A new protocol for the syntheses of (E)-3-benzylidenechroman-4-ones: A simple synthesis of the methyl ether of bonducellin

Article abstract of DOI:10.1039/a804796k

Development of a simple new methodology for the synthesis of (E)-3-benzylidenechroman-4-ones using methyl 3-aryl-3-hydroxy-2-methylenepropanoates, the Baylis-Hillman adducts derived from methyl acrylate, and the application of this methodology for the syn

Full text of DOI:10.1039/a804796k

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A new protocol for the syntheses of (E)-3-benzylidenechroman-4-ones: a simple
synthesis of the methyl ether of bonducellin
Deevi Basavaiah,*† Manickam Bakthadoss and Subramanian Pandiaraju
School of Chemistry, University of Hyderabad, Hyderabad-500 046, India
Development of a simple new methodology for the synthesis
of (E)-3-benzylidenechroman-4-ones using methyl 3-aryl-
3-hydroxy-2-methylenepropanoates, the Baylis–Hillman ad-
ducts derived from methyl acrylate, and the application of
this methodology for the synthesis of the methyl ether of
bonducellin, an important natural product, and 3-(4-me-
thoxybenzylidene)-6-methoxychroman-4-one, an antifungal
agent, are described.
construction of the benzylidene moiety via acid or base
catalyzed aldol condensation with aryl aldehydes.6–8 However,
to the best of our knowledge, there is no report in the literature
of the synthesis of (E)-3-benzylidenechroman-4-one involving
the initial preparation of the benzylidene moiety and then the
construction of the chroman-4-one ring system. We herein
disclose the first such methodology, thus developing a new
protocol for the synthesis of (E)-3-benzylidenechroman-4-ones
using methyl 3-aryl-3-hydroxy-2-methylenepropanoates, the
Baylis–Hillman adducts derived from methyl acrylate.
The (E)-3-benzylidenechroman-4-one moiety occupies a spe-
cial place in the field of heterocycles as this skeleton is an
integral part of many natural products and biologically active
The Baylis–Hillman reaction9–13 has attracted the attention of
organic chemists in recent years as this reaction provides
synthetically useful multifunctional molecules which have been
successfully employed in various stereoselective processes. In
continuation of our interest in the Baylis–Hillman reaction14–17
we have examined the possible application of methyl
(2Z)-2-bromomethylalk-2-enoates‡ 5 derived from methyl
3-hydroxy-2-methylenealkanoates for the synthesis of
(E)-3-benzylidenechroman-4-ones 8 according to Scheme 1.
We first selected (2E)-2-phenoxymethyl-3-phenylprop-
2-enoic acid 7a, which was obtained via the reaction of allyl
O
O
OH
OMe
OH
HO
O
MeO
O
OH
Autumnalin 2
Bonducellin 1
O
O
OH
OMe
O
O
i
R
OMe
MeO
O
OH
R
OMe
MeO
O
Eucomin 3
Antifungal agent 4
OPh
6a–g
(65–90%)
Br
5a–g
molecules. For example, bonducellin 1 is an important natural
product occurring in Caesalpinia bonducella1 and Caesalpinia
pulcherrima.2 Autumnalin 23 and Eucomin 34 are interesting
naturally occurring molecules present respectively in Eucomis
autumnalis GRAEB (Liliaceae) and Eucomis bicolor BAK
ii
O
O
R
R
OH
iii
(Liliaceae).
(E)-3-(4-Methoxybenzylidene)-6-methoxychro-
O
OPh
7a–g
(78–93%)
man-4-one 4 is an antifungal agent.5 Therefore the development
of simple, general and new protocols for the synthesis of the
(E)-3-benzylidenechroman-4-one skeleton is of considerable
importance today in synthetic organic chemistry.
8a–g
(80–94%)
R = Ph, p-MeC6H4, o-MeC6H4, p-EtC6H4,
p-PriC6H4, p-MeOC6H4, Pr
The classical and most of the literature methods for the
synthesis of (E)-3-benzylidenechroman-4-ones involve the
initial synthesis of the chroman-4-one skeleton, followed by the
Scheme 1 Reagents and conditions: i, PhOH, K2CO3, acetone, reflux, 3 h;
ii, KOH, H2O, acetone, room temp., 14 h; iii, TFAA, CH2Cl2, reflux, 1 h
Table 1 Synthesis of (E)-3-benzylidene- or (E)-3-alkylidene-chroman-4-ones (5?6?7?8)
Allyl bromidea
R
Producta,b
Yieldc (%)
Producta,d
Yielde (%)
Productf,g,h
Yieldi (%)
5a
5b
5c
5d
5e
5f
Ph
6a
6b
6c
6d
6e
6f
73
75
87
90
71
77
65
7a
7b
7c
7d
7e
7f
87
83
93
92
84
90
78
8aj
8b
8c
8d
8e
8f
91
94
90
93
91
92
80
p-MeC6H4
o-MeC6H4
p-EtC6H4
p-PriC6H4
p-MeOC6H4
Pr
5g
6g
7g
8g
a
b
See footnote ∑. All reactions were carried out in 10 mmol scale of bromide with 10 mmol of phenol in the presence of K2CO3 in acetone at reflux
temperature for 3 h. c Yields of pure esters obtained after silica gel column chromatography (3% EtOAc–hexane). d Hydrolysis of these esters was carried
out on a 5 mmol scale with aq. KOH–acetone at room temperature. e Isolated yields of the pure acids after crystallization. f See footnote **. g All the reactions
were carried out on a 1 mmol scale for the acid with TFAA ( 1 mmol) in refluxing CH2Cl2 for 1 h. h All the products gave satisfactory IR, 1H NMR (200
MHz), 13C NMR (50 MHz) and mass spectral data and elemental analyses. i Yields of the pure chromanones obtained after crystallization (8a–f) from EtOAc–
hexane (2:98) or after silica gel column chromatography (8g) (3% EtOAc–hexane). j See footnote §.
Chem. Commun., 1998
1639

