Darzens reaction promoted by KF/alumina: A novel stereoselective method for rapid and efficient synthesis of trans-α,β-epoxy ketones

Article abstract of DOI:10.1080/00397910701316292

The Darzens condensation of α-chloroacetophenone with various aromatic aldehydes mediated by potassium fluoride on alumina at room temperature resulted in formation of good to excellent yields of trans-α,β-epoxy ketones in short time periods. Copyright Ta

Full text of DOI:10.1080/00397910701316292

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Darzens Reaction Promoted by KF/Alumina:
A Novel Stereoselective Method for Rapid
and Efficient Synthesis of trans‐α,β‐Epoxy
Ketones
Ali Sharifi a , Roghiyeh Salimi a , Mojtaba Mirzaei a & M. Saeed Abaee a
a Chemistry and Chemical Engineering Research Center of Iran , Tehran, Iran
Published online: 30 Jun 2007.
To cite this article: Ali Sharifi , Roghiyeh Salimi , Mojtaba Mirzaei & M. Saeed Abaee (2007) Darzens Reaction
Promoted by KF/Alumina: A Novel Stereoselective Method for Rapid and Efficient Synthesis of trans‐α,β‐Epoxy
Ketones, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 37:11, 1825-1832, DOI: 10.1080/00397910701316292
To link to this article: http://dx.doi.org/10.1080/00397910701316292
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Synthetic Communicationsw, 37: 1825–1832, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701316292
Darzens Reaction Promoted by KF/
Alumina: A Novel Stereoselective Method
for Rapid and Efficient Synthesis of trans-
a,b-Epoxy Ketones
Ali Sharifi, Roghiyeh Salimi, Mojtaba Mirzaei, and
M. Saeed Abaee
Chemistry and Chemical Engineering Research Center of Iran,
Tehran, Iran
Abstract: The Darzens condensation of a-chloroacetophenone with various aromatic
aldehydes mediated by potassium fluoride on alumina at room temperature resulted in
formation of good to excellent yields of trans-a,b-epoxy ketones in short time periods.
Keywords: darzens reaction, solid-phase synthesis, KF/alumina, a, b-epoxy ketones
The push toward development of green and environmentally benign chemistry
in the past three decades has dictated the use of safer and less hazardous
reagents and media capable of inducing versatile organic transformations
with fewer side products and solvent requirements.[1] In this context,
potassium fluoride on alumina (KF/Al2O3)[2] has emerged as a very
powerful solid-phase reagent for various organic functional manipulations
such as ring-closure reactions,[3] epoxidation of alkenes,[4] ether
synthesis,[5] amide[6] and amine[7] chemistry, Michael addition,[8] aldol
condensation,[9] rearrangement processes,[10] and cycloaddition reactions.[11]
A number of advantages are associated with the use of this reagent, such as
avoiding the cleavage step usually required in solid-phase syntheses,[12]
Received in the U.K. June 29, 2006
Address correspondence to A. Sharifi, Chemistry and Chemical Engineering
Research Center of Iran, P. O. Box 14335-186, Tehran, Iran. E-mail: sharifi@ccerci.
ac.ir
1825

1826
A. Sharifi et al.
decrease of solvent use, no special handling requirements, easy monitoring of
reactions, and convenient workup procedure by removal of the solid from the
reaction mixture via a simple filtration.
Condensation of a-halo carbonyl moieties with aldehydes and ketones,
known as the Darzens reaction, is one of the most versatile tools in
synthetic organic chemistry for the preparation of a,b-epoxy carbonyl
compounds.[13] In addition, this reaction is a very powerful method for one-
carbon homologation of aldehydes and ketones.[14] The Darzens reaction is
traditionally carried out in the presence of strong bases and mechanistically
includes an aldol reaction of an a-halo carbonyl compound with an
aldehyde to form a C-C bond followed by an intramolecular annulation of
the intermediate halohydrin compound to form an epoxy product. Many
alterations to the traditional procedure of the reaction were made in recent
years to enhance the synthetic applications of the Darzens reaction by the
use of phase-transfer catalysts,[15] enantioselective reagents,[16] aqueous
alkaline medium,[17] ammonium ylides,[18] and Lewis acid catalysis.[19]
Despite these modifications, use of strong basic media is still required[17] in
many of these procedures, or stoichiometric amounts of an expensive
reagent are used.[15] Moreover, the majority of available methods involve
Darzens reactions of haloacetate esters, and not much investigation on a-halo-
ketones side has been carried out. A search in the literature reveals a report by
Yamawaki et al. containing a single example of a Darzens reaction performed
in the presence of KF/Al2O3 in benzene.[20] Based on this example and in con-
tinuation of our previous experiences with solid-phase chemistry,[21] we
decided to evaluate the generality of Darzens reactions of a-haloketones
with aromatic aldehydes in the presence of KF/Al2O3 under more environ-
mentally benign conditions (Scheme 1).
Table 1 presents the results obtained from the condensation of
a-chloroacetophenone
1
with various aldehydes bearing electron-
withdrawing or electron-releasing groups 2a–j. We first examined the
reaction using a suspension of KF/Al2O3 in a 1:1 mixture of a-chloroace-
tophenone and benzaldehyde at room temperature. The course of the
reaction was monitored by thin-layer chromatography (TLC) and gas
chromatography (GC) until complete disappearance of the starting
aldehyde was observed, in less than 2 h. Simple extraction of the mixture
by ethyl acetate and removal of the volatile portion showed formation of
a single trans product 3a in 92% yield (entry 1).
Scheme 1.

