Hammet constants effects in microwave cascade etherification-cyclization- krapcho reaction to access [2,3]-dihydrobenzofuran-3-ones from salicylic derivatives

Article abstract of DOI:10.1080/00397911.2010.533806

Two methods were evaluated for the synthesis of substituted [2,3]-dihydro-2-methyl-benzofuran-3-ones from corresponding salicylate esters under microwave irradiation. A two-step sequence via ether intermediates was convenient for various substituted salic

Full text of DOI:10.1080/00397911.2010.533806

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Hammet Constants Effects in Microwave
Cascade Etherification-Cyclization-
Krapcho Reaction to Access [2,3]-
Dihydrobenzofuran-3-ones from Salicylic
Derivatives
Daniel Farran a & Philippe Bertrand a
a Laboratoire Synthèse et Réactivité des Substances Naturelles,
Université de Poitiers, Poitiers, France
Accepted author version posted online: 06 Sep 2011.Version of
record first published: 16 Dec 2011.
To cite this article: Daniel Farran & Philippe Bertrand (2012): Hammet Constants Effects in Microwave
Cascade Etherification-Cyclization-Krapcho Reaction to Access [2,3]-Dihydrobenzofuran-3-ones from
Salicylic Derivatives, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 42:7, 989-1001
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Synthetic Communications1, 42: 989–1001, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.533806
HAMMET CONSTANTS EFFECTS IN MICROWAVE
CASCADE ETHERIFICATION-CYCLIZATION-KRAPCHO
REACTION TO ACCESS [2,3]-DIHYDROBENZOFURAN-
3-ONES FROM SALICYLIC DERIVATIVES
Daniel Farran and Philippe Bertrand
`
Laboratoire Synthese et Reactivite des Substances Naturelles, Universite de
Poitiers, Poitiers, France
´
´
´
GRAPHICAL ABSTRACT
Abstract Two methods were evaluated for the synthesis of substituted [2,3]-dihydro-
2-methyl-benzofuran-3-ones from corresponding salicylate esters under microwave
irradiation. A two-step sequence via ether intermediates was convenient for various substi-
tuted salicylate derivatives, while the second strategy involving a one-pot procedure was
efficient for electron-donating substituted salicylates. Results allowed correlation of the
Hammett constants effects in the intramolecular cyclization of O-ethoxycarbonyl ether
of salicylic esters.
Keywords Benzofuranone; Hammet constants; Krapcho reaction; microwave; salicylate
INTRODUCTION
Benzofuranes, dihydrobenzofuranes, and their corresponding 2,3-dihydro-3-
one derivatives are structures found in a variety of molecules possessing biological
activity such as the receptor a-2 antagonist efaroxan 1[1] or the PPARa agonist 2
(Fig. 1).[2] These heterocycles are also part of natural products such as the insecti-
cides rocaglamide 3[3] and vasinfectins 4.[4] An alternative and shorter synthesis of
diversely substituted 2-methyl-2,3-dyhydro-benzofuran-3 is a major point of interest.
Benzofuranones 6 were prepared in several steps from triflate[5] or by Friedel–
Crafts methodology with AlCl3 or polyphosphoric acid (PPA).[6] However, a more
Received October 15, 2010.
Address correspondence to Philippe Bertrand, Laboratoire Synthese et Reactivite des Substances
`
Naturelles, Universite de Poitiers, CNRS UMR 6514, 40 Avenue du Recteur Pineau, Poitiers 86022,
´
´
´
France. E-mail: philippe.bertrand@univ-poitiers.fr
989

990
D. FARRAN AND P. BERTRAND
Figure 1. Natural and synthetic benzofurane derivatives.
Scheme 1. Conventional preparation of benzofuranones 6 from salicylate derivatives 7a. (i) Esterification;
(ii) etherification; (iii) cyclization; and (iv) decarboxylation.
classical synthesis (Scheme 1) involves etherification of salicylic derivatives 8 with
esters under alkaline conditions to yield ethers 10. Subsequent ether side-chain
deprotonation using MeONa=MeOH or NaH=tetrahydrofuran (THF) led to the
intramolecular attack of the carbonyl ester group to afford 11.[7] Finally, the desired
benzofuranone 6 was generated after decarboxylation on heating or via acidic
hydrolysis.[8] In the case of aryl substituted benzofuranones, this strategy is parti-
cularly convenient as several salicylic acids 7 as well as esters 8 are commercially
available. In addition, various 2-alkyl substituents can be easily introduced using
appropriate a-halogenated esters 9. This three-step synthesis was improved
during our work on histone deacetylases (HDAC) inhibitor 5, where a cascade
etherification=cyclization=decarboxylation was developed.[9] We here report our
attempts to generalize this reaction.
RESULTS AND DISCUSSION
The thermal method used for the synthesis of 2-methyl-benzofuranones 6a and
6b[9] was extended to other substrates with results reported in Table 1. This method
apparently suffered from some disadvantages, as the bromo- and nitro- derivatives

