Efficient synthetic approach to heterocycles possessing the 3,3-disubstituted-2,3-dihydrobenzofuran skeleton via diverse palladium-catalyzed tandem reactions

Article abstract of DOI:10.1016/j.tet.2007.02.035

Various palladium-catalyzed cascade reactions of O-alkylated 2-iodophenol were explored in order to synthesize novel dihydrobenzofurans. An efficient tandem cyclization/anion capture reaction was developed to yield 3,3-disubstituted-2,3-dihydrobenzofurans. A small library of these compounds was prepared with a parallel organic synthesizer. A multi-component version of this reaction involving 2-iodophenol, an alkylating agent and a nucleophile, provided the same products. The methoxycarbonyl-substituted heterocyclic ring was hydrolyzed to a free acid, which could be used for further transformations.

Full text of DOI:10.1016/j.tet.2007.02.035

Tetrahedron 63 (2007) 3340–3349
Efficient synthetic approach to heterocycles possessing the
3,3-disubstituted-2,3-dihydrobenzofuran skeleton via
diverse palladium-catalyzed tandem reactions
b
a
a,
Magali Szlosek-Pinaud,a,y Philippe Diaz, Jean Martinez and Frederic Lamaty
*
ꢀ ꢀ
a
´
´
Laboratoire des Aminoacides, Peptides et Proteines (LAPP), UMR 5810-CNRS-Universites Montpellier 1 et 2,
Place Eugeꢁne Bataillon, 34095 Montpellier Cedex 5, France
bGalderma R&D, 635, route des Lucioles, BP 87, 06902 Sophia Antipolis Cedex, France
Received 6 December 2006; revised 8 February 2007; accepted 9 February 2007
Available online 13 February 2007
Abstract—Various palladium-catalyzed cascade reactions of O-alkylated 2-iodophenol were explored in order to synthesize novel dihydro-
benzofurans. An efficient tandem cyclization/anion capture reaction was developed to yield 3,3-disubstituted-2,3-dihydrobenzofurans. A
small library of these compounds was prepared with a parallel organic synthesizer. A multi-component version of this reaction involving
2-iodophenol, an alkylating agent and a nucleophile, provided the same products. The methoxycarbonyl-substituted heterocyclic ring was
hydrolyzed to a free acid, which could be used for further transformations.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
synthetic approaches, transition metal-catalyzed reactions
are part of the most attractive methodologies, since they
can directly lead to complicated molecules from readily
accessible starting materials under mild conditions.9 Palla-
dium-catalyzed cascades in particular, provide versatile
and efficient methods for the assembly of a wide range
of organic compounds via carbon–carbon and carbon–
heteroatom bond formation.10–14 These cascades usually
proceed under mild conditions and are tolerant of a
wide variety of functional groups. They allow the access
to a high degree of molecular complexity in a one-pot
protocol, where conventional methodology would require
multi-step synthesis.15 Such reactions minimize reactor
time and waste, whilst offering interesting synthetic
solutions.
Naturally occurring substituted-2,3-dihydrobenzofurans
are an important class of biologically active oxygen-
containing heterocycles. Natural products possessing the
dihydrobenzofuran skeleton exhibit a wide range of
biological activities. For example (Fig. 1), Megapodiol is
an anti-leukaemic agent,1 Conocarpan is an anti-cancer
agent,2 and Furaquinocines are antibiotics.3 Some other
derived compounds present cytotoxic and anti-protozoal
activities.4
Therefore, organic chemists have made extensive efforts
to develop new chemical processes to produce elaborate
heterocyclic structures.5–8 Among the variety of new
To our knowledge, only few Pd-catalyzed cascade reac-
tions have been used to efficiently build 3,3-disubsti-
tuted-2,3-dihydrobenzofurans, using very simple starting
materials.16,17 In a preliminary study, we have described
the first examples of Pd-catalyzed multi-component
reactions involving methyl bromomethylacrylate in an
allylation followed by another Pd-catalyzed process
(Heck and/or Suzuki reactions).18,19 We report herein a
more extensive study of different Pd-catalyzed cascades
Me
Me
O
O
OH
OH
Me
Me
O
Conocarpan
Megapodiol
Figure 1. Structures of biologically active dihydrobenzofurans.
starting with
a
Pd-catalyzed allylic alkylation of
* Corresponding author. Fax: +33 (0) 4 67 14 48 66; e-mail addresses:
frederic.lamaty@univ-montp2.fr; m.szlosek@ism.u-bordeaux1.fr
2-iodophenol by methyl bromomethylacrylate, allowing
introduction of diversity in a very simple manner
(Scheme 1).
y
ꢁ
Present address: ISM, UMR-CNRS 5255, Groupe Synthese, Universite
Bordeaux 1, 351, cours de la liberation, 33405 Talence Cedex, France.
ꢀ
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.035

M. Szlosek-Pinaud et al. / Tetrahedron 63 (2007) 3340–3349
3341
O
one pot version
CO2Me
H- capture
O
OH
I
CO2Me
Br
+
CO2Me
I
Heck reaction
1
2
3
O
CO2Me
Cross-coupling
CO2Me
O
one pot version
CO2Me
R
Scheme 1. General strategy for the synthesis of 3,3-disubstituted-2,3-dihydrobenzofuran derivatives.
2. Results and discussion
a mixture of dioxane/water (9/1) providing 5 in 70% yield
(Scheme 2).
2.1. Pd-catalyzed tandem cyclization-hydride capture
This sequence (alkylation, cyclization/hydride capture, and
saponification) was performed on a gram scale with an
overall yield of 45%. Furthermore, we decided to realize
this reaction sequence in a one-pot version, starting from
1 and 2. Compound 4 was obtained in 40% yield with
the advantage of avoiding intermediate purification using
sodium formate as a hydride source, Pd(OAc)2 as a catalyst
and Cs2CO3 as base in the presence of tetrabutylammo-
nium chloride (n-Bu4NCl), in acetonitrile, at 80 ꢀC. Initial
reduction of Pd(OAc)2 with HCOONa generates the active
Pd(0) species denoted Pd(0)Ln in Scheme 3. The reaction
proceeded firstly via alkylation of the phenoxide by allylic
bromide 2,20 providing 3. Oxidative addition of 3 to Pd(0)
The allylic alkylation of 2-iodophenol 1 using methyl bromo-
methylacrylate 2, and Cs2CO3 as a base was performed in
acetonitrile at 80 ꢀC, leading to the corresponding alkylated
compound 3 in 89% yield (Scheme 2). Pd-catalyzed tandem
cyclization-hydride capture was achieved using a mixture of
tributylamine and formic acid as a hydride source, and
Pd(OAc)2 as catalyst, in acetonitrile at 60 ꢀC. Thus, the 3,3-
disubstituted-2,3-dihydrobenzofuran 4 was obtained in 80%
yield from a 5-exo-trig cyclization followed by trapping
of the resulting alkylpalladium complex with a hydride
(Scheme 2). To get the corresponding carboxylic acid, com-
pound 4 was hydrolyzed with aqueous sodium hydroxide in
One pot version
Pd(OAc)2, HCOONa
Cs2CO3, n-Bu4NCl
CH3CN, 80 °C
40%
O
OH
I
O
Cs2CO3
Pd(OAc)2
CO2Me
Br
+
CO2Me
CH3CN, 80 °C
89%
CH3CN, 60 °C
Bu3N/HCOOH
80%
I
CO2Me
1
2
3
4
O
NaOH aq.