Darzens Reaction Promoted by KF/Alumina
1827
Table 1. Darzens reaction of aldehydes 2a–j with 1 in the presence of KF/Al2O3
Entry
1
Aldehyde
C6H5CHO
Product
Yielda (%)
92
2
3
4
4-MeC6H4CHO
4-MeOC6H4CHO
3-MeOC6H4CHO
90
83
95
5
6
4-ClC6H4CHO
2-ClC6H4CHO
96
92
7
8
4-NO2C6H4CHO
2-NO2C6H4CHO
94
99
9
4-BrC6H4CHO
4-CF3C6H4CHO
93
97
10
aIsolated yields.
The promoting effect of the solid support was examined by stirring a
mixture of the two reactants in the absence of KF or alumina. In these
cases, formation of only small quantities of 1a was detected after several
hours, and the majority of the starting materials were recovered. In addition,
when the reaction was repeated in a solution of benzene using Ando’s
procedure,[20] only 65% of trans 3a was obtained after 24 h, illuminating
the devastating effect of the solvent.
To illustrate the generality of the reaction, other aldehydes bearing
electron-releasing groups (entries 2–4) or electron-withdrawing groups
(entries 5–10) were subjected to the same conditions. Similarly, reactions
completed within 1–2 h to form exclusively trans products 3b–j in

1828
A. Sharifi et al.
Scheme 2.
83–99% yield. Products were characterized by spectroscopic methods, and
the results were matched with those available in the literature.[18a,20a]
Additional test reactions were conducted to examine the substrate depen-
dency of this procedure by subjecting a mixture of tert-butyl 2-chloroacetate
and benzaldehyde to the same reaction conditions. As a result, 97% of two
geometric isomers of 4 were obtained with a low cis/trans stereoselectivity
of 1/2. A similar mixture in benzene gave only 68% of 4 with the same stereo-
selectivity after 10 h (Scheme 2).
In conclusion, we disclose a novel and efficient procedure for Darzens
reactions of a-chloroacetophenone with aldehydes promoted by KF/Al2O3
under very mild conditions. Use of inexpensive reagents, the generality of
the reaction, sole formation of trans compounds in short time periods, and
use of no other additives or solvent are the advantages of the present work.
Further studies to apply this methodology to other a-halo carbonyl
compounds are also under investigation.
Experimental
Melting points were determined with a Buchi melting-point apparatus and are
uncorrected. IR spectra were recorded using KBr disks on a Bruker Vector-22
infrared spectrometer. NMR spectra were obtained on a FT-NMR Bruker
Ultra ShieldTM (500 MHz) as CDCl3 solutions using TMS as internal
standard reference. Elemental analyses were performed using a Thermo
Finnigan Flash EA 1112 instrument. GC-MS spectra were obtained on a
Fisons 8000 Trio instrument at ionization potential of 70 eV. TLC exper-
iments were carried out on precoated silica-gel plates using hexane/EtOAc
(5:1) as the eluent. GC experiments were performed using a Varian
CP-3800 instrument equipped with capillary column CP-SIL 5 CB with
length of 30 m and 0.32 i.d. Compounds 3a–3c,[22] 3e,[22] 3g,[22] and 3j[23]
have been previously reported. Reagents were purchased from commercial
sources. Aldehydes were purified before use.
Preparation of KF/Alumina[24]
To a stirred solution of potassium fluoride (20 g) in water (150 ml), neutral
alumina (60–80 mesh, 30 g) in water (150 ml) was added. After 30 min, the
water was evaporated in a rotary evaporator at ꢀ608C. When most of the

