The Aldol Reaction under High-Intensity Ultrasound: A Novel Approach to an Old Reaction

Article abstract of DOI:10.1002/ejoc.200300369

We have employed high-intensity ultrasound (HIU) to reinvestigate the aldol reaction (AR) in water. A number of aldols that under usual conditions would undergo elimination were isolated in acceptable to good yields. Within 15-30 min, acetophenone reacted with non-enolizable aldehydes to afford the aldol exclusively, while under conventional conditions (stirring or heating under reflux) the same compounds either failed to react or gave, after several hours, the enone, often in complex product mixtures. A library of polyols was obtained starting from a series of acetophenones and excess formaldehyde. Benzaldehyde reacted with a series of 1,3-dicarbonyl compounds to afford the corresponding bis(benzylidene) adducts. The results proved to be highly reproducible because the relevant sonochemical parameters were rigorously controlled. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300369

FULL PAPER
The Aldol Reaction under High-Intensity Ultrasound: A Novel Approach to an
Old Reaction
Giancarlo Cravotto,*[a] Alberto Demetri,[a] Gian Mario Nano,[a] Giovanni Palmisano,[b]
Andrea Penoni,[b] and Silvia Tagliapietra[a]
Keywords: Aldol reactions / Synthesis design / Synthetic methods
We have employed high-intensity ultrasound (HIU) to rein-
vestigate the aldol reaction (AR) in water. A number of aldols
that under usual conditions would undergo elimination were
starting from a series of acetophenones and excess formalde-
hyde. Benzaldehyde reacted with a series of 1,3-dicarbonyl
compounds to afford the corresponding bis(benzylidene) ad-
isolated in acceptable to good yields. Within 15−30 min, ace- ducts. The results proved to be highly reproducible because
tophenone reacted with non-enolizable aldehydes to afford
the aldol exclusively, while under conventional conditions
(stirring or heating under reflux) the same compounds either
failed to react or gave, after several hours, the enone, often in
complex product mixtures. A library of polyols was obtained
the relevant sonochemical parameters were rigorously con-
trolled.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
use of transition metal catalysts (Rh, Ni, V),[6] to solvent-
free reactions mediated by magnesium hydrogen sulfate,[7]
to supported reagents[8] and anion-exchange resins.[9]
The aldol reaction (AR), one of the oldest organic reac-
tions,[1] has been extensively studied and exploited after
Kane discovered in 1838 that mesityl oxide can be made by
self-condensation of acetone;[2] the reaction still remains a
common synthetic method and the most important reaction
of enolate ions.[3] In the AR a new CϪC bond is formed
and up to two new adjacent stereocenters can be generated
simultaneously. Because the aldol motif is present in many
molecules of great interest, the AR has been widely used to
prepare stereochemically complex products. In recent years,
a number of methods have been developed to perform
asymmetric ARs.[4] Although the AR can be catalysed by
acids, and many variants employing neutral conditions have
been described,[3] basic catalysis in protic solvent is used
most commonly. Yields are often compromised by self-con-
densation, polycondensation, generation of regioisomeric
enols, and dehydration of aldols, which is sometimes fol-
lowed by Michael addition (e.g., Robinson annulation). To
minimize competing processes, a useful modification, the
Mukaiyama AR,[5] has been developed in which an enol
silyl ether is reacted with carbonyl compounds in the pres-
ence of a Lewis acid. Recently, the focus has shifted to the
Aldols are raw materials for the production of lubricants,
surface coatings and synthetic resins;[10] moreover, they are
important intermediates in the synthesis of polyols.[11]
In the present work, we applied high-intensity ultrasound
(HIU) to base-catalyzed AR in water to prepare a wide
range of aldols and polyols, mainly from acetophenones as
starting materials. In the last decade the use of water as
a reaction solvent or co-solvent has attracted considerable
attention in synthetic organic chemistry.[12] Aqueous media
have several advantages for conventional procedures. Be-
sides eliminating the need to dry solvents and substrates
before use, they often bring out peculiar reactivities and
selectivities that are not observed under anhydrous con-
ditions. Reagents and catalysts have been developed that
work well in aqueous media, and for the AR in particu-
lar.[13] For aqueous AR, Chan introduced a tin- or zinc-
mediated cross-coupling of halo-ketones with aldehydes;[14]
other authors have described aqueous Mukaiyama-type re-
actions.[15]
We found that, under HIU, these reactions take place
with good yields in aqueous heterogeneous systems, gener-
ally without requiring any catalyst. Water is a common sol-
vent in sonochemistry because its good cavitation energy
has a maximal effect around room temperature.[16] It has
been widely reported that ultrasound, when compared with
conventional conditions, enhances reaction rates[17] and
product yields in addition to sometimes changing the reac-
tion pathway (‘‘sonochemical switching’’).[18] Generally,
[a]
`
Dipartimento di Scienza e Tecnologia del Farmaco, Universita
di Torino,
Via Giuria 9, 10125 Torino, Italy
Fax: (internat.) ϩ39-011-6707687
E-mail: giancarlo.cravotto@unito.it
Dipartimento di Scienze Chimiche, Fisiche e Matematiche;
[b]
`
Universita dell’Insubria,
Via Valleggio 11, 22100 Como, Italy
4438
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300369
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The Aldol Reaction under High-Intensity Ultrasound
FULL PAPER
ultrasound accelerates a reaction by a more intimate mixing
of reagents and enhances the activity of an insoluble cata-
lyst by enlarging its surface area.[19] Reactions may also be
accelerated because highly reactive radical species are
formed during cavitation; in this case, sonochemical switch-
ing may occur. Although sonochemical ARs have appeared
in the literature previously, starting in the early 1980s,[20] to
the best of our knowledge, none has been reported to serve
as a general method for the preparation of aldols. More
recently, ultrasound has also been applied to closely related
reactions, viz. the Knoevenagel condensation[21] and the Re-
formatsky reaction.[22] Our approach to the synthesis of al-
dols in water will hopefully contribute to the development
of ‘‘green’’ procedures.[23]
Table 2. AR of acetophenone (4 mmol) and non-enolizable alde-
hydes (4 mmol) in water in the presence of NaOH (0.125 mmol)
under HIU (18 kHz, 280 W; 20 °C)
Results and Discussion
We chose the well-known reaction between acetophenone
and benzaldehyde (Scheme 1) as a suitable model to optim-
ise conditions and to compare results with those from con-
ventional methods. Because TLC did not afford a sufficient
separation of reagents and products,[24] we followed the co-
urse of the reaction by HPLC (µ-Porasil, Waters) and
found that no 1,3-diphenylpropenone was formed. The re-
sults are displayed in Table 1. Addition of a surfactant[25]
caused a dramatic effect: a very small amount of Aliquat
336 (0.2Ϫ0.5%) sufficed to reverse the aldol/enone ratio, af-
fording the former one exclusively in every case. Following
this success, we reacted acetophenone with a series of non-
enolizable aldehydes (Table 2, 1Ϫ13).