Dioxane/H2O
70%
CO2H
5
Scheme 2. Synthesis of compound 4 by Pd-catalyzed tandem cyclization/hydride capture in one or two steps.

3342
M. Szlosek-Pinaud et al. / Tetrahedron 63 (2007) 3340–3349
O
HCOO-
CO2
O
CO2Me
4
CO2Me
6
PdLnI
OH
I
1
Pd(0)Ln
Cs2CO3
Br
CO2Me
2
CO2Me
CO2Me
O
I
O
PdLnI
3
Scheme 3. One-pot version of the tandem alkylation/cyclization/hydride capture.
followed by cyclic carbopalladation of the olefin provided
alkylpalladium 6. Hydride trapping, followed by reductive
elimination generated the final product 4 and recycled Pd(0).
2.3. Pd-catalyzed tandem cyclization/cross-coupling
Different nucleophiles were studied, such as organometallic
compounds, to end the synthetic sequence by a cross-cou-
pling reaction in order to improve the structural complexity
of the resulting compounds. Since it has been shown in the
literature that the cascade could be controlled by the trans-
metalating reagent, we studied the Stille coupling with tin,
known to be slower than with other metals.
Followingtheseresults, weintroducedan additionalsourceof
structural diversity, without changing the starting materials,
in order to decorate the basic scaffold with more complicated
functionalities than a methyl group. The idea was to trap the
intermediate alkylpalladium by various nucleophiles rather
than a hydride, which would offer a diversity source. The ma-
jor challengewas to obtain the correct chronology for the suc-
cessive steps and avoid direct coupling before the cyclization.
Stille coupling: Conditions of introduction of a phenyl
group by a Pd-catalyzed tandem cyclization/Stille coupling
sequence were studied, involving trimethyl(phenyl)tin
(PhSnMe3) (Scheme 5).
2.2. Pd-catalyzed tandem cyclization/Heck reaction
We studied the cyclization step followed by an intermolecu-
lar Heck reaction, using methyl acrylate 7 as a model sub-
strate, avoiding direct coupling reaction leading to 9.
The reaction was performed, in the presence of n-Bu4NCl,
and Pd(OAc)2 in THF at 60 ꢀC overnight leading to a mixture
of the desired compound 11a (50%) and of the compound
10 (50%) due to the direct coupling reaction. The 1,3-
dimethyl-1-2-imidazolidinone (DMI) was added to this sys-
tem as a co-solvent. In this case, no direct coupling was
observed, only the desired compound 11a was obtained in
70% yield.
No ideal conditions were found to obtain title compound
8 as the sole product of the reaction. In fact, the best results
were obtained by using Et3N as a base, DMF as solvent, in
the presence of n-Bu4NCl. Under these reaction conditions,
and after 18 h of reaction, we obtained only a mixture of
the desired compounds 8 (64%), the product 9, resulting
from the direct coupling reaction (25%), compound 4, result-
ing from the hydride capture (10%) and some iodophenol 1,
resulting from degradation of 3 (Scheme 4).
Following these promising results, other organometallics
were used to introduce a structural diversity, employing di-
verse terminating cross-coupling reactions. The best results
were obtained with the Suzuki coupling.
Pd(OAc)2
CO2Me
O
OH
OH
I
O
O
CO2Me
+
+
+
I
CO2Me
CO2Me
7
CO2Me
3
CO2Me
8
1
9
4
Scheme 4. Pd-catalyzed tandem cyclization/Heck reaction.

M. Szlosek-Pinaud et al. / Tetrahedron 63 (2007) 3340–3349
3343
O
Pd(OAc)2, n-Bu4NCl
CO2Me
O
+
O
PhSnMe3, THF, 60 °C
CO2Me
Ph
CO2Me
Ph
10
I
11a
3
O
Pd(OAc)2, n-Bu4NCl
PhSnMe3, THF, 60 °C
DMI
CO2Me
Ph
11a
70%
N
N
O
DMI
Scheme 5. Pd-catalyzed tandem cyclization/Stille coupling.
Table 1. 3,3-Disubstituted-2,3-dihydrofurans 11
Suzuki coupling: The major advantage of this sequence is
the existence of a large variety of commercially available
boronic acid derivatives, especially aromatic derivatives.
To compare the Suzuki coupling with the results previously
obtained with the Stille coupling, we used the phenylboronic
acid (PhB(OH)2). Usual conditions for the Suzuki coupling
had to be adapted. Indeed, to perform cyclization/Suzuki
coupling most catalytic systems include the presence of
phosphines. In our study, the reaction rate was dramatically
reduced when triphenylphosphine was used as a ligand. Fur-
thermore, an aqueous medium, which is considered as a stan-
dard condition for the Suzuki cross-coupling of arylboronic
acids, had to be avoided due to the potential hydrolysis
of the methyl ester. Phosphine-free system in the presence
of a tretraalkylammonuim salt was efficient in this reaction,
previously reported for the Heck reaction21 and the Suzuki
coupling.22 It has been shown that the combination of
Pd(OAc)2 with n-Bu4NCl in the presence of a base generated
colloidal palladium nanoparticles, which are involved in the
catalytic cycle.22 These conditions allowed us to get the title
compound 11a in 54% yield (Scheme 6).
Compound
Ar
Yield of
Yield of
11(%)a
12(%)a
a
b
c
d
e
f
g
h
i
C6H5–
54
56
56
60
71
73
66
82
68
85
49
66
73
79
53
70
—
b
4-MeO–C6H4–
3-NO2–C6H4–
2-Me–C6H4–
3,4-(OMe)2–C6H3–
3,4,5-(OMe)3–C6H2–
2-Cl–C6H4–
b
—
—
b
64
71
70
78
65
69
55
73
71
91
95
3-Cl–C6H4–
4-Cl–C6H4–
j
k
l
m
n
o
3,4-(Cl)2–C6H3–
2-CF3–C6H4–
4-CF3O–C6H4–
4-AcO–C6H4–
4-CH3O(CH2)2OCH2O–C6H4–
4-CH2]CH–C6H4–
p
q
78
50
88
81
71
b
O
O
r
—
Pd(OAc)2, K2CO3
CO2Me
n-Bu4NCl, DMF
PhB(OH)2, 80 °C
I
a
CO2Me
Ph
Yield of isolated compounds.
The hydrolysis was not performed.
11a
3
b
54%
Scheme 6. Pd-catalyzed tandem cyclization/Suzuki coupling using
PhB(OH)2.
Thus, 18 products were obtained using this methodology,
in moderate to good yields. Most of them were converted
into their corresponding carboxylic acid derivatives 12a
and 12e–q, using the conditions described for the synthesis
of 5.23
This result, associated with the very simple reaction
conditions, led us to test the parallel synthesis of the dihydro-
benzofurans using an organic synthesizer (Argonaut Quest
210 Parallel Synthesizer) and different arylboronic acids
(Scheme 7). Table 1 reports the yields of 3,3-disubstituted-
2,3-dihydrobenzofurans obtained. Electron donating, with-
drawing or bulky substituents can be present on the aromatic
ring.
This sequence was performed in a one-pot version,
starting from 1 and 2, with different arylboronic acids
(Scheme 8).
O
O
O
Pd(OAc)2, K2CO3
CO2Me
NaOH
Dioxane/H2O
n-Bu4NCl, DMF
ArB(OH)2, 80 °C
I
CO2Me
Ar
CO2H
Ar
3
11a-r
12a, 12e-r
Scheme 7. Pd-catalyzed tandem cyclization/Suzuki coupling using various arylboronic acids followed by a saponification reaction.

