Two new bis-β-diketones as ligands for novel systems in supramolecular chemistry

Article abstract of DOI:10.1081/SCC-120015554

Claisen condensations of 1,3-diacetyl-2-hydroxy-5-methylbenzene with esters gave two new outstanding tetraketone ligands. The optimized procedure was developed into a multi-grams scale preparation of 1,3-bis-(3-oxo-3-phenyl-propionyl)-2-hydroxy-5-methylbe

Full text of DOI:10.1081/SCC-120015554

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Two New bis -β-Diketones as Ligands for Novel
Systems in Supramolecular Chemistry
Guillem Aromí , Patrick Gamez , Paula Carrero Berzal , Willem L. Driessen &
Jan Reedijk
To cite this article: Guillem Aromí , Patrick Gamez , Paula Carrero Berzal , Willem L. Driessen &
Jan Reedijk (2003) Two New bis -β-Diketones as Ligands for Novel Systems in Supramolecular
Chemistry, Synthetic Communications, 33:1, 11-18, DOI: 10.1081/SCC-120015554
To link to this article: http://dx.doi.org/10.1081/SCC-120015554
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 1, pp. 11–18, 2003
Two New bis-b-Diketones as Ligands for Novel
Systems in Supramolecular Chemistry
Guillem Aromı, Patrick Gamez, Paula Carrero Berzal,
Willem L. Driessen, and Jan Reedijk*
Leiden Institute of Chemistry, Gorlaeus Laboratories,
Leiden University, Leiden, The Netherlands
ABSTRACT
Claisen condensations of 1,3-diacetyl-2-hydroxy-5-methylbenzene
with esters gave two new outstanding tetraketone ligands. The opti-
mized procedure was developed into a multi-grams scale preparation
of 1,3-bis-(3-oxo-3-phenyl-propionyl)-2-hydroxy-5-methylbenzene.
Key Words: Claisen condensation; O-donor ligand; Polynucleating
ligand.
*Correspondence: Jan Reedijk, Leiden Institute of Chemistry, Gorlaeus
Laboratories, Leiden University, Einsteinweg 55, P.O. Box 9502, 2300 RA,
Leiden, The Netherlands. Fax: þ31-71-527-4671; E-mail: reedijk@chem.
leidenuniv.nl.
11
DOI: 10.1081/SCC-120015554
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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12
Aromı et al.
Since the late 80s, the design and synthesis of supramolecular
polynuclear metal complexes has been a topic of great interest.[1–3]
Intramolecular electronic interactions between metal centers can strongly
influence magnetic,[4] redox,[5] and spectroscopic[6,7] properties of coordi-
nation compounds. Polyketone ligands offer considerable potential for
the preparation of such fascinating supramolecular assemblies.[1,8–12]
The synthesis of the tetraketones, depicted below, is based upon two
well-known organic reactions (Sch. 1).
The first step is a Friedel–Craft acylation of 4-methylphenol (1) t o
1,3-diacetyl-2-hydroxy-5-methylbenzene (2). The synthesis of 2 was
described by Mandal and Nag.[11] Slight modifications of the published
method led to a small increase of the yield from 42% to 46% of highly
pure 2. This could be achieved with a longer reaction time (overnight
instead of 3 h), and by purifying the product by distillation under reduced
[11]
pressure and notby crystallization from a chloroform solution.
The second step is a Claisen condensation. One approach to synthe-
size tetraketone 6 is to start from 2-hydroxy-5-methyl-isophthalic acid
dimethyl ester (7) and condense it with acetophenone (8) (Sch. 2) using
experimental conditions similar to those published by Bailey et al.,[10]
Scheme 1.
Scheme 2.