MICROWAVE SYNTHESIS OF BENZOFURANONES
991
Table 1. Thermal preparation of [2,3]-dihydrobenzofuran-3-ones 6 from salicylate esters 8a,ba
Entry
8
R
6
Yieldc (%)
1
2
3
4
5
6
8a
8b
8g
8h
8i
Hb
4-NMe2
6a
6b
6g
6h
6i
42
86
b
[4,5]-benzo
[3,4]-benzo
4-NO2
44d
30d
Decomposition
8d
8l
5-Br
6l
aReagents and conditions (see sequence in Scheme 1): (ii) K2CO3 (1 equiv.), 9 (1 equiv.), DMF, rt,
overnight; (iii) DMF, reflux, 4 h; (iv) HCl 6 N.
bSee reference 5 for more details.
cYield of isolated product after flash chromatography.
dYield after acidic hydrolysis.
gave poor yields (Table 1, entries 5 and 6). Moreover, different thermal behaviors
were noticed during the cascade etherification=cyclization=decarboxylation, depend-
ing on the salicylate ring substitution. For compounds 8a, 8 g, 8 h, and 8l, a mixture
of benzofuranones 6 and nondecarboxylated intermediates 11 was obtained. (Table 1,
entries 1 and 3–5). In the case of 8b, the reaction was complete (Table 1, entry 2). The
process leading to this final decarboxylation is related to the Krapcho reaction.[10]
Parameters have been reported for a powerful Krapcho decarboxylation: (i) methyl
esters are easy to decarboxylate, (ii) dimethylsulfoxide (DMSO) must be chosen in
preference to dimethylformamide (DMF), and (iii) LiCl, NaCN, or NaCl, are more
efficient salts than KBr.[11] In this respect, the results obtained in our preliminary
experiments were discordant as DMF was the solvent and formation of potassium
bromide occurred during the etherification. The salicylate substituent emerged as
an important issue to explore. An improved procedure is herein presented, leading
to compounds 6.
Studies were directed toward initial cyclization under microwave irradiation.[12]
Bogdal et al. described the synthesis of phenol ethers such as 10 by microwave-
assisted phase-transfer catalysis using tetrabutyl ammonium bromide.[13] Unfortu-
nately, in our case, these conditions afforded a mixture from which no valuable com-
pounds were detected, and ethers 10 were finally prepared under classical conditions
(K2CO3, DMF, 9). The conversion of ethers 10 into benzofuranones 6 was evaluated
on derivative 10c with a range of bases, additives, and solvents (Table 2). DMF
appeared to be the most appropriate solvent, with DMSO furnishing complex mix-
tures (Table 2, entries 1 and 2). After 40 min at 300 W and 170 ꢀC, the cyclization of
ether 10c was completed, giving a mixture of 6c, 11c, and an undetermined aromatic
compound in a 1:0.27:0.56 ratio (Table 2, entry 3). The temperature of 170 ꢀC was
programmed for DMF (boiling point 154 ꢀC) to artificially maintain the 300 W
irradiation as long as possible during the experiments and to have the maximum
possible cyclization to 6 or 11. This was also the case for the other solvents used
in this work, but depending on the solvent nature, the irradiation was not always
at its maximum during the reactions. In the case of acetonitrile, for instance, which
has a lower boiling point, the maximum irradiation was never reached (at least a
maximum of 200–250 W was observed). However, for all solvents, we maintained
300 W. We postulated that the formation of compound 11c released a methanolate