3344
M. Szlosek-Pinaud et al. / Tetrahedron 63 (2007) 3340–3349
O
3. Conclusion
OH
Pd(OAc)2, K2CO3
Br
+
We have developed a very simple and an efficient method for
the synthesis of a wide range of functionalized 3,3-disubsti-
tuted-2,3-dihydrobenzofurans, from commercially available
2-iodophenol, and methyl bromomethylacrylate via Pd-cat-
alyzed tandem cyclization/Suzuki cross-coupling. Those
conditions could be directly applied to automated synthesis
leading to libraries of functionalized heterocyclic building
blocks. This strategy will now be extended to more function-
alized phenols and other 1,1-disubstituted alkenes, to intro-
duce additional diversity and structural complexity. Finally,
an asymmetric version of this reaction is currently under-
way, in order to control the configuration of the newly cre-
ated stereogenic center.
CO2Me
CO2Me
n-Bu4NCl, DMF
ArB(OH)2, 80 °C
I
1
2
R
11a-d, 11r
Scheme 8. One-pot allylation/cyclization/Suzuki coupling cascade.
In the catalytic cycle, the formation of the alkylpalladium 6
was followed by a transmetallation step with phenylboronate
(from the reaction of PhB(OH)2 with the base and/or anions
present in the reaction medium). Finally, the reductive elim-
ination generates the title compound 11a and recycles Pd(0)
(Scheme 9).
BX3
O
O
-
PhB(OH)2
PhBX3
CO2Me
CO2Me
PdLnPh
11a
Ph
O
CO2Me
PdLnI
6
OH
Pd(0)Ln
I
1
Cs2CO3
Br
CO2Me
2
CO2Me
O
CO2Me
O
PdLnI
I
3
Scheme 9. Cascade allylation/cyclization/Suzuki coupling.
To our knowledge, only few examples of allylations com-
bined with a Pd-catalyzed process are described in the liter-
ature.18,19,24–28
4. Experimental section
4.1. General
Table 2 reports the yields of 3,3-disubstituted-2,3-dihydro-
benzofurans obtained from five different arylboronic acids,
ArB(OH)2. As observed before, electron donating and with-
drawing substituents can be present on the aromatic ring.
However, substitution at the ortho position led to lower
yields.
All reagents were commercially available and used without
purification. IR spectra were recorded on Perkin Elmer FT
Paragon 1000 spectrometer. 1H and 13C NMR analyses were
€
performed with a Bruker AC 400 MHz and 200 MHz. IR
spectra were recorded on Perkin Elmer FT Paragon 1000
spectrometer. Mass spectra were recorded on JEOL JSM
DX300-SX 102 spectrometer, with 3-nitrobenzyl alcohol
(NBA) or a mixture glycerol/thioglycerol (50/50, v/v)
(GT) as matrix.
Table 2. One-pot synthesis of 3,3-disubstituted-2,3-dihydrofurans
11
R
Yield (%)a
4.1.1. 2-(3-Methoxycarbonylallyloxyl)-iodobenzene (3).
To a solution of methyl-2-bromomethacrylate 2 (3.52 g,
16.67 mmol) in CH3CN (160 mL) were added Cs2CO3
a
b
c
d
r
H
45b
50
40
28
57
4-OMe
3-NO2
2-Me
4-Ph
(4.47 g, 13.36 mmol) and 2-iodophenol
1
(2.1 g,
9.54 mmol). The resulting mixture was stirred for 5 h at
80 ꢀC, cooled to room temperature, diluted with Et2O, and
filtered over Celite. The organic layer was washed with
a
Yield of isolated compounds.
Compound 11a was obtained as the sole product (74% NMR yield).
b

M. Szlosek-Pinaud et al. / Tetrahedron 63 (2007) 3340–3349
3345
brine, dried over MgSO4, filtered, and concentrated. Column
chromatography (silica gel, hexane/CH2Cl2: 1/1) afforded
2.71 g (89%) of 3: H NMR (250 MHz, CDCl3) d 3.78 (s,
3H), 4.21 (d, 1H, J¼9.2 Hz), 5.02 (d, 1H, J¼9.2 Hz), 6.78
(d, 1H, J¼8.1 Hz), 6.87 (td, 1H, J¼7.5 Hz, J¼0.8 Hz),
7.16 (td, 1H, J¼7.7 Hz, J¼1.3 Hz), 7.31 (dd, 1H,
J¼7.5 Hz, J¼1.2 Hz); 13C NMR (100 MHz, CDCl3)
d 24.54, 52.60, 79.98, 110.54, 121.36, 124.76, 129.68,
130.05, 159.80, 180.37; IR (film) n 3084, 3020, 2973,
2929, 2849, 1704, 1597, 1482, 1462, 1410, 1296, 1238,
1
3H), 4.76 (d, 2H, J¼1.7 Hz), 6.23 (d, 1H, J¼1.2 Hz), 6.42
(d, 1H, J¼1.3 Hz), 6.70 (td, 1H, J¼7.6 Hz, J¼1.1 Hz),
6.80 (d, 1H, J¼8.2 Hz), 7.26 (td, 1H, J¼8.6 Hz,
J¼1.5 Hz), 7.74 (dd, 1H, J¼7.8 Hz, J¼1.5 Hz); 13C NMR
(100 MHz, CDCl3) d 52.46, 67.30, 86.87, 112.83, 123.41,
127.26, 129.95, 135.43, 139.9, 157.12, 166.19; IR (film)
n 3024, 3000, 2949, 2844, 1717, 1636.5, 1581, 1475, 1438,
1396, 1313, 1278, 1250, 1195, 1155, 1121, 1056, 1036,
1018, 956, 868, 817, 748, 642 cmꢁ1; MS (FAB+, GT)
m/z¼319 (MH+), 233, 149, 131; HRMS for C11H12O3I
(MH+): calcd 318.9831 found 318.9843.
1177, 1154, 1068, 1017, 988, 833, 752, 685, 622 cmꢁ1
;
MS (FAB+, NBA) m/z¼178 (M+), 133 (M+ꢁCO2H), 105,
89, 77; HRMS for C10H10O3 (M+): calcd 178.0630 found
178.0624.
4.1.4. 3-Methylacrylate-3-methoxycarbonyl-2,3-di-
hydrobenzofuran (8). To a solution of 3 (60.3 mg,
0.19 mmol) in DMF (4 mL) were added Et3N (53 mL,
0.38 mmol), n-Bu4NCl (63.3 mg, 0.228 mmol), a solution
of Pd(OAc)2 (4.4 mg, 0.019 mmol) in DMF (1 mL), and
methyl acrylate 7 (18.9 mL, 0.209 mmol). The resulting mix-
ture was stirred for 16 h at 80 ꢀC, cooled to room tempera-
ture, diluted with Et2O, and filtered over Celite. This
organic layer was washed with brine, dried over MgSO4, fil-
tered, and concentrated affording a mixture of 8, as a major
compound (64% by NMR), 9, 4, and 1.
