Novel 2-pyrone synthesis via Michael addition of mandelic acid enolate to trans-1,2-diaroylethenes

Article abstract of DOI:10.1016/j.tetlet.2004.09.052

4-Aroyl-6-aryl-3-phenyl-2-pyrones are synthesized from a mandelic acid dioxolanone. 4-Aroyl-6-aryl-3-phenyl-2-pyrones are prepared in a three-step procedure involving the Michael addition of a cis-2,5-disubstituted-1,3- dioxolan-4-one, derived from mandelic acid, to trans-1,2-diaroylethenes, cyclisation to a furan under acidic conditions and lactonisation. The 2-pyrones can be also obtained directly from the Michael products under prolonged or strong acidic treatment with little decrease in yield.

Full text of DOI:10.1016/j.tetlet.2004.09.052

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8583–8586
Novel 2-pyrone synthesis via Michael addition of mandelic acid
enolate to trans-1,2-diaroylethenes
*
´ ´
Santiago Barroso, Gonzalo Blay, Isabel Fernandez and Jose R. Pedro
´ ` ´
Departament de Quımica Organica, Facultat de Quımica, Universitat de Valencia, C/Dr. Moliner 50,
46100 Burjassot (Valencia), Spain
`
`
Received 4 June 2004; revised 6 September 2004; accepted 7 September 2004
Available online 30 September 2004
This paper is dedicated to the memory of Dr. Juan Carlos del Amo, member of the RSEQ, deceased in the 11-M terrorist attack in Madrid
Abstract—4-Aroyl-6-aryl-3-phenyl-2-pyrones are prepared in a three-step procedure involving the Michael addition of a cis-2,5-
disubstituted-1,3-dioxolan-4-one, derived from mandelic acid, to trans-1,2-diaroylethenes, cyclisation to a furan under acidic con-
ditions and lactonisation. The 2-pyrones can be also obtained directly from the Michael products under prolonged or strong acidic
treatment with little decrease in yield.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
reagents.11 In many cases these procedures lead to c-
alkylidene butenolides instead of pyrones and when
carried out with nonsymmetric alkynes two 2-pyrone
regioisomers may be obtained. Recently, a K2CO3-cata-
lysed 1,4-addition of malonic esters to allenic ketones
to give b,c-unsaturated enones, which are lactonised to
2-pyrones has been reported.12
2-Pyrones have found a wide variety of applications in
organic synthesis as dienes in Diels–Alder reactions1
and as precursors to other carbo-2 and heterocyclic
systems.3 The 2-pyrone moiety is also present in a large
number of biologically active compounds4 and recently,
low molecular weight 2-pyrones as well as 4-hydroxy-2-
pyrones have been shown to be potent HIV-1 protease
inhibitors.5 4-Alkenyl/alkynyl-2-pyrones are associated
with antimicrobial, human ovarium carcinoma
(A2780) and human chronic myelogenous leukaemia
(K562) inhibitory properties as well.6 Consequently the
synthesis of 2-pyrones with different substitution
patterns presents an interesting challenge that has
deserved considerable efforts.
As part of our recent research13 we have reported the
Michael reaction of the enolate of a mandelic acid dioxo-
lanone with simple a,b-unsaturated ketones to give a-
hydroxy-c-ketoacids, which were transformed into
chiral 1,4-dicarbonyl compounds.13c
In this communication we report the Michael addition
of the enolate of a mandelic acid dioxolanone to trans-
1,2-diaroylethenes and the transformation of the result-
ing compounds into 4-aroyl-2-pyrones. Despite the fact
that an acyl group at this position seems an excellent
precursor for further functionalisation, the number of
procedures for the preparation of 4-acyl-2-pyrones is
very scarce.
Further to the introduction of substituents into the
preformed 2-pyrone ring7 a number of methods for the
construction of this moiety either by traditional ap-
proaches8 or by procedures involving transition metal
catalysed reactions9 have been reported. A number of
these methods involve the lactonisation of 4-alkynoic
acids promoted by palladium10 or by electrophilic
The first step in our synthetic sequence (Scheme 1) is the
Michael addition of the enolate of cis-2,5-disubstituted-
1,3-dioxolan-4-one 1, prepared from mandelic acid and
pivalaldehyde,14 to trans-1,2-diaroylethenes 2, which
can be obtained by Friedel–Crafts acylation of aromatic
compounds with fumaroyl chloride.15
Keywords: Dioxolanone; Lactones; Enones; Hydroxyacids.
