Reaction of ethyl acetoacetate and 2'-hydroxychalcones: Efficient route to 9-aryl-6H-benzo[c]chromen-6-ones

Article abstract of DOI:10.4314/bcse.v28i2.12

The reaction of ethyl acetoacetate and 2'-hydroxychalcones under atmospheric air to furnish a series of functionalized 6H-benzo[c]chromen-6-ones in moderate yields is reported. The reaction proceeds through trans-esterification, intra-molecular Michael addition, Robinson annulation and oxidative aromatization.

Full text of DOI:10.4314/bcse.v28i2.12

Bull. Chem. Soc. Ethiop. 2014, 28(2), 289-294.
Printed in Ethiopia
DOI: http://dx.doi.org/10.4314/bcse.v28i2.12
ISSN 1011-3924
 2014 Chemical Society of Ethiopia
SHORT COMMUNICATION
REACTION OF ETHYL ACETOACETATE AND 2′-HYDROXYCHALCONES:
EFFICIENT ROUTE TO 9-ARYL-6H-BENZO[C]CHROMEN-6-ONES
Ishmael B. Masesane* and Ofentse Mazimba
Department of Chemistry, University of Botswana, Private Bag 00704, Gaborone, Botswana
(Received April 19, 2013; revised November 15, 2013)
ABSTRACT. The reaction of ethyl acetoacetate and 2′-hydroxychalcones under atmospheric air to furnish a
series of functionalized 6H-benzo[c]chromen-6-ones in moderate yields is reported. The reaction proceeds
through trans-esterification, intra-molecular Michael addition, Robinson annulation and oxidative aromatization.
KEY WORDS: 2′-Hydroxychalcones, Ethyl acetoacetate, 6H-Benzo[c]chromen-6-ones, Trans-esterification,
Michael addition, Robinson annulation, Oxidative aromatization
INTRODUCTION
6H-Benzo[c]chromen-6-ones are an interesting class of coumarins that occur in a number of
pharmacologically active natural products such as alternariol, automnariol and autumnariniol [1,
2]. These compounds and their analogs have been reported as specific inhibitors of the growth
of endothelic cells and oestrogen receptors [3]. 6H-benzo[c]chromon-6-ones therefore represent
core structures for the synthesis of pharmaceuticals.
A limited number of synthetic procedures have been reported for the synthesis of 6H-
benzo[c]chromen-6-ones and these methods involves three or more steps, less accessible
starting materials and the availability of chromones as starting material. These procedures
include the [3+3] cyclizations of 1,3-bis(silyl enol ethers) with 1-(silyloxy)alk-1-en-3-ones [4-
6], reactions of 3-formylcoumarin with 1,3-bis(silylenol ethers) [7, 8], sequential [3+3] Suzuki
cyclization reactions [9], Bu3SnH mediated radical cyclisation [10], coupling of benzoic acid
with benzoquinone using the electrophilic Ir(III) catalyst [11] and the reactions of chromones
with 1,3-dicarbonyl compounds [12, 13]. There is, therefore, a need to develop synthetically
useful methodologies for the preparation of 6H-benzo[c]chromen-6-ones using readily available
starting materials. Thus, we describe in this paper a facile procedure for the synthesis of 9-
phenyl-6H-benzo[c]chromen-6-ones involving the reaction of ethyl acetoacetate and chalcones
derived from the condensation of salicylaldehyde and acetophenone derivatives.
RESULTS AND DISCUSSIONS
The conditions for the preparation of the 2′-hydroxychalcones were originally worked out by our
group in connection with our approach to the synthesis of flavans [14]. Employing this known
procedure, a series of 2′-hydroxychalcones 8-13 were prepared through the reaction of
salicylaldehyde 1 and acetophenone derivatives 2-7 in excellent yields (Scheme 1).
__________
*Corresponding author. E-mail: masesane@mopipi.ub.bw

290
Ishmael B. Masesane and Ofentse Mazimba
O
O
CHO
OH
i)
R
+
R
OH
8 (R = H)
1
2 (R =H)
3
9
(R = o-OMe)
(R = o-OMe)
4 (R = m-OMe)
5 (R = p-OMe)
6 (R = p-Br)
10 (R = m-OMe)
11 (R = p-OMe)
12 (R = p-Br)
7 (R = 3,4-diOMe)
13 (R = 3,4-diOMe)
Scheme 1. Reagents and conditions: i) 50% NaOH (aq), EtOH, 60 oC, 2 h, 8 (88%), 9 (88%), 10
(86%), 12 (87%), 13 (86%).