992
D. FARRAN AND P. BERTRAND
Table 2. 170 ꢀC and 300 W microwave irradiation on 1 mmol of 10c
Entry
Time (min)
Solvent(s) (mL)
Additive(s) (equiv.)
10c/11c/6cc
1
2
3
4
10
10
40
20
DMF (1)
DMSO (1)
DMF (1)
DMF (1)
K2CO3 (1.5)
K2CO3 (1.5)
1:0.24:0.04
d
—
0:0.27:1.0
0:0.45:1.0
K2CO3 (1.5)
K2CO3 (1.0)
KBr (1.0)
K2CO3 (0.25)
5
6
20
40
20
40
20
15
10
10
10
DMF (1)
DMF (1)
DMF (1)
0:0.52:1.0
0:0.57:1.0
1.0:0.13:0
0:0.47:1.0
0:0.33:1.0
0:0.11:1.0
0:0.05:1.0
0:0.05:1.0
1:0:0.03
KBr (1.0)
K2CO3 (0.25)
KBr (1.0)
K2CO3 (0.25)
7a
8
KBr (1.0)
K2CO3 (0.5), KBr (1.0)
KHCO3(1.0)
DMF (1)
MeOH (0.1)
DMF (1)
9
K2CO3 (0.5), KBr (1.0)
KHCO3 (1.0)
MeOH (0.1)
DMF (1)
10
11
12
13
K2CO3 (0.5), KBr (1.0)
KHCO3 (1.0)
MeOH (0.1)
DMF (1)
K2CO3 (0.5), KBr (1.0)
KHCO3 (1.0)
MeOH (0.5)
DMF (1)
K2CO3 (0.5), KBr (1.0)
KHCO3 (1.0)
MeOH (1)
DMF (1)
K2CO3 (0.5), KBr (1.0)
KHCO3 (1.0)
K2CO3 (0.5)
14b
15
10
10
MeOH (1)
DMF (1)
MeOH (0.5)
1:0:0
0:0.05:1.0
K2CO3 (0.5)
aExperiment performed at 140 ꢀC.
bExperiment performed at 70 ꢀC (higher temperature was not accessible with our apparatus because of
high-pressure limitation).
cRatio evaluated on 1H NMR spectrum of the crude material.
dDecomposition was observed.
anion able to promote the reaction and the amount of K2CO3 was reduced. In the
same time, KBr was added for its potential role in the decarboxylation. At 170 ꢀC,
although cyclization of 10c was complete, decarboxylation was not totally achieved
(Table 2, entries 4–6). At lower temperature (140 ꢀC), small amounts of 11c were
formed and compound 6c was not detected (Table 2, entry 7). Taking into consider-
ation the mechanism of the full sequence, etherification produces KHCO3 and KBr
while decarboxylation leads to the formation of methanolate. This prompted us to
explore the use of a K2CO3=KBr=KHCO3=MeOH mixture (Table 2, entries 8–10).
Surprisingly, under these conditions, decreasing the reaction time remarkably
improved the formation of 6c vs. 11c. The next series of attempts suggested that
the presence of both DMF and methanol was critical, ideally in a 1:0.5 ratio
(Table 2, entries 11–14). Entry 13 showed also that additive salts finally were not
required, and we were pleased to establish efficient conditions for the conversion
of ether 10c into benzofuranone 6c (Table 2, entry 15).
Several ethers 10 were then submitted to this protocol. The simplest ether 10a
gave 6a as the single product in greater yield than reported[9] (Table 3, entry 1).

MICROWAVE SYNTHESIS OF BENZOFURANONES
993
Table 3. Conversion of ethers 10 into benzofuranones 6 using microwave irradiation
Entry
10
R
Product(s)
Yielda (%)
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10h
10i
H
6a
6b
71
85
4-NMe2
4-OMe
5-OMe
[3,4]-benzo
4-NO2
4-Cl
6c
6d
79
46
6h
—
0
Decomposition
7=22
10k
10l
6k/12k
6l
5-Br
44
aYield of isolated product after flash chromatography.
Compounds 10 bearing electron-donating groups on the aromatic moiety were easily
converted into corresponding benzofuranones (Table 3, entries 2–4). Compound 10h
gave no reaction and was recovered (Table 3, entry 5). Introduction of an electron-
withdrawing group on the aromatic ring was detrimental for the reaction, with
decomposition being observed for the nitro derivative 10i (Table 3, entry 6). The bro-
mide derivative 10l gave the benzofuranone 6l in moderate yield (Table 3, entry 8).
Unexpectedly, in the case of 10k, the major product resulted from a SNAr reaction
between two molecules of 6k to give 12k (Table 3, entry 7). This undesired reaction
suggested that the presence of an electron withdrawing group in compound 6
reinforced the acidity of the a hydrogen of the carbonyl group. In the case of nitro
derivative 10i, it could lead to polymerization and explain the difficulty of isolating
the corresponding benzofuranone.
We then examined the preparation of benzofuranones 6 from derivatives 8
under microwave irradiation using compound 8b as the model (Table 4, entry 1),
Table 4. 300 W microwave irradiation on 2 mmol of 8ba
Product ratiob (%)
Entry
9 (equiv.)
Temperature (ꢀC)
Time (min)
8b
10b
11b
6b
1
2
3
4
1
155
145
160
170
30
30
90
90
16
—
8
—
50
—
—
4
—
—
—
45
5
1
1.1
1.25
74
83
—
aReagents: DMF (1 mL), K2CO3 (1.5 equiv.).
bRatio evaluated on 1H NMR spectrum of the crude material.