All of the aldehydes gave the aldol in acceptable to good
yields, with two exceptions: vanillin (12) and ferrocenecar-
boxaldehyde (13) gave no aldol (for 12, 1 equiv. of base was
also added to convert the phenolic group to phenolate);
after further addition of base and prolonged sonication,
these reactions gave the enones instead. Because much in-
formation is available on the conventional AR with benzal-
dehyde, we used it to extend our comparative investigation
further. In our hands, benzaldehyde reacted very fast with
acetone to afford the corresponding aldol (4-hydroxy-4-
phenylbutan-2-one) in good yield (72%); with acetaldehyde,
surprisingly, it yielded cinnamaldehyde as the only product
(79%). Reacting benzaldehyde with a number of 1,3-dicar-
bonyl compounds afforded, in all cases, the corresponding
2:1 adducts.
The present approach provides easy access to bis(benzyli-
dene) derivatives (Table 3). Under these conditions, β-te-
tronic acid and ethyl acetylacetate gave no reaction or
underwent hydrolysis, respectively.
The AR between acetophenones and excess formal-
dehyde (50 equiv.) is a convenient procedure for obtaining
libraries of new polyols. We carried out these reactions at
20 kHz and 250 W because preliminary optimisation tests
Scheme 1. AR of acetophenone with non-enolizable aldehydes
Table 1. AR conditions of acetophenone (4 mmol) and benzal-
dehyde (4 mmol) in water in the presence of NaOH (0.125 mmol)
Conditions
Time (min)
Yield ratio, A:B
Vigorous stirring, 20 °C
Vigorous stirring, 70 °C
Vigorous Stirring, 20 °C
ϩ Aliquat 336[a]
30
30
15
8:12
0:30
trace:51
HIU 18 kHz, 20 °C, 280 W
U.S. 18 kHz, 20 °C, 280 W,
Aliquat 336
15
15
73:0
trace:82
HIU 18 kHz, 20 °C, 400 W
HIU 20 kHz, 20 °C, 280 W
HIU 34 kHz, 20 °C, 250 W
HIU 34 kHz, 20 °C, 220 W,
Aliquat 336
US cleaner bath, 35 kHz,
20 °C, 140 W
15
15
30
30
77: trace
72:0
49:0
0:31
60
17:0
[a]
Methyltrioctylammonium chloride.
Eur. J. Org. Chem. 2003, 4438Ϫ4444
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4439

G. Cravotto, A. Demetri, G. M. Nano, G. Palmisano, A. Penoni, S. Tagliapietra
FULL PAPER
Only 12 of the 42 aldols and polyols here reported have
been described previously.[26] We have also examined some
stereochemical aspects of these reactions in a few prelimi-
nary experiments. Our operating conditions did not influ-
ence the diastereoselectivity of the AR: although propi-
ophenone reacted with 4-nitrobenzaldehyde, 3-nitrobenzal-
dehyde and pyridine 3-carboxaldehyde[27] to afford the cor-
responding aldols in good yields (30 min; 69, 77 and 72%,
respectively), the poor diastereoisomeric excess (monitored
by GC: OV1, film 0.4 µm) observed previously[28] was
hardly improved (10Ϫ13% vs. 7Ϫ8%).
Table 3. AR of benzaldehyde (4 mmol) with 1,3-dicarbonyl com-
pounds (8 mmol) in water in the presence of NaOH (0.125 mmol)
under HIU (18 kHz, 280 W; 20 °C)
We attempted to use -proline as a chiral catalyst for son-
ochemical asymmetric ARs both in water and, more con-
ventionally, in DMSO. In either case, the aldols arising
from acetophenone reacting with 4-nitrobenzaldehyde, 3-
nitrobenzaldehyde and pyridine 3-carboxaldehyde (5, 7 and
11, respectively; Table 2) exhibited uniformly poor values of
ee (Ͻ 20%), a result at variance with a published report.[29]
We achieved separation of enantiomers, which had failed
when using various chiral GC columns, by chiral HPLC
using hexane/2-propanol as eluent.[30]
had shown that yields were somewhat higher under these
conditions. After 1 h of sonication at 20 °C we isolated the
derivatives listed in Scheme 2 and Table 4. Because of their
dense functionalization, these compounds are potential
starting materials for the synthesis of polymers and dendri-
mers. Longer reaction times caused an increase of c and
even more of d; working at 5 °C reduced the formation of a.
Conclusion
The above series of ARs, when carried out in aqueous
suspension under HIU, afforded a number of aldols that
usually cannot be isolated in practical yields because they
undergo elimination immediately. Our approach offers re-
ady access to polyols and bis-benzylidene adducts.