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1,3-bis-(3-Oxo-3-phenyl-propionyl)-2-hydroxy-5-methylbenzene
13
or earlier by Wittig.[13] Differentreaciotn solvenst (THF, otluene,
DME) combined with various bases (Na, NaH, t-BuOK) were
employed.
As all trials led to mixtures of several compounds with only small
amountof desirable 6, and because its purification was not possible due
to the presence of side products with comparable boiling points and
polarities, it was decided to use another strategy. This approach deals
with the reaction of 1,3-diacetyl-2-hydroxy-5-methylbenzene (2) with
ethyl benzoate (4) (Sch. 1). Once again, the deprotonation of 2 was
attempted with Na, NaH, or t-BuOK and the Claisen condensation
was performed in THF, toluene, or DME. A good yield of 72% was
obtained with NaH in DME. Fifteen grams of pure 1,3-bis-(3-oxo-3-
phenyl-propionyl)-2-hydroxy-5-methylbenzene (6) could be prepared
after neutralization of the sodium salt with aqueous HCl. This optimized
procedure can be applied to a large variety of esters and thus it is very
versatile: the synthesis of numerous attractive tetraketone ligands can be
imagined by diversifying the two adducts.
A second tetraketone 5, derived from previously reported[10] 1,3-bis-
(3-oxo-3-methyl-propionyl)-2-hydroxy-5-methylbenzene, was also pre-
pared (Sch. 1). The phenolic group of 2 was first protected with a
benzyl group. The Claisen condensation of resulting 1,3-diacetyl-2-ben-
zyloxy-5-methylbenzene (3) with ethyl acetate was accomplished by slight
modification of the procedure reported by Bailey et al.,[10] and earlier by
Martin et al.[14] 1,3-bis-(3-Oxo-3-methyl-propionyl)-2-benzyloxy-5-
methylbenzene (5) was obtained in 25% yield.
In summary, we have successfully prepared two new compounds
containing in the same molecule two b-diketone units and a phenoxy
group. These symmetric multidentate O-donor ligands have been synthe-
sized with the aim of assembling transition metal centers into species
exhibiting new topologies and innovative magnetic properties. In a pre-
liminary study, unique coordination compounds of great interest have
recently been obtained using 1,3-bis-(3-oxo-3-phenyl-propionyl)-
2-hydroxy-5-methylbenzene (6).[15,16]
EXPERIMENTAL SECTION
Solvents and chemicals were commercially available as either reagent
grade (absolute ethanol, 60% NaH, hexane, dichloromethane, ethyl acet-
ate, diethyl ether, tetrahydrofuran, anhydrous MgSO4, KOH, t-BuOK,
benzyl bromide, nitrobenzene, acetyl chloride, p-cresol, ethyl benzoate),

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14
Aromı et al.
or as analytical grade (AlCl3, toluene, methanol, 1,2-dimethoxyethane),
and were used as received unless stated otherwise. Tetrahydrofuran was
freshly distilled over sodium benzophenone before use.
The syntheses of all organic compounds were performed under an
inert atmosphere, but their purification was commonly performed in air.
Melting points were obtained with the use of a Buchi apparatus and are
uncorrected. Infrared spectra were recorded on a Perkin–Elmer Paragon
1000 spectrophotometer, and peaks are reported in cmꢀ1 1H NMR
.
and 13C NMR spectra were recorded on a Jeol JNM FX-200 (200 MHz)
instrument or on a Bruker DPX 300 spectrometer (300 MHz). Chemical
shifts are reported in ꢀ (parts per million) relative to an internal standard of
tetramethylsilane. Mass spectrometry experiments were performed on
a Finnigan MAT TSQ-700 equipped with a custom made electrospray
interface (ESI). Spectra are collected by constant infusion of the analyte
dissolved in methanol/water with 1% acetic acid. Elemental analyses were
performed at the Microanalytical Department of Leiden University, using
a Perkin–Elmer Series II CHNS/O Analyzer 2400.
Preparation of 1,3-Diacetyl-2-hydroxy-5-methylbenzene (2)
This diketone was prepared by the method reported by Mandal and
Nag[11] with slight modifications. A 3-L 3-necked round-bottom flask was
fitted with a magnetic stirring bar, a reflux condenser, and a pressure
equalizing addition funnel. AlCl3 (200 g, 1.5 mol) was dissolved in
300 mL of nitrobenzene by stirring. p-Cresol (1) (27 g, 0.25 mol) was
added to the resulting solution and the reaction vessel was then placed
into an ice-water bath to keep the temperature below 10ꢁC. Acetyl chlor-
ide (60 g, 0.75 mol) was added dropwise over a period of 1.5 h. After
completion of the addition, the temperature was slowly raised to 60ꢁC
over a period of 3 h using an oil bath, and the reaction was continued at
this temperature overnight. The reaction mixture was then cooled by
surrounding the flask with crushed ice. Ice-cooled 6 M HCl (400 mL)
was carefully added (CAUTION: brisk evolution of HCl gas took
place at this stage!). The reaction mixture became highly viscous due to
the precipitation of an aluminum complex. The speed of the stirrer
was increased to the maximum. After the complete addition of the acid
solution, the mixture was filtered through a glass-filter. The inorganic
precipitate was washed several times with toluene. The liquid phases
were combined and evaporated under reduced pressure to remove toluene
and traces of water. The remaining brown solution was distilled to

