Unexpected lactonization accompanying addition of ethyl acetoacetate to chalcones derived from 3-acetylthiophene

Article abstract of DOI:10.1135/cccc2010150

Chalcone derivatives containing thiophene ring were prepared by the condensation of 3-acetylthiophene with aromatic aldehydes in excellent yields. The addition of ethyl acetoacetate to chalcone derivatives 3a-3h in the presence of solid NaOH in CH₂Cl₂ resulted in the formation of the mixture of bicyclic lactone derivatives 5a-5h and 6-(ethoxycarbonyl) cyclohexenone derivatives 6a-6h.

Full text of DOI:10.1135/cccc2010150

Unexpected Lactonization
1255
UNEXPECTED LACTONIZATION ACCOMPANYING ADDITION OF
ETHYL ACETOACETATE TO CHALCONES DERIVED FROM
3-ACETYLTHIOPHENE
1,
2
Yakup BUDAK * and Esra FINDIK
Department of Chemistry, Faculty of Arts and Sciences, Gaziosmanpasa University,
1
2
60250 Tokat, Turkey; e-mail: ybudak@gop.edu.tr, esrafndk@gop.edu.tr
Received December 17, 2010
Accepted May 24, 2011
Published online September 26, 2011
Chalcone derivatives containing thiophene ring were prepared by the condensation of
3-acetylthiophene with aromatic aldehydes in excellent yields. The addition of ethyl
acetoacetate to chalcone derivatives 3a–3h in the presence of solid NaOH in CH2Cl2 resulted
in the formation of the mixture of bicyclic lactone derivatives 5a–5h and 6-(ethoxy-
carbonyl)cyclohexenone derivatives 6a–6h.
Keywords: Chalcone; Ethyl acetoacetate; Cyclization; Lactonization; Cyclohexenones;
Lactones; Cycloaddition.
Chalcones and the corresponding heterocyclic analogs are valuable inter-
mediates in organic synthesis1 and exhibit a multitude of biological activi-
ties2. From a chemical point of view, an important feature of chalcones is
the ability to act as activated unsaturated systems in conjugated addition
reactions of carbanions in the presence of basic catalysts3. This type reac-
tion may be exploited with the aim to obtain highly functionalized cyclo-
hexene derivatives4, but commonly used for the preparation of 3,5-diaryl-
6-(ethoxycarbonyl)cyclohexenones via Michael addition of ethyl aceto-
acetate. The mentioned cyclohexenones are efficient compounds in build-
ing spiro compounds5 or intermediates in the synthesis of fused hetero-
cycles such as benzoselenadiazoles, benzothiadiazoles6, benzopyrazoles and
benzisoxazoles7 or carbazole derivatives8. The Michael addition of 1,3-di-
carbonyl compounds to chalcone, the catalyst plays a key role in directing
the reaction to different final products. Weaker base catalysts such as
Na2CO3, K2CO3, piperidine, quaternary ammonium hydroxide, tertiary
amines have higher product selectivity, affording only Michael adduct.
When Michael reaction was catalyzed by strong bases such as KF/Al2O3,
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 10, pp. 1255–1261
© 2011 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2010150

1256
Budak, Findik:
NaOH, KOH, etc., 6-type compounds were formed via further aldol conden-
sation9,10
.
RESULTS AND DISCUSSION
This paper reports the synthesis of unexpected lactone derivatives 5a–5h
besides 6-ethoxycarbonylcyclohexenones 6a–6h from the reaction of ethyl
acetoacetate with chalcone 3a–3h in the presence of NaOH at room tem-
perature.
A similar lactones structure and spectral results have been previously
obtained by Jung et al.11,12 from the thermal cycloaddition of ketene
dimethyl- or diethyl acetal with 2-oxo-2H-pyran-5-carboxylate derivatives.