Experimental Section
General: Reactions were monitored by TLC on Merck 60 F254
(0.25 mm) plates, which were visualized by UV inspection and/or
staining with 5% H2SO4 in ethanol and heating. Merck silica gel
was used for column chromatography (CC). Melting points: Büchi
SMP-20 (uncorrected). IR: Shimadzu FT-IR 8001 spectrophoto-
1
meter. NMR: Bruker 300 Advance (300 MHz and 75 MHz for H
1
and 13C, respectively). For H NMR: CDCl3 as solvent, CHCl3 at
δ ϭ 7.26 ppm as reference. For 13C NMR: CDCl3 as solvent,
CDCl3 at δ ϭ 77.0 ppm as reference. The chemical shifts (δ) are
given in ppm, and the coupling constants (J) in Hz. Low-resolution
mass spectra (LRMS): Finnigan-MAT TSQ70 in chemical ioniz-
ation mode with isobutane as the reactant gas. GC analysis: Shim-
adzu GC-14 B equipped with a Shimadzu C-R6A Chromatopac
integrator. HPLC analysis: Thermo-Quest Spectra Series P200,
equipped with a UV-Vis Jasco 875-UV detector or a Gilson 133
refractive index refractometer, and a Millipore 740 Waters inte-
grator. Commercially available reagents and solvents were used
without further purification unless otherwise noted. All the reac-
tions were performed on a flat-bottomed tube, made in Teflon
(diameter: 35 mm; thickness: 1 mm; volume: 40 mL), inserted in
the thermostatic bath (for temperatures as low as Ϫ20 °C) of the
sonochemical reactor. For some comparison of sonication effects,
we used an Elma TS540 cleaner bath at 35 kHz (nominal operating
frequency: 140 W).
Scheme 2. AR of different acetophenones with formaldehyde
Table 4. ARs of acetophenones and excess aq. formaldehyde (50
equiv.) under HIU (20 kHz, 250 W, 1 h, 20 °C)
Compound
R
Yield ratio (%)
a
b
c
d
19
20
21
22
23
24
H
20
9
19
5
18
12
15
14
30
14
22
39
34
27
2-OCH3
2-Cl
4-Cl
4-NO2
3-CH3CO
Ͻ 2[a]
11
Ͻ 2[a]
11
10
14
2[a]
4
Ͻ 2[a]
18
[a]
Determined by HPLC (CHCl3/acetone, 3:2; µ-Porasil Waters).
The sonochemical apparatus (Scheme 3) used in the present work
was designed for stringent control of the reaction conditions. The
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Eur. J. Org. Chem. 2003, 4438Ϫ4444

The Aldol Reaction under High-Intensity Ultrasound
FULL PAPER
transducer, consisting of two high-efficiency pre-stressed piezo-
electric rings, is lodged in a Delrin housing that can be cooled by
a flow of refrigerated oil. Indeed, the whole probe system (compris-
ing the transducer, the booster and the immersion horn) is refriger-
(0.5 mL, 0.125 mmol) were added to the Teflon tube. The mixture
was sonicated for 1 h using an immersion horn operating at 20 kHz
and 250 W, whilst the temperature was maintained at 20 °C. The
reactions were monitored by TLC using mixtures of hexane/EtOAc
ated by an oil forced-circulation circuit connected to an oilϪfreon or CHCl3/MeOH as eluents. The products were recovered by fil-
heat exchanger; this system is cooled in turn by a refrigerator unit. tration through a sintered disc filter funnel and extracted with
The frequency can be tuned between 17 and 45 kHz and the power
can be varied up to a maximum output of 1000 W. To achieve opti-
mal acoustic efficiency, the reactor can rotate eccentrically around
the horn and the probe can be made to move alternatively up and
down by a predetermined excursion at a chosen speed. Transducer
resonance is maintained by a true motional feedback network.
Electrical and acoustic parameters may be monitored thereby to
give full process information. Reactions were performed in a Te-
flon tube (thickness: 1 mm) inserted in a Delrin reactor that
was thermostatted by four Peltier modules.
CHCl3/MeOH (49:1). The residue was purified by CC (PE/EtOAc
or CHCl3/MeOH).
4-Ethyl-3-hydroxy-1-phenylpent-4-en-1-one (3): Yield: 424 mg
(52%). Yellow oil. IR (liquid film): ν˜ ϭ 3374, 1682, 1356, 1279,
1211, 1086, 1026 cmϪ1. 1H NMR (CDCl3): δ ϭ 7.98 (d, J ϭ 7.1 Hz,
2 H), 7.60 (m, 1 H), 7.49 (t, J ϭ 7.7 Hz, 2 H), 5.18 (s, 1 H), 4.95
(s, 1 H), 4.74 (m, 1 H), 3.24 (m, 2 H), 2.16 (m, 2 H), 1.13 (t, J ϭ
7.4 Hz, 3 H) ppm. 13C NMR (CDCl3): δ ϭ 200.95, 152.13, 137.18,
133.98, 129.10, 128.54, 109.35, 71.10, 44.60, 25.23, 12.61 ppm. Rf ϭ
0.15 (hexane/EtOAc, 9:1). CIMS: m/z ϭ 205 [M ϩ H]ϩ, 187 [M ϩ
H Ϫ H2O]ϩ. C13H16O2 (204.1): calcd. C 76.44, H 7.90; found C
76.50, H 7.86.
3-Hydroxy-3-(3-nitrophenyl)-1-phenylpropan-1-one
(7):
Yield:
823 mg (76%). White crystals. M.p. 124 °C. IR (KBr disk): ν˜ ϭ
1
3513, 1674, 1524, 1350, 1213, 760, 691 cmϪ1. H NMR (CDCl3):
δ ϭ 8.33 (s, 1 H), 8.16 (d, J ϭ 8.1 Hz, 1 H), 7.96 (d, J ϭ 7.3 Hz,
2 H), 7.80 (d, J ϭ 7.7 Hz, 1 H), 7.69 (t, J ϭ 8.2 Hz, 1 H), 7.55 (d,
J ϭ 7.9 Hz, 1 H), 7.47 (t, J ϭ 7.5 Hz, 2 H), 5.46 (m, 1 H), 3.42
(m, 2 H) ppm. 13C NMR (CDCl3): δ ϭ 199.91, 148.76, 145.68,
136.64, 134.34, 132.45, 129.91, 129.20, 128.59, 122.92, 121.28,
69.47, 47.43 ppm. Rf ϭ 0.19 (hexane/EtOAc, 7:3). CIMS: m/z ϭ
272 [M ϩ H]ϩ, 254 [M ϩ H Ϫ H2O]ϩ. C15H13NO4 (271.1): calcd.
