Straightforward and Regioselective Access to Unsaturated α-Benzyl Butyrolactones

Article abstract of DOI:10.1002/ejoc.201700895

The efficient preparation of various substituted α-benzyl unsaturated butyrolactones is described. The palladium-mediated C–C bond formation that uses α-bromomethylbutenolide and boron derivatives as coupling partners accounts for the key step of this syn

Full text of DOI:10.1002/ejoc.201700895

A Journal of
Accepted Article
Title: Straightforward and regioselective access to α-benzyl
unsaturated butyrolactones
Authors: Damien Prim, Arbia Talbi, Talia talia.bsaibess@hotmail.com,
Mohamed Lotfi Efrit, Hédi M’Rabet, and Anne Gaucher
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
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the VoR from the journal website shown below when it is published
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700895
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700895
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201700895
FULL PAPER
Straightforward and regioselective access to α-benzyl
unsaturated butyrolactones
[a,b]
[b]
[a]
[a]
[b]
Arbia Talbi,
Talia Bsaibess, Mohamed Lotfi Efrit, Hédi M’Rabet,* Anne Gaucher and Damien
[b]
Prim*
2
Abstract: The efficient preparation of variously substituted α-benzyl
the Nostoclides and Maculalactones B and C families as well as
in their emerging β-H analogues (figure 1).
3
unsaturated butyrolactones is described. The palladium-mediated C-
C
bond formation at α-bromomethylbutenolide using boron
The joint presence of these structural common features
motivated the developments of various approaches to
independently install all fragments at the butenolide frame. Main
key steps consist in the selective installation of a benzyl and a
arylvinylidene group in both α and γ positions of the butenolide
derivatives as coupling partners accounts for the key step of the
sequence. Our strategy exclusively afforded the endocyclic-adduct
which represented an alternative to Heck-type reactions. The
synthesis and characterization of two new nostoclide analogues is
also reported.
core. If the installation of
butenolides is described from the unsubstituted parent lactone
γ arylvinylidene fragments to
4
5
or during the construction of the heterocycle, the selective
installation of benzyl fragment remains challenging. Among
possible routes towards such targets, those involving a key
Introduction
6
metal-catalysed installation of substituents at the butyrolactone
core have recently received particular attention (scheme 1).
Although selective, the introduction of the benzyl fragment at α-
bromo butyrolactone by means of the Negishi-type coupling is
The butenolide subunit represents an appealing heterocyclic
platform which can be found in a vast array of pharmacologically
active natural and non-natural products. For example, the
1
association of
a
butenolide core with
a
benzyl and an
3a
scarcely reported. In fact, only the unsubstituted benzyl group
arylvinylidene group is of specific interest due to phytotoxic,
cytotoxic and marine anti-fouling activities of such molecules.
was installed in the appropriate α-position. Interestingly, recent
investigations on the reactivity of α-methylene butyrolactones
under various Pd-catalyzed arylation conditions evidenced that
O
O
O
the selective production of α-benzyl unsaturated butyrolactones
7
(
endocyclic-adduct in scheme 1) is not trivial. Indeed, mixtures
R
O
O
O
of both endocyclic and exocyclic adducts are usually obtained in
moderate to poor selectivities using Mirozoki-Heck, Matsuda-
Heck or C-H arylation strategies.
O
Cl
OH
O
Nostoclides
O
O
Negishi-type benzylation strategy
Br
[
Pd], PhCH2ZnBr
-
H analogues
O
O
O
Maculalactone B and C
O
one example
Figure 1. Molecular structure of nostoclides, maculalactone B or C (left) and
recent β-H analogues (right).
Mirozoki-Heck, Matsuda-Heck and C-H arylation strategies
[
Pd]
[
Pd]
Indeed, the presence of these structural key elements but more
importantly the precise α and γ positions of the benzyl and an
+
O
O
O
O
O
O
O
O
endocyclic adduct exocyclic adduct
A
Selective Suzuki strategy
[
a]
b]
Université de Tunis El Manar, Faculté des Sciences de Tunis,
Laboratoire de Synthèse Organique Sélective et Hétérocyclique-
Evaluation de l’Activité Biologique, 2092 Tunis, Tunisie.