The chalcone derivatives 3a–3h were synthesized according to our re-
cently published reports13,14 (Scheme 1). We recently performed the reac-
tion of 3a–3h with ethyl acetoacetate in the presence of t-BuOK, and
obtained the cyclohexenone derivatives 6a–6h as single products in excel-
lent yield14. This study, solid NaOH was used instead of t-BuOK for the
same reaction. The unexpected lactone derivatives 5a–5h were isolated as
well as the cyclohexenone derivatives 6a–6h (Scheme 2, Table I). The com-
pounds 5 and 6 were purificated by column chromatography on silica gel
or preparative TLC using n-hexane/EtOAc as eluent.
O
O
O
O
R
NaOH / EtOH
r.t, 3-4 h
COOC2H5
H
+
+
R
S
S
3a-h
4
2a-h
1
R
Compound
NaOH / CH2Cl2
r.t, 3-4 h
a
4-CH3O-C6H4
C6H5
b
c
d
e
3-Br-C6H4
S
O
O
R
O
3-CH3-C6H4
O
O
O
+
4-CH3-C6H4
2-CH3O-C6H4
2-Cl-C6H4
R
6a-h
5a-h
f
S
g
h
4-Cl-C6H4
SCHEME 1
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Unexpected Lactonization
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TABLE I
Synthesized compounds 5a–5h and 6a–6h
Reagent
Products
3
5
m.p., yield (%)
100–101 °C, 59
6
m.p., yield (%)
O
O
O
S
O
106–107 °C, 38
O
O
O
H3CO
S
6a
H3CO
H3CO
S
O
O
5a
3a
3b
S
S
O
O
O
O
O
O
viscous oil, 52
154–155 °C, 63
viscous oil, 55
116–117 °C, 46
139–140 °C, 35
111–112 °C, 42
6b
S
5b
O
O
S
S
O
O
O
O
S
S
6c
Br
5c
3c
3d
Br
Br
O
O
S
S
O
O
O
O
O
O
S
S
6d
5d
CH3
CH3
CH3
O
O
O
O
O
O
viscous oil, 52
147–148 °C, 47
H3C
5e
H3C
6e
S
H3C
3e
O
O
S
S
S
O
O
O
O
H3CO
O
H3CO
O
O
viscous oil, 46
viscous oil, 51
viscous oil, 41
99–100 °C, 42
viscous oil, 45
145–146 °C, 51
OCH3
6f
S
S
S
S
S
S
5f
3f
O
O
O
O
Cl
O
Cl
O
O
Cl
6g
3g
5g
O
O
O
O
O
Cl
Cl
Cl
5h
6h
3h
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Budak, Findik:
The structures of cyclohexenones 6a–6h were determined by the spectral
data and comparison with an authentic sample14,15. The structures of all
1
new lactones 5a–5h were corroborated through their IR, H and 13C NMR
spectra and elemental analysis. The IR spectra of these compounds revealed
two sharp strong absorption bands around 1682–1662 (νC=O ketone) and
1739–1724 (νC=O ester) cm–1. These absorption bands confirm the presence
of the ester group and the carbonyl group, respectively. In the 1H NMR
spectra of compounds 5a–5h, absence of the signal of the ethoxy group and
lack of any signal in the olefinic region indicate the intramolecular lacton-
ization. An addition to this, in 13C NMR spectra of 5a–5h the signal at δ ~
74 ppm arising from C–O bond supports the lactone structure.
The formation mechanism of lactone derivatives 5a–5h explained
Scheme 2. Michael addition of ethyl acetoacetate to chalcone 3 gives ad-
ducts 7 which is converted to carbanionic intermediate 8 by action of base.
Intermediate 8 is transformed to 9 via intramolecular cyclization. While the
intramolecular transesterification of intermediate 9 gives bicyclic lactone
derivatives 5a–5h (Scheme 2a), the loss of H2O from the intermediate 9
gives cyclohexenones 6a–6h (Scheme 2b).
O
O
O
O
H2C
O
H3C
O
NaOH
O
O
NaOH / CH2Cl2
r.t, 3-4 h
+ 4
3a-h
S
S
R
R
8
7
O
O
R
O
O
R
S
O
O
O
a
b
O
-H2O
- EtOH
O
S
S
R
O
6a-h
5a-h
9
SCHEME 2
In conclusion, the new bicyclolactones 5a–5h were isolated besides
cyclohexenone derivatives 6a–6h from the reaction of chalcone derivatives
3a–3h with ethyl acetoacetate (4) in the presence of solid NaOH in CH2Cl2
under mild reaction conditions. We assume that the thiophene ring and
the slow reaction in the presence of solid NaOH are essential for the forma-
tion of lactone derivatives.