C 66.41, H 4.83; found C 66.50, H 4.81.
3-(3,4-Dimethoxyphenyl)-3-hydroxy-1-phenylpropan-1-one
(8):
Yield: 846 mg (74%). White solid. M.p. 124 °C. IR (KBr disk): ν˜ ϭ
3511, 1684, 1595, 1516, 1262, 1140, 1022, 764, 698 cmϪ1. 1H NMR
(CDCl3): δ ϭ 7.98 (d, J ϭ 8.1 Hz, 2 H), 7.58 (t, J ϭ 7.5 Hz, 1 H),
7.47 (t, J ϭ 7.6 Hz, 2 H), 7.02 (s, 1 H), 6.96 (d, J ϭ 8.2 Hz, 1 H),
6.87 (d, J ϭ 8.2 Hz, 1 H), 5.30 (m, 1 H), 3.92 (s, 3 H), 3.89 (s, 3
H), 3.38 (d, J ϭ 6.5 Hz, 2 H) ppm. 13C NMR (CDCl3): δ ϭ 200.67,
149.57, 148.94, 137.03, 136.11, 134.06, 129.12, 128.56, 118.33,
111.55, 109.44, 70.34, 56.38, 56.31, 47.86 ppm. Rf ϭ 0.21 (hexane/
EtOAc, 7:3). CIMS: m/z ϭ 287 [M ϩ H]ϩ, 269 [M ϩ H Ϫ H2O]ϩ.
C17H18O4 (286.1): calcd. C 71.31, H 6.34; found C 70.69, H 6.41.
Scheme 3. Sonochemical reactor: 1) transducer and booster, 2)
horn, 3) thermostatted reactor, 4) eccentric rotation, 5) vertical ex-
cursion, 6) refrigeration system with oil forced-circulation circuit
General Procedure for 1؊13: Both reactants (acetophenone and al-
dehyde, 4 mmol each), water (6 mL) and 0.25  NaOH (0.5 mL,
0.125 mmol) were added to the above-mentioned Teflon tube.
The mixture was sonicated for 15Ϫ30 min at 18 kHz and 280 W
using an immersion horn, whilst maintaining the temperature at 20
°C. The reactions were monitored by TLC using hexane/EtOAc or
CHCl3/MeOH as eluents. After extraction with CHCl3 or EtOAc
(10 mL, 3 times), a wash with brine (10 mL), drying (MgSO4) and
removal of the solvent, the residue was purified by CC (PE/EtOAc).
3-[(4-Dimethylamino)phenyl]-3-hydroxy-1-phenylpropan-1-one (9):
Yield: 667 mg (62%). Yellow oil. IR (liquid film): ν˜ ϭ 3510, 1649,
1
1564, 1377, 1344, 1167, 1016, 816 cmϪ1. H NMR (CDCl3): δ ϭ
7.98 (d, J ϭ 8.1 Hz, 2 H), 7.59 (d, J ϭ 7.3 Hz, 1 H), 7.48 (t, J ϭ
7.5 Hz, 2 H), 7.33 (d, J ϭ 8.4 Hz, 2 H), 6.77 (d, J ϭ 8.5 Hz, 2 H),
5.28 (m, 1 H), 3.38 (m, 2 H), 2.97 (s, 6 H) ppm. 13C NMR (CDCl3):
δ ϭ 197.42, 140.64, 137.40, 132.91, 130.82, 128.64, 128.42, 128.21,
113.34, 69.23, 48.83, 43.6 ppm. Rf ϭ 0.20 (hexane/EtOAc, 8:2).
CIMS: m/z ϭ 251 [M ϩ H Ϫ H2O]ϩ. C17H19NO2 (269.1): calcd. C
75.81, H 7.11; found C 75.95, H 7.16.
General Procedure for 14؊18: Benzaldehyde (4 mmol), a 1,3-dicar-
bonyl compound (8 mmol), water (6 mL) and 0.25  NaOH
(0.5 mL, 0.125 mmol) were added to the Teflon tube. The mixture
was sonicated for 1 h at 18 kHz and 280 W using an immersion
horn, whilst the temperature was maintained at 20 °C. The reac-
tions were monitored by TLC using hexane/EtOAc or CHCl3/
MeOH as eluents. In most cases, the product was recovered easily
by filtration through a sintered disc filter funnel; sometimes a
further extraction with CHCl3 or EtOAc was needed. The residue
was purified by crystallization or by CC (PE/EtOAc).
3-Hydroxy-3-(4-methoxyphenyl)-1-phenylpropan-1-one (10): Yield:
379 mg (37%). White solid. M.p. 112 °C. IR (KBr disk): ν˜ ϭ 3515,
1686, 1590, 1520, 1268, 1140, 1025, 765, 695 cmϪ1 1H NMR
.
(CDCl3): δ ϭ 7.98 (d, J ϭ 8.1 Hz, 2 H), 7.57 (t, J ϭ 7.5 Hz, 1 H),
7.46 (t, J ϭ 7.5 Hz, 2 H), 6.95 (d, J ϭ 8.2 Hz, 2 H), 6.85 (d, J ϭ
8.2 Hz, 2 H), 5.29 (m, 1 H), 3.90 (s, 3 H), 3.38 (d, J ϭ 6.5 Hz, 2
H) ppm. Rf ϭ 0.24 (hexane/EtOAc, 7:3). CIMS: m/z ϭ 257 [M
ϩ H]ϩ. C16H16O3 (256.1): calcd. C 74.98, H 6.29; found C 74.96,
H 6.40.