E-mail: mrabet.fst@gmail.com
Université de Versailles Saint Quentin-en-Yvelines, Institut Lavoisier
de Versailles-UMR CNRS 8180, 45 avenue des Etats-Unis, 78035
Versailles, France.
Br
[Pd]
[
Pd]
This work
O
O
O
O
O
O
[
1
exclusive
B
Scheme 1. Comparison of arylation strategies from α-bromo butyrolactone
and α-methylene butyrolactone (literature) and bromolactone 1 (this work).
E-mail: damien.prim@.uvsq.fr
Supporting information for this article is given via a link at the end of
the document.
arylvinylidene fragments at the butenolide core can be found in
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European Journal of Organic Chemistry
10.1002/ejoc.201700895
FULL PAPER
The presence of both adducts plausibly originates from
competitive syn-β-elimination processes from intermediate A.
One way to enhance selectivity would be to favor only one syn-
β-elimination process. In this context, the nature of the coupling
partner, the electronic effects of substituents, the nature of the
base and the possible presence of a chelating group at the
butyrolactone substrate indeed strongly affect the endo-
/
exocyclic adduct distribution but lead at best to the endocyclic
target as the major product. In order to circumvent the syn-β-
elimination process arising from carbopalladation of the α-
methylene butyrolactones, we anticipated that switching from
Heck-type to Suzuki strategy starting from bromolactone 1
through intermediate B would represent an appealing alternative
and exclusively afford the expected endocyclic adduct.
The objective of our work is mainly to provide a selective route
towards α-benzyl unsaturated butyrolactones from the readily
available parent bromomethylbutenolide 1. According to figure 2,
the key Pd mediated C-C bond formation will be followed by the
installation of arylvinylidene fragment at the γ position giving an
easy access to maculalactone B or C and nostoclide β-H
analogues.
Scheme 2. Selective access to variously α-functionalized unsaturated
butyrolactones 3-9.
The presence of a nitro group allowed forming the expected
Suzuki-Miyaura product 7 in 42% albeit 42h were required to
ensure completion of the reaction. Both methoxy- and
trismethoxy-benzene boronic acids afforded lactones 8 and 9 in
45 and 79% yields respectively.
A further objective was the installation of aryl groups bearing
nucleophilic hydroxyl or amino groups. To this end, we reacted
Figure 2. Strategy towards maculalactone
analogues.
B or C and nostoclide β-H
2-(hydroxymethyl)phenylboronic acid cyclic monoester 10 with
the bomomethylbutenolide under the aforementioned
1
conditions. The expected hydroxymethyl derivative 11 was
isolated in a high 78% yield after 4h of reaction course (scheme
Results and Discussion
3
). Disappointingly, attempts to couple 2-hydroxyphenylboronic
We started our investigations to determine suitable conditions to
selectively transform bromolactone 1 into targeted lactone 3-9
8
acid 12 failed. The corresponding coupling product 13 could not
be isolated, regardless of the modulations of experimental
conditions such as reaction time (from 30min to 2h) or
temperature (30 °C to reflux), the amount of boronic acid (1 to 2
eq.). In each case, intractable mixtures of several products were
obtained, presumably arising from OH-induced ring opening of
the lactone.
and 11. Disappointingly, the use of Pd(OAc)
10%)/Cs CO (3 eq.) as the catalytic system in the presence or
absence of Bu
contrast, Pd(dppf)Cl
2 3
(5%)/Ph P
(
2
3
9
4
NBr as an additive revealed ineffective. In
(7%) in combination with CsF (2.5 eq.) as
2
the base in refluxing THF afforded a clean and complete
conversion of the starting bromide towards the expected α-
benzylbutyrolactone 3 in 90% yield. Under these conditions no
isomerisation of the double bond to the potential exo-adduct was
observed (scheme 2). With these conditions in hand, we
extended the scope of the Suzuki-Miyaura coupling to various
boronic acids. Reactions were run until disappearance of the
starting material in TLC. Results obtained are gathered in
scheme 2. 2,3-Dihydrobenzofuran- and pyren-boronic acids
smoothly reacted to afford the corresponding butyrolactones 4
(
in 1h) and 5 (in 18h) as single products in 73 and 85% isolated
yields respectively. We next focused on the installation of
substituted aromatics at the butenolide scaffold. In this context,
2-styryl boronic acid could be efficiently coupled to afford vinyl
derivative 6 in 66% yield. Finally, boronic acids bearing electron
Scheme 3. Installation of aryl groups bearing hydroxyl substitutents.
withdrawing and electron releasing groups were tested.