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Unexpected Lactonization
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EXPERIMENTAL
Melting points were measured on Electrothermal 9100 apparatus. IR spectra (KBr or liquid)
were recorded on a Jasco FT/IR-430 spectrometer (ν, cm–1). 1H and 13C NMR spectra were re-
corded on a Bruker Avance III instrument (400 MHz). As internal standards served TMS
(δ 0.00) for 1H NMR and CDCl3 (δ 77.0) for 13C NMR spectroscopy (δ, ppm; J, Hz). The mul-
tiplicities of the signals in the 1H NMR spectra are abbreviated by s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), br (broad) and combinations thereof. Elemental analy-
ses were obtained from a LECO CHNS 932 elemental analyzer.
Synthesis of 5a–5h and 6a–6h. General Procedure
A solution of chalcone derivatives 3a–3h (1 mmol) and ethyl acetoacetate (4) (1 mmol) in
CH2Cl2 (10 ml) was stirred at room temperature for 3–4 h in the presence of solid NaOH
(1 mmol). After the reaction was completed, the reaction mixture was extracted with
CH2Cl2. The extract was washed with H2O, and dried (Na2SO4). The solvent was evaporated
(45 °C, 2.6 kPa). Crude products were purified by column chromatography on silica gel or
preparative TLC (20 × 20 cm plates, 2 mm thickness) using n-hexane/EtOAc (9:1) as eluent.
8-(4-Methoxyphenyl)-1-(thiophen-3-yl)-2-oxabicyclo[2.2.2]octane-3,5-dione (5a): White crystals,
m.p. 100–101 °C, yield 59%. IR (KBr): 3029 (s), 2919 (m), 1726 (s) (νC=O ester), 1672 (s)
(νC=O ketone), 1218 (s), 771 (s). 1H NMR (400 MHz, CDCl3): 7.38–7.37 m, 1 H, 7.29–7.24 m,
1 H, 7.16–7.04 m, 2 H, 6.88–6.84 m, 1 H, 6.72–6.70 m, 2 H, 3.82 d, J = 7.6, 1 H, 3.75 s, 3 H,
(-OCH3), 3.01–2.96 m, 1 H, 2.74–2.66 m, 1 H, 2.58–2.52 m, 1 H, 2.29–2.24 m, 1 H,
2.18–2.12 m, 1 H. 13C NMR (100 MHz, CDCl3): 178.4, 176.9, 157.9, 145.6, 136.5, 128.1,
126.2, 125.2, 120.9, 113.9, 74.3, 55.2, 47.9, 46.2, 41.9, 36.5. For C18H16O4S (328.4) calcu-
lated: 65.84% C, 4.91% H, 9.76% S; found: 65.76% C, 4.97% H, 9.79% S.
8-Phenyl-1-(thiophen-3-yl)-2-oxabicyclo[2.2.2]octane-3,5-dione (5b): Liquid, yield 52%.
IR (KBr): 3033 (s), 2979 (m), 1724 (s) (νC=O ester), 1668 (s) (νC=O ketone), 1218 (s), 771 (s).
1H NMR (400 MHz, CDCl3): 7.38–7.35 m, 1 H, 7.33–7.27 m, 1 H, 7.24 m, 1 H, 7.17–7.13 m,
2 H, 7.08–7.04 m, 1 H, 6.98–6.92 m, 2 H, 2.93–2.83 m, 2 H, 2.61 q, 1 H, J = 7.2, 2.49–2.40 m,
2 H, 2.16–2.04 m, 1 H. 13C NMR (100 MHz, CDCl3): 173.6, 173.2, 148.2, 146.4, 128.4, 127.6,
126.7, 126.1, 125.9, 120.8, 74.7, 48.6, 47.7, 41.5, 37.9. For C17H14O3S (298.4) calculated:
68.44% C, 4.73% H, 10.75% S; found: 68.56% C, 4.61% H, 10.78% S.