4.1.2. 3-Methyl-3-methoxycarbonyl-2,3-dihydrobenzo-
furan (4). To a solution of Bu3N (2.77 mL, 11.62 mmol)
in acetonitrile (60 mL) was added HCOOH (0.219 mL,
5.81 mmol). The resulting mixture was stirred for 10 min
at room temperature. To this mixture were then added a solu-
tion of 3 (1.68 g, 5.28 mmol) in CH3CN (10 mL), and a solu-
tion of Pd(OAc)2 (118.5 mg, 0.528 mmol) in CH3CN
(2 mL). The resulting mixture was stirred for 17 h at
60 ꢀC, cooled to room temperature and concentrated. The
residue was dissolved in Et2O, and the resulting organic
layer was washed with brine, dried over MgSO4, filtered,
and concentrated. The residue was dissolved finally in hex-
ane and filtered over alumina and concentrated affording
811 mg (80%) of 4.
4.1.5. 3-Benzyl-3-methoxycarbonyl-2,3-dihydrobenzo-
furan (11a). Stille conditions: To a solution of 3 (200.4 mg,
0.629 mmol) and DMI (0.240 mL, 2.2 mmol) in THF
(12 mL) were added n-Bu4NCl (209.75 mg, 0.755 mmol),
a solution of Pd(OAc)2 (14.12 mg, 0.063 mmol) in THF
(1 mL), and Me3PhSn (0.137 mL, 0.755 mmol). The result-
ing mixture was stirred for 17 h at 60 ꢀC, cooled to room
temperature, diluted with Et2O, and filtered over Celite.
This organic layer was washed with brine, dried over
MgSO4, filtered, and concentrated. Column chromatography
(silica gel, hexane/CH2Cl2: 1/1) afforded 118 mg (70%)
of 11a.
One-pot version: To a solution of 2 (58.3 mg, 0.326 mmol)
in CH3CN (5 mL) were added Cs2CO3 (318.8 mg,
0.979 mmol),
1
(51.2 mg, 0.233 mmol), HCOONa
(21.9 mg, 0.326 mmol), Pd(OAc)2 (5.23 mg, 0.023 mmol),
and n-Bu4NCl (77.4 mg, 0.280 mmol). The resulting mix-
ture was stirred for 17 h at 80 ꢀC, cooled to room tempera-
ture and concentrated. The residue was dissolved in Et2O,
and the resulting organic layer was washed with brine, dried
over MgSO4, filtered, and concentrated. The residue was dis-
solved in hexane and filtered over alumina and concentrated
Suzuki conditions: To
a solution of 3 (106.6 mg,
0.335 mmol) in DMF (6 mL) were added K2CO3 (92.6 mg,
0.670 mmol), n-Bu4NCl (111.7 mg, 0.402 mmol), a solution
of Pd(OAc)2 (7.5 mg, 0.0335 mmol) in DMF (1 mL), and
a solution of Ph(BOH)2 (44.9 mg, 0.368 mmol) in DMF
(2 mL). The resulting mixture was stirred for 15 h at
80 ꢀC, cooled to room temperature filtered over Celite and
concentrated. Column chromatography (silica gel, hexane/
CH2Cl2: 1/1) afforded 48.5 mg (54%) of 11a.
1
affording 18 mg (40%) of 4: H NMR (250 MHz, CDCl3)
d 1.57 (s, 3H), 3.69 (s, 3H), 4.21 (d, 1H, J¼9 Hz), 5.02 (d,
1H, J¼9 Hz), 6.76–6.89 (m, 2H), 7.14 (td, 1H, J¼7.7 Hz,
J¼1.4 Hz), 7.28 (dd, 1H, J¼7.5 Hz, J¼1.3 Hz); 13C NMR
(100 MHz, CDCl3) d 24.95, 52.71, 53.12, 80.38, 110.42,
121.22, 124.68, 129.75, 130.40, 159.79, 174.62; IR (film)
n 3030, 2952, 2896, 2849, 2796, 1732, 1597, 1482, 1462,
1222, 1137, 1107, 1068, 1017, 987 cmꢁ1; MS (FAB+,
NBA) m/z¼192 (M+), 149, 133 (M+ꢁCO2Me), 97, 81, 72,
55, 43, 29; HRMS for C11H12O3 (M+): calcd 192.0786 found
192.0787.
One-pot version: To a solution of 2 (48.9 mg, 0.273 mmol)
in DMF (3 mL) were added K2CO3 (110.15 mg, 0.955
mmol), 1 (50.1 mg, 0.228 mmol), n-Bu4NCl (76 mg,
0.274 mmol), a solution of Pd(OAc)2 (5.12 mg, 0.0273
mmol) in DMF (1 mL), and Ph(BOH)2 (30.54 mg,
0.3 mmol). The resulting mixture was stirred for 15 h at
80 ꢀC, cooled to room temperature filtered over Celite and
concentrated. Column chromatography (silica gel, hexane/
4.1.3. 3-Methyl-2,3-dihydrobenzofuran-3-carboxylic
acid (5). To a solution of 4 (1.15 g, 5.99 mmol) in a mixture
of dioxane/H2O (9/1) (50 mL) was added aqueous solution
of NaOH (2 M) (13.5 mL, 26.95 mmol). The resulting mix-
ture was stirred for 4 h at room temperature and concen-
trated. The residue was dissolved in H2O, and the aqueous
layer was extracted three times with Et2O, acidified by add-
ing HCl (1 N) until pH¼1–3 and extracted three times with
Et2O. The combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated affording
746 mg (70%) of 5: 1H NMR (250 MHz, CDCl3) d 1.60 (s,
1
CH2Cl2: 1/1) afforded 27.5 mg (45%) of 11a: H NMR
(250 MHz, CDCl3) d 3.12 (d, 1H, J¼13.7 Hz), 3.50 (d,
1H, J¼13.7 Hz), 3.76 (s, 3H), 4.53 (d, 1H, J¼9.5 Hz),
4.91 (d, 1H, J¼9.5 Hz), 6.81 (d, 1H, J¼8 Hz), 6.94 (td,
1H, J¼7.5 Hz, J¼0.9 Hz), 7.03–7.07 (m, 2H), 7.19–7.30
(m, 4H), 7.41 (dd, 1H, J¼7.5 Hz, J¼1.2 Hz); 13C NMR
(100 MHz, CDCl3) d 44.46, 52.93, 58.10, 77.01, 110.48,
121.09, 125.52, 127.51, 128.84, 129.99, 130.01, 136.59,

3346
M. Szlosek-Pinaud et al. / Tetrahedron 63 (2007) 3340–3349
159.94, 173.28; IR (film) n 3030, 2953, 2923, 2849, 1733,
1596, 1480, 1459, 1436, 1315, 1293, 1226, 1098, 1088,
1022, 979, 877, 834, 798, 753, 701 cmꢁ1; MS (FAB+,
NBA) m/z¼268 (M+), 209 (M+ꢁCO2Me), 177
(M+ꢁCH2Ph), 149, 105, 91, 69, 55, 43, 41, 29; HRMS for
C17H16O3 (M+): calcd 268.1099 found 268.1081.
130.45, 136.27, 138.47, 148.52, 159.92, 172.80; IR (film)
n 3056, 2955, 2927, 2850, 1732, 1583, 1531, 1481, 1461,
1436, 1353, 1266, 1230, 1101, 1024, 986, 894, 806,
737 cmꢁ1
;
MS (FAB+, GT) m/z¼314 (MH+), 254
(M+ꢁCO2Me), 242, 177 (M+ꢁCH2Ar), 147, 136, 110;
HRMS for C17H16O5N (MH+): calcd 314.1028 found
314.1039.