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R1
R2
O
O
O
134.43, 135.85, 137.44, 161.17, 182.17; m/z 236 (M+); Calc. for C16H12O2:
C, 81.34; H, 5.12. Found: C, 81.45; H, 5.12%.
OMe
OMe HO
¶ The reaction of methyl (2Z)-2-bromomethylhex-2-enoate 5g with phenol
in the presence of K2CO3 also provided ca. 15% of a side product,
presumably methyl 2-methylene-3-phenoxyhexanoate (SN2A product).
However, the major compound methyl (2E)-2-phenoxymethylhex-2-enoate
6g was obtained in pure form after silica gel column chromatography (3%
EtOAc–hexane).
R1
i
MeO
MeO
Br
5f
R2
9 R1 = H, R2 = OMe (60%)
10 R1 = OMe, R2 = H (52%)
∑ The (Z)-stereochemistry of the molecules 5 and the (E)-stereochemistry of
ii
1
the molecules 6 and 7 were confirmed by H NMR spectral analysis. It is
well documented in the literature that in the 1H NMR spectrum the chemical
shifts of the vinylic b-proton cis to the ketone, ester and acid carbonyl
groups and of the corresponding vinylic trans b-proton are well-
differentiated and vinylic cis b-protons appear downfield in comparison
with trans protons (ref. 20). The (Z)-stereochemistry of the allyl bromides
5 was assigned on the basis of the chemical shift values of the b-vinylic
protons, i.e. d 7.78–7.91 (when R = Ar) and 6.97 (when R = Pr) (refs. 18,
21). The (E)-stereochemistry of the molecules 6, 7 and 9–12 was assigned
on the basis of the chemical shift values of the b-vinylic protons, i.e. d
8.02–8.25 (when R = Ar) and 6.93–7.11 (when R = Pr) (refs. 18, 22).
** It is well established that in the 1H NMR spectra of 3-benzylidene-
chroman-4-ones the vinylic b- proton cis to the carbonyl group appears at d
ca. 7.7 (refs. 4, 23) while the corresponding trans b-proton appears at d ca.
6.7 (ref. 4). In the case of compounds 4, 8a–f and 13 the vinylic b-protons
appear at d 7.81–7.96. Hence (E)-stereochemistry was assigned to the
compounds 4, 8a–f and 13. In the case of butylidenechroman-4-one 8g (R
= Pr) the vinylic b-proton appears at d 7.04. Therefore (E)-stereochemistry
was assigned to 8g.
O
O
O
R1
R2
iii
OH
R1
MeO
MeO
O
13 R1 = H, R2 = OMe (76%)
(Bonducellin methyl ether)
R2
11 R1 = H, R2 = OMe (94%)
12 R1 = OMe, R2 = H (92%)
4 R1 = OMe, R2 = H (81%)
(Antifungal agent)
Scheme 2 Reagents and conditions: i, K2CO3, acetone, reflux, 3 h; ii, KOH,
H2O, acetone, room temp., 14 h; iii, TFAA, CH2Cl2, reflux, 1 h
bromide 5a‡ with phenol followed by hydrolysis, as a substrate
having a benzylidene moiety. Treatment of 7a with TFAA in
