Bis(acetylaryl) podands in the synthesis of fluorine-containing bis(β-diketones) joined by a polyether spacer

Article abstract of DOI:10.1007/s11172-010-0365-z

O-Alkylation of 2-acetylphenols with α,ω-dichloro derivatives of oligoethylene glycols in the presence of KOH and Al₂O₃ in DMF gave the corresponding podands. Their condensation with ethyl trifluoroacetate afforded fluorine-containin

Full text of DOI:10.1007/s11172-010-0365-z

Russian Chemical Bulletin, International Edition, Vol. 59, No. 11, pp. 2122—2125, November, 2010
2122
Bis(acetylaryl) podands in the synthesis of fluorineꢀcontaining
bis(βꢀdiketones) joined by a polyether spacer
D. L. Chizhov, P. A. Slepukhin, I. G. Ovchinnikova, O. V. Fedorova, G. L. Rusinov,
V. I. Filyakova, and V. N. Charushin
I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22/20 ul. S. Kovalevskoi, 620041 Ekaterinburg, Russian Federation.
Fax: +7 (343) 369 3058. Eꢀmail: vif@ios.uran.ru
OꢀAlkylation of 2ꢀacetylphenols with α,ωꢀdichloro derivatives of oligoethylene glycols in
the presence of KOH and Al2O3 in DMF gave the corresponding podands. Their condensation
with ethyl trifluoroacetate afforded fluorineꢀcontaining bis(βꢀdiketones) with the aryl fragꢀ
ments linked by conformationally flexible polyether spacers.
Key words: the Williamson reaction, Oꢀalkylation, phenols, podands, ethyl trifluoroacetate,
organofluorine compounds, βꢀdiketones, nanosized alumina, Xꢀray diffraction analysis.
Scheme 1
The ability of acyclic polyethers (podands) to form
lipophilic molecular complexes with metal ions and orꢀ
ganic molecules are widely used in organic and analytical
chemistry (phaseꢀtransfer catalysis, complexing agents,
and extracting agents); the tendency of podands toward
intraꢀ and intermolecular noncovalent bonding is of interꢀ
est for supramolecular chemistry.1—3 Podands can be modꢀ
ified, e.g., by attaching various polyfunctional and heteroꢀ
cyclic fragments to the ends of the polyoxyethylene chain.
In particular, very promising is the synthesis of podands
containing terminal 1,3ꢀdicarbonyl fragments that can not
only chelate most metal ions but also undergo various
transformations and heterocyclizations. The synthetic poꢀ
tential of 1,3ꢀdicarbonyl fragments provides prerequisites
for the design of new podands. Podands and macrocycles
with 1,3ꢀdicarbonyl fragments have been reported;4 however,
the literature data on their fluorineꢀcontaining analogs are
lacking. At the same time, it is known that a combination
of electronic and steric factors makes fluorineꢀcontaining
compounds substantially different in reactivity from nonꢀ
fluorinated analogs. In addition, fluorinated organic molꢀ
ecules are more volatile and more lipophilic and penetrate
better across cell membranes, which enhances their biologꢀ
ical activity or changes the spectrum of their action. In
some cases, fluorine atoms are involved in specific interꢀ
molecular interactions.5 Earlier,6 we have reported on the
synthesis of bis(aryl) podands modified with the fragments
of fluoroalkylꢀcontaining 1,3ꢀenamino ketones.
2, 3: n = 1 (a), 2 (b)
Bis(acetylaryl) podands 3a,b were obtained by the Wilꢀ
liamson reactions of 2ꢀhydroxyacetophenone (1) with
α,ωꢀdichloro derivatives of diꢀ and triethylene glycols 2a,b.
As applied to compound 1, the Williamson reaction is
usually accompanied by side processes (in particular, its
selfꢀcondensation), which considerably lowers the yield of
the target product. For instance, bis(acetylaryl) podand
3a has been obtained earlier7 in 30% yield by heating comꢀ
pounds 1 and 2a with NaOH in a molar ratio of 2 : 1 : 2
(DMF, 95 °C, 100 h). We found that in the presence of
KOH at 100 °C, the yields of products 3a and 3b are 21
and 18%, respectively, even in 12 h. At longer reaction
times, the yields increase only slightly. Addition of basic
Al2O3 (10 mol.%) doubles the yields of compounds 3a,b;
in the presence of the same amount of nanosized Al2O3
(20—50 nm), their yields increase by a factor of 2.7—3
In the present work, we developed a preparative synꢀ
thesis of bis(acetylaryl) podands and the corresponding
fluorineꢀcontaining bis(βꢀdiketones) with conformationꢀ
ally flexible polyether spacers linking the aryl fragments
(Schemes 1 and 2).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2068—2071, November, 2010.
1066ꢀ5285/10/5911ꢀ2122 © 2010 Springer Science+Business Media, Inc.