With the required 2′-hydroxychalcones in hand, we were in a position to study their
reactions with ethyl acetoacetate. To this end, a solution of the 2-hydroxychalcone 8 and ethyl
acetoacetate 14 in CH3OH in the presence of diethylamine was stirred at 60 oC and the reaction
monitored by TLC. Workup by acidification using 4 M HCl and recrystalization of the resulting
crude product from ethanol gave 6H-benzo[c]chromen-6-one 17 in 56% yield, Scheme 2.
Alternatively, this reaction can also be mediated by K2CO3 or Et2NH/K2CO3 (1:0.5 mole ratio)
at room temperature to afford 6H-benzo[c]chromen-6-one 17 at 56% yields. The product was
1
characterized on the basis of NMR experiments and the H NMR peaks around δ11.33 (s)
assigned to the chelated proton of the hydroxyl group and those resonating at δ7.34 (d) and
δ7.82 (d) assigned to the meta-coupled H-8 and H-10 protons (3J = 1.5 Hz) were found to be
diagnostic.
The Michael addition of active methylene compounds to chalcones is well documented [15-
20]. On the basis of these precedents, the formation of chromenone 17 was thought to proceed
by first a Michael addition of ethyl acetoacetate 14 to chalcone 8 followed by intra-molecular
trans-esterification and intramolecular Aldol condensation to give intermediate 15. In an effort
to isolate intermediate 15, the reaction of 8 and 14 was repeated under an atmosphere of
nitrogen. Suprisingly, the trans-esterification product 18 was detected (by proton NMR) in the
crude product instead of the Michael addition product. However, all attempts to purify 18 using
column chromatography led to cyclisation and oxidative aromatization to give chromenone 17.
These results suggested that intermediate 18 was highly unstable species when exposed to
atmospheric air. We thus propose that trans-esterification between acetoacetate 14 and
hydroxychalcone 8 proceeds first to give ester 18 followed by an intra-molecular Michael
addition to give coumarin 19 and finally an intramolecular Aldol condensation to afford
dihydrochromenone 15 (Scheme 2).
Oxidative aromatization of intermediate 15 is the last reaction involved in the synthesis of
chromenone 17. It is instructive to note that there is precedent for atmospheric air mediated
oxidative aromatization of cyclohexadienes [21]. In the context of intermediate 15, a keto-enol
tautomerization would proceed to give cyclohexadiene 16 which undergoes oxidative
aromatization to afford chromenone 17 (Scheme 2).
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Short Communication
291
Scheme 2. Reagents and conditions: i) Et2NH, MeOH, 60 oC.
Employing the procedure described above, 2′-hydroxychalcone derivatives 9, 10, 11, 12 and
13 were reacted with 14 to give 6H-benzo[c]chromen-6-ones 20-24 in 51-59% yields (Scheme
3). The methoxy and the bromo groups did not have any significant effect on the yields of this
reaction.
o
Scheme 3. Reagents and Conditions: i) Et2NH, MeOH, 60 C, 20 (51%), 21 (57%), 22 (51%),
23 (59%), 24 (58%).
In conclusion, we have reported a facile synthesis of 6H-benzo[c]chromen-6-ones in
moderate yields from the reactions of 2′-hydroxychalcones and ethyl acetoacetate. The
procedure involves four reactions in one-pot and uses readily available starting materials.
Bull. Chem. Soc. Ethiop. 2014, 28(2)

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Ishmael B. Masesane and Ofentse Mazimba
EXPERIMENTAL
Representative Procedure. To a solution of 2′-hydroxychalcone 1 (0.54 g, 2.4 mmol) in CH3OH
(20 mL) was added diethylamine (0.71 g, 4.8 mmol). Ethyl acetoacetate (0.32 g, 2.4 mmol) was
o
then added and the reaction mixture was stirred at 60 C and was monitored by TLC. Upon
completion of the reaction, the reaction mixture was acidified using hydrochloric acid (4 M) and
the resulting precipitate was collected by filtration and recrystallized from ethanol to afford 7-
hydroxy-9-phenyl-6H-benzo[c]chromen-6-one 17 as a white solid. Yield 56%, m.p. 211-213 oC.
νmax (neat) 2941, 1676, 1203, 1083 cm-1; 1H NMR (300 MHz, CDCl3): 7.34 (1H, d, J = 1.5 Hz,
H-8), 7.40 (1H, dd, J = 8.7, 1.5 Hz, H-3), 7.42 (1H, d, J = 8.7 Hz, H-4), 7.51 (1H, m, H-4′),
7.53 (1H, dd, J = 8.7, 1.8 Hz, H-3), 7.59 (2H, dd, J = 8.7, 2.1 Hz, H-3’, 5’), 7.73 (2H, dd, J =
8.7, 2.1 Hz, H-2′, 6′,), 7.82 (1H, d, J = 1.5 Hz, H-10), 8.15 (1H, d, H-1, J = 8.1), 11.44 (1H, s,
-OH); 13C NMR (75 MHz, CDCl3): 104.9 (C-6a), 111.1 (C-10), 115.0 (C-8), 117.8 (C-4), 118.4
(C-10b), 123.3 (C-1), 125.1 (C-3), 127.4 (C-2′ and 6′), 129.0 (C-4′), 129.1 (C-3′ and 5′), 130.7
(C-3), 135.5 (C-1′), 139.5 (C-10a), 150.3 (C-9), 150.8 (C-4a), 162.7(C-6), 165.3 (C-7). HRMS-
EI: Found: M+ 288.0790, C20 H14O4. Calcd. for m/z 288.0786.