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European Journal of Organic Chemistry
10.1002/ejoc.201700895
FULL PAPER
The use of 2-aminophenylboronic acid 14 led to surprising
1
results (scheme 4). Careful analysis of H NMR of the coupling
crude material allowed identifying two major products. The
O
O
presence of the expected coupling product 15 could be
undoubtedly evidenced thanks to the characteristic H NMR
R
O
O
BF3K (1.2 eq.)
1
F
F3C
O
17
1
8
fingerprint of protons H5, H6 which resonated at 4.78 and 4.06
ppm respectively and aromatic proton H7 in ortho to the amine
substituent which resonated at 6.68 ppm for 1H. Unfortunately,
we were not able to fully characterize this product due to rapid
degradation upon purification attempts (see ESI).
cat.syst., conditions
Br
O
O
O
1
O
O
OHC
CH3
19
20
Table 1. Cross-Coupling of 3-(Bromomethyl)furan-2(5H)-one 1 with Potassium
arylltrifluoroborates
[
a]
Entry
1
Cat. syst.(%)
Conditions
Product
17
Yield(%)
Pd(dppf)Cl
5%)
Cs CO
2
A
30
(
2
3
(3 eq.)
2
3
4
Pd(OAc)
10%),
PPh (20%)
Cs CO (3 eq.)
2
A
B
17
17
17
10
Scheme 4. Coupling of 2-aminophenylboronic acid 14 to butenolide
chemical shifts in ppm).
1
(
(
3
2
3
In contrast, we were able to isolate compound 16 in a fair 60%
Pd(OAc)2
(10%),
-
1
yield. Substituted butenolide 16 has been fully characterized. H
PPh (20%)
3
CO (3 eq.)
3
NMR spectrum displays a clear fingerprint including protons H5,
H6 which resonated at 4.79 and 4.09 ppm respectively and both
aromatic protons H7 which resonated at 6.63 ppm for 2H.
K
2
Pd(dppf)Cl
(5%)
2
C
C
55
The obtention of butenolide 16 likely arise from a sequence
including one hydrodeborylation step and the formation of the C-
N bond through nucleophilic substitution of the bromine atom.
Under our reaction conditions, the formation of C-N bond most
likely takes place prior to the hydrodeborylation process. Indeed,
amination of bromomethylbutenolide usually occurs at room
2 3
K CO (3 eq.)
5
6
Pd(dppf)Cl
5%)
2
17
18
-
(
[
b]
Pd(dppf)Cl
(5%)
2
C
C
C
40
1
0
temperature as already stated.
Attempts to vary the
2 3
K CO (3 eq.)
experimental conditions as well as the ratio of reactants
invariably led to the formation of nucleophilic substitution product
[a]
7
8
Pd(dppf)Cl
(5%)
2
19
20
65
-
16. The use of lesser nucleophilic acetamido boronic acid, failed
2 3
K CO (3 eq.)
to react either in the nucleophilic substitution or the coupling
reaction.
[
c]
Pd(dppf)Cl
5%)
CO
2
As an alternative to boronic acids, we next tested the ability of
aryltrifluoroborates to couple with bromomethylbutenolide 1.
(
K
2
3
(3 eq.)
1
1
Based on protocols developed by Molander
Pd(dppf)Cl (5%)/Cs CO (3 eq.) as the catalytic system and the
base in the cross coupling of 4-fluorophenyltrifluoroborate and
butenolide 1 (table 1, entry1). After 60 min in refluxing THF/H O,
the expected fluoroderivative 17 was obtained in 30% yield.