*
Corresponding author. Tel.: +34 963544329; fax: +34 963544328;
e-mail: jose.r.pedro@uv.es
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.052

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S. Barroso et al. / Tetrahedron Letters 45 (2004) 8583–8586
corresponding products 3 with good yields and diastereo-
O
O
H
LDA
H
O
selectivities (Table 1). It is worth remarking that the dia-
stereoselectivity of the reaction increases with the
presence of electron-releasing groups on the aromatic
ring of the diaroylethene.
Ar
+
Ar
O
tBu
Ph
O
2
1
O
O
O
Ar
O
O
O
tBu
By acid treatment of compounds 3, a lactonisation reac-
tion by nucleophilic attack of the side chain ketone
group enol to the dioxolanone carbonyl group (1,5-
dicarbonyl system) and dehydration would lead to 4-aro-
yl-2-pyrones 5. However the possibility of a cyclisation
process through the 1,4-dicarbonyl system to give a
furan 4 could not be excluded. In fact either compound
4 or 5 can be obtained by acid treatment of compound 3
depending on the reaction conditions. So when
compound 3a was heated in boiling benzene or toluene
with a Dean–Stark apparatus a product identified as
furan 4a was obtained in 71% yield. Under prolonged
treatment a new product appeared in the reaction
mixture, which was identified as the 2-pyrone 5a. This
product was most probably formed from furan 4a
through an equilibrating open ring enol form (Scheme
2). Addition of water (1–10equiv) did not prevent the
formation of the furan although it seemed to speed up
the formation of the 2-pyrone product. Treatment of
Michael adduct 3a with TsOH–H2O in xylene–H2O at
reflux gave directly the 2-pyrone 5a in a one-pot
procedure (45% yield), still through the intermediate
furan 4a, which was observed by TLC of the reaction
mixture. On the other hand, treatment of isolated furan
4a under similar conditions also gave the 2-pyrone 5a
with a 72% yield. The overall yield of 2-pyrone obtained
in this way, through the isolated furan, was 51% from
3a, somehow higher than the yield obtained in the
one-pot procedure (45%).
Ph
TsOH
H
O
Ar
O
tBu
Ph
Toluene
Ar
Ar
O
3
4
Ar
O
TsOH
xylene-H2O
Ph
Ar
O
O
5
Scheme 1.
1,2-Di-(40-toluoyl)ethene 2a was used as test substrate
for the Michael addition. The addition of 2a to a pre-
formed solution of the lithium enolate of dioxolanone
1 at ꢀ78ꢁC gave a mixture of two Michael products
3a, with 90% yield, in a 74:26 diastereomeric ratio.
NOEs experiments carried out with the major product
showed interaction between the signal at d 0.93 (s), cor-
responding to the t-Bu group, and the signal at d 7.78
(dd, J = 8.2, 1.5Hz) corresponding to the 2-H of the
phenyl group. Also, irradiation at the signal of the C–
H of the dioxolanone ring (d 5.53) gave NOE with the
signal of a 4-toluoyl proton at d 8.01 (d, J = 8.1Hz).
Similarly for the minor product, NOEs between the sig-
nals at 0.73 and at d 7.70 (dd, J = 8.1, 1.5Hz), as well as
between the signals at d 5.15 (s) and at d 8.02 (d,
J = 8.2Hz) were observed. These results indicate that
in both cases the t-Bu and phenyl groups are in cis dis-
position. The two diastereomers differ in the configura-
tion of the newly created stereogenic centre of the side
chain16 and result from the approach of the enedione
from the less hindered face of the enolate, opposite to
the t-Bu group, as expected according to the principle
of self-regeneration of stereocentres by Seebach et al.17
The presence of HMPA and the inversion in the order
of addition of the reagents, which were crucial for the
yield and diastereoselectivity in the addition of the eno-
late of 1 to simple enones,13c resulted in this case in a
lower yield.
Thus the final procedure that we have carried out
involved three steps, namely Michael addition of the
enolate of 1 to the diaroylethene 2, cyclisation to
the furan ring 4 and lactonisation to the 2-pyrone 5.
The results of these reactions for different compounds
are shown in Table 1.
In summary, we present a new method for the synthesis
of substituted 2-pyrones. The presence of an aroyl group
at position 4 of the pyrone ring thus formed should
allow further functional modification at this position.