994
D. FARRAN AND P. BERTRAND
Table 5. Influence of the cation of carbonate salts and solvent on decarboxylation
of 8aa
Entry
Cation
Solvent
11a:6ab
1
2
3
4
5
Liþ
Naþ
Csþ
Kþ
DMF
DMF
DMF
DMF
DMSO
9:1
1:1
1.06:1
0.18:1
2.67:1
Kþ
aReagents and conditions: 8a (2 mmol), methyl 2-bromopropionate 9 (2.5 mmol),
carbonate salt (3 mmol), solvent (1 mL), 170 ꢀC, 300 W, 90 min.
bRatio evaluated on 1H NMR spectrum of the crude material.
at 300 W and 170 ꢀC in DMF. The initial etherification of phenol 8b appeared as a
limiting step and a compromise was found between reaction time and complete
etherification. An excess of bromide 9 (1.25 equivalents) finally gave compound 6b
as the sole product (Table 4, entries 3 and 4). Lower temperatures furnished mainly
the ether 10b (Table 4, entry 2). According to Krapcho,[11] several carbonate salts
=
were examined to improve the decarboxylation of 8a (R H, Table 5). Only Na2CO3
or Cs2CO3 gave interesting results, although K2CO3 remained the most efficient salt
in our cases. DMSO was the best solvent for the Krapcho reaction but gave no
improvement in our case (Table 5, entry 5). The best conditions for direct formation
of benzofuranones 6 from 8 remained K2CO3, DMF, 300 W, and 170 ꢀC and were
applied to other salicylate methyl esters 8 (Table 6).
Compounds bearing electron-donating groups were easily converted into cor-
responding benzofuranones 6 in moderate to good yields (Table 6, entries 1–7). Some
Table 6. Microwave assisted direct preparation of [2,3]-dihydro-benzofuran-3-ones 6 from 8
Products yielda (%)
Entry
8
R
8
10
11
6
1
2
8a
8b
8c
8e
8f
H
—
—
—
—
—
—
—
—
—
—
—
—
—
—
11
—
—
17
—
—
—
60
83
80
71
52
50
30
4-NMe2
4-OMe
4-Me
3
4
5
5-Me
6
8g
8h
8i
[4,5]-benzo
[3,4]-benzo
4-NO2
5-NO2
4-Cl
7
8
Decomposition
Decomposition
9
8j
10
11
8k
8l
—
—
—
—
—
—
10
10
5-Br
aYield of isolated product after flash chromatography.

MICROWAVE SYNTHESIS OF BENZOFURANONES
995
Table 7. 300 W microwave irradiation on halogenated and nitro salicylatesa
Products yieldc (%)
Entry
8, R
Time (min.)
Temp. (ꢀC)
Solvent
8
10
11
6
12
1
2
3
4
5
6
7
8k, 4-Cl
8l, 5-Br
8k,4-Cl
8l,5-Br
60
60
170
170
100
130
100
60
DIPEA
DIPEA
NMM
NMM
CH3CN
DMF
Mixtured
Mixtured
60
60
—
—
—
—
—
19
39
—
3
15
4
30
—
—
—
—
8l,5-Br
8i,4-NO2
8i,4-NO2
60
5
5 þ 30b
100
100
—
—
—
—
—
—
2
155
DMF
aReagents: K2CO3 (1.5 equiv.), 9 (1.25 equiv.).
b5 min at 60 ꢀC followed by 30 min at 155 ꢀC.
cYield of isolated product after flash chromatography.
dWe were not able to analyze this complex mixture.
amounts of nondecarboxylated intermediate 11 were generated with less donating
groups (Table 6, entries 1 and 4). However, this microwave-assisted one-pot pro-
cedure gave better yields than the respective thermal experiments and ratios 11 vs.
6 were highly in favor of decarboxylated derivatives. No traces of benzofuranones
were detected in mixtures obtained from nitro derivatives 8i and 8j (Table 6, entries
8 and 9). For halogenated compounds, benzofuranones 6k and 6l were isolated
in poor yields (Table 6, entries 10 and 11), and it is noteworthy that the two-step
strategy was more efficient in these cases.
To optimize microwave reactions in the nitro and halogenated series, other sol-
vents were investigated (Table 7). Attempts with diisopropylethylamine (DIPEA) at
170 ꢀC failed, leading to complex mixtures (Table 6, entries 1 and 2). Despite our
efforts, N-methylmorpholine (NMM) did not furnish a significant improvement
Figure 2. Yield of 6 ¼ f (Hammett constant). (Figure is provided in color online.)