Darzens Reaction Promoted by KF/Alumina
1829
water has been removed, the remaining mixture was heated to 140–1508C and
maintained at that temperature under vacuum (5 mmHg) for 6 h to give 50 g of
KF-alumina reagent.
Typical Darzens Procedure
A mixture of the aldehyde (10 mmol), ketone 1 (11 mmol), and KF/Al2O3
(5 g) was stirred at room temperature until TLC and GC experiments
showed complete disappearance of the starting aldehyde. The mixture was
extracted with EtOAc (3 ꢀ 50 mL), the extracts were combined, and the
volatile portion was removed under reduced pressure. The product was
purified with short column chromatography over silica-gel using hexane/
EtOAc (7:1), if necessary.
Data
trans-2,3-Epoxy-1-(3-methoxyphenyl)-3-phenylpropan-1-one (3d)
White crystals were obtained in 95% yield, mp 79–808C; IR (KBr, cm21
)
1
1682, 1591, 1257; H NMR (CDCl3) d 3.87 (s, 3H), 4.10 (d, 1H, J ¼ 2 Hz),
4.32 (d, 1H, J ¼ 2 Hz), 6.94–6.97 (m, 2H), 7.02 (d, 1H, J ¼ 7.5 Hz), 7.35
(dd, 1H, J ¼ 7.5, 7.5 Hz), 7.53 (dd, 2H, J ¼ 7.5, 7.5 Hz), 7.66 (dd, 1H,
J ¼ 7.5, 7.5 Hz), 8.05 (dd, 2H, J ¼ 1.5, 8.5 Hz); 13C NMR (CDCl3) d 55.8,
59.7, 61.4, 111.3, 115.2, 118.7, 128.8, 129.3, 130.3, 134.5, 135.9, 137.6,
160.5, 193.5; MS (70 eV) m/z (%): 254 (Mþ), 225, 149, 105. Calcd. for
C16H14O3: C, 75.57; H, 5.55. Found: C, 75.34; H, 5.47.
trans-2,3-Epoxy-1-(2-chlorophenyl)-3-phenylpropan-1-one (3f)
White crystals were obtained in 92% yield, mp 72–738C; IR (KBr, cm21
)
1
1687, 1228, 1022; H NMR (CDCl3) d 4.21 (d, 1H, J ¼ 2 Hz), 4.44 (d, 1H,
J ¼ 2 Hz), 7.35 (dd, 2H, J ¼ 3.5, 7 Hz), 7.40–7.45 (m, 2H), 7.54 (dd, 2H,
J ¼ 7.5, 7.5 Hz), 57.66 (dd, 1H, J ¼ 7.5, 9.5 Hz), 8.09 (d, 2H, J ¼ 7.5 Hz);
13C NMR (CDCl3) d 7.6, 60.5, 126.6, 127.7, 128.8, 129.3, 129.8, 130.2,
133.7, 134.2, 134.5, 135.8, 193.2; MS (70 eV) m/z (%): 258 (Mþ), 223,
165, 105. Calcd. for C15H11ClO2: C, 69.64; H, 4.29. Found: C, 69.47; H, 4.24.
trans-2,3-Epoxy-1-(2-nitrophenyl)-3-phenylpropan-1-one (3h)
Light pink crystals were obtained in 99% yield, mp 109–1108C; IR (KBr,
1
cm21) 1686, 1332, 1227; H NMR (CDCl3) d 4.26 (d, 1H, J ¼ 2 Hz), 4.67
(d, 1H, J ¼ 2 Hz), 7.52 (dd, 2H, J ¼ 7.5, 8 Hz), 7.59 (ddd, 1H, J ¼ 4, 5.5,
9 Hz), 7.65 (dd, 1H, J ¼ 7.5, 7.5 Hz), 7.77 (d, 2H, J ¼ 4 Hz), 8.05 (dd, 2H,

1830
A. Sharifi et al.
J ¼ 1, 8.5 Hz), 8.24 (d, 1H, J ¼ 8 Hz); 13C NMR (CDCl3) d 58.1, 60.0, 125.4,
127.8, 128.9, 129.3, 129.9, 133.0, 134.5, 135.1, 135.8, 147.9, 192.9; MS
(70 eV) m/z (%): 269 (Mþ), 183, 135, 105. Calcd. for C15H11NO4: C,
66.91; H, 4.12. Found: C, 66.70; H, 4.06.
trans-2,3-Epoxy-1-(4-bromophenyl)-3-phenylpropan-1-one (3i)
White crystals were obtained in 93% yield, mp 88–898C; IR (KBr, cm21
)
1
1663, 1438, 1297; H NMR (CDCl3) d 4.08 (d, 1H, J ¼ 2 Hz), 4.29 (d, 1H,
J ¼ 2 Hz), 7.29 (d, 2H, J ¼ 8.5 Hz), 7.52–7.58 (m, 4H), 7.66 (dd, 1H,
J ¼ 7, 7.5 Hz), 8.04 (dd, 2H, J ¼ 1, 8 Hz); 13C NMR (CDCl3) d 59.2, 61.3,
123.5, 127.9, 128.8, 129.4, 132.4, 134.6, 135.0, 135.8, 193.1; MS (70 eV)
m/z (%): 302 (Mþ), 275, 194, 105. Calcd. for C15H11BrO2: C, 59.43; H,
3.66. Found: C, 59.19; H, 3.58.
ACKNOWLEDGMENT
Partial financial support by the Ministry of Science, Research, and Technology
of Iran is gratefully acknowledged.
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