General Procedure for 19؊22: Acetophenone (4.0 mmol), formal-
3-Ferrocenyl-1-phenylprop-2-en-1-one (13): Yield: 467 mg (37%).
dehyde [37% (w/w) solution in water (20 mL)] and 0.25  NaOH Dark yellow oil. IR (liquid film): ν˜ ϭ 1663, 1601, 1591, 1578, 1224,
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G. Cravotto, A. Demetri, G. M. Nano, G. Palmisano, A. Penoni, S. Tagliapietra
FULL PAPER
1015, 696 cmϪ1. 1H NMR (CDCl3): δ ϭ 7.99 (d, J ϭ 7.1 Hz, 2 H),
7.77 (d, J ϭ 15.4 Hz, 1 H), 7.58 (m, 1 H), 7.50 (t, J ϭ 7.7 Hz, 2 69 mg (9%). Yellow oil. IR (liquid film): ν˜ ϭ 3400, 1663, 1597,
2-Hydroxymethyl-1-(2-methoxyphenyl)prop-2-en-1-one (20a): Yield:
1
H), 7.14 (d, J ϭ 15.4 Hz, 1 H), 4.61 (s, 2 H), 4.50 (s, 2 H), 4.19 (s,
1464, 1248, 1022, 758 cmϪ1. H NMR (CDCl3): δ ϭ 7.78 (d, J ϭ
6 H) ppm. 13C NMR (CDCl3): δ ϭ 189.78, 146.73, 138.54, 128.38, 7.7 Hz, 1 H), 7.50 (t, J ϭ 8.3 Hz, 1 H), 7.00 (m, 2 H), 6.12 (s, 1
119.07, 69.55 ppm. Rf ϭ 0.45 (hexane/EtOAc, 8:2). CIMS: m/z ϭ
317 [M ϩ H]ϩ.
H), 5.76 (s, 1 H), 4.49 (br. s, 2 H), 3.80 (s, 3 H) ppm. Rf ϭ 0.62
(CHCl3/acetone, 1:1). CIMS: m/z ϭ 193 [M ϩ H]ϩ. C11H12O3
(192.1): calcd. C 68.74, H 6.29; found C 68.00, H 6.33.
1,1Ј-Dihydroxy-2,2Ј-(phenylmethylene)bis(cyclohex-1-ene)-3,3Ј-
dione (14): Yield: 886 mg (71%). White solid. M.p. 193 °C. IR (KBr
disk): ν˜ ϭ 1721, 1633, 1603, 1377, 1192, 1030, 949 cmϪ1. 1H NMR
(CDCl3): δ ϭ 7.20Ϫ7.11 (m, 3 H), 6.99 (m, 2 H), 5.97 (s, 1 H), 3.39
(br. s, OH, 2 H), 2.50Ϫ1.78 (m, 12 H) ppm. 13C NMR (CDCl3):
δ ϭ 192.51, 191.29, 138.25, 128.56, 126.88, 126.25, 116.84, 33.97,
33.31, 33.40, 20.52 ppm. Rf ϭ 0.62 (hexane/EtOAc, 1:1). CIMS:
m/z ϭ 313 [M ϩ H]ϩ, 215. C19H20O4 (312.1): calcd. C 73.06, H
6.45; found C 73.20, H 6.37.
3-Hydroxy-1-(2-methoxyphenyl)propan-1-one (20b): Yellow oil.
Rf ϭ 0.55 (CHCl3/acetone, 1:1). CIMS: m/z ϭ 181 [M ϩ H]ϩ.
3-Hydroxy-2-hydroxymethyl-1-(2-methoxyphenyl)propan-1-one
(20c): Yield: 92 mg (11%). Yellow oil. IR (liquid film): ν˜ ϭ 3400,
1
1651, 1455, 1265, 1100, 1025, 800 cmϪ1. H NMR (CDCl3): δ ϭ
7.44 (m, 2 H), 7.10 (m, 2 H), 3.94 (m, 4 H), 3.88 (s, 3 H), 3.51 (m,
1 H) ppm. Rf ϭ 0.31 (CHCl3/acetone, 1:1). CIMS: m/z ϭ 211 [M
ϩ H]ϩ,193 [M ϩ H Ϫ H2O]ϩ. C11H14O4 (210.1): calcd. C 62.85,
H 6.71; found C 62.82, H 6.59.
4,4Ј-Dihydroxy-6,6Ј-dimethyl-3,3Ј-(phenylmethylene)bis(pyran)-2,2Ј-
dione (15): Yield: 1.128 g (83%). White solid. M.p. 176 °C. IR (KBr
3-Hydroxy-2,2-bis(hydroxymethyl)-1-(2-methoxyphenyl)propan-1-
1
disk): ν˜ ϭ 1676, 1610, 1566, 1410, 993, 835, 725 cmϪ1. H NMR
one (20d): Yield: 134 mg (14%). Yellow oil. IR (liquid film): ν˜ ϭ
(CDCl3): δ ϭ 7.55 (t, J ϭ 6.9 Hz, 2 H), 7.46 (t, J ϭ 7.1 Hz, 1 H),
7.33 (d, J ϭ 7.8 Hz, 2 H), 6.38 (s, 2 H), 6.29 (s, 1 H), 2.52 (s, 6 H)
ppm. 13C NMR (CDCl3): δ ϭ 162.11, 135.98, 128.84, 127.01,
126.81, 103.71, 35.17, 20.01 ppm. Rf ϭ 0.23 (hexane/EtOAc, 1:1).
CIMS: m/z ϭ 341 [M ϩ H]ϩ, 201. C19H16O6 (340.1): calcd. C
67.05, H 4.74; found C 67.22, H 4.70.
1
3400, 1684, 1597, 1456, 1260, 1022, 800 cmϪ1. H NMR (CDCl3):
δ ϭ 7.64 (d, J ϭ 7.7 Hz, 1 H), 7.49 (m, 1 H), 6.99 (m, 2 H), 4.08
(m, 6 H), 3.87 (s, 3 H) ppm. Rf ϭ 0.29 (CHCl3/acetone, 1:1). CIMS:
m/z ϭ 241 [M ϩ H]ϩ. C12H16O5 (240.1): calcd. C 59.99, H 6.71;
found C 58.39, H 6.89.
1-(2-Chlorophenyl)-2-hydroxymethylprop-2-en-1-one (21a): Yield:
149 mg (19%). Yellow oil. IR (liquid film): ν˜ ϭ 3400, 1663, 1591,
1,1Ј-Dihydroxy-5,5,5Ј,5Ј-tetramethyl-2,2Ј-(phenylmethylene)bis-
(cyclohex-1-ene)-3,3Ј-dione (17): Yield: 1.001 g (68%). White solid.
