Preparation of 5-aryl-3-oxo-δ-lactones by the potassium carbonate-promoted condensation of aromatic aldehydes and ethyl acetoacetate in ethanol

Article abstract of DOI:10.1080/00397910701796493

5-Aryl-3-oxo-δ-lactones (6-aryl-dihydro-2H-pyran-2,4(3H)-diones) were prepared by the potassium carbonate-promoted condensation of aromatic aldehydes and ethyl acetoacetate in absolute ethanol. Benzaldehyde and substituted benzaldehydes bearing an alkoxy

Full text of DOI:10.1080/00397910701796493

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Preparation of 5‐Aryl‐3‐Oxo‐δ‐Lactones
by the Potassium Carbonate–Promoted
Condensation of Aromatic Aldehydes and
Ethyl Acetoacetate in Ethanol
Brad Andersh a , Jessica Gereg a , Mical Amanuel a & Carl Stanley a
a Department of Chemistry and Biochemistry, Bradley University, Peoria,
Illinois, USA
Published online: 27 Feb 2008.
To cite this article: Brad Andersh , Jessica Gereg , Mical Amanuel & Carl Stanley (2008) Preparation of
5‐Aryl‐3‐Oxo‐δ‐Lactones by the Potassium Carbonate–Promoted Condensation of Aromatic Aldehydes and Ethyl
Acetoacetate in Ethanol, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:4, 482-488, DOI: 10.1080/00397910701796493
To link to this article: http://dx.doi.org/10.1080/00397910701796493
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Synthetic Communicationsw, 38: 482–488, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701796493
Preparation of 5-Aryl-3-Oxo-d-Lactones by
the Potassium Carbonate–Promoted
Condensation of Aromatic Aldehydes and
Ethyl Acetoacetate in Ethanol
Brad Andersh, Jessica Gereg, Mical Amanuel,
and Carl Stanley
Department of Chemistry and Biochemistry, Bradley University, Peoria,
Illinois, USA
Abstract: 5-Aryl-3-oxo-d-lactones (6-aryl-dihydro-2H-pyran-2,4(3H)-diones) were
prepared by the potassium carbonate–promoted condensation of aromatic aldehydes
and ethyl acetoacetate in absolute ethanol. Benzaldehyde and substituted benzal-
dehydes bearing an alkoxy group (2 or 3 position), a chlorine atom (2, 3, or 4
position), a nitro group (3 or 4 position), a cyano group (4 position), or an acetyl
group (4 position) react in high yields under these conditions.
Keywords: aromatic aldehyde, 6-aryl-dihydro-2H-pyran-2,4(3H)-dione, 5-aryl-3-oxo-
d-lactone, ethyl acetoacetate, potassium carbonate
While investigating conditions for Knoevenagel condensation reactions, we dis-
covered that a side product, 5-(2-allyloxyphenyl)-3-oxo-d-lactone (1), often
formed when inorganic bases were used for the reaction between 2-allyloxyben-
zaldehyde and ethyl acetoacetate. Upon further investigation, we found that
potassium carbonate in ethanol induced the condensation of 2-allyloxybenzal-
dehyde and ethyl acetoacetate to generate 1 in 93% isolated yield [Eq. (1)]:
Received in the USA August 17, 2007
Address correspondence to Brad Andersh, Department of Chemistry and Biochem-
istry, Bradley University, Peoria, IL 61625, USA. E-mail: bja@bradley.edu
482

5-Aryl-3-oxo-b-lactones
483
This result is surprising because carbonate salts have seen use as bases for
Knoevenagel condensation (Eq. 1) reactions[1] and because the reaction
proceeds via the addition of the less stable conjugate base of ethyl aceto-
acetate, which is being generated by the weak base carbonate.
The synthesis of 5-aryl-3-oxo-d-lactones is of interest because they
exhibit a wide variety of biological activities. For example, 5-phenyl-3-oxo-
d-lactone has shown antioxidant,[2] molluscicidal,[3] and antinociceptive
activity.[4] In addition, the products from the condensation of 5-phenyl-3-
oxo-d-lactone, 2,6-disubstituted anilines, and triethyl orthoformate show anti-
fungal properties,[5] and 5-phenyl-3-oxo-d-lactone derivatives have been
shown to be effective HIV protease inhibitors.[6]
Previous syntheses of 5-substituted-3-oxo-d-lactones most commonly
involve trapping the preformed dianion of ethyl acetoacetate with an
aldehyde or a ketone. Hydrolysis of the resulting hydroxyketoester (2)
followed by treatment with hydrochloric acid then affords the desired
lactone (Scheme 1).[7]
Scheme 1. Formation of 5-substitued-3-oxo-d-lactones from the dianion of ethyl
acetoacetate.
It has also been shown that hetero Diels–Alder reactions between
aromatic aldehydes and diene (3) yield 5-aryl-3-oxo-d-lactones after hydroly-
sis of the adduct [Eq. (2)].[8] However, the lengthy synthesis of diene 3[9] has
limited the use of this method.
The procedure described herein has several advantages over the previously
published methods: 1) Strong bases are not necessary for our method. 2) Highly