Bis(acetylaryl) podands
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 11, November, 2010 2123
Scheme 2
F(3)
C(1)
F(2)
C(8A)
C(7A)
O(4)
C(9A)
O(1A)
F(1)
C(2)
C(3)
C(10A)
C(11A)
C(6A)
O(3)
C(12A)
C(4)
C(5)
C(5A)
C(4A)
O(3A)
O(2)
C(12)
C(6)
C(10)
C(3A)
C(7)
C(2A)
C(11)
C(9)
F(1C)
F(2C)
O(4A)
C(8)
C(1A)
F(3C)
Fig. 1. General view of structure 4a with the atomic numbering
adopted in crystallographic experiments (the symmetryꢀequivaꢀ
lent atoms are indicated with letters).
n = 1 (a), 2 (b)
ing terminal (aryl) groups, which is characteristic of the
earlier described chalcone podands.8 The torsion angle of
the polyether fragment O(1)—C(11)—C(12)—O(2) is
66.51°. The angle between the planes of the aryl rings is
78.85°. The keto enol fragments are oriented in opposite
directions from the central axis C2 of the molecule, being
involved in no additional intraꢀ or intermolecular short
contacts (see Fig. 1). Either keto enol fragment is coplaꢀ
nar with the aromatic ring (the largest deviation of the
atoms from the meanꢀsquare plane is 0.12 Å for the termiꢀ
nal C(1) atom). The bond lengths and bond angles in this
fragment are close to standard values (Table 2). The lengthꢀ
ening of the C(4)—O(3) and C(2)—C(3) bonds compared
to the O(4)—C(2) and C(3)—C(4) bonds (see Table 2)
indicates the enolized carbonyl group at the aromatic subꢀ
stituent. The keto enol fragments are in the Uꢀconformaꢀ
tion stabilized by the intramolecular hydrogen bond
O(3)—H(3B)...O(4) (O(3)—H(3B), 0.820 Å; H(3B)...O(4),
1.767 Å; the angle O(3)H(3B)O(4), 150.22°; O(3)...O(4),
2.512(3) Å). The F atoms of the trifluoromethyl group are
disordered in three positions with populations of 0.4, 0.4,
and 0.2. Because of the overlap of their thermal ellipsoids,
the F atoms were refined in a partial isotropic approximaꢀ
(see Scheme 1, Table 1). The above effects can be exꢀ
plained by chelating adsorption of 2ꢀhydroxyacetophenone
1 and/or its potassium salt at Al2O3. This deactivates the
carbonyl group, thus preventing compound 1 from comꢀ
petitive selfꢀcondensation but not from the Williamson
reaction.
Condensation of bis(acetylaryl) podands 3a,b with
ethyl trifluoroacetate in the presence of LiH gave fluorineꢀ
containing bis(βꢀdiketones) 4a,b in 50—80% yields. In
the products obtained, the 1,3ꢀdicarbonyl fragments are
linked by conformationally flexible polyether spacers (see
Scheme 2).
The molecular formulas and structures of bis(βꢀdiꢀ
ketones) 4a,b were proved by elemental analysis, IR specꢀ
troscopy, and H and 19F NMR spectroscopy. According
to 1H NMR spectra in CDCl3, compounds 4a,b are symꢀ
metrical and completely enolized. The spectra show one
set of signals, in particular, broadened singlets at δ ~15.2
(OH) and singlets at δ 7.15—7.17 (=CH). The 19F NMR
spectra of compounds 4a,b contain a singlet at δ 85.38
(CF3).
1
Structure 4a was confirmed by Xꢀray diffraction analꢀ
ysis. The molecule is in the special position on axis C2
(Fig. 1) and has an Sꢀshaped configuration with approachꢀ
Table 2. Selected bond lengths d and bond angles ω in strucꢀ
ture 4a
Bond
d/Å
Angle*
ω/deg
Table 1. Effect of Al2O3 on the yields of products 3a,b
C(4)—O(3) 1.299(3) C(12)#1—O(2)—C(12) 110.6(3)
Product
Yield* (%)
O(4)—C(2) 1.230(3) C(10)—O(1)—C(11)
C(3)—C(2) 1.381(3) C(4)—C(3)—C(2)
C(3)—C(4) 1.375(3) O(3)—C(4)—C(3)
C(4)—C(5) 1.456(3) O(4)—C(2)—C(3)
C(2)—C(1) 1.503(4)
118.86(18)
120.8(2)
118.9(2)
125.6(3)
Without Al2O3 Basic Al2O3 Nanosized Al2O3
3a
3b
21
18
42
39
57
54
* The reaction time is 12 h.
* The symmetry operation code is #1 –x, y, –z.