4.1.6. 3-Benzyl-2,3-dihydrobenzofuran-3-carboxylic acid
(12a). To a solution of 11a (28 mg, 0.104 mmol) in a mixture
of dioxane/H2O (9/1) (10 mL) was added aqueous solution
of NaOH (2 M) (0.235 mL, 0.470 mmol). The resulting mix-
ture was stirred for 4 h at room temperature and concen-
trated. The residue was dissolved in H2O, and the aqueous
layer was extracted three times with Et2O, acidified with
1 N HCl until pH¼1–3 and extracted three times with
Et2O. The combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated affording
18.5 mg (70%) of 10a: 1H NMR (250 MHz, CDCl3) d 3.09
(d, 1H, J¼13.8 Hz), 3.47 (d, 1H, J¼13.8 Hz), 4.46 (d, 1H,
J¼9.6 Hz), 4.84 (d, 1H, J¼9.6 Hz), 6.75 (d, 1H, J¼8 Hz),
6.90 (t, 1H, J¼7.4 Hz), 7.01–7.05 (m, 2H), 7.14–7.21 (m,
4H), 7.38 (d, 1H, J¼7.6 Hz); 13C NMR (100 MHz, CDCl3)
d 44.00, 57.95, 76.64, 110.59, 121.24, 125.51, 127.64,
128.24, 128.93, 130.04, 130.31, 136.28, 159.97, 178.29;
IR (film) n 3082, 3030, 2959, 2926, 2850, 1702, 1596,
1480, 1460, 1410, 1315, 1291, 1276, 1239, 1099, 1088,
1022, 973, 834, 751, 701 cmꢁ1; MS (FABꢁ, NBA)
m/z¼253 (MꢂꢁH), 209 (MꢂꢁCO2H), 46; HRMS for
C16H13O3 (MꢂꢁH): calcd 253.0865 found 253.0860.
4.1.9. 3-(2-Methylbenzyl)-3-methoxycarbonyl-2,3-di-
hydrobenzofuran (11d). Synthesized according to the
procedure described for the preparation of 11a, using 2-
methylphenylboronic acid, followed by column chromato-
graphy (silica gel, hexane/CH2Cl2: 1/1) afforded 11d (60%
1
and 28% one-pot version): H NMR (250 MHz, CDCl3)
d 2.05 (s, 3H), 3.13 (d, 1H, J¼14.7 Hz), 3.45 (d, 1H,
J¼14.7 Hz), 3.71 (s, 3H), 4.38 (d, 1H, J¼9.4 Hz), 4.92 (d,
1H, J¼9.4 Hz), 6.77 (d, 1H, J¼8 Hz), 6.81–6.88 (m, 2H),
7.03–7.11 (m, 2H), 7.15 (dd, 1H, J¼7.8 Hz, J¼1.4 Hz),
7.19–7.23 (m, 2H); 13C NMR (100 MHz, CDCl3) d 20.10,
40.76, 53.02, 57.63, 77.62, 110.46, 121.09, 125.75,
126.36, 127.35, 128.91, 129.13, 129.96, 130.93, 135.20,
137.55, 159.87, 173.68; IR (film) n 3054, 2988, 2954,
2844, 1734, 1596, 1481, 1461, 1459, 1436, 1266, 1228,
1022, 986, 896, 739, 705 cmꢁ1; MS (FAB+, NBA)
m/z¼283 (MH+), 223 (M+ꢁCO2Me), 177 (M+ꢁCH2Ar),
105, 77, 39, 27; HRMS for C18H19O3 (MH+): calcd
283.1334 found 283.1318.
4.1.10. 3-(3,4-Dimethoxybenzyl)-2,3-dihydrobenzo-
furan-3-carboxylic acid (12e). Synthesized using 3,4-di-
methoxyphenylboronic acid to afford 11e (71%).
Compound 11e was transformed according to the procedure
4.1.7. 3-(4-Methoxybenzyl)-3-methoxycarbonyl-2,3-di-
hydrobenzofuran (11b). Synthesized according to the
procedure described for the preparation of 11a, using 4-
methoxyphenylboronic acid, followed by column chromato-
graphy (silica gel, hexane/CH2Cl2: 2/3) afforded 11b (56%
1
described for preparation of 12a to afford 12e (64%): H
NMR (250 MHz, CDCl3) d 3.07 (d, 1H, J¼13.8 Hz), 3.33
(d, 1H, J¼13.8 Hz), 3.58 (s, 3H), 3.78 (s, 3H), 4.45 (d, 1H,
J¼9.5 Hz), 4.83 (d, 1H, J¼9.5 Hz), 6.39 (d, 1H,
J¼1.7 Hz), 6.61 (dd, 1H, J¼8.0 Hz, J¼1.6 Hz), 6.71 (t,
2H, J¼8.0 Hz), 6.89 (t, 1H, J¼7.4 Hz), 7.17 (t, 1H,
J¼7.4 Hz), 7.39 (d, 1H, J¼7.2 Hz); 13C NMR (100 MHz,
CDCl3) d 43.65, 55.97, 56.20, 58.09, 76.50, 110.65,
111.42, 113.06, 121.18, 122.30, 125.54, 128.09, 128.59,
130.31, 148.60, 149.04, 160.13, 179.36; IR (film) n 3076,
3004, 2931, 2832, 1705, 1592, 1515, 1478, 1460, 1415,
1315,ꢁ1261, 1238, 1152, 1139, 1026, 971, 749 cmꢁ1; MS
(FAB , NBA) m/z¼313 (MꢂꢁH), 314 (Mꢂ), 46; HRMS for
C18H17O5 (MꢂꢁH): calcd 313.1076 found 313.1066.
1
and 50% one-pot version): H NMR (250 MHz, CDCl3)
d 3.00 (d, 1H, J¼13.8 Hz), 3.36 (d, 1H, J¼13.8 Hz), 3.70
(s, 3H), 3.73 (s, 3H), 4.45 (d, 1H, J¼9.5 Hz), 4.83 (d, 1H,
J¼9.5 Hz), 6.74 (d, 3H, J¼8.6 Hz), 6.84–7.00 (m, 3H),
7.15 (td, 1H, J¼7.8 Hz, J¼1.3 Hz), 7.34 (dd, 1H,
J¼7.5 Hz, J¼1.2 Hz); 13C NMR (100 MHz, CDCl3)
d 43.68, 52.90, 55.59, 58.26, 77.00, 110.44, 114.21,
121.04, 125.55, 128.58, 128.81, 129.94, 131.02, 159.09,
159.95, 173.37; IR (film) n 3065–2998, 2952, 2924, 2849,
1732, 1610, 1596, 1583, 1513, 1480, 1461, 1440, 1291,
1274, 1247, 1179, 1114, 1097, 1035, 980, 936, 835, 793,
755 cmꢁ1; MS (FAB+, NBA) m/z¼299 (MH+), 239
(M+ꢁCO2Me), 214, 121, 177 (M+ꢁCH2Ar), 69, 57, 41,
29; HRMS for C18H19O4 (MH+): calcd 299.1283 found
299.1283.
4.1.11. 3-(3,4,5-Trimethoxybenzyl)-2,3-dihydrobenzo-
furan-3-carboxylic acid (12f). Synthesized according to
the procedure described for the preparation of 11a, using
3,4,5-dimethoxyphenylboronic acid to afford 11f (73%).