M.p. 191 °C. IR (KBr disk): ν˜ ϭ 3400, 1595, 1375, 1250, 1045, 870,
694 cmϪ1. 1H NMR (CDCl3): δ ϭ 12.18 (br. s, OH, 2 H), 7.37 (m,
2 H), 7.28 (d, J ϭ 6.8 Hz, 1 H), 7.21 (d, J ϭ 7.7 Hz, 2 H), 5.69 (s,
1 H), 2.45 (m, 8 H), 1.34 (s, 6 H), 1.21 (s, 6 H) ppm. 13C NMR
(CDCl3): δ ϭ 195.7, 148.8, 133.4, 132.0, 130.3, 128.3, 128.2, 117.1,
116.8, 111.7, 106.2, 55.6, 40.0 ppm. Rf ϭ 0.71 (hexane/EtOAc, 3:7).
CIMS: m/z ϭ 369 [M ϩ H]ϩ, 231 and 229 [M Ϫ dimedone unit]ϩ.
C23H28O4 (368.2): calcd. C 74.97, H 7.66; found C 74.68, H 7.46.
1
1433, 1094, 1053, 980, 756 cmϪ1. H NMR (CDCl3): δ ϭ 7.41 (m,
2 H), 7.34 (m, 2 H), 6.26 (s, 1 H), 5.75 (s, 1 H), 4.52 (br. s, 2 H)
ppm. 13C NMR (CDCl3): δ ϭ 197.50, 147.43, 138.46, 131.50,
131.15, 130.97, 129.77, 129.42, 126.93, 62.01 ppm. Rf ϭ 0.69
(CHCl3/acetone, 1:1). CIMS: m/z ϭ 197 [M ϩ H]ϩ. C10H9ClO2
(196.0): calcd. C 61.08, H 4.61; found C 60.79, H 4.57.
1-(2-Chlorophenyl)-3-hydroxypropan-1-one (21b): Yellow oil. IR
(liquid film): ν˜ ϭ 3400, 1690, 1535, 1413, 1199, 1070, 870, 710
cmϪ1. Rf ϭ 0.64 (CHCl3/acetone, 1:1). CIMS: m/z ϭ 185 [M ϩ
H]ϩ.
2-Hydroxymethyl-1-phenylprop-2-en-1-one (19a): Yield: 129 mg
(20%). Yellow oil. IR (liquid film): ν˜ ϭ 3306, 1651, 1447, 1321,
1-(2-Chlorophenyl)-3-hydroxy-2-hydroxymethylpropan-1-one (21c):
Yellow oil. Rf ϭ 0.48 (CHCl3/acetone, 1:1). CIMS: m/z ϭ 215 [M
ϩ H]ϩ.
1
978, 741 cmϪ1. H NMR (CDCl3): δ ϭ 7.77 (d, J ϭ 7.2 Hz, 2 H),
7.58 (m, 1 H), 7.47 (t, J ϭ 7.7 Hz, 2 H), 6.17 (s, 1 H), 5.83 (s, 1
H), 4.52 (m, 2 H) ppm. 13C NMR (CDCl3): δ ϭ 198.42, 146.65,
137.75, 132.95, 129.84, 128.74, 127.82, 63.63 ppm. Rf ϭ 0.67
(CHCl3/acetone, 1:1). CIMS: m/z ϭ 163 [M ϩ H]ϩ. C10H10O2
(162.1): calcd. C 66.65, H 6.71; found C 66.50, H 6.58.
1-(2-Chlorophenyl)-3-hydroxy-2,2-bis(hydroxymethyl)propan-1-one
(21d): Yield: 214 mg (22%). Yellow oil. IR (liquid film): ν˜ ϭ 3400,
1701, 1591, 1431, 1026, 970, 762 cmϪ1 1H NMR (CDCl3): δ ϭ
.
7.45 (m, 1 H), 7.36 (m, 3 H), 3.93 (br. s, 6 H) ppm. Rf ϭ 0.44
(CHCl3/acetone, 1:1). CIMS: m/z ϭ 245 [M ϩ H]ϩ. C11H13ClO4
(244.1): calcd. C 54.00, H 5.36; found C 53.78, H 5.26.
3-Hydroxy-2-hydroxymethyl-1-phenylpropan-1-one (19c): Yield:
100 mg (14%). Yellow oil. IR (liquid film): ν˜ ϭ 3400, 1676, 1597,
1449, 1258, 1217, 1041, 963 cmϪ1. 1H NMR (CDCl3): δ ϭ 7.96 (d,
J ϭ 8.2 Hz, 2 H), 7.58 (m, 1 H), 7.47 (td, J ϭ 8.7, 2.6 Hz, 2 H),
4.03 (m, 4 H), 3.78 (m, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 202.19,
136.54, 134.00, 129.24, 129.20, 62.49, 50.75 ppm. Rf ϭ 0.32
(CHCl3/acetone, 1:1). CIMS: m/z ϭ 181 [M ϩ H]ϩ 163 [M ϩ H Ϫ
H2O]ϩ. C10H12O3 (180.1): calcd. C 66.65, H 6.71; found C 66.00,
H 7.61.
1-(4-Chlorophenyl)-2-hydroxymethylprop-2-en-1-one (22a): Yield:
38 mg (5%). Yellow oil. IR (liquid film): ν˜ ϭ 3260, 1649, 1587,
1
1312, 1094, 1073, 984, 789 cmϪ1. H NMR (CDCl3): δ ϭ 7.72 (d,
J ϭ 8.5 Hz, 2 H), 7.45 (d, J ϭ 8.5 Hz, 2 H), 6.17 (s, 1 H), 5.80 (s,
1 H), 4.50 (m, 2 H) ppm. Rf ϭ 0.67 (CHCl3/acetone, 1:1). CIMS:
m/z ϭ 197 [M ϩ H]ϩ. C10H9ClO2 (190.0): calcd. C 61.08, H 4.61;
found C 60.52, H 4.66.