2124
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 11, November, 2010
a
Chizhov et al.
Thus, we developed simple and convenient methods
for the synthesis of bis(acetylaryl) podands 3 and fluorineꢀ
containing bis(βꢀdiketones) 4 with polyether spacers.
These methods have undoubted advantages over the known
fourꢀstep route to similar nonfluorinated structures.4 By
using reactions familiar with fluorineꢀcontaining 1,3ꢀdiꢀ
ketones and bis(βꢀdiketones), the dicarbonyl (keto enol)
fragments of compounds 4 can be transformed into other
functional groups or involved in heterocyclizations retainꢀ
ing the polyether fragment to obtain bis(1ꢀaminopropenꢀ
3ꢀones), bis(pyrazoles), bis(isoxazoles), bis(pyrimidines),
bis(benzodiazepines), etc.12
b
0
Experimental
The course of the reactions was monitored by TLC on Siluꢀ
fol UVꢀ254 plates with CHCl3 as an eluent. Spots were visuꢀ
alized in aqueous solutions of copper acetate and KMnO4.
1H and 19F NMR spectra were recorded on a Bruker DRXꢀ400
spectrometer (400 (1H) and 376 MHz (19F)) with SiMe4
and C6F6 as the internal standards, respectively. IR spectra
were recorded on a Spectrum One B FTIR spectrometer (Perꢀ
kin—Elmer).
c
Fig. 2. Molecular packing of compound 4a along the axis b.
tion (insertion of the instruction ISOR 0.01 into the ins.file
of the SHELXL software).
The molecular packing of compound 4a consists of its
molecules stacked along the axis b (Fig. 2), the spaꢀ
tial orientation of the molecules being identical in all
stacks (Fig. 3).
It should be noted that the Cambridge Crystallographic
Data Collection contains only three 1,3ꢀdiketone strucꢀ
tures with trifluoromethyl and aryl substituents at the
dicarbonyl pentad. In those structures,9—11 the carbonꢀ
yl group at the aromatic substituent is enolized, which
is well consistent with our Xꢀray diffraction data for comꢀ
pound 4a.
Xꢀray diffraction analysis was carried out for a colorless crysꢀ
tal stub (0.43×0.36×0.28 mm) on an Xcalibur 3 automatic fourꢀ
circle diffractometer with a CCD detector according to a stanꢀ
dard procedure (MoꢀKα radiation, graphite monochromator,
ω scan mode, scan step 1°, T = 295(2) K). No absorption correcꢀ
tion was applied. The crystal is monoclinic, space group C2;
the unit cell parameters: a = 19.438(6) Å, b = 4.5630(9) Å,
c = 15.404(6) Å, β = 122.297(12)°, V = 1154.8(6) Å3, Z = 2 for
the molecular formula C24H20F6O7; dcalc = 1.537 g cm–3
,
μ = 0.143 mm–1, F(000) = 548, θ scan range 2.77—26.44°. The
number of measured reflections is 3461; the number of indepenꢀ
dent reflections is 1315 (Rint = 0.0180), including 719 reflections
with I > 2σ(I). The scan completeness for θ = 26.44° is 97.3%.
The structure was determined and refined with the SHELX proꢀ
gram package.13 The structure was solved by the direct method
and refined by the fullꢀmatrix leastꢀsquares method on F2. All
nonꢀhydrogen atoms were refined anisotropically; the hydrogen
atoms were located geometrically and refined using a riding
model with dependent thermal parameters. Final residuals are
R1 = 0.0286 and wR2 = 0.0545 for the reflections with I > 2σ(I))
and R1 = 0.0620 and wR2 = 0.0574 for all reflections (S = 1.007).
The maximum and minimum residual electron densities are 0.084
and –0.077 e Å–3, respectively.
c
0
The Xꢀray diffraction data obtained have been depoꢀ
sited with the Cambridge Crystallographic Data Center
(No. 796 588) and are available from www.ccdc.cam.ac.uk/
data_request/cif.
b
a
Acetylaryl podands 3a,b. 2ꢀHydroxyacetophenone (0.14 mol),
KOH (0.14 mol), and 10 mol.% basic alumina (Chemapol 5/40)
or nanosized alumina (0.007 mol) prepared by the gasꢀphase
method14 were added to a solution of α,ωꢀdichloro derivative 2
(0.07 mol) in DMF (100 mL). The reaction mixture was stirred
at 100 °C for 12 h and filtered. The filtrate was diluted with water
(700 mL). The resulting precipitate was filtered off and purified
by flash chromatography (SiO2, chloroform). The eluate was
concentrated; the product was washed on a filter with a small
Fig. 3. Molecular packing of compound 4a running parallel to
the plane ab.

