the same carbon atom in O-adamantyl derivative
should have sp2 hybridization). According to the spec-
tral data, compounds IIIa–IIIj exist in the diketone
form, in contrast to initial fluorine-containing 1,3-di-
ketones which exist mainly as enol tautomer [6].
Additional supports to the diketone structure of the
synthesized compounds were obtained by X-ray anal-
ysis of a single crystal of compound IIIi (the X-ray
diffraction data will be reported elsewhere) and by
The IR spectra of compounds IIIb, IIIc, and IIIj
were recorded in KBr on a UR-20 instrument. The
1H NMR spectra were measured on Bruker DAX-500
(500.13 MHz; IIIa–IIIh; DMSO-d6) and Bruker AC-
200 spectrometers (200.13 MHz; IIIi; CDCl3). The
mass spectra (electron impact, 70 eV) were obtained
on Kratos MS-30 (IIIc–IIIj) and Finnigan MAT
INCOS-50 instruments (IIIb). Initial fluorinated
1,3-diketones IIa–IIj were synthesized according to
the procedures reported in [12].
Fluorine-containing 2-(1-adamantyl)-1,3-dike-
tones (general procedure). A solution of freshly sub-
limed compound I in anhydrous diethyl ether was
added dropwise to 1.5–2 equiv of 1,3-diketone IIa–IIj
under dry deoxygenated nitrogen. The mixture was
heated to the boiling point and was kept boiling under
reflux for 1.5–2 h. When the reaction was complete,
the solvent and excess initial 1,3-diketone were dis-
tilled off, and the residue was purified by distillation
under reduced pressure (IIIa, IIIi) or recrystallization
from isopropyl alcohol (IIIb–IIId).
1
comparison of the H NMR spectrum of IIIi with the
spectra of the other products.
Presumably, C-adamantylation of fluorine-contain-
ing β-diketones follows Scheme 2. High nucleophilic-
ity of compound I [9] favors initial proton transfer
from 1,3-diketone II to 1,3-dehydroadamantane, and
recombination of the cation–anion couple thus formed
gives the corresponding fluorine-containing 2-(1-ada-
mantyl)-1,3-diketone. Reactions of stable organic
cations with anions are commonly regarded as a ther-
modynamically controlled process leading to bonding
of electrophile (organic cation) at the most basic and
3-(1-Adamantyl)-1,1,1,5,5,5-hexafluoropentane-
2,4-dione (IIIa) was obtained from 10 g (48 mmol) of
1,1,1,5,5,5-hexafluoropentane-2,4-dione and 4 g
(30 mmol) of compound I. Yield 8.5 g (83%), colorless
viscous liquid, bp 129–131°C (10 mm), nD20 = 1.4382.
1H NMR spectrum, δ, ppm: 1.55–1.7 m (12H, CH2,
Ad), 1.98 s (3H, CH, Ad), 4.9 s (1H, CH). Mass spec-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 8 2008

ADAMANTYL-CONTAINING FLUORINATED 1,3-DIKETONES
1159
trum, m/z (Irel, %): 342 (2.3) [M]+, 245 (4.6)
[CF3C(O)CHAd]+, 135 (100) [Ad]+, 97 (7) [C(O)CF3]+,
69 (48) [CF3]+.
(1H, Harom). Mass spectrum, m/z (Irel, %): 394 (23)
[M]+, 297 (9) [C7H5O2C(O)CHAd]+, 149 (100)
[C(O)C7H5O2]+, 135 (49) [Ad]+, 121 (47) [C7H5O2]+,
69 (6) [CF3]+.
2-(1-Adamantyl)-4,4,4-trifluoro-1-phenylbutane-
1,3-dione (IIIb) was obtained from 10 g (46 mmol) of
4,4,4-trifluoro-1-phenylbutane-1,3-dione and 4 g
(30 mmol) of compound I. Yield 9.7 g (93%), colorless
crystals, mp 95–96°C. IR spectrum, ν, cm–1: 2912,
2-(1-Adamantyl)-4,4,4-trifluoro-1-(2-furyl)-
butane-1,3-dione (IIIf) was synthesized from 5 g
(24 mmol) of 4,4,4-trifluoro-1-(2-furyl)butane-1,3-di-
one and 2 g (15 mmol) of compound I. Yield 4.9 g
(97%), colorless crystals, mp 56–57°C. 1H NMR spec-
trum, δ, ppm: 1.63–1.72 m (12H, CH2, Ad), 1.95 s (3H,
CH, Ad), 4.95 s (1H, CH), 6.75 s (1H, CH2), 7.75 s
(1H, CH), 8.05 s (1H, CH). Mass spectrum, m/z
(Irel, %): 340 (42) [M]+, 243 (82) [C4H3OC(O)CHAd]+,
95 (100) [C4H3OC(O)]+, 135 (78) [Ad]+, 69 (22)
[CF3]+, 67 (60) [C4H3O]+.