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1,3-bis-(3-Oxo-3-phenyl-propionyl)-2-hydroxy-5-methylbenzene
15
remove nitrobenzene and the acylation side product, 2-hydroxy-5-methy-
lacetophenone. Pure 1,3-diacetyl-2-hydroxy-5-methylbenzene (2) was
obtained by further distilling the residue (T ¼ 105–116ꢁC, P ¼
0.1 mmHg). Twenty-two grams of light-yellow crystals of 2 were obtained
(yield ¼ 46%). M.p. 74–75ꢁC. IR (neat): ꢁ ¼ 2921, 1664, 1636, 1447, 1357,
1
1245, 1158, 976, 962, 829, 582 cmꢀ1. H NMR (CDCl3): ꢀ ¼ 2.34 (s, 3H,
CH3), 2.68 (s, 6H, CH3), 7.79 (s, 2H, CaromH), 13.13 (s, 1H, OH) ppm.
13C NMR (CDCl3): 20.2 (CH3), 29.4 (CH3), 123.8 (Carom), 127.6 (Carom),
136.8 (CaromH), 160.5 (CaromOH), 201.6 (C¼O) ppm. Anal. calcd. for
C11H12O3 (192.21): C, 68.74; H, 6.29; O, 24.97. Found C, 68.83; H,
5.92; O, 25.25.
Preparation of 1,3-Diacetyl-2-benzyloxy-5-methylbenzene (3)
In a 250-mL double-necked flask fitted with a reflux condenser,
1,3-Diacetyl-2-hydroxy-5-methylbenzene (2) (9.6 g, 0.05 mol) was dis-
solved in 100 mL of EtOH. KOH (5.61 g, 0.1 mol) was added followed
by addition of benzyl bromide (17.1 g, 0.1 mol). This mixture was refluxed
for 6 h. After cooling, the reaction mixture was filtered and the solvent
was removed under reduced pressure. The residue was taken up with
CH2Cl2 and the resulting organic solution was washed with a
2 N NaOH aqueous solution. The organic phase was separated and dried
over MgSO4. The solventwas evaporated under reduced pressure to give
the crude compound. The side product, benzylethylether, was distilled
outand 15.6 g of pure 3 was obtained as a yellow oil which solidified
(yield ¼ 53%). M.p. 44.5–45.5ꢁC. IR (neat): ꢁ ¼ 2923, 1676, 1447, 1251,
1
1217, 965, 739, 701, 570, 541 cmꢀ1. H NMR (CDCl3): ꢀ ¼ 2.37 (s, 3H,
CH3), 2.58 (s, 6H, CH3), 4.87 (2, 2H, CH2), 7.36 (s, 5H, CaromH), 7.51 (s,
2H, CaromH) ppm. 13C NMR (CDCl3): 20.5 (CH3), 30.7 (CH3), 79.4
(CH2), 128.3 (CaromH), 128.5 (CaromH), 128.6 (CaromH), 133.2
(CaromH), 134.2 (Carom), 134.8 (Carom), 135.5 (Carom), 153.9 (CaromO),
200.4 (C¼O) ppm. Anal. calcd. for C18H18O3 (282.33): C, 76.57; H,
6.43; O, 17.00. Found C, 76.93; H, 6.74; O, 16.33.
Preparation of 1,3-bis-(3-Oxo-3-methyl-propionyl)-2-benzyloxy-5-
methylbenzene (5)
Sixty percent oil dispersion NaH (1.6 g, 0.04 mol) was introduced in a
1-L double-necked round-bottom flask under argon fitted with a reflux