Compound 11f was transformed according to the procedure
4.1.8. 3-(3-Nitrobenzyl)-3-methoxycarbonyl-2,3-di-
hydrobenzofuran (11c). Synthesized according to the
procedure described for the preparation of 11a, using 3-
nitrophenylboronic acid, followed by column chromato-
graphy (silica gel, hexane/CH2Cl2: 2/3) afforded 11c (56%
1
described for preparation of 12a to afford 12f (71%): H
NMR (250 MHz, CDCl3) d 3.13 (d, 1H, J¼13.8 Hz), 3.38
(d, 1H, J¼13.8 Hz), 3.68 (s, 6H), 3.81 (s, 3H), 4.51 (d, 1H,
J¼9.5 Hz), 4.91 (d, 1H, J¼9.5 Hz), 6.23 (s, 2H), 6.80 (d,
1H, J¼8.0 Hz), 6.96 (t, 1H, J¼7.5 Hz), 7.23 (t, 1H,
J¼7.9 Hz), 7.44 (d, 1H, J¼7.5 Hz); 13C NMR (100 MHz,
CDCl3) d 44.21, 56.33, 58.00, 61.26, 76.49, 107.13,
110.67, 121.20, 125.51, 128.07, 130.37, 131.80, 137.51,
153.39, 160.09, 178.95; IR (film) n 3079, 3000, 2940,
2838, 1731, 1704, 1592, 1510, 1482, 1462, 1423, 1337,
1239, 1128, 1004, 977, 833, 755 cmꢁ1; MS (FABꢁ, NBA)
1
and 40% one-pot version): H NMR (250 MHz, CDCl3)
d 3.26 (d, 1H, J¼13.6 Hz), 3.48 (d, 1H, J¼13.6 Hz), 3.80
(s, 3H), 4.48 (d, 1H, J¼9.6 Hz), 4.89 (d, 1H, J¼9.6 Hz),
6.77 (d, 1H, J¼8 Hz), 6.97 (t, 1H, J¼7.5 Hz), 7.19–7.45
(m, 4H), 7.88 (br s, 1H), 8.11 (d, 1H, J¼8.2 Hz); 13C
NMR (100 MHz, CDCl3) d 43.83, 53.24, 57.86, 76.84,
110.69, 121.36, 122.67, 124.96, 125.36, 127.82, 129.63,

M. Szlosek-Pinaud et al. / Tetrahedron 63 (2007) 3340–3349
3347
m/z¼343 (MꢂꢁH), 299, 46; HRMS for C19H19O6 (MꢂꢁH):
3,4-dichlorophenylboronic acid to afford 11j (85%). Com-
pound 11j was transformed according to the procedure
described for preparation of 12a to afford 12j (69%): H
calcd 343.1182 found 343.1194.
1
4.1.12. 3-(2-Chlorobenzyl)-2,3-dihydrobenzofuran-3-
carboxylic acid (12g). Synthesized according to the
procedure described for the preparation of 11a, using 2-
chlorophenylboronic acid to afford 11g (66%). Compound
11g was transformed according to the procedure described
for preparation of 12a to afford 12g (70%): 1H NMR
(250 MHz, CDCl3) d 3.36 (d, 1H, J¼14.4 Hz, H), 3.63 (d,
1H, J¼14.4 Hz, H), 4.48 (d, 1H, J¼9.6 Hz), 4.90 (d, 1H,
J¼9.6 Hz), 6.74 (d, 1H, J¼8.0 Hz), 6.87–6.92 (m, 2H),
7.00–7.18 (m, 3H), 7.27–7.38 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 39.96, 57.59, 76.56, 110.65, 121.27,
125.63, 127.21, 127.86, 128.96, 130.22, 130.43, 131.30,
134.30, 135.43, 160.10, 179.21 (CO); IR (film) n 3064,
3024, 2961, 2850, 1703, 1595, 1480, 1461, 1443, 1317,
NMR (250 MHz, CDCl3) d 3.09 (d, 1H, J¼13.8 Hz), 3.35
(d, 1H, J¼13.8 Hz), 4.42 (d, 1H, J¼9.6 Hz), 4.85 (d, 1H,
J¼9.6 Hz), 6.72–6.85 (m, 2H), 6.92 (t, 1H, J¼7.4 Hz),
7.09 (d, 1H, J¼2.0 Hz), 7.18–7.27 (m, 2H), 7.35 (d, 1H,
J¼7.5 Hz); 13C NMR (100 MHz, CDCl3) d 42.85, 57.73,
76.44, 110.79, 121.45, 125.34, 127.47, 129.40, 130.67,
130.79, 131.93, 132.06, 132.85, 136.35, 159.95, 178.69;
IR (film) n 3065, 2993, 2954, 2929, 1704, 1595, 1481,
1462, 1398, 1316, 1279, 1238, 1134, 1032, 977, 834,
756 cmꢁ1; MS (FABꢁ, NBA) m/z¼321 (MꢂꢁH), 277
35
(MꢂꢁCO2H), 46; HRMS for C16H11O3 Cl2 (MꢂꢁH): calcd
321.0085 found 321.0076.
4.1.16. 3-(2-Trifluoromethylbenzyl)-2,3-dihydrobenzo-
furan-3-carboxylic acid (12k). Synthesized according to
the procedure described for the preparation of 11a, using
2-(trifluoromethyl)phenylboronic acid to afford 11k (49%).
Compound 11k was transformed according to the procedure
1288, 123ꢁ9, 1162, 1131, 1022, 975, 834, 751, 678 cmꢁ1
;
MS (FAB , NBA) m/z¼287 (MꢂꢁH), 243 (MꢂꢁCO2H),
223, 46; HRMS for C16H12O335Cl (MꢂꢁH): calcd
287.0475 found 287.0468.
1
described for preparation of 12a to afford 12k (55%): H
4.1.13. 3-(3-Chlorobenzyl)-2,3-dihydrobenzofuran-3-
carboxylic acid (12h). Synthesized according to the
procedure described for the preparation of 11a, using 3-
chlorophenylboronic acid to afford 11h (78%). Compound
11h was transformed according to the procedure described
for preparation of 12a to afford 12h (78%): 1H NMR
(250 MHz, CDCl3) d 3.08 (d, 1H, J¼13.8 Hz), 3.41 (d,
1H, J¼13.8 Hz), 4.44 (d, 1H, J¼9.6 Hz), 4.85 (d, 1H,
J¼9.6 Hz), 6.76 (d, 1H, J¼8.0 Hz), 6.91 (t, 2H, J¼
7.5 Hz), 7.00 (s, 1H), 7.09–7.19 (m, 3H), 7.33 (d, 1H,
J¼6.1 Hz); 13C NMR (100 MHz, CDCl3) d 43.50, 57.82,
76.53, 110.70, 121.37, 125.41, 127.83, 127.89, 128.32,
130.14, 130.25, 130.52, 134.69, 138.22, 159.97, 178.56;
IR (film) n 3080, 3022, 2959, 2926, 2851, 1704, 1596,
1573, 1481, 1462, 1430, 1409, 1316, 1277, 1239, 1209,
1082, 1022, 976, 833, 793, 752, 684 cmꢁ1; MS (FABꢁ,
NBA) m/z¼287 (MꢂꢁH), 243 (MꢂꢁCO2H), 223, 46;
NMR (250 MHz, CDCl3) d 3.42 (d, 1H, J¼15.8 Hz), 3.78
(d, 1H, J¼15.6 Hz), 4.26 (d, 1H, J¼9.7 Hz), 5.02 (d, 1H,
J¼9.7 Hz), 6.77 (d, 1H, J¼8.1 Hz), 6.93 (t, 2H, J¼
7.4 Hz), 7.18–7.25 (m, 1H), 7.29–7.32 (m, 2H), 7.39 (d,
1H, J¼7.6 Hz), 7.63 (d, 1H, J¼6.2 Hz); 13C NMR
(100 MHz, CDCl3) d 38.78, 56.90, 76.68, 110.74, 121.42,
126.05, 126.87, 126.93, 127.53, 128.01, 130.07, 130.36,
130.67, 132.28, 135.41, 160.04, 179.37 (CO); IR (film)
n 3073, 3007, 2954, 2908, 1704, 1608, 1596, 1482, 1462,
1312, 1240, 1167, 1120ꢁ, 1062, 1039, 1022, 975, 837, 769,
755 cmꢁ1; MS (FAB , NBA) m/z¼321 (MꢂꢁH), 277
(MꢂꢁCO2H), 46; HRMS for C17H12O3F3 (MꢂꢁH): calcd
321.0739 found 321.0749.