484
B. Andersh et al.
toxic solvents are not used in our reaction. The dianion method often employs
the use of an anion stabilizers such as hexamethylphosphoramide (HMPA)
along with the solvent, tetrahydrofuran (THF). 3) Our method is procedurally
less complex. The dianion method requires three chemical reactions (anion
addition, hydrolysis, and lactonization) to produce the desired compound, and
the hetero Diels–Alder method requires the multiple-step synthesis of diene
3. Our method requires only one reaction; the aldehyde, ethyl acetoacetate,
and potassium carbonate are mixed in ethanol and stirred for 16–24 h at
458C, followed by an acidic workup.
As shown in Table 1, aromatic aldehydes bearing an array of dissimilar
electronic substituents are tolerated by these conditions. The generation of
lactones from 3- or 4-nitrobenzaldehyde is especially noteworthy given that
de Aguiar Amaral et al. reported difficulty with the preparation of the
desired d-lactone by the treatment of 4-nitrobenzaldehyde with the dianion
of ethyl acetoacetate.[4]
Table 1. Isolated yields of 5-aryl-3-oxo-d-lactones
Entry
Z
Isolated yield (%)
a
b
c
d
e
f
2-(O-CH2CH55CH2)
2-(MeO)
3-(MeO)
H
93
89
73
88
79
76
72
65
75
56
82a
2-Cl
3-Cl
g
h
i
4-Cl
3-NO2
4-NO2
4-CN
4-COCH3
j
k
aIsolated by trituration from ether.
Although our method is easier to perform than previously published
methods, it does have limitations. For example, enolizable aldehydes (i.e.,
heptanal), yield self-condensation (aldol) products as the major products. In
addition, ketones do not react under these conditions. For example, no
reaction was observed when benzophenone or 4-chloroacetophenone was
used in the reaction. However, the difference in reactivity of aldehydes and
ketones provides the opportunity to perform the cyclization on an aldehyde
in the presence of an unprotected ketone (Table 1, entry k).

5-Aryl-3-oxo-b-lactones
485
In summary, 5-aryl-3-oxo-d-lactones can be prepared in high yields by
the potassium carbonate–promoted condensation of aromatic aldehydes and
ethyl actetoacetate in absolute ethanol. The presence of substituents, with
varying electronic contribution, on the aromatic ring of the aldehyde is
tolerated by these conditions. Although this method has some limitations, it
provides a noteworthy alternative to previously published methods.
EXPERIMENTAL
Benzaldehyde, 3-methyoxybenzaldehyde, 3-nitrobenzaldehyde, 4-nitrobenzal-
dehyde, and 4-acetylbenzaldehyde were purchased from Aldrich Chemical
Company and used without further purification. 2-Chlorobenzaldehyde,
3-chlorobenzaldehyde, 4-chlorobenzaldehyde, o-anisaldehyde, and ethyl acet-
oacetate were purchased from Acros Organics and used without further purifi-
cation. 4-Cyanobenaldehyde was purchased from Alfa Aesar and used without
further purification. 2-Allyloxybenzaldehye was prepared from salicylalde-
hyde.[10] Ethanol was purchased from Quantum Chemical Corporation and
distilled under nitrogen from sodium. NMR spectra were collected on a
1
JEOL Eclipse þ spectrometer (300 MHz, H). Mass spectra were collected at
the University of Illinois School of Chemical Sciences Mass Spectrometry Lab-
oratory on a VG 70-VSE 8-kV double-focusing sector mass spectrometer
[electron ionization (70 eV), chemical ionization (CH4)].
Procedure
The aldehyde (2 mmol), ethanol (2 mL, distilled from sodium), ethyl aceto-
acetate (2 mmol), and potassium carbonate (4 mmol) were added to a flame-
dried, 15-mm ꢀ 100-mm, screw-cap centrifuge tube under nitrogen. The
septa and the nitrogen-filled balloon were replaced with the centrifuge cap,
and the tube was placed in an oil bath at 458C and heated overnight (16–
24 h). After cooling the tube to room temperature, the reaction mixture was
transferred to a separatory funnel using 20 mL of ethyl acetate, and then
10 mL of 1 M HCl (aq.) were slowly added. The aqueous layer was
extracted with two additional portions (2 ꢀ 15 mL) of ethyl acetate. The
combined organic extracts were dried over Na2SO4, filtered, concentrated,
and purified by flash chromatography.
Data
6-(2-(Allyloxy)phenyl)-dihydro-2H-pyran-2,4(3H)-dione (Entry a)
1H NMR (CDCl3) d 7.49 (dd, J ¼ 7.7, 1.6, 1H), 7.35 (ddd, J ¼ 8.2, 7.7, 1.6,
1H), 7.06 (dt, J ¼ 7.4, 0.8, 1H), 6.90 (dd, J ¼ 8.2, 0.8 1H), 6.02 (m, 2H),