1
2884 (C–H); 1764 (C=O). H NMR spectrum, δ, ppm:
1.59–1.62 q (6H, CH2, Ad), 1.7–1.73 q (6H, CH2, Ad),
1.92 s (3H, CH, Ad), 5.45 s (1H, CH), 7.6 t (2H,
Harom), 7.75 t (1H, Harom), 8.15 d (2H, Harom). Mass
spectrum, m/z (Irel, %): 350 (10) [M]+, 253 (4.6)
[PhC(O)CHAd]+, 245 (5) [CF3C(O)CHAd]+, 135 (20)
[Ad]+, 105 (100) [PhCO]+, 77 (50) [Ph]+, 69 (2.5)
[CF3]+.
2-(1-Adamantyl)-4,4,4-trifluoro-1-(2-thienyl)-
butane-1,3-dione (IIIg) was obtained from 6 g
(27 mmol) of 4,4,4-trifluoro-1-(2-thienyl)butane-1,3-
dione and 2 g (15 mmol) of compound I. Yield 4.8 g
2-(1-Adamantyl)-1-(4-chlorophenyl)-4,4,4-tri-
fluorobutane-1,3-dione (IIIc) was obtained from 12 g
(48 mmol) of 1-(4-chlorophenyl)-4,4,4-trifluoro-
butane-1,3-dione and 4 g (30 mmol) of compound I.
Yield 10 g (87%), colorless crystals, mp 129–130°C.
IR spectrum, ν, cm–1: 2900, 2848 (C–H); 1768, 1668
1
(90%), colorless crystals, mp 112–113°C. H NMR
spectrum, δ, ppm: 1.64–1.75 m (12H, CH2, Ad), 1.96 s
(3H, CH, Ad), 5.15 s (1H, CH), 7.25 t (1H, CH2), 8.1 d
(1H, CH), 8.3 d (1H, CH). Mass spectrum, m/z
(Irel, %): 356 (30) [M]+, 259 (76) [C4H3SC(O)CHAd]+,
110 (100) [C(O)C4H3S]+, 135 (71) [Ad]+, 83 (30)
[C4H3S]+, 69 (16) [CF3]+.
1
(C=O). H NMR spectrum, δ, ppm: 1.6–1.62 q (6H,
CH2, Ad), 1.7–1.72 q (6H, CH2, Ad), 1.9 s (3H, CH,
Ad), 5.45 s (1H, CH), 7.65 d (2H, Harom), 8.2 d (2H,
Harom). Mass spectrum, m/z (Irel, %): 384 (10) [M]+,
287 (21) [ClC6H4C(O)CHAd]+, 245 (11) [CF3C(O)-
CHAd]+, 135 (76) [Ad]+, 139 (100) [C(O)ClC6H4]+,
111 (49) [ClC6H4]+, 69 (6) [CF3]+.
2-(1-Adamantyl)-4,4,4-trifluoro-1-[4-(1H-pyrrol-
1-yl)phenyl]butane-1,3-dione (IIIh) was obtained
from 6 g (21 mmol) of 4,4,4-trifluoro-1-[4-(1H-pyrrol-
1-yl)phenyl]butane-1,3-dione and 2 g (15 mmol) of
compound I. Yield 5.9 g (95%), colorless crystals,
mp 126–127°C. 1H NMR spectrum, δ, ppm: 1.62–1.7 m
(12H, CH2, Ad), 1.96 s (3H, CH, Ad), 5.42 s (1H, CH),
6.35 s (2H, CH), 7.55 s (2H, CH), 7.8 d (2H, Harom),
8.25 d (2H, Harom). Mass spectrum, m/z (Irel, %): 415
(41) [M]+, 318 (6) [C4H4NC6H4C(O)CHAd]+, 170
(100) [C(O)C4H4NC6H4]+, 135 (44) [Ad]+, 142 (53)
[C4H4NC6H4]+, 69 (6) [CF3]+.
2-(1-Adamantyl)-1-(3,4-dimethoxyphenyl)-4,4,4-
trifluorobutane-1,3-dione (IIId) was obtained from
6.2 g (22 mmol) of 1-(3,4-dimethoxyphenyl)-4,4,4-tri-
fluorobutane-1,3-dione and 2 g (15 mmol) of com-
pound I. Yield 5.7 g (93%), colorless crystals, mp 146–
1
147°C. H NMR spectrum, δ, ppm: 1.62–1.78 m (12H,
CH2, Ad), 1.93 s (3H, CH, Ad), 3.85 s and 3.92 s (3H
each, OCH3), 5.3 s (1H, CH), 7.1 d (2H, Harom), 7.5 s
(1H, Harom), 7.85 d (1H, Harom). Mass spectrum, m/z
(Irel, %): 410 (46) [M]+, 313 (12) [(CH3O)2C6H4-
C(O)CHAd]+, 165 (100) [(CH3O)2C6H4CO]+, 135 (43)
[Ad]+, 137 (24) [(CH3O)2C6H4]+, 69 (3) [CF3]+.