996
D. FARRAN AND P. BERTRAND
(Table 7, entry 4). Nevertheless, some interesting results were noticed at lower
temperatures. At 100 ꢀC, 8k underwent an intermolecular reaction to yield the dimer
12k already seen in the two-step approach (Table 7, entry 3). The same temperature
in acetonitrile allowed a quantitative conversion of 8l into ether 10l, which affords an
alternative to Bogdal’s procedure (Table 7, entry 5).[13] A complete etherification,
carried out in DMF with mild heating, was also observed for nitro derivative 8i
(Table 7, entry 6). This crude material was then subjected to extra microwave
irradiation at a higher temperature and decomposition occurred (Table 7, entry 7).
These results confirmed that temperature around 150–170 ꢀC was necessary for an
efficient cyclization into benzofuranone but nitro and halogenated compounds were
not stable in these conditions. The yield variability in benzofuranone 6 prompted us
to correlate our results by the Hammett constants.[14] The methyl ester group on the
aromatic moiety was chosen as reference, and meta and para effects were considered.
A graphical representation of these data clearly indicated that a relation between
isolated yields for the direct preparation of 6 from 8 and Hammett constants can
be proposed (Fig. 2).
CONCLUSION
In conclusion, a new microwave-assisted route for the preparation of
[2,3]-dihydrobenzofuran-3-ones 6 is reported. A two-step methodology involving a
preliminary etherification of salicylate esters allowed the access to benzofuranones.
This approach is particularly attractive for halogenated derivatives as it opens the
way to various substituents using organometallic chemistry. A direct and easy con-
version of salicylate esters into benzofuranones 6 was also developed. This one-pot
protocol was suitable for compounds bearing electron-donating groups. An alterna-
tive microwave-assisted method is proposed to prepare ethers 10. The reactivity of
salicylate derivatives has been correlated by the Hammett constants, and this study
may be used as a predictive tool. Further studies are currently devoted to the use of
these benzofuranones as valuable scaffolds for the synthesis of biologically relevant
compounds.
EXPERIMENTAL
Salicylate Ethers 10
K2CO3 (0.152 g, 1.1 mmol) and methyl 2-bromopropionate 9 (0.14 mL,
1.25 mmol) were added to a solution of salicylate ester 8 (1 mmol) in dry DMF
(1 mL). After 12 h, the mixture was diluted with AcOEt (5 mL), washed with 1 N
HCl (5 mL), and dried (MgSO4). The crude residue was then concentrated and
purified by column chromatography (petroleum ether=EtOAc; 85=15), providing 10.
4-Methoxy-2-(1-methoxycarbonyl-ethoxy)-benzoic acid methyl ester
10c. Prepared from 8c (5.12 g, 28 mmol) and isolated as oil (7.66 g, 94%). 1H
NMR (400 MHz, CDCl3): d 1.67 (d, 3H, J ¼ 6.8 Hz), 3.78 (s, 3H), 3.80 (s, 3H),
3.86 (s, 3H), 4.77 (q, 1H, J ¼ 6.8 Hz), 6.40 (s, 1H), 6.56 (d, 1H, J ¼ 8.4 Hz), 7.86
(d, 1H, J ¼ 8.4 Hz); 13C NMR (100 MHz, CDCl3): d 18.5, 51.7, 52.4, 55.5, 74.6,