486
B. Andersh et al.
5.32 [m (two poorly resolved dq, J ¼ 17.3, 1.7, and J ¼ 10.4, 1.4), 2H], 4.58
[m (poorly resolved dq, J ¼ 5.5, 1.4), 2H], 3.76 (d, J ¼ 19, 1H), 3.52
(d, J ¼ 19, 1H), 3.04 (dd, J ¼ 18.4, 3.0, 1H), 2.69 (dd, J ¼ 18.4, 11.3, 1H).
HRMS (M þ H) calcd. for C14H15Oþ4 247.0970; found 247.0965.
6-(2-Methoxyphenyl)-dihydro-2H-pyran-2,4(3H)-dione (Entry b)
1H NMR (CDCl3) d 7.49 (dd, J ¼ 7.4, 1.6, 1H), 7.39 (ddd, J ¼ 8.3, 7.4, 1.6,
1H), 7.07 (dt, J ¼ 7.4, 1.1, 1H), 6.92 (dd, J ¼ 8.3, 0.8 1H), 6.01 (dd,
J ¼ 11.3, 3.0, 1H), 3.83 (s, 3H), 3.75 (d, J ¼ 19, 1H), 3.53 (d, J ¼ 19, 1H),
3.03 (dd, J ¼ 18.4, 3.0, 1H), 2.68 (dd, J ¼ 18.4, 11.3, 1H). HRMS (M þ H)
calcd. for C12H13Oþ4 221.0814; found 221.0812.
6-(3-Methoxyphenyl)-dihydro-2H-pyran-2,4(3H)-dione (Entry c)
1H NMR (CDCl3) d 7.34 (t, J ¼ 7.7, 1H), 6.93 (m, 3H), 5.68 (dd, J ¼ 9.6, 3.8,
1H), 3.84 (s, 3H), 3.66 (d, J ¼ 19, 1H), 3.48 (d, J ¼ 19, 1H), 2.96 (dd,
J ¼ 18.4, 3.8, 1H), 2.87 (dd, J ¼ 18.4, 9.6, 1H). HRMS (M þ H) calcd. for
C12H13Oþ4 221.0814; found 221.0815.
6-(Phenyl)-dihydro-2H-pyran-2,4(3H)-dione (Entry d)
1H NMR (CDCl3) d 7.42 (m, 5H), 5.71 (dd, J ¼ 9.6, 4.1, 1H), 3.67 (d, J ¼ 19,
1H), 3.49 (d, J ¼ 19, 1H), 2.97 (dd, J ¼ 18.4, 4.1, 1H), 2.89 (dd, J ¼ 18.4, 9.6,
1H). HRMS (M þ ) calcd. for C11H10O3 190.0630; found 190.0632.
6-(2-Chlorophenyl)-dihydro-2H-pyran-2,4(3H)-dione (Entry e)
1H NMR (CDCl3) d 7.64 (dd, J ¼ 7.4, 1.9, 1H), 7.38 (m, 3H), 6.06 (dd,
J ¼ 11.8, 2.7, 1H), 3.81 (d, J ¼ 19, 1H), 3.58 (d, J ¼ 19, 1H), 3.11 (dd,
J ¼ 18.4, 2.7, 1H). 2.61 (dd, J ¼ 18.4, 11.8, 1H). HRMS (M þ H) calcd. for
C11H10ClOþ3 225.0319; found 225.0313.
6-(3-Chlorophenyl)-dihydro-2H-pyran-2,4(3H)-dione (Entry f)
1H NMR (CDCl3) d 7.43 (m, 1H), 7.38 (m, 2H), 5.67 (dd, J ¼ 10.7, 3.6, 1H),
3.69 (d, J ¼ 19, 1H), 3.52 (d, J ¼ 19, 1H), 2.97 (dd, J ¼ 18.4, 3.6, 1H), 2.83
(dd, J ¼ 18.4, 10.7, 1H). HRMS (M þ H) calcd. for C11H10ClOþ3 225.0319;
found 225.0314.
6-(4-Chlorophenyl)-dihydro-2H-pyran-2,4(3H)-dione (Entry g)
1H NMR (CDCl3) d 7.42 (br d, J ¼ 8.5, 1H), 7.34 (br d, J ¼ 8.5, 1H), 5.67 (dd,
J ¼ 10.2, 3.3, 1H), 3.68 (d, J ¼ 19, 1H), 3.50 (d, J ¼ 19, 1H), 2.95 (dd,