4.1.17. 3-(4-Trifluoromethoxybenzyl)-2,3-dihydrobenzo-
furan-3-carboxylic acid (12l). Synthesized according to
the procedure described for the preparation of 11a, using
4-(trifluoroacetyl)phenylboronic acid to afford 11l (66%).
Compound 11l was transformed according to the procedure
35
HRMS for C16H12O3 Cl (MꢂꢁH): calcd 287.0475 found
287.0474.
1
described for preparation of 12a to afford 12l (73%): H
4.1.14. 3-(4-Chlorobenzyl)-2,3-dihydrobenzofuran-3-
carboxylic acid (12i). Synthesized according to the
procedure described for the preparation of 11a, using 4-
chlorophenylboronic acid to afford 11i (65%). Compound
11i was transformed according to the procedure described
for preparation of 12a to afford 12i (65%): 1H NMR
(250 MHz, CDCl3) d 3.13 (d, 1H, J¼13.8 Hz), 3.43 (d,
1H, J¼14.0 Hz), 4.47 (d, 1H, J¼9.6 Hz), 4.88 (d, 1H,
J¼9.6 Hz), 6.80 (d, 1H, J¼8.1 Hz), 6.91–7.00 (m, 3H),
7.15–7.26 (m, 3H), 7.40 (d, 1H, J¼7.6 Hz); 13C NMR
(100 MHz, CDCl3) d 43.21, 57.89, 76.51, 110.70, 121.35,
125.44, 127.78, 129.07, 130.49, 131.39, 133.66, 134.64,
159.96, 179.03; IR (film) n 3084, 3028, 2952, 2925, 2884,
1704, 1596, 1481, 1462, 1408, 1317, 1296, 1238, 1094,
NMR (250 MHz, CDCl3) d 3.11 (d, 1H, J¼13.9 Hz), 3.43
(d, 1H, J¼13.9 Hz), 4.43 (d, 1H, J¼9.6 Hz), 4.85 (d, 1H,
J¼9.6 Hz), 6.75 (d, 1H, J¼8.0 Hz), 6.91 (t, 1H, J¼
7.5 Hz), 7.03 (s, 4H), 7.17 (td, 1H, J¼7.6 Hz, J¼1.3 Hz),
7.34 (d, 1H, J¼6.4 Hz); 13C NMR (100 MHz, CDCl3)
d 43.08, 57.87, 76.53, 110.71, 121.29, 121.36, 125.37,
127.81, 128.89, 130.52, 131.42, 134.91, 148.86, 159.95,
178.88; IR (film) n 3046–2931, 1704, 1596, 1510, 1482,
1462, 1416, 1258, 1222, 1166, 1111, 1021, 976, 835,
753 cmꢁ1; MS (FABꢁ, NBA) m/z¼337 (MꢂꢁH), 293
(MꢂꢁCO2H), 46; HRMS for C17H12O4F3 (MꢂꢁH): calcd
337.0688 found 337.0679.
4.1.18. 3-(4-Acetylbenzyl)-2,3-dihydrobenzofuran-3-carb-
oxylic acid (12m). Synthesized according to the procedure
described for the preparation of 11a, using 4-acetylphenyl-
boronic acid to afford 11m (73%). Compound 11m was
transformed according to the procedure described for prepa-
1016, 975, 835 cmꢁ1
;
MS (FABꢁ, NBA) m/z¼287
(MꢂꢁH), 243 (MꢂꢁCO2H), 223, 46; HRMS for
35
C16H12O3 Cl (MꢂꢁH): calcd 287.0475 found 287.0475.
1
4.1.15. 3-(3,4-Dichlorobenzyl)-2,3-dihydrobenzofuran-3-
carboxylic acid (12j). Synthesized according to the
procedure described for the preparation of 11a, using
ration of 12a to afford 12m (70%): H NMR (250 MHz,
CDCl3) d 2.57 (s, 3H), 3.22 (d, 1H, J¼13.7 Hz), 3.52 (d,
1H, J¼13.7 Hz), 4.48 (d, 1H, J¼9.6 Hz), 4.89 (d, 1H,

3348
M. Szlosek-Pinaud et al. / Tetrahedron 63 (2007) 3340–3349
J¼9.6 Hz), 6.78 (d, 1H, J¼8.1 Hz), 6.95 (t, 1H, J¼7.2 Hz),
7.14 (d, 2H, J¼8.2 Hz), 7.22 (t, 1H, J¼7.6 Hz), 7.41 (d, 1H,
J¼7.6 Hz), 7.83 (d, 2H, J¼8.2 Hz,); 13C NMR (100 MHz,
CDCl3) d 26.98, 43.79, 57.75, 76.58, 110.70, 121.37,
125.43, 127.85, 128.89, 128.96, 130.37, 130.50, 136.37,
141.99, 159.95, 178.11, 198.70; IR (film) n 3054–2931,
1731, 1704, 1682, 1607, 1571, 1481, 1461, 1415, 1360,
1268, 1238, 1186, ꢁ1119, 1021, 973, 835, 753, 737,
703 cmꢁ1; MS (FAB , NBA) m/z¼295 (MꢂꢁOH).
7.69 (m, 1H), 7.73–7.77 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 44.18, 58.07, 76.65, 110.66, 121.31, 125.56,
126.28, 126.60, 128.00, 128.03, 128.12, 128.32, 128.58,
128.99, 130.37, 132.89, 133.75, 133.86, 159.99, 178.93;
IR (film) n 3054–2860, 1704, 1596, 1508, 1481, 1461,
1367, 1315, 1239, 1154, 1099, 1022, 975, 821, 751 cmꢁ1
;
MS (FABꢁ, NBA) m/z¼303 (MꢂꢁH), 259 (MꢂꢁCO2H),
46; HRMS for C20H15O3 (MꢂꢁH): calcd 303.1021 found
303.1010.