7-Hydroxy-9-(2-methoxyphenyl)-6H-benzo[c]chromen-6-one 20. Yield 51%, white solid, m.p.
o
153-155 C; νmax (neat): 3077, 2924, 1667, 1274, 1079 cm-1; 1H NMR (300 MHz, CDCl3): 3.78
(3H, s, -OCH3), 6.98 (1H, dd, J = 8.7, 0.9 Hz, H-3′), 7.04 (1H, dd, J = 7.5, 0.9 Hz, H-5′), 7.19
(1H, d, J = 1.2 Hz, H-8), 7.25 (1H, dd, J = 8.1, 1.2 Hz, H-4′,), 7.30 (1H, dd, J = 7.8, 1.5 Hz, H-
4), 7.32 (1H, dd, J = 7.8, 1.5 Hz, H-3), 7.34 (1H, dd, J = 7.2, 1.2 Hz, H-6′), 7.45 (1H, ddd, J =
8.1, 7.2, 1.5 Hz, H-2,), 7.68 (1H, d, J = 1.2 Hz, H-10), 8.00 (1H, dd, J = 8.1, 1.5 Hz, H-1),
11.26 (1H, s, -OH); 13C NMR (75 MHz, CDCl3): 55.7 (OMe), 104.7 (C-6a), 111.5 (C-3′), 113.8
(C-10), 117.7 (C-8), 117.8 (C-4), 118.6 (C-10b), 121.0 (C-5′), 123.4 (C-1), 125.1 (C-3), 129.0
(C-1′), 130.1 (C-2), 130.5 (C-4′), 130.6 (C-6′), 134.6 (C-10a), 148.2 (C-9), 150.7 (C-4a), 156.5
(C-2′), 161.9 (C-7), 165.4 (C-6);; HRMS-EI: found: M+ 318.0895, C20 H14O4. Calcd. for m/z
318.0892.
7-Hydroxy-9-(3-methoxyphenyl)-6H-benzo[c]chromen-6-one 21. Yield 57%, white solid, m.p.
152-154 oC; νmax (neat): 3076, 2924, 1683, 1205, 1081 cm-1; 1H NMR (300 MHz, CDCl3): 3.83
(3H, s, -OCH3), 6.93 (1H, dt, J = 7.2, 2.4, 0.9 Hz, H-4′), 7.15 (1H, t, J = 2.1 Hz, H-2′), 7.22
(1H, dd, J = 8.7, 2.4 Hz, H-6′), 7.23 (1H, d, J = 1.5 Hz, H-8), 7.28 (1H, dd, J = 7.2, 1.2 Hz, H-
2), 7.31 (1H, t, J = 1.2 Hz, H-4), 7.38 (1H, ddd, J = 8.1, 7.8, 1.5 Hz, H-5′), 7.48 (1H, ddd, J =
8.4, 7.2, 1.5 Hz, H-3), 7.71 (1H, d, J = 1.5 Hz, H-10), 8.04 (1H, dd, J = 8.1, 1.5 Hz, H-1), 11.35
(1H, s, OH); 13C NMR (75 MHz, CDCl3): 55.4 (OMe), 105.0 (C-6a), 111.2 (C-10), 113.2 (C-2′),
114.3 (C-4′), 115.1 (C-8), 117.8 (C-4), 118.4 (C-10b), 119.8 (C-6′), 123.4 (C-1), 125.2 (C-2),
130.1 (C-5′), 130.7 (C-3), 135.5 (C-10a), 141.0 (C-1′), 150.2 (C-9), 150.8 (C-4a), 160.1 (C-3′),
162.3 (C-7), 165.3 (C-6); HRMS-EI: found: M+ 318.0900, C20 H14O4. Calcd. for m/z 318.0892.
7-Hydroxy-9-(4-methoxyphenyl)-6H-benzo[c]chromen-6-one 22. Yield 51%, white solid, m.p.