5-Aryl-3-oxo-b-lactones
487
J ¼ 18.4, 3.6, 1H), 2.82 (dd, J ¼ 18.4, 10.4, 1H). HRMS (M þ H) calcd. for
C11H10ClOþ3 225.0319; found 225.0327.
6-(3-Nitrophenyl)-dihydro-2H-pyran-2,4(3H)-dione (Entry h)
1H NMR (CD3OD) d 8.38 (br s, 1H), 8.25 (br d, J ¼ 8.0, 1H), 7.90 (br d,
J ¼ 8.0, 1H), 7.68 (br t, J ¼ 8.2), 5.66 (dd, J ¼ 11.5, 4.1, 1H), 2.87 (dd,
J ¼ 17.3, 11.5, 1H), 2.75 (dd, J ¼ 17.3, 4.1, 1H). HRMS (M þ H) calcd. for
C11H10NOþ5 236.0559; found 236.0562.
6-(4-Nitrophenyl)-dihydro-2H-pyran-2,4(3H)-dione (Entry i)
1H NMR (CD3OD) d 8.29 (br d, J ¼ 8.8, 1H), 7.74 (br d, J ¼ 8.8, 1H),
5.66 (dd, J ¼ 11.3, 5.0, 1H), 2.84 (dd, J ¼ 17.3, 11.3, 1H), 2.74 (dd,
J ¼ 17.3, 5.0, 1H). HRMS (M þ H) calcd. for C11H10NOþ5 236.0559; found
236.0553.
4-(4,6-Dioxotetrahydro-2H-pyran-2-yl)benzonitrile (Entry j)
1H NMR (CD3OD) d 7.79 (d, J ¼ 8.5, 2H), 7.67 (d, J ¼ 8.5, 2H), 5.60 (dd,
J ¼ 11.5, 4.7, 1H), 2.82 (dd, J ¼ 17.3, 11.5, 1H), 2.71 (dd, J ¼ 17.3, 4.7,
1H). HRMS (M þ H) calcd. for C12H9NOþ3 216.0661; found 216.0665.
6-(4-Acetylphenyl)-dihydro-2H-pyran-2,4(3H)-dione (Entry k)
1H NMR (CD3OD) d 8.04 (d, J ¼ 8.2, 2H), 7.61 (d, J ¼ 8.2, 2H), 5.59
(dd, J ¼ 11.5, 4.4, 1H), 2.84 (dd, J ¼ 17.3, 11.5, 1H), 2.71 (dd,
J ¼ 17.3, 4.4, 1H). HRMS (M þ H) calcd. for C13H13Oþ4 233.0814; found
233.0820.
ACKNOWLEDGMENTS
We thank the Annie E. Casey Foundation, the U.S. Department of Labor, in
collaboration with the City of Peoria Workforce Development Department,
the Ruby Worner Foundation, and Bradley University (Special Emphasis
Fund) for their financial support of this project.
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