2-Alkylidene-benzo[1,3]dioxin-4-ones: A new class of compounds

Article abstract of DOI:10.1016/S0040-4039(01)00996-0

A new class of compounds, 2-alkylidene-benzo[1,3]dioxin-4-ones, have been synthesised by cyclisation of the corresponding o-acyloxy benzoyl chlorides with triethylamine. The 2-methylene-benzo[1,3]dioxin-4-one acts as a prodrug for aspirin and is a useful intermediate in the synthesis of new aspirin prodrugs.

Full text of DOI:10.1016/S0040-4039(01)00996-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5231–5233
2-Alkylidene-benzo[1,3]dioxin-4-ones: a new class of compounds
Pierre Babina and Bernard Bennetaub,*
aLaboratoire de Pharmacie Chimique, Universite´ Bordeaux II, Place de la Victoire, 33000 Bordeaux, France
bLCOO UMR 5802 CNRS, Universite´ Bordeaux I, 351 cours de la Libe´ration, 33405 Talence, France
Received 2 April 2001; accepted 11 June 2001
Abstract—A new class of compounds, 2-alkylidene-benzo[1,3]dioxin-4-ones, have been synthesised by cyclisation of the corre-
sponding o-acyloxy benzoyl chlorides with triethylamine. The 2-methylene-benzo[1,3]dioxin-4-one acts as a prodrug for aspirin
and is a useful intermediate in the synthesis of new aspirin prodrugs. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results
In the past, we have described a synthesis of chromenes
by thermal cyclisation of keto-ylids,1 according to the
following pathway.
Instead of the keto-ylid, we isolated the methylene-
benzo[1,3]dioxin-4-one 1 and the phosphonium salt was
fully recovered. Another experiment under the same
In the course of our studies on phyto-oestrogens,2,3 we
are pursuing the synthesis of new isoflavones intermedi-
ates containing a methyl group at C2. On the basis of
our previous work, we attempted to obtain the required
keto-ylid by reaction of acetoxy benzoyl chloride with a
benzyltriphenylphosphonium salt in the presence of
triethylamine to generate in situ the benzylidenetri-
phenylphosphorane:
experimental conditions, but without the phosphonium
salt, led to the same result.
Under these conditions, the expected keto-ylid could
not be obtained.
Surprisingly, this product and the entire class of these
2-alkylidene-benzo[1,3]dioxin-4-ones are unknown in
the literature. In order to evaluate the scope of the
reaction, experiments were conducted with other
acyloxy benzoyl chlorides.
All the reactions were performed in toluene,4 at 110°C
for 15 h, except for product 5. The results are sum-
marised in Table 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00996-0