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16
Aromı et al.
condenser, and a pressure equalizing addition funnel. The NaH was
washed twice with hexane. The hexane was removed employing a
double-tipped needle (cannula). Ethylacetate (29 mL, excess) was
added. The reaction vessel was cooled using an ice bath. Then, 1,3-dia-
cetyl-2-benzyloxy-5-methylbenzene (3) (2.8 g, 0.01 mol) was carefully
adjoined, dropwise, to the NaH suspension (hydrogen gas was given
off and the reaction was found exothermic!). After completion of the
addition, the reaction mixture was heated to reflux and the boiling main-
tained for 2 h. Upon cooling to room temperature, diethyl ether was
added until the precipitation of the tetraketone sodium salt. This preci-
pitate was isolated on a glass-filter and washed twice with 200 mL of
diethyl ether. The tetraketone salt was hydrolyzed by adding 200 mL of
a 15% HOAc aqueous solution. An insoluble bleak oil immediately
appeared which was extracted with diethylether. The organic layer was
dried over MgSO4 and after evaporation of Et2O, the solid was washed
with hexane. Zero point nine gram of brown crystals of 5 were obtained
(yield ¼ 25%). M.p. 94ꢁC. IR (neat): ꢁ ¼ 2924, 1616, 1575, 1213, 958, 813,
738, 699, 556 cmꢀ1. 1H NMR (CDCl3): ꢀ ¼ 2.09 (s, 6H, CH3), 2.39 (s, 3H,
CH3), 4.82 (s, 2H, CH2–O), 6.34 (s, 2H, CenolH), 7.34 (s, 5H, CaromH),
7.66 (s, 2H, CaromH), 15.86 (s, 2H, Cenol–OH) ppm. 13C NMR (CDCl3):
20.7 (CH3), 25.5 (CH3), 78.2 (CH2), 101.9 (¼CH), 128.5 (CaromH), 128.6
(CaromH), 130.7 (CaromH), 133.4 (Carom), 134.4 (Carom), 136.1 (Carom),
153.9 (Carom), 182.5 (Cenol–OH), 193.6 (C¼O) ppm. Anal. calcd. for
C22H22O5 (366.41): C, 72.12; H, 6.05; O, 21.83. Found C, 72.10; H,
5.90; O, 22.00.
Preparation of 1,3-bis-(3-Oxo-3-phenyl-propionyl)-2-hydroxy-
5-methylbenzene (6)
Sixty percent oil dispersion NaH (15 g, 0.375 mol) was introduced in
a 1-L double-necked round-bottom flask under argon fitted with a reflux
condenser, and a pressure equalizing addition funnel. The NaH
was washed twice with hexane. The hexane was removed employing a
cannula. Four hundred milliliter of 1,2-dimethoxyethane (DME) were
introduced followed by 1,3-diacetyl-2-hydroxy-5-methylbenzene (2)
(10 g, 0.052 mol). The reaction vessel was then cooled to 0ꢁC and a solu-
tion of ethyl benzoate (4) (18 g, 0.12 mol) in 300 mL of DME was care-
fully added, dropwise (hydrogen gas was given off and the reaction was
exothermic!). The reaction mixture turned yellow after a few minutes.
After completion of the addition of 4, the mixture was heated and

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1,3-bis-(3-Oxo-3-phenyl-propionyl)-2-hydroxy-5-methylbenzene
17
slowly brought to reflux within 2 h. After refluxing overnight, the flask
was cooled to 0ꢁC using an ice-water bath and water was cautiously
added in order to neutralize the excess of NaH. Concentrated HCl
aqueous solution was employed to bring the pH to 1 (pH paper). The
crude product was extracted with Et2O. The organic phase was dried over
MgSO4 and the solvent was removed under reduced pressure. Before
dryness, the yellow precipitate (11 g) was collected by filtration. The
filtrate was evaporated to dryness and the residue was stirred in 200 mL
of EtOH absolute. The yellow solid (4 g) was collected by filtration.
Fifteen grams of pure 6 was obtained (yield ¼ 72%). M.p. 153ꢁC. IR
(neat): ꢁ ¼ 1597, 1558, 1539, 1238, 814, 784, 755, 726, 681, 613 cmꢀ1
.
1H NMR (CDCl3): ꢀ ¼ 1.54 (s, 3H, CH3), 7.18 (s, 2H, CenolH),
7.40–7.60 (overlapped dd and d, 6H, CaromH), 7.91 (s, 2H, CaromH),
8.00 (d, J ¼ 7 Hz, 4H, CaromH), 13.29 (s, 1H, Carom–OH), 16.14 (s, 2H,
C
enol–OH) ppm. 13C NMR (CDCl3): ꢀ ¼ 20.5 (CH3), 95.8 (Cenol–H),
121.9 (Carom), 127.1 (CaromH), 128.0 (Carom), 128.7 (CaromH), 132.5
(CaromH), 134.5 (Carom), 134.8 (CaromH), 160.2 (Carom–OH), 182.2
(Cenol–OH), 188.7 (C¼O) ppm. ESI MS, m/z 401 [M þ H]þ, 383
[(MꢀPh) þ AcOH]þ 355 [(MꢀPhCO) þ AcOH]þ. Anal. calcd. for
C25H20O5 (400.42): C, 74.99; H, 5.03; O, 19.98. Found C, 75.42; H,
4.98; O, 19.60.
ACKNOWLEDGMENTS
This work was supported by the Dutch National Research School
Combination Catalysis (HRSMC and NIOK) and the European Union,
under the contract HPMF-C7-1999-00/13 (Marie Curie Fellowship).
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Received in the UK January 2, 2002