MICROWAVE SYNTHESIS OF BENZOFURANONES
997
102.3, 106.5, 113.7, 133.95, 159.3, 163.9, 165.9, 172.3; HR-EIMS MNaþ, found:
291.0846. C13H16O6Na requires 291.08446.
5-Methoxy-2-(1-methoxycarbonyl-ethoxy)-benzoic acid methyl ester
1
10d. Prepared from 8d (1.25 g, 6.87 mmol) and isolated as oil (1.65 g, 90%). H
NMR (400 MHz, CDCl3): d 1.69 (d, 3H, J ¼ 6.8 Hz), 3.71 (s, 3H), 3.75 (s, 3H),
3.86 (s, 3H), 4.64 (q, 1H, J ¼ 6.8 Hz), 6.88 (d, 1H, J ¼ 9.0 Hz), 6.94 (dd, 1H,
J ¼ 3.1, 9.0 Hz), 7.30 (d, 1H, J ¼ 3.1 Hz); 13C NMR (100 MHz, CDCl3): d 18.6,
52.2, 52.3, 55.8, 76.3, 115.8, 119.3, 119.5, 122.9, 151.4, 154.5, 166.3, 172.7; HR-EIMS
MNaþ, found: 291.0844. C13H16O6Na requires 291.08446.
1-(1-Methoxycarbonyl-ethoxy)-naphthalene-2-carboxylic acid methyl
ester 10h. Prepared from 8h (2.02 g, 10 mmol) as light brown solid (2.2 g, 75%).
1H NMR (400 MHz, CDCl3): d 1.61 (d, 3H, J ¼ 6.9 Hz), 3.71 (s, 3H), 3.93 (s, 3H),
4.85 (q, 1H, J ¼ 6.8 Hz), 7.50–7.59 (m, 2H), 7.61 (d, 1H, J ¼ 8.7 Hz), 7.81 (dd, 1H,
J ¼ 1.8, 7.4 Hz), 7.87 (d, 1H, J ¼ 8.7 Hz), 8.41 (br d, 1H, J ¼ 7.4 Hz); 13C NMR
(100 MHz, CDCl3): d 18.6, 52.2, 52.4, 80.2, 118.8, 124.0, 124.5, 126.5, 126.8,
127.6, 128.6, 129.3, 136.7, 155.6, 166.7, 172.1; HR-EIMS MNaþ, found: 311.0887.
C16H16O5Na requires 311.08954.
4-Nitro-2-(1-methoxycarbonyl-ethoxy)-benzoic acid methyl ester
10i. Prepared from 8i (8.27 g, 42 mmol) and isolated as white solid (9.6 g, 81%).1H
NMR (400 MHz, CDCl3): d 1.74 (d, 3H, J ¼ 6.8 Hz), 3.82 (s, 3H), 3.96 (s, 3H),
4.93 (q, 1H, J ¼ 6.8 Hz), 7.70 (d, 1H, J ¼ 1.9 Hz), 7.90 (dd, 1H, J ¼ 1.9, 8.5 Hz),
7.94 (d, 1H, J ¼ 8.5 Hz); 13C NMR (100 MHz, CDCl3): d 18.3, 52.6, 52.7, 74.3,
109.4, 116.1, 127.3, 132.4, 150.4, 157.3, 165.1, 171.1; HR-EIMS MNaþ, found:
306.0590. C12H13NO7Na requires 306.05897.
4-Chloro-2-(1-methoxycarbonyl-ethoxy)-benzoic acid methyl ester
10k. Prepared from 8k (11.1 g, 59.5 mmol) and isolated as pale orange solid
(14.0 g, 86%). 1H NMR (400 MHz, CDCl3): d 1.67 (d, 3H, J ¼ 6.8 Hz), 3.78 (s,
3H), 3.89 (s, 3H), 4.77 (q, 1H, J ¼ 6.8 Hz), 6.85 (d, 1H, J ¼ 1.9), 7.02 (dd, 1H,
J ¼ 1.9, 8.4 Hz), 7.77 (d, 1H, J ¼ 8.4 Hz); 13C NMR (100 MHz, CDCl3): d 18.6,
52.3, 52.6, 74.7, 115.9, 120.0, 122.1, 133.1, 139.2, 158.0, 165.7, 171.9; HR-EIMS
MNaþ, found: 295.0349. C12H13O5 35ClNa requires 295.03492.
5-Bromo-2-(1-methoxycarbonyl-ethoxy)-benzoic Acid Methyl Ester
10l. Prepared from 8l (10.32 g, 44.7 mmol) and isolated as yellow solid (12.2 g,
1
86%). H NMR (400 MHz, CDCl3): d 1.67 (d, 3H, J ¼ 6.8 Hz), 3.78 (s, 3H), 3.89
(s, 3H), 4.77 (q, 1H, J ¼ 6.8 Hz), 6.85 (d, 1H, J ¼ 1.9), 7.02 (dd, 1H, J ¼ 1.9,
8.4 Hz), 7.77 (d, 1H, J ¼ 8.4 Hz); 13C NMR (100 MHz, CDCl3): d 18.5, 52.3, 52.5,
74.7, 117.3, 123.3, 134.5, 136.0, 156.4, 165.1, 172.0; HR-EIMS MNaþ, found
338.9844. C12H13O5 79BrNa requires 338.9844.
Ether 10 preparation by microwave procedure. K2CO3 (0.207 g,
1.5 mmol) and methyl 2-bromopropionate 9 (0.14 mL, 1.25 mmol) were added to a
solution of salicylate ester 8i (0.197 g, 1 mmol) in DMF (1 mL). The mixture was
heated at 60 ꢀC for 5 min under stirring and 300 W microwave irradiation power.
After cooling to ambient temperature, AcOEt (5 mL) was added. The resulting
organic layer was washed with 1 N HCl (5 mL) and dried on MgSO4. The crude