3-Hydroxy-2,2-bis(hydroxymethyl)-1-phenylpropan-1-one
(19d):
Yield: 252 mg (30%). Yellow oil. IR (liquid film): ν˜ ϭ 3400, 1674,
1-(4-Chlorophenyl)-3-hydroxypropan-1-one (22b): Yield: 29 mg
1597, 1464, 1234, 1026, 955, 700 cmϪ1
.
1H NMR (CDCl3): δ ϭ (4%). Yellow oil. IR (liquid film): ν˜ ϭ 3360, 1693, 1589, 1464, 1261,
7.76 (m, 2 H), 7.46 (m, 3 H), 4.06 (br. s, 6 H) ppm. 13C NMR
1093, 820, 719 cmϪ1. H NMR (CDCl3): δ ϭ 7.92 (d, J ϭ 8.5 Hz,
2 H), 7.58 (m, 1 H), 7.47 (d, J ϭ 8.6 Hz, 2 H), 4.05 (t, J ϭ 5.3 Hz,
1
(CDCl3): δ ϭ 207.36, 135.41, 132.76, 130.11, 128.95, 62.14,
51.83 ppm. Rf ϭ 0.28 (CHCl3/acetone, 1:1). CIMS: m/z ϭ 211 [M 2 H), 3.22 (t, J ϭ 5.3 Hz, 2 H) ppm. Rf ϭ 0.59 (CHCl3/acetone,
ϩ H]ϩ. C11H14O4 (210.1): calcd. C 62.85, H 6.71; found C 63.27,
1:1). CIMS: m/z ϭ 185 [M ϩ H]ϩ, 167 [M ϩ H Ϫ H2O]ϩ.
H 7.59.
C9H9ClO2 (184.0): calcd. C 58.55, H 4.91; found C 58.50, H 4.78.
4442
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4438Ϫ4444

The Aldol Reaction under High-Intensity Ultrasound
FULL PAPER
1-(4-Chlorophenyl)-3-hydroxy-2-hydroxymethylpropan-1-one (22c): 1-(3-Acetylphenyl)-3-hydroxy-2-hydroxymethylpropan-1-one (24c):
Yield: 94 mg (11%). Yellow oil. IR (liquid film): ν˜ ϭ 3400, 1676, Yield: 124 mg (14%). Yellow oil. IR (liquid film): ν˜ ϭ 3400, 1682,
1
1
1589, 1402, 1252, 1093, 1045, 960, 841 cmϪ1. H NMR (CDCl3): 1597, 1361, 1200, 1047, 816 cmϪ1. H NMR (CDCl3): δ ϭ 8.39 (s,
δ ϭ 7.92 (d, J ϭ 8.6 Hz, 2 H), 7.47 (d, J ϭ 8.6 Hz, 2 H), 4.06 (d,
1 H), 8.03 (m, 2 H), 7.46 (t, J ϭ 7.7 Hz, 1 H), 3.91 (m, 4 H), 3.80
J ϭ 7.8 Hz, 4 H), 3.78 (m, 1 H), 2.78 (br. s, 1 H) ppm. Rf ϭ 0.38 (m, 1 H), 2.52 (s, 3 H) ppm. 13C NMR (CDCl3): δ ϭ 202.33,
(CHCl3/acetone, 1:1). CIMS: m/z ϭ 215 [M ϩ H]ϩ, 187 [M ϩ H 198.12, 137.82, 137.23, 133.34, 133.14, 129.66, 128.55, 62.24, 51.36,
Ϫ H2O]ϩ. C10H11ClO3 (214.0): calcd. C 55.96, H 5.17; found C
56.03, H 5.30.
27.10 ppm. Rf ϭ 0.38 (CHCl3/acetone, 1:1). CIMS: m/z ϭ 223 [M
ϩ H]ϩ, 205 [M ϩ H Ϫ H2O]ϩ. C12H14O4 (222.1): calcd. C 64.85,
H 6.35; found C 65.00, H 6.48.
1-(4-Chlorophenyl)-3-hydroxy-2,2-bis(hydroxymethyl)propan-1-one
(22d): Yield: 380 mg (39%). Yellow oil. IR (liquid film): ν˜ ϭ 3536,
1728, 1678, 1591, 1460, 1280, 1074, 1035, 833, 743 cmϪ1. 1H NMR
(CDCl3): δ ϭ 7.74 (d, J ϭ 8.4 Hz, 2 H), 7.42 (d, J ϭ 8.5 Hz, 2 H),
4.04 (s, 6 H) ppm. Rf ϭ 0.31 (CHCl3/acetone, 1:1). 13C NMR
(CDCl3): δ ϭ 206.11, 140.86, 138.20, 133.93, 129.35, 58.85,
56.01 ppm. CIMS: m/z ϭ 245 [M ϩ H]ϩ. C11H13 ClO4 (244.1):
calcd. C 54.00, H 5.36; found C 54.05, H 5.30.
1-(3-Acetylphenyl)-3-hydroxy-2,2-bis(hydroxymethyl)propan-1-one
(24d): Yield: 272 mg (27%). Yellow oil. IR (liquid film): ν˜ ϭ 3400,
1
1685, 1597, 1427, 1362, 1211, 1022, 687 cmϪ1. H NMR (CDCl3):
δ ϭ 8.31 (s, 1 H), 8.06 (d, J ϭ 7.4 Hz, 1 H), 7.93 (d, J ϭ 7.5 Hz,
1 H), 7.53 (t, J ϭ 7.6 Hz, 1 H), 4.02 (s, 6 H), 2.62 (s, 3 H) ppm.
13C NMR (CDCl3): δ ϭ 207.59, 198.28, 133.11, 131.96, 131.18,
129.65, 127.36, 64.58, 50.83, 23.06 ppm. Rf ϭ 0.29 (CHCl3/acetone,
1:1). CIMS: m/z ϭ 253 [M ϩ H]ϩ. C13H16O5 (252.1): calcd. C
61.90, H 6.39; found C 61.65, H 6.30.