4.1.19. 3-[4-(1,3,6-Trioxaheptane)benzyl]-2,3-dihydro-
benzofuran-3-carboxylic acid (12n). Synthesized accord-
ing to the procedure described for the preparation of 11a,
using 4-(1,3,6-trioxaheptane)phenylboronic acid to afford
11n (79%). Compound 11n was transformed according to
the procedure described for preparation of 12a to afford
4.1.22. 3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-
methylenylnaphtyl)-2,3-dihydrobenzofuran-3-carbox-
ylic acid (12q). Synthesized according to the procedure
described for the preparation of 11a, using 5,5,8,8-tetra-
methyl-5,6,7,8-tetrahydro-2-naphtylboronic acid to afford
11q (81%). Compound 11q was transformed according to
the procedure described for preparation of 12a to afford 12
(88%): 1H NMR (250 MHz, CDCl3) d 1.136 and 1.143 (2s,
6H), 1.25 (s, 6H), 1.63 (s, 4H), 3.09 (d, 1H, J¼13.8 Hz),
3.46 (d, 1H, J¼13.8 Hz), 4.50 (d, 1H, J¼9.5 Hz), 4.90 (d,
1H, J¼9.5 Hz), 6.80 (d, 1H, J¼8.0 Hz), 6.86–6.97 (m, 4H),
7.17–7.19 (m, 1H), 7.44 (dd, 1H, J¼7.6 Hz, J¼1.1 Hz);
13C NMR (100 MHz, CDCl3) d 31.99, 32.12, 32.23, 32.30,
34.39, 34.47, 35.41, 35.42, 43.76, 58.03, 76.64, 110.52,
121.18, 125.58, 127.03, 127.22, 128.18, 128.39, 130.17,
133.02, 144.08, 145.29, 159.97, 179.16; MS (FABꢁ, NBA)
m/z¼363 (MꢂꢁH), 319 (MꢂꢁCO2H), 46.
1
12n (91%): H NMR (250 MHz, CDCl3) d 3.09 (d, 1H,
J¼13.9 Hz), 3.37 (s, 3H), 3.45 (d, 1H, J¼13.9 Hz), 3.54–
3.57 (m, 2H), 3.79–3.83 (m, 2H), 4.50 (d, 1H, J¼9.5 Hz),
4.88 (d, 1H, J¼9.5 Hz), 6.79 (d, 1H, J¼8.0 Hz), 6.90–7.01
(m, 5H), 7.22 (td, 1H, J¼7.8 Hz, J¼1.4 Hz), 742 (dd, 1H,
J¼7.5 Hz, J¼1.1 Hz); 13C NMR (100 MHz, CDCl3)
d 43.18, 58.05, 59.36, 68.01, 72.01, 76.59, 93.85, 110.54,
116.63, 116.68, 121.08, 125.48, 128.34, 129.64, 129.69,
130.22, 131.12, 156.82, 159.96, 178.48; IR (film) n 3165,
3015, 2923, 2908, 2822, 1731, 1704, 1610, 1596, 1511,
1481, 1461, 1398, 1367, 13ꢁ14, 1224, 1180, 1165, 1098,
1003, 836 cmꢁ1; MS (FAB , NBA) m/z¼357 (MꢂꢁH),
313 (MꢂꢁCO2H), 46; HRMS for C20H21O6 (MꢂꢁH): calcd
357.1338 found 357.1340.
4.1.23. 3-(4-Phenylbenzyl)-3-methoxycarbonyl-2,3-di-
hydrobenzofuran (11r). Synthesized according to the
procedure described for the preparation of 11a, using 4-
biphenylboronic acid, followed by column chromatography
(silica gel, hexane/CH2Cl2: 1/1) afforded 11r (71% and 57%
one-pot version): 1H NMR (250 MHz, CDCl3) d 3.20 (d, 1H,
J¼13.7 Hz), 3.57 (d, 1H, J¼13.7 Hz), 3.82 (s, 3H) 4.60 (d,
1H, J¼9.5 Hz), 4.98 (d, 1H, J¼9.5 Hz), 6.86 (d, 1H,
J¼8 Hz), 6.99 (td, 1H, J¼7.4 Hz, J¼0.8 Hz), 7.15 (d, 2H,
J¼8.2 Hz), 7.27 (td, 1H, J¼8.6 Hz, J¼1.4 Hz), 7.39–7.56
(m, 6H), 7.62 (d, 2H, J¼7.0 Hz); 13C NMR (100 MHz,
CDCl3) d 44.10, 53.00, 58.14, 77.06, 110.54, 121.14,
125.53, 127.41, 127.53, 127.71, 128.82, 129.19, 130.07,
130.44, 135.66, 140.36, 141.05, 159.97, 173.31; IR (film)
n 3063, 3030, 2954, 2928, 2855, 1732, 1596, 1481, 1460,
1435, 1409, 1328, 1314, 1298, 1276, 1228, 1118, 1097,
1076, 1022, 1008, 981, 880, 836, 763, 699 cmꢁ1; MS
(FAB+, NBA) m/z¼573, 483, 392, 366, 345 (MH+), 344
(M+), 307, 289, 167, 91, 55, 41; HRMS for C23H21O3
(MH+): calcd 345.1491 found 345.1500.
4.1.20. 3-(4-Vinylbenzyl)-2,3-dihydrobenzofuran-3-carb-
oxylic acid (12o). Synthesized according to the procedure
described for the preparation of 11a, using 4-vinylphenyl-
boronic acid to afford 11o (53%). Compound 11o was trans-
formed according to the procedure described for preparation
of 12a to afford 12o (95%):1H NMR (250 MHz, CDCl3)
d 3.14 (d, 1H, J¼13.8 Hz), 3.50 (d, 1H, J¼13.8 Hz), 4.51
(d, 1H, J¼9.5 Hz), 4.89 (d, 1H, J¼9.5 Hz), 5.23 (dd, 1H,
J¼10.9 Hz, J¼0.6 Hz), 5.71 (dd, 1H, J¼17.6 Hz,
J¼0.7 Hz), 6.67 (q, 1H, J¼17.6 Hz, J¼10.9 Hz), 6.80 (d,
1H, J¼8.1 Hz), 6.95 (td, 1H, J¼7.5 Hz, J¼0.9 Hz), 7.04
(d, 2H, J¼8.2 Hz), 7.20–7.31 (m, 3H), 7.43 (dd, 1H,
J¼7.5 Hz, J¼1.3 Hz); 13C NMR (100 MHz, CDCl3)
d 43.73, 58.00, 76.60, 110.62, 114.31, 121.27, 125.52,
126.76, 127.00, 128.20, 130.24, 130.33, 135.87, 136.69,
136.78, 136.87, 159.97, 178.97; IR (film) n 3086, 3023,
2953, 2924, 1704, 1630, 1596, 1512, 1481, 1462, 1407,
1316, 1294, 1239, 1119, 1099, 1021, 974, 912, 835 cmꢁ1
;
MS (FABꢁ, NBA) m/z¼279 (MꢂꢁH), 235 (MꢂꢁCO2H),
46; HRMS for C18H15O3 (MꢂꢁH): calcd 279.1021 found
279.1029.
Acknowledgements
We thank Galderma S. A. (Sophia-Antipolis) and the CNRS
for financial support. We thank Yann Brouillette for his help
in proof-reading the manuscript.
4.1.21. 3-(1-Methylenylnaphtyl)-2,3-dihydrobenzofuran-
3-carboxylic acid (12p). Synthesized according to the
procedure described for the preparation of 11a, using 1-
naphtylboronic acid to afford 11p (78%). Compound 11p
was transformed according to the procedure described for
preparation of 12a to afford 12p (50%): 1H NMR
(250 MHz, CDCl3) d 3.26 (d, 1H, J¼13.8 Hz), 3.64 (d,
1H, J¼13.8 Hz), 4.54 (d, 1H, J¼9.6 Hz), 4.87 (d, 1H, J¼
9.6 Hz), 6.76 (d, 1H, J¼8.1 Hz), 6.93 (t, 1H, J¼7.1 Hz),
7.12–7.24 (m, 2H), 7.39–7.44 (m, 3H), 7.50 (s, 1H), 7.63–
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