3-(1-Adamantyl)-1,1,1-trifluoro-5,5-dimethyl-
hexane-2,4-dione (IIIi) was obtained from 10 g
(51 mmol) of 1,1,1-trifluoro-5,5-dimethylhexane-2,4-
dione and 4 g (30 mmol) of compound I. Yield 8.5 g
(86%), colorless liquid, nD20 = 1.4790, bp 165–167°C
(7 mm). 1H NMR spectrum, δ, ppm: 1.1 s (9H, CH3),
1.54–1.65 m (6H, CH2, Ad), 1.75–1.8 m (6H, CH2,
Ad), 1.94 s (3H, CH, Ad), 4.82 s (1H, CH). Mass
spectrum, m/z (Irel, %): 330 (2) [M]+, 233 (1.8)
[t-BuC(O)CHAd]+, 86 (20) [HC(O)Bu-t], 135 (25)
[Ad]+, 69 (3) [CF3]+, 57 (100) [t-Bu]+.
2-(1-Adamantyl)-1-(1,3-benzodioxol-5-yl)-4,4,4-
trifluorobutane-1,3-dione (IIIe) was obtained from
6 g (23 mmol) of 1-(1,3-benzodioxol-5-yl)-4,4,4-tri-
fluorobutane-1,3-dione and 2 g (15 mmol) of com-
pound I. Yield 5.2 g (88%), colorless crystals, mp 121–
1
122°C. H NMR spectrum, δ, ppm: 1.63–1.7 m (12H,
CH2, Ad), 1.85 s (3H, CH, Ad), 5.3 s (1H, CH), 6.2 s
(2H, CH2), 7.1 d (1H, Harom), 7.65 s (1H, Harom), 7.87 d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 8 2008

BUTOV et al.
1160
3. Welch, J.T., Tetrahedron, 1987, vol. 43, p. 3123.
2-(1-Adamantyl)-4,4-difluoro-1-phenylbutane-
4. Furin, G.G., Ftorsoderzhashchie geterotsiklicheskie soe-
dineniya. Sintez i primenenie (Fluorine-Containing
Heterocyclic Compounds. Synthesis and Applications),
Moscow: Nauka, 2001.
5. Morozov, I.S., Petrov, V.I., and Sergeeva, S.A., Farma-
kologiya adamantanov (Pharmacology of Adaman-
tanes), Volgograd: Volgograd. Med. Akad., 2001.
6. Pashkevich, K.I., Saloutin, V.I., and Postovskii, I.Ya.,
Usp. Khim., 1981, vol. 50, p. 325.
7. No, B.I., Butov, G.M., Mokhov, V.M., and Par-
1,3-dione (IIIj) was obtained from 10 g (50 mmol) of
4,4-difluoro-1-phenylbutane-1,3-dione and 4 g
(30 mmol) of compound I. Yield 9.7 g (98%), colorless
crystals, mp 64–65°C. IR spectrum, ν, cm–1: 2892,
2848 (C–H); 1748, 1668 (C=O). 1H NMR spectrum, δ,
ppm: 1.54–1.86 m (12H, CH2, Ad), 1.96 s (3H, CH,
Ad), 4.96 s (1H, CH), 5.66 t (1H, CHF2), 7.27 s (1H,
Harom), 7.47–7.66 m (2H, Harom), 7.99–8.03 m (2H,
Harom). Mass spectrum, m/z (Irel, %): 332 (24) [M]+, 253
(21) [PhC(O)CHAd]+, 105 (100) [PhCO]+, 135 (76)
[Ad]+, 77 (17) [Ph]+, 51 (6) [CF3]+.
shin, G.Yu., Russ. J. Org. Chem., 2003, vol. 39, p. 1668.
8. No, B.I., Butov, G.M., Mokhov, V.M., and Par-
shin, G.Yu., Russ. J. Org. Chem., 2002, vol. 38, p. 1377.
REFERENCES
9. Shchapin, I.Yu., Belopushkin, S.I., and Tyurin, D.A.,
Dokl. Ross. Akad. Nauk, 2000, vol. 372, p. 60.
1. Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications, Filler, R., Kobayashi, Y., and
Yagupolskii, L.M., Eds., Amsterdam: Elsevier, 1993.
10. Stohrer, W.D. and Hoffmann, R., J. Am. Chem. Soc.,
1972, vol. 94, p. 779.
11. Shevelev, S.A., Usp. Khim., 1970, vol. 39, p. 1773.
2. Walker, S.B., Fluorine Compounds as Agrochemicals,
12. Katsuyama, I., Ogawa, S., and Yamaguchi, Y., Synthesis,
Old Glossop (UK): Fluorochem Ltd., 1990.
1997, p. 1321.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 8 2008