This procedure is short and simple and the starting
materials are readily available. The extension of this
methodology to other Michael acceptors and/or
hydroxyacids for the preparation of 2-pyrones with
different substitution patterns is under study.
Under the optimised conditions, a number of diaroyl-
ethenes 2 reacted with the enolate of 1 to give the
Table 1. Synthesis of compounds 3, 4 and 5
Entry
Ar
Yield 3 (%)
3 dr
Yield 4 (%)
Yielda 5 (%)
1
2
3
4
5
6
a
b
c
d
e
f
4-Toluoyl
Phenyl
90
97
95
80
91
63
83:17
74:26
84:16
90:10
71:29
67:33
71
88
73
67
64
72
72 (45)
64 (48)
73 (46)
64 (37)
60 (30)
58 (36)
3,4-Dimethylphenyl
4-Methoxyphenyl
4-Fluorophenyl
4-Chlorophenyl
a Yields in brackets refer to compound 5 obtained directly from 3 in one step (xylene–H2O).

S. Barroso et al. / Tetrahedron Letters 45 (2004) 8583–8586
8585
(d), 128.9 (d), 129.0 (d), 129.3 (d), 133.3 (s), 133.9 (s),
137.4 (s), 144.1 (s), 144.3 (s), 172.7 (s), 195.6 (s), 200.1
(s).
O
O
O
O
O
OH
Ar
H+
tBu
tBu
Ph
O
Ph
Ar
H2O
2.2. Cyclisation to furan 4a
Ar
Ar
O
O
O
4
A solution containing compound 3a (diastereomer mix-
ture) (249mg, 0.51mmol) and TsOHÆH2O (24mg,
0.13mmol) in benzene (30mL) was heated at reflux in
a Dean–Stark system for 24h. After this time, the sol-
vent was removed under reduced pressure and the resi-
due chromatographed using hexane–diethyl ether to
tBu CHO
Ar
-
Ar
O
Ph
OH
O
Ph
O
give 169mg (71%) of furan 4a: mp 62–65ꢁC (hexane–
-H2O
Ar
O
Ar
O
25
EtOAc); ½aꢁ þ 107 (c 1.8, CHCl3); MS (EI) 466 (M+,
D
5
32), 336 (14), 57 (100); HRMS 466.2104, C31H30O4 re-
quired 466.2144; 1H NMR (CDCl3): d 0.88 (9H, s),
2.28 (3H, s), 2.34 (3H, s), 5.01 (1H, s), 6.85 (1H, s),
7.05 (2H, d, J = 7.8Hz), 7.18 (2H, d, J = 7.8Hz), 7.30–
7.40 (3H, m), 7.47 (2H, d, J = 8.4Hz), 7.54 (2H, dd,
J = 8.1, 1.5Hz), 7.60 (2H, d, J = 8.4Hz); 13C NMR
(CDCl3): d 21.2 (q), 21.3 (q), 23.5 (q), 33.9 (s), 82.1
(s), 107.3 (d), 107.6 (d), 116.3 (s), 123.8 (d), 127.1 (d),
127.3 (s), 128.4 (d), 128.5 (d), 128.9 (d), 129.5 (d),
137.7 (s), 137.8 (s), 137.9 (s), 152.0 (s), 152.8 (s), 172.6
(s).
Scheme 2.
2. Typical experimental procedure
2.1. Michael addition of cis-2,5-disubstituted-1,3-dioxo-
lan-4-one 1 to trans-1,2-di-(40-toluoyl)ethene 2a
A solution of dioxolanone (S,S)-1 (220mg, 1mmol) in
1.5mL of dry THF was added to a ꢀ78ꢁC pre-cooled
solution prepared from 0.625mL of a 2M commercial
solution of LDA in heptane–THF–ethylbenzene
(1.25mmol) and 2mL of THF. After 30min, a solution
of 2a (303mg, 1.15mmol) in 1.5mL of THF was added
dropwise and 10min after, the reaction was quenched
with the addition of saturated aqueous NH4Cl (3mL).