236-238 oC; νmax (neat): 3124, 2924, 1681, 1209, 1041 cm-1; 1H NMR (300 MHz, CDCl3): 3.94
(3H, s, OCH3), 7.08 (2H, d, J = 8.7 Hz, H-3′, 5′), 7.31 (1H, d, J = 1.5 Hz, H-8), 7.40 (1H, dd, J
= 8.4, 1.2 Hz, H-2,), 7.43 (1H, dd, J = 8.1, 1.1 Hz, H-4), 7.54 (1H, ddd, J = 8.4, 8.1, 1.5 Hz,
H-3), 7.70 (2H, d, J = 8.7 Hz, H-2′ and 6′), 7.81 (1H, d, J = 1.5 Hz, H-10), 8.16 (1H, dd, J =
8.1, 1.5 Hz, H-1), 11.40 (1H, s, -OH); 13C NMR (75 MHz, CDCl3): 55.4 (OMe), 104.4 (C-6a),
110.5 (C-10), 114.4 (C-8), 114.5 (C-3′ and 5′), 117.8 (C-4), 123.4 (C-1), 125.1 (C-2), 128.6
(C-2′ and 6′), 130.6 (C-3), 131.8 (C-1′), 135.4 (C-10b), 149.9 (C-10a), 150.8 (C-9), 160.6
(C-4a), 162.7 (C-7 and 4′), 165.4 (C-6); HRMS-EI: found: M+ 318.0899, C20 H14O4. Calcd. for
m/z 318.0892.
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9-(4-Bromophenyl)-7-hydroxy-6H-benzo[c]chromen-6-one 23. Yield 59%, white solid, m.p.
202-204 oC; νmax (neat): 3135, 2920, 1674, 1203, 1083 cm-1; 1H NMR (300 MHz, CDCl3): 7.16
(1H, d, J = 1.2 Hz, H-8), 7.29 (1H, dd, J = 8.7, 1.5 Hz, H-4), 7.34 (1H, dd, J = 7.5, 1.5 Hz, H-
2), 7.43 (1H, dd, J = 7.2, 1.5 Hz, H-3), 7.48 (2H, d, J = 8.7, 2.1 Hz, H-2′ and 6′), 7.56 (2H, dd, J
= 8.7, 2.1 Hz, H-3′ and 5′), 7.66 (1H, d, J = 1.2 Hz, H-10), 8.05 (1H, dd, J = 8.1, 1.2 Hz, H-1),
11.33 (1H, s, -OH); 13C NMR (75 MHz, CDCl3): 105.2 (C-6a), 110.9 (C-10), 114.8 (C-8), 117.9
(C-4), 118.2 (C-4′), 123.4 (C-1), 123.5 (C-10b), 125.2 (C-2), 129.0 (C-2′ and 6′), 130.9 (C-3),
132.3 (C-3′ and 5′), 135.6 (C-1′), 138.4 (C-10a), 149.0 (C-9), 150.8 (C-4a), 162.7 (C-7), 165.2
(C-6); HRMS-EI: found: M+ 365.9893 (99), M++2 367.9875 (100), C19 H11BrO3. Calcd. for m/z
365.9892.
7-Hydroxy-9-(3,4-dimethoxyphenyl)-6H-benzo[c]chromen-6-one 24. Yield 58%, white solid,
m.p. 148-150 oC; νmax (neat): 3050, 2930, 1680, 1205, 1049 cm-1; 1H NMR (300 MHz, CDCl3):
3.90 (3H, s, OCH3), 3.93 (3H, s, OCH3), 6.65 (1H, br, H-5′), 6.69 (1H, dd, J = 1.2 Hz, H-2′),
7.29 (1H, d, J = 1.2 Hz, H-8), 7.37 (1H, dd, J = 1.2 Hz, H-6′), 7.38 (1H, ddd, J = 8.7, 7.2, 1.2
Hz, H-3), 7.42 (1H, dd, J = 8.7, 1.2 Hz, H-4), 7.56 (1H, ddd, J = 8.1, 7.2, 1.5 Hz, H-2), 7.79
(1H, d, J = 1.2 Hz, H-10), 8.09 (1H, dd, J = 8.1, 1.2 Hz, H-1), 11.36 (1H, s, -OH); 13C NMR (75
MHz, CDCl3): 55.5 (OMe), 55.7 (OMe), 104.3 (C-6a), 99.2 (C-5′), 105.0 (C-2′), 113.6 (C-10),
117.4 (C-8), 117.7 (C-4), 118.7 (C-10b), 121.8 (C-10a), 123.4 (C-1), 125.0 (C-6′), 130.4 (C-2),
131.3 (C-3), 134.5 (C-1′), 148.0 (C-9), 150.7 (C-4′), 157.7 (C-3′), 161.5 (C-4a), 161.9 (C-7),
165.4 (C-6); HRMS-EI: found: M+ 348.0993, C21 H16O5. Calcd. for m/z 348.0998.
ACKNOWLEDGEMENTS
We thank the Royal Society of Chemistry and the University of Botswana for financial support
and Dr Sichilongo for mass spectrometry experiments.
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