998
D. FARRAN AND P. BERTRAND
residue was then concentrated and purified by column chromatography (petroleum
ether=AcOEt; 85=15), providing 10i as a white solid (0.283 g, 100%).
Compound 10l also prepared as 10i from ester 8l (0.230 g, 1 mmol) in acetoni-
trile (1 mL), K2CO3 (0.207 g, 1.5 mmol) and methyl 2-bromopropionate 9 (0.14 mL,
1.25 mmol) as a yellow solid (0.316 g, 100%).
Synthesis of [2,3]-Dihydro-benzofuran-3-ones 6 from Salicylate
Ethers 10
K2CO3 (0.069 g, 0.5 mmol) were added to a solution of salicylate ether 10
(1 mmol) in DMF=MeOH (1 mL=0.5 mL). The mixture was heated at 170 ꢀC for
10 min under stirring and 300 W microwave irradiation power. After cooling to
ambient temperature, the mixture was diluted with EtOAc (5 mL). The resulting
organic layer was washed with 1 N HCl (5 mL) and dried (MgSO4). The crude resi-
due was then concentrated and purified by column chromatography (petroleum
ether=EtOAc; 85=15), providing 6.
5-Methoxy-2-methyl-benzofuran-3-one 6d. Prepared from 10d (0.268 g,
1
1 mmol) and isolated as a colorless oil (0.083 g, 46%). H NMR (400 MHz, CDCl3):
d 1.50 (d, 3H, J ¼ 7.2 Hz), 3.77 (s, 3H), 4.62 (q, 1H, J ¼ 7.2 Hz), 6.99–7.03 (m, 2H),
7.22 (dd, 1H, J ¼ 2.9, 8.9 Hz); 13C NMR (100 MHz, CDCl3): d 14.3, 56.0, 82.7, 104.2,
114.5, 120.3, 128.2, 155.0, 167.9, 202.9; HR-EIMS MNaþ, found 201.0530.
C10H10O3Na requires 201.05276.
6-Chloro-2-methyl-benzofuran-3-one 6k. Prepared from 10k (0.273 g,
1
1 mmol) and isolated as a colorless oil (0.013 g, 7%). H NMR (400 MHz, CDCl3):
d 1.51 (d, 3H, J ¼ 7.2 Hz), 2.43 (s, 3H), 4.62 (q, 1H, J ¼ 7.1 Hz), 6.89 (m, 2H), 7.54
(dd, 1H, J ¼ 1.2, 7.3 Hz); 13C NMR (100 MHz, CDCl3): d 18.4, 83.7, 111.0, 117.7,
119.8, 130.9, 141.4, 170.0, 203.9; HR-EIMS MNaþ, found 205.0041. C9H7O2 35ClNa
requires 205.00323.
Dimer 12k[15]. Prepared from 10k (0.273 g, 1 mmol) and isolated as a colorless
1
oil (0.072 g, 22%). H NMR (400 MHz, CDCl3): d 1.51 (d, 3H, J ¼ 8.0 Hz), 2.40 (s,
3H), 4.64 (q, 1H, J ¼ 8.0 Hz), 6.54 (d, 1H, J ¼ 2.0 Hz), 6.78 (dd, 1H, J ¼ 4.0,
8.0 Hz), 7.13 (m, 2H), 7.42 (dd, 1H, J ¼ 4.0, 8.0 Hz), 7.60 (d, 1H, J ¼ 8 Hz); 13C
NMR (100 MHz, CDCl3): d 16.9, 17.5, 86.1, 94.8, 112.3, 114.4, 120.0, 123.3,
127.6, 129.9, 132.9, 135.2, 139.0, 140.9, 169.3, 170.2, 200.8, 201.6; HR-EIMS MNaþ,
found 351.0406. C18H13O4 35ClNa requires 351.04001.
5-Bromo-2-methyl-benzofuran-3-one 6l. Prepared from 10l (0.316 g,
1
1 mmol) and isolated as a colorless oil (0.099 g, 44%). H NMR (400 MHz, CDCl3):
d 1.45 (d, 3H, J ¼ 7.2 Hz), 4.60 (q, 1H, J ¼ 7.2 Hz), 6.94 (d, 1H, J ¼ 8.7 Hz), 7.60 (dd,
1H, J ¼ 2.2, 8.7 Hz), 7.69 (d, 1H, J ¼ 2.2 Hz); 13C NMR (100 MHz, CDCl3): d 16.5,
82.8, 114.5, 115.5, 122.3, 127.1, 140.7, 171.3, 201.1; HR-EIMS MNaþ, found
249.0231. C9H7O2 79BrNa requires 249.01972.