8-(3-Bromophenyl)-1-(thiophen-3-yl)-2-oxabicyclo[2.2.2]octane-3,5-dione (5c): White crystals,
m.p. 154–155 °C, yield 65%. IR (KBr): 3027 (s), 2974 (m), 1726 (s) (νC=O ester), 1662 (s)
(νC=O ketone), 1220 (s), 773 (s). 1H NMR (400 MHz, CDCl3): 7.33–7.30 m, 1 H, 7.23–7.19 m,
2 H, 7.10–7.06 m, 1 H, 7.05 s, 1 H, 6.94–6.92 m, 1 H, 6.88–6.87 m, 1 H, 2.91–2.83 m, 2 H,
2.63 q, 1 H, J = 7.2, 2.49–2.44 m, 2 H, 2.09–2.02 m, 1 H. 13C NMR (100 MHz, CDCl3):
173.7, 173.5, 149.2, 148.3, 130.6, 130.5, 128.9, 126.7, 126.6, 125.8, 121.7, 120.8, 74.4, 48.3,
47.9, 41.6, 37.8. For C17H13BrO3S (376.0) calculated: 54.12% C, 3.47% H, 8.50% S; found:
54.21% C, 3.39% H, 8.45% S.
1-(Thiophen-3-yl)-8-m-tolyl-2-oxabicyclo[2.2.2]octane-3,5-dione (5d): Liquid, yield 55%.
IR (KBr): 3018 (s), 2915 (m), 1726 (s) (νC=O ester), 1662 (s) (νC=O ketone), 1220 (s), 773 (s).
1H NMR (400 MHz, CDCl3): 7.38–7.36 m, 1 H, 7.24–7.23 m, 1 H, 7.03 t, 1 H, J = 7.6,
6.95–6.94 m, 1 H, 6.88–6.86 m, 1 H, 6.74–6.72 m, 1 H, 6.69 s, 1 H, 2.91–2.86 m, 1 H,
2.83–2.78 m, 1 H, 2.62 q, 2 H, J = 14.4, 2.49–2.38 m, 1 H, 2.18 s, 3 H (-CH3), 2.13–2.06 m,
1 H. 13C NMR (100 MHz, CDCl3): 173.7, 172.1, 148.1, 146.4, 137.3, 128.3, 126.7, 126.7,
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125.9, 124.5, 120.9, 120.8, 74.7, 48.6, 47.6, 41.4, 37.7, 21.5. For C18H16O3S (312.4) calcu-
lated: 69.21% C, 5.16% H, 10.26% S; found: 69.28% C, 5.12% H, 10.35% S.
1-(Thiophen-3-yl)-5-p-tolyl-2-oxabicyclo[2.2.2]octane-3,8-dione (5e): Liquid, yield 52%.
IR (KBr): 3091 (s), 3013 (m), 1739 (s) (νC=O ester), 1672 (s) (νC=O ketone), 1592 (s), 1287 (s),
1168 (s), 794 (s). 1H NMR (400 MHz, CDCl3): 7.39–7.35 m, 1 H, 7.28–7.19 m, 1 H, 7.04 t,
1 H, J = 7.5, 6.90–6.89 m, 1 H, 6.84–6.80 m, 1 H, 6.72–6.68 m, 1 H, 6.60 s, 1 H, 2.91–2.86 m,
1 H, 2.83–2.78 m, 1 H, 2.62 q, 2 H, J = 14.2, 2.49–2.38 m, 1 H, 2.35 s, 3 H (-CH3), 2.24–2.22 m,
1 H. 13C NMR (100 MHz, CDCl3): 183.9, 179.1, 144.2, 143.2, 141.0, 132.1, 131.8, 129.7,
128.5, 127.5, 126.4, 121.7, 75.0, 50.2, 49.6, 43.4, 38.7, 22.8. For C18H16O3S (312.4) calcu-
lated: 69.21% C, 5.16% H, 10.26% S; found: 69.33% C, 5.18% H, 10.14% S.