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P. Babin, B. Bennetau / Tetrahedron Letters 42 (2001) 5231–5233
Table 1. 2-Alkylidene-benzo[1,3]dioxin-4-ones obtained
lene-benzo[1,3]dioxin-4-one 1 acts as a prodrug for
aspirin5 and can be seen as a ‘dehydroaspirin’.
Addition of other protic compounds, such as an alco-
hol and carboxylic acids, to 1 occurs without subse-
quent ring opening. Moderate yields of the
corresponding Markovnikov addition products are
obtained (Table 2).
Product
R1
R2
Yield (%)b
The ortho ester 7 has already been described by Senning
et al. and is obtained by reaction of 2-acetoxybenzoyl
chloride with the corresponding alcohol.6 The ortho
ester 8 was also obtained by Senning et al., by treat-
ment of aspirin with trifluoroacetic anhydride, then
addition of triethylamine.7 However, this method only
allows synthesising the ortho esters corresponding to
the condensation of two molecules of the starting o-ace-
toxy benzoic acid. In contrast, intermediate 1 allows the
preparation of new original aspirin prodrugs by addi-
tion of carboxylic acids to the double bond5 as illus-
trated by 9.
1
2
3
H
CH3
CHꢀCH2
OCH3
m-Tolyl
(CH2)5
H
H
H
H
H
(CH2)5
60
67 (Z/E)
33 (Z/E)
46 (Z/E)
27 (Z/E)
58
4
5a
6
a 100°C/2 h.
b Isolated yields.
Preliminary experiments indicate that 1 is hydrolysed
under mild conditions to yield aspirin.
In summary, we disclose here a new class of com-
pounds: 2-alkylidene-benzo[1,3]dioxin-4-ones. Com-
pound 1 acts as a new aspirin prodrug and is also a key
intermediate for the design of new aspirin prodrugs.
More detailed studies on the addition of protic deriva-
tives to 1 and their pharmacological activities are in
progress in our laboratory.
After 1 h, 1 is converted into aspirin quantitatively. The
formation of aspirin is presumably due to the addition
of water onto the exocyclic double bond, followed by
opening of the heterocyclic ring. Therefore, the 2-methy-
References
1. Babin, P.; Dunogue`s, J.; Petraud, M. Tetrahedron 1981,
37, 1131.
2. Le Houe´rou, C.; Pelissero, C.; Lamothe, V.; Le Menn, F.;
Babin, P.; Bennetau, B. Tetrahedron 2000, 56, 295.
3. Pelissero, C.; Le Houe´rou, C.; Lamothe, V.; Le Menn, F.;
Babin, P.; Bennetau, B. J. Agric. Food Chem. 2000, 48,
305.
Table 2. Addition products
4. Typical procedure: Triethylamine (12 g, 0.12 mol) was
added to a solution of 2-acetoxybenzoyl chloride (19.2 g,
0.1 mmol) in toluene (100 mL). The mixture was heated
for 15 h at 110°C. After cooling, the organic layer was
filtered and evaporated under reduced pressure. The crude
product was purified by distillation to give the product 1.
New derivatives: Compound 1 solid (60%); bp 71–72°C/0.1
1
Entry
1
A–H
Product
Yield (%)a
60
Torr; mp 46°C; IR (KBr) 3071, 1770, 1682, 1615, 1468. H
NMR (250 MHz, CDCl3): 3.98 (s, 2H), 6.95 (dd, 1H,
3J=7.8 Hz, 4J=0.9 Hz), 7.10 (ddd, 1H, 3J=7.8 Hz,
3J=7.8 Hz, 4J=0.9 Hz), 7.55 (ddd, 1H, 3J=7.8 Hz,
7
4
3
4
3J=7.8 Hz, J=1.6 Hz), 7.82 (dd, 1H, J=7.8 Hz, J=1.6
Hz); with C6D6: 3.98 (dd, 2H, 2J=2.3 Hz). 13C NMR (50.3
MHz, CDCl3): 73.1 (CH2), 110.8 (C), 115.3–123.4–129.0–
136.9 (4CH), 154.3–154.8 (2C), 156.2 (CO). Compound 2
was purified by distillation: oil (67%); bp 99–100°C/0.5
Torr; IR (KBr) 1770, 1709, 1613, 1594. 1H NMR (250
MHz, CDCl3): 1.64 and 1.67 (2d, 3H, Z and E, 3J=7.1
Hz), 4.48 (q, 1H, 3J=7.1 Hz), 6.98 and 7.07 (2d, 1H, Z
2
8
9
57
41
3
and E, J=8.4 Hz), 7.17 (m, 1H), 7.60 (m, 1H), 7.90 (dd,
1H, 3J=7.8 Hz, 4J=1.6 Hz). 13C NMR (50.3 MHz,
CDCl3): 8.11 and 8.24 (CH3), 84.9 and 85.0 (CH), 111.5
and 11.7 (C), 115.1 and 115.6 (CH), 123.3 and 123.5 (CH),
3
H3C–COOH
a Isolated yields.