The reaction mixture was diluted with EtOAc
(100mL) and washed with saturated aqueous NH4Cl
(2 · 10mL) and brine (2 · 10mL) and dried. Column
chromatography with hexane–EtOAc gave 362mg
(75%) and 74mg (15%) of two diastereomeric products
2.3. Lactonisation to 2-pyrone 5a
A solution containing furan 4a (57mg, 0.12mmol),
TsOHÆH2O (13mg, 0.07mmol) and water (40lL,
2.2mmol)18 in xylene (7mL) was heated at reflux
(140ꢁC) for 40h. After this time, the solvents were
removed under reduced pressure and the residue chro-
matographed using hexane–diethyl ether to give 34mg
(72%) of compound 5a: mp 202–204ꢁC (hexane–
EtOAc); MS (EI) 380 (60), 352 (100), 261 (15), 119
(65); HRMS 380.1406, C26H20O3 required 380.1412;
1H NMR (CDCl3): d 2.33 (3H, s), 2.41 (3H, s), 6.69
(1H, s), 7.13 (2H, d, J = 8.1Hz), 7.15–7.25 (3H, m),
7.27 (2H, d, J = 8.1Hz), 7.34 (2H, dd, J = 8.1, 1.8Hz),
7.66 (2H, d, J = 8.1Hz), 7.77 (2H, d, J = 8.1Hz); 13C
NMR (CDCl3): d 21.5 (q), 21.8 (q), 100.4 (d), 122.6
(s), 125.6 (d), 128.0 (s), 128.1 (d), 128.7 (d), 129.4 (d),
129.7 (d), 129.8 (d), 129.9 (d), 131.9 (s), 132.6 (s),
141.8 (s), 145.5 (s), 150.8 (s), 160.1 (s), 161.9 (s), 194.5
(s).
3a. Major diastereomer: mp 70–72ꢁC (hexane–EtOAc);
25
½aꢁ þ 95 (c 0.4, CHCl3); MS (EI) 484 (M+, 1), 466
D
(5), 219 (16), 144 (14), 119 (100); HRMS 484.2246,
C31H32O5 required 484.2250; 1H NMR (CDCl3): d
0.93 (9H, s), 2.37 (3H, s), 2.42 (3H, s), 3.19 (1H, dd,
J = 18.0, 4.0Hz), 3.71 (1H, dd, J = 18.0, 8.0Hz), 4.82
(1H, dd, J = 8.0, 4.0Hz), 5.53 (1H, s), 7.18 (2H, d,
J = 8.1Hz), 7.20–7.50 (5H, m), 7.67 (2H, d, J =
8.1Hz), 7.78 (2H, dd, J = 8.2, 1.5Hz), 8.01 (1H, d,
J = 8.1Hz); 13C NMR (CDCl3): d 21.6 (q), 21.7 (q),
23.6 (q), 35.1 (s), 37.0 (t), 50.2 (d), 81.7 (s), 110.2 (d),
125.4 (d), 128.1 (d), 128.2 (d), 128.3 (d), 128.9 (d),
129.0 (d), 129.3 (d), 133.5 (s), 134.3 (s), 137.2 (s), 144.1
Acknowledgements
This work was financially supported by the Spanish
Government (MCYT, project BQU2001-3017) and by
Generalitat Valenciana (AVCYT, Grupos 03/168).
(s), 144.3 (s), 172.2 (s), 196.3 (s), 199.9 (s). Minor dia-
25
stereomer: mp 85–87ꢁC (hexane–EtOAc); ½aꢁ ꢀ 84 (c
D
0.3, CHCl3); MS (EI) 484 (M+, 1), 466 (6), 381 (10),
144 (11), 119 (100); HRMS 484.2253 C31H32O5 required
484.2250; 1H NMR (CDCl3): d 0.73 (9H, s), 2.38 (3H, s),
2.42 (3H, s), 3.56 (1H, dd, J = 18.4, 7.2Hz), 3.67 (1H,
dd, J = 18.4, 4.9Hz), 4.94 (1H, dd, J = 7.2, 4.9Hz),
5.15 (1H, s), 7.17 (2H, d, J = 8.2Hz), 7.20–7.40 (5H,
m), 7.66 (2H, d, J = 8.2Hz), 7.70 (2H, dd, J = 8.1,
1.5Hz), 8.02 (1H, d, J = 8.2Hz); 13C NMR (CDCl3): d
21.5 (q), 21.6 (q), 23.3 (q), 35.0 (s), 37.3 (t), 51.2 (d),
81.6 (s), 110.3 (d), 125.8 (d), 128.1 (d), 128.3 (d), 128.4
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16. The configuration of this stereogenic centre was not
determined because it was found that both diastereomers
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