MICROWAVE SYNTHESIS OF BENZOFURANONES
999
Synthesis of [2,3]-Dihydro-benzofuran-3-ones 6 from Salicylate
Esters 8
K2CO3 (0.414 g, 3 mmol) and methyl 2-bromopropionate 9 (0.28 mL,
2.5 mmol) were added to a solution of salicylate ester 8 (2 mmol) in DMF (1 mL).
The mixture was heated at 170 ꢀC for 90 min under stirring and 300 W microwave
irradiation power. After cooling to ambient temperature, EtOAc (5 mL) was added.
The resulting organic layer was washed with 1 N HCl (5 mL) and dried (MgSO4).
The crude residue was then concentrated and purified by column chromatography
(petroleum ether=EtOAc; 85=15), providing 6.
6-Methoxy-2-methyl-benzofuran-3-one 6c. Prepared from 8c (0.268 g,
1
1 mmol) and isolated as a colorless oil (0.142 g, 80%). H NMR (400 MHz, CDCl3):
d 1.52 (d, 3H, J ¼ 6.7 Hz), 3.80 (s, 3H), 3.86 (s, 3H), 3.89 (s, 3H), 4.65 (q, 1H,
J ¼ 6.7 Hz), 6.51 (s, 1H), 6.4 (d, 1H, J ¼ 8.3 Hz), 7.55 (d, 1H, J ¼ 8.3 Hz); 13C
NMR (100 MHz, CDCl3): d 16.6, 55.9, 82.8, 96.2, 111.7, 113.5, 125.5, 168.4,
174.9, 200.2; HR-EIMS MNaþ, found 201.0528. C10H10O3Na requires 201.05276.
2,6-Dimethyl-benzofuran-3-one 6e. Prepared from 8e (0.252 g, 1 mmol)
1
and isolated as a yellow solid (0.115 g, 71%). H NMR (400 MHz, CDCl3): d 1.44
(d, 3H, J ¼ 7.2 Hz), 2.27 (s, 3H), 4.54 (q, 1H, J ¼ 7.1 Hz), 6.93 (dd, 1H, J ¼ 1.6,
7.4 Hz), 7.35 (m, 2H); 13C NMR (100 MHz, CDCl3): d 16.4, 20.6, 82.0, 113.1,
120.3, 123.7, 131.5, 139.3, 170.9, 202.6; HR-EIMS MNaþ, found 185.0580.
C10H10O2Na requires 185.05785.
2,6-Dimethyl-3-oxo-2,3-dihydro-benzofuran-2-carboxylic acid methyl
ester 11e. Prepared from 8e (0.252 g, 1 mmol) and isolated as a colorless oil
1
(0.037 g, 17%). H NMR (400 MHz, CDCl3): d 2.38 (s, 3H), 2.43 (s, 3H), 3.92 (s,
3H), 7.00 (dd, 1H, J ¼ 0.5, 7.3 Hz), 7.14 (t, 1H, J ¼ 0.4 Hz), 7.39 (d, 1H, J ¼ 7.9 Hz);
13C NMR (100 MHz, CDCl3): d 17.3, 22.0, 52.0, 91.0, 109.8, 117.7, 120.4, 129.7,
147.0, 161.6, 170.6, 203.1; HR-EIMS MNaþ, found 243.0731. C12H12O4Na requires
243.07356.
2,5-Dimethyl-benzofuran-3-one 6f. Prepared from 8f (0.252 g, 1 mmol) and
isolated as a colorless oil (0.084 g, 52%). 1H NMR (400 MHz, CDCl3): d 1.51 (d, 3H,
J ¼ 7.2 Hz), 2.43 (s, 3H), 4.62 (q, 1H, J ¼ 7.1 Hz), 6.89 (m, 2H), 7.54 (dd, 1H, J ¼ 1.2,
7.3 Hz); 13C NMR (100 MHz, CDCl3): d 16.5, 22.5, 82.1, 113.5, 118.0, 123.5, 124.0,
150.0, 173.0, 201.9; HR-EIMS MNaþ, found 185.0577. C10H10O2Na requires
185.05785.
2-Methyl-naphtho[2,3-b]furan-3-one 6g. Prepared from 8g (0.288 g,
1 mmol) and isolated as a colorless oil (0.99 g, 50%). 1H NMR (400 MHz, CDCl3): d
1.58 (d, 3H, J ¼ 7.2 Hz), 4.72 (q, 1H, J ¼ 7.2 Hz), 7.38 (m, 2H), 7.55 (td, 1H, J ¼ 1.2,
6.8 Hz), 7.78 (d, 1H, J ¼ 8.5 Hz), 7.91 (d, 1H, J ¼ 8.4 Hz); 13C NMR (100 MHz,
CDCl3): d 16.8, 81.9, 107.6, 121.3, 124.7, 126.1, 127.4, 129.7, 130.9, 139.7, 140.7,
165.7, 203.1; HR-EIMS MNaþ: found 221.0576. C13H10O2Na requires 221.05785.
2-Methyl-naphtho[1,2-b]furan-3-one 6h. Prepared from 8h (0.288 g,
1
1 mmol) and isolated as a colorless oil (0.59 g, 30%). H NMR (400 MHz, CDCl3):
d 1.64 (d, 3H, J ¼ 7.2 Hz), 4.85 (q, 1H, J ¼ 7.2 Hz), 7.45 (d, 1H, J ¼ 8.5 Hz), 7.56

1000
D. FARRAN AND P. BERTRAND
(d, 1H, J ¼ 8.5 Hz), 7.60 (td, 1H, J ¼ 1.1, 7.0 Hz), 7.71 (td, 1H, J ¼ 1.3, 7.0 Hz), 7.88
(d, 1H, J ¼ 8.3 Hz), 8.25 (md, 1H, J ¼ 7.1 Hz); 13C NMR (100 MHz, CDCl3): d 16.8,
81.9, 105.6, 118.6, 123.9, 124.2, 124.8, 125.8, 127.5, 129.4, 137.2, 171.5, 203.1;
HR-EIMS MNaþ, found 221.0581. C13H10O2Na requires 221.05785.
6-Nitro-2-methyl-benzofuran-3-one 6l. 1H NMR (400 MHz, CDCl3): d
1.45 (d, 3H, J ¼ 7.2 Hz), 4.60 (q, 1H, J ¼ 7.2 Hz), 6.94 (d, 1H, J ¼ 8.7 Hz), 7.60
(dd, 1H, J ¼ 2.2, 8.7 Hz), 7.69 (d, 1H, J ¼ 2.2 Hz); 13C NMR (100 MHz, CDCl3): d
16.5, 82.8, 114.5, 115.5, 122.3, 127.1, 140.7, 171.3, 201.1; HR-EIMS MNaþ, found:
249.0231. C9H7O2 79BrNa requires 249.01972.
ACKNOWLEDGMENT
´
The authors thank La Ligue Contre le Cancer and Canceropole Grand Ouest
ˆ
for funding this research.
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