2-Hydroxymethyl-1-(4-nitrophenyl)prop-2-en-1-one (23a): Yield:
149 mg (18%). Yellow oil. IR (liquid film): ν˜ ϭ 3526, 1651, 1522,
1
1354, 988, 739 cmϪ1. H NMR (CDCl3): δ ϭ 8.28 (d, J ϭ 8.7 Hz,
Acknowledgments
2 H), 7.87 (d, J ϭ 8.7 Hz, 2 H), 6.30 (s, 1 H), 5.83 (s, 1 H), 4.53
(br. s, 2 H) ppm. Rf ϭ 0.70 (CHCl3/acetone, 1:1). CIMS: m/z ϭ
208 [M ϩ H]ϩ. C10H9NO4 (207.1): calcd. C 57.97, H 4.38; found
C 57.52, H 4.56.
This work was supported by MIUR (Fondi ex-40%, project: ‘‘Ad-
dotti supra-molecolari tra β-ciclodestrine (e suoi multimeri) e com-
plessi paramagnetici di GdIII per applicazioni diagnostiche medi-
ante Risonanza Magnetica Imaging."). We are indebted to G. Om-
iccioli and E. Vazzoler (TEKIMP srl, Via Serenissima 20, 31033
Castelfranco Veneto Ϫ TV, Italy) for projecting and assembling the
sonochemical apparatus. A part of this work has been described in
the degree thesis of G. Borrello.
3-Hydroxy-1-(4-nitrophenyl)propan-1-one (23b): Yellow oil. Rf
0.62 (CHCl3/acetone, 1:1). CIMS: m/z ϭ 196 [M ϩ H]ϩ.
ϭ
3-Hydroxy-2-hydroxymethyl-1-(4-nitrophenyl)propan-1-one (23c):
Yield: 90 mg (10%). Yellow oil. IR (liquid film): ν˜ ϭ 3400, 1682,
1
1526, 1350, 1042, 855 cmϪ1. H NMR (CDCl3): δ ϭ 8.33 (d, J ϭ
[1]
8.9 Hz, 2 H), 8.12 (d, J ϭ 8.9 Hz, 2 H), 4.07 (d, J ϭ 5.0 Hz, 4 H),
3.78 (m, 1 H), 2.76 (br. s, 1 H) ppm. Rf ϭ 0.55 (CHCl3/acetone,
1:1). CIMS: m/z ϭ 226 [M ϩ H]ϩ. C10H11NO5 (225.1): calcd. C
53.33, H 4.92; found C 54.01, H 4.90.
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3-Hydroxy-2,2-bis(hydroxymethyl)-1-(4-nitrophenyl)propan-1-one
(23d): Yield: 347 mg (34%). Yellow oil. IR (liquid film): ν˜ ϭ 3484,
1686, 1528, 1350, 1015, 860, 718 cmϪ1 1H NMR (CDCl3): δ ϭ
.
[4] [4a]
D. T. Machajewski, C.-H. Wong, Angew. Chem. Int. Ed.
[4b]
8.28 (d, J ϭ 8.8 Hz, 2 H), 7.85 (d, J ϭ 8.3 Hz, 2 H), 3.98 (s, 6 H)
ppm. 13C NMR (CDCl3): δ ϭ 204.30, 155.36, 144.96, 130.71,
127.55, 60.31, 54.21 ppm. Rf ϭ 0.32 (CHCl3/acetone, 1:1). CIMS:
m/z ϭ 256 [M ϩ H]ϩ. C11H13NO6 (255.1): calcd. C 51.77, H 5.13;
found C 51.65, H 5.37.
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1-(3-Acetylphenyl)-2-hydroxymethylprop-2-en-1-one (24a): Yield:
98 mg (12%). Yellow oil. IR (liquid film): ν˜ ϭ 3450, 1700, 1651,
[6d]
L. J. Gazzard, W. B.
Motherwell, D. A. Sandham, J. Chem. Soc., Perkin Trans. 1
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1
1597, 1360, 1259, 1022, 785 cmϪ1. H NMR (CDCl3): δ ϭ 8.30 (s,
1 H), 8.14 (d, J ϭ 7.7 Hz, 1 H), 7.93 (d, J ϭ 6.9 Hz, 1 H), 7.57 (d,
J ϭ 7.7 Hz, 1 H), 6.22 (s, 1 H), 5.81 (s, 1 H), 4.53 (s, 2 H), 2.64 (s,
3 H) ppm. 13C NMR (CDCl3): δ ϭ 197.66, 146.64, 138.23, 137.59,
134.01, 132.30, 129.55, 129.23, 128.25, 63.25, 26.12 ppm. Rf ϭ 0.68
(CHCl3/acetone, 1:1). CIMS: m/z ϭ 205 [M ϩ H]ϩ. C12H12O3
(204.1): calcd. C 70.57, H 5.92; found C 70.01, H 5.76.
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1-(3-Acetylphenyl)-3-hydroxypropan-1-one (24b): Yield: 138 mg
(18%). Yellow oil. IR (liquid film): ν˜ ϭ 3354, 1680, 1668, 1597,
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V. Serra-Holm, T. Salmi, P. Maki-Arvela, E. Paatero, L. P.
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1
1360, 1197, 1055, 787 cmϪ1. H NMR (CDCl3): δ ϭ 8.45 (s, 1 H),
8.10 (d, J ϭ 7.7 Hz, 2 H), 7.53 (m, 1 H), 4.00 (t, J ϭ 5.36 Hz, 2
H), 3.25 (m, 2 H), 2.59 (s, 3 H) ppm. 13C NMR (CDCl3): δ ϭ
200.03, 197.59, 137.91, 137.45, 133.27, 132.64, 129.57, 128.20,
58.32, 41.1, 27.1 ppm. Rf ϭ 0.57 (CHCl3/acetone, 1:1). CIMS: m/
z ϭ 193 [M ϩ H]ϩ, 175 [M ϩ H Ϫ H2O]ϩ. C11H12O3 (192.1):
calcd. C 68.74, H 6.29; found C 68.03, H 6.28.
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Eur. J. Org. Chem. 2003, 4438Ϫ4444
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4443

G. Cravotto, A. Demetri, G. M. Nano, G. Palmisano, A. Penoni, S. Tagliapietra
FULL PAPER
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