Bis(acetylaryl) podands
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 11, November, 2010 2125
amount of methanol and dried in air. The yields of compounds
3a,b are given in Table 1.
7.50 (m, 2 H, Ar); 7.99 (dd, 2 H, Ar, J = 7.6 Hz, J = 1.3 Hz);
15.18 (br.s, 2 H, 2 OH). 19F NMR (CDCl3), δ: 85.38 (s).
IR (Nujol, suspension), ν/cm–1: 3159 (=CH); 1600, 1567
(C=O—C=C).
1,5ꢀBis(2ꢀacetylphenoxy)ꢀ3ꢀoxapentane (3a), colorless neeꢀ
dles. The yield was 57%, m.p. 76—77 °C. Found (%): C, 70.23;
H, 6.53. C20H22O5. Calculated (%): C, 70.17; H, 6.43. 1H NMR
(DMSOꢀd6), δ: 2.50 (s, 6 H, Me); 3.88—3.90, 4.24—4.26 (both m,
8 H, O—CH2—CH2); 7.01 (dd, 2 H, Ar, J = 8.3 Hz, J = 7.7 Hz);
7.16 (d, 2 H, Ar, J = 7.7 Hz); 7.51 (ddd, 2 H, Ar, J = 8.3 Hz,
J = 7.7 Hz, J = 1.8 Hz); 7.57 (dd, 2 H, Ar, J = 7.7 Hz, J = 1.8 Hz).
IR (Nujol, paste), ν/cm–1: 1660 (C=O); 1257, 1145, 1060, 1040
(C—O—C).
1,8ꢀBis(2ꢀacetylphenoxy)ꢀ3,6ꢀdioxaoctane (3b), colorless
needles. The yield was 54%, m.p. 73—74 °C. Found (%):
C, 68.42; H, 6.68. C22H26O6. Calculated (%): C, 68.39; H, 6.73.
1H NMR (DMSOꢀd6), δ: 2.54 (s, 6 H, Me); 3.62 (s, 4 H,
O—CH2); 3.79—4.82, 4.19—4.21 (both m, 8 H, O—CH2—CH2);
7.00 (ddd, 2 H, Ar, J = 8.3 Hz, J = 7.7 Hz, J = 0.8 Hz); 7.14 (dd,
2 H, Ar, J = 8.4 Hz, J = 0.8 Hz); 7.50 (ddd, 2 H, Ar, J = 8.4 Hz,
J = 7.6 Hz, J = 2.0 Hz); 7.56 (dd, 2 H, Ar, J = 7.6 Hz, J = 2.0 Hz).
IR (Nujol, paste), ν/cm–1: 1661 (C=O); 1255, 1145, 1062, 1040
(C—O—C).
We are grateful to A. E. Ermakov, M. A. Uimin, and
A. A. Mysik (Institute of the Physics of Metals, Ural
Branch of the Russian Academy of Sciences) for providing
nanosized alumina samples.
This work was financially supported by the Council on
Grants at the President of the Russian Federation (State
Support Program for Leading Scientific Schools, Grant
NShꢀ65261.2010.3), the State Contract 02 740 11 0260,
and the Ural Branch of the Russian Academy of Sciences
(Program 09ꢀTꢀ3ꢀ1024 IRI).
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Received March 25, 2010;
in revised form October 19, 2010