5-(2-Methoxyphenyl)-1-(thiophen-3-yl)-2-oxabicyclo[2.2.2]octane-3,8-dione (5f): liquid, yield
46%. IR (KBr): 3104 (s), 3020 (m), 1730 (s) (νC=O ester), 1682 (s) (νC=O ketone), 1652 (s),
1592 (s), 1247 (s), 1027 (s), 752 (s). 1H NMR (400 MHz, CDCl3): 7.38–7.36 m, 1 H, 7.19–7.13 m,
1 H, 6.95–6.89 m, 2 H, 6.82–6.74 m, 1 H, 6.59–6.54 m, 2 H, 3.93 m, 1 H, 3.85 s, 3 H,
(-OCH3), 3.27–3.02 m, 1 H, 2.84–2.81 m, 1 H, 2.47–2.27 m, 1 H, 2.21–2.20 m, 1 H,
2.08–1.90 m, 1 H. 13C NMR (100 MHz, CDCl3): 179.1, 178.4, 158.8, 143.4, 139.6, 129.2,
126.3, 126.1, 120.7, 111.2, 76.0, 55.6, 50.2, 42.0, 37.2, 31.6. For C18H16O4S (328.4) calcu-
lated: 65.84% C, 4.91% H, 9.76% S; found: 65.56% C, 4.82% H, 9.70% S.
5-(2-Chlorophenyl)-1-(thiophen-3-yl)-2-oxabicyclo[2.2.2]octane-3,8-dione (5g): Liquid, yield
51%. IR (KBr): 3100 (s), 3060 (m), 1730 (s) (νC=O ester), 1672 (s) (νC=O ketone), 1230 (s),
752 (s). 1H NMR (400 MHz, CDCl3): 7.48–7.41 m, 1 H, 7.24–7.21 m, 2 H, 7.12–7.07 m, 1 H,
7.05 m, 1 H, 6.98–6.94 m, 1 H, 6.90–6.85 m, 1 H, 3.02–2.98 m, 2 H, 2.66 m, 1 H, 2.48- 2.43 m,
2 H, 2.12–1.99 m, 1 H. 13C NMR (100 MHz, CDCl3): 175.8, 173.3, 148.5, 148.3, 130.3, 129.2,
128.2, 126.9, 126.5, 125.4, 120.0, 119.7, 74.6, 53.1, 50.0, 42.8, 34.7. For C17H13ClO3S
(332.8) calculated: 61.35% C, 3.94% H, 9.63% S; found: 61.42% C, 3.87% H, 9.72% S.
5-(4-Chlorophenyl)-1-(thiophen-3-yl)-2-oxabicyclo[2.2.2]octane-3,8-dione (5h): Liquid, yield
41%. IR (KBr): 3090 (s), 3010 (m), 1727 (s) (νC=O ester), 1682 (s) (νC=O ketone), 1650 (s),
1598 (s), 1247 (s), 1022 (s), 767 (s). 1H NMR (400 MHz, CDCl3): 7.42–7.38 m, 1 H, 7.28–7.26 m,
1 H, 7.18 m, 1 H, 7.07–7.04 m, 1 H, 6.90–6.88 m, 1 H, 6.82–6.78 m, 1 H, 6.69 m, 1 H,
3.05–2.99 m, 1 H, 2.90–2.88 m, 1 H, 2.50 m, 2 H, 2.38–2.31 m, 1 H, 2.25–2.16 m, 1 H.
13C NMR (100 MHz, CDCl3): 177.2, 175.2, 148.3, 144.1, 139.4, 133.2, 130.1, 128.2, 127.6,
127.4, 75.1, 49.8, 45.7, 42.8, 38.7. For C17H13ClO3S (332.8) calculated: 61.35% C, 3.94% H,
9.63% S; found: 61.31% C, 3.87% H, 9.68% S.
The authors are indebted to the Department of Chemistry (Gaziosmapasa University) and Scientific
Research Projects Commission of Gaziosmanpasa University (Project No. 2009/26) for financial
support.
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