CH2Cl2 provided the desired (E)-3-benzylidenechroman-4-one
8a§ in 91% yield. Encouraged by this success we prepared a
representative class of (E)-3-benzylidenechroman-4-ones 8b–f
using (2E)-3-aryl-2-phenoxymethylprop-2-enoic acids 7b–f
obtained from methyl 3-aryl-3-hydroxy-2-methylenepropa-
noates (Scheme 1, Table 1). With a view to the generalization of
this methodology we also synthesized (E)-3-butylidene-
chroman-4-one 8g (R = Pr) (Table 1) starting from methyl
(2Z)-2-bromomethylhex-2-enoate 5g.¶
1 K. K. Purushothaman, K. Kalyani, K. Subramaniam and S. P.
Shanmughanathan, Indian J. Chem., Sect. B, 1982, 21, 383.
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products, ed. W. Herz, H. Grisebach and G. W. Kirby, Springer-Verlag,
New York, 1981, vol. 40, pp. 105–252.
The efficiency of this methodology has been demonstrated
via the synthesis of the methyl ether of bonducellin 13 and
(E)-3-(4-methoxybenzylidene)-6-methoxychroman-4-one 4, an
antifungal agent, according to Scheme 2.
7 S. Malhotra, V. K. Sharma and V. S. Parmar, J. Chem. Res. (S), 1988,
179.
In conclusion, we have developed a new protocol for the
synthesis of (E)-3-benzylidenechroman-4-ones involving the
initial synthesis of the benzylidene moiety, followed by
construction of the chroman-4-one system. Further application
of this methodology for the synthesis of biologically active
molecules is in progress in our laboratory.
We thank DST (New Delhi ) for funding this research project.
We thank UGC (New Delhi) for COSIST and the Special
Assistance Program at the School of Chemistry, University of
Hyderabad, Hyderabad. M. B. thanks UGC (New Delhi) and
S. P. thanks CSIR (New Delhi) for their research fellowships.
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2787.
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Footnotes and References
† E-mail: dbsc@uohyd.ernet.in
‡ The (Z)-allyl bromides 5 were prepared from the corresponding
3-hydroxy-2-methylenealkanoates following the literature method (ref.
18).
OH
O
O
HBr, H2SO4
CH2Cl2
R
OMe
R
OMe
Br
§ Selected data for 8a: mp 110–111 °C (lit. 110–112 °C) (ref. 19);
nmax(KBr)/cm21 1668, 1601; dH(200 MHz, CDCl3) 5.35 (d, 2 H, J 1.6)
6.95–7.60 (m, 8 H), 7.88 (s, 1 H), 8.03 (d, 1 H, J 7.8); dC(50 MHz, CDCl3)
67.63, 117.93, 121.91, 122.06, 127.96, 128.74, 129.46, 129.99, 130.97,
Received in Cambridge, UK, 5th May 1998; revised manuscript received
22nd June 1998; 8/04796K
1640
Chem. Commun., 1998