P. Babin, B. Bennetau / Tetrahedron Letters 42 (2001) 5231–5233
5233
3
4
3
129.6 (CH), 137.0 and 137.1 (CH), 149.1 (C), 155.6 and
155.9 (C), 157.4 and 157.5 (CO). Some peaks are split into
two due to the presence of Z/E isomers. Compound 3 was
purified by distillation: oil (33%); bp 103–104°C/0.5 Torr;
IR (KBr): 1774, 1681, 1617, 1606. 1H NMR (250 MHz,
CDCl3): 5.0 (m, 1H), 5.1–5.2 (m, 2H), 6.55 (m, 1H), 7.05
(m, 1H), 7.18 (m, 1H), 7.61 (m, 1H), 7.91 (m, 1H). 13C
NMR (50.3 MHz, CDCl3): 91.9 and 92.2 (CH), 112.2 (C),
115.0 and 115.2 (CH2), 118.7 and 118.8 (CH), 123.9 and
124.1 (CH), 127.7 and 127.8 (CH), 129.7 (CH), 137.4
(CH), 150.1 and 150.2 (C), 156.7 and 156.8 (C), 157.5 and
157.6 (CO). Some peaks are split into two due to the
presence of Z/E isomers. 4 was purified by distillation: oil
(46%); bp 108–109°C/0.5 Torr; IR (KBr): 1771, 1731,
1614, 1591. 1H NMR (250 MHz, CDCl3): 3.51 and 3.53
(2s, 3H), 5.7 and 5.72 (2s, 1H), 6.86–7.08 (m, 2H), 7.46 (m,
1H), 7.77 (dd, 1H, 3J=7.8 Hz, 4J=1.7 Hz). 13C NMR
(50.3 MHz, CDCl3): 60.8 and 60.9 (CH3), 115.8 and 115.9
(C), 119.0 and 119.1 (CH), 123.7 and 124.2 (CH), 128.8
(CH), 130.0 and 130.1 (CH), 136.9 and 137.6 (CH), 142.6
and 142.8 (C), 156.1 (C), 157.4 (CO). Some peaks are split
into two due to the presence of Z/E isomers. Compounds
5a–b were purified by chromatography (SiO2, pentane/
dichloromethane 1:1): solid (27%). Compound 5a: mp
93°C; IR (KBr): 1771, 1681, 1609, 1593. 1H NMR (250
MHz, CDCl3): 2.46 (s, 3H), 5.57 (s, 1H), 7.08–7.38 (m,
3J=7.6 Hz, J=7.8 Hz, J=1.7 Hz), 8.04 (dd, 1H, J=7.8
Hz, 4J=1.6 Hz). 13C NMR (50.3 MHz, CDCl3): 21.2
(CH3), 91.3 (CH), 111.2 (C), 115.8 (CH), 123.8 (CH),
125.2 (CH), 127.4 (CH), 128.5 (CH), 128.9 (CH), 129.8
(CH), 132.3 (C), 135.5 (CH), 138.1–149.4–155.9 (3C),
156.4 (CO). Compound 5b: mp 102°C; IR (KBr): 1758,
1677, 1613, 1593. 1H NMR (250 MHz, CDCl3): 2.41 (s,
3
3H), 5.49 (s, 1H), 7.08 (d, 1H, J=8.0 Hz), 7.14–7.38 (m,
3
3
4H), 7.47 (d, 1H, J=7.9 Hz), 7.67 (ddd, 1H, J=7.6 Hz,
4
3
4
3J=7.8 Hz, J=1.7 Hz), 8.01 (dd, 1H, J=7.8 Hz, J=1.6
Hz). 13C NMR (50.3 MHz, CDCl3): 21.5 (CH3), 91.7
(CH), 112.6–115.9–124.2–125.0–127.3–128.4–128.9–129.9
(8CH), 133.1 (C), 137.3 (CH), 138.3–149.9–156.2 (3C),
156.7 (CO). 6 was purified by distillation: solid (58%); bp
130–131°C/0.5 Torr; mp 30°C; IR (KBr): 1769, 1710, 1612,
1
1591. H NMR (250 MHz, CDCl3): 1.50 (s, 6H), 2.22 (s,
3
4
4H), 7.01 (dd, 1H, J=8.3 Hz, J=0.6 Hz), 7.10 (ddd, 1H,
3J=7.7 Hz, 3J=7.8 Hz, 4J=0.6 Hz), 7.54 (ddd, 1H,
3
4
3
3J=8.3 Hz, J=7.7 Hz, J=1.7 Hz), 7.88 (dd, 1H, J=7.8
Hz, 4J=1.7 Hz). 13C NMR (50.3 MHz, CDCl3): 25.3–
25.6–28.3–28.7–28.8 (5CH2), 102.5–102.3 (2C), 115.6–
123.2–129.8–136.8 (4CH), 141.7–156.7 (2C), 158.8 (CO).
5. Babin, P.; Bennetau B.; Dunogue`s, J. Rhodia Chimie,
1999, FR99/04656; 2000 WOFR0000974.
6. Ankersen, M.; Senning, A. Acta Chem. Scand. 1989, 43,
793.
7. Falborg, L.; Senning, A. Acta Chem. Scand. 1993, 47, 514.
3
4H), 7.44 (s, 1H), 7.55 (d, 1H, J=7.8 Hz), 7.77 (ddd, 1H,
.