Under experimental conditions A, using Pd(OAc) (10%) and
PPh (20%) as the catalytic system instead of Pd(dppf)Cl
starting butenolide was only poorly converted into the product 17
entry 2). Moving from THF/H O to MeOH as the solvent led the
reactants unchanged even after 18h at reflux (entry 3). Finally
best results were obtained using conditions C and K CO (3 eq.)
as the base (entry 4). Only 20min in refluxing toluene/H
we used
2
2
3
2
[a] Conditions A: THF/H O, 10:1 reflux 60 min; Conditions B: MeOH reflux 18h;
Conditions C:Toluene/H O, 10:1 reflux 20 min. [b] 30min. [c] 60min
2
2
In addition, under conditions C, we were able to isolated new
benzylbutenolides 18 and 19, bearing trifluoromethyl and methyl
groups in 40 and 65% yields respectively (entries 6 and 7). Only
the 4-formylphenyltrifluoroborate remained reluctant to coupling
under these conditions (entry 8).
Finally, we describe the preparation of two new nostoclide
analogues 21 and 22. Installation of the γ-vinylidene fragment at
lactones 4 and 5 was realized using a one pot-two step
2
3
2
,
(
2
2
3
2
O
mixture were required to fully convert the starting materials into
the expected target in 55% yield. Control experiment run without
1
2
sequence (scheme 5). Analogues 21 and 22, display a
butenolide core bearing an γ-methoxyphenylvinylidene group
and either a dihydrobenzofuranylmethyl or pyrenylmethyl pattern
2 3
the presence of K CO evidenced the mandatory use of a base
for this transformation.
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European Journal of Organic Chemistry
10.1002/ejoc.201700895
FULL PAPER
located α to the unsaturated lactone. Both analogues 21 and 22
were isolated in fair 48 and 52% yields respectively.
by addition of water (10 mL), the organic layer was then separated and
the aqueous phase was extracted twice with CH
extraction), the combined organic extracts were then washed with brine
5 mL), dried over anhydrous MgSO , filtered, and concentrated under
reduced pressure. The crude residue was purified by column
2 2
Cl (20 mL for each
(
4
O
O
O
2 2
chromatography on silica gel, using CH Cl /petroleum ether mixtures of
increasing polarity as eluent.
O
O
O
OMe
OMe
1
) TBDMSOTf, DIPEA,
O
4
rt, 1h
O
2
1 48%
1
3
-Benzylfuran-2(5H)-one 3. Colorless oil; Yield: (88 mg, 90%); H NMR
MeO
CHO
or
or
O
3
(300 MHz, CDCl ): δ = 7.36-7.23 (m, 5H), 6.94 (s, 1H), 4.76 (d, J = 1.8
13
O
Hz, 2H), 3.61 (s, 2H); C NMR (75 MHz, CDCl
3
): δ = 173.9, 145.5, 137.3,
2
) DBU, reflux, 16 h
1
34.3, 128.9, 128.8, 126.8, 70.2, 31.5; HRMS (ESI) calcd. for C11H O
11 2
+
[M+H] 175.0681, found 175.0682. Physical data are in accordance with
5
22 52%
6
literature.
Scheme 5. Synthesis of two new nostoclide analogues.
3-((2,3-Dihydrobenzofuran-5-yl)methyl)furan-2(5H)-one 4. Yellow oil;
1
Yield: (89 mg, 73%); H NMR (300 MHz, CDCl
3
): δ = 7.08 (s, 1H), 6.97 (d,
J = 9.0 Hz, 1H), 6.96 (s, 1H), 6.73 (d, J = 9.0 Hz, 1H), 4.77 (d, J = 2.1 Hz,
13
2H), 4.56 (t, J = 9.0 Hz, 2H), 3.53 (s, 2H), 3.20 (t, J = 9.0 Hz, 2H);
C
Conclusions
3
NMR (75 MHz, CDCl ): δ = 174.1, 159.0, 145.4, 134.7, 129.3, 128.4,
1
C
27.6, 125.5, 109.2, 71.3, 70.3, 31.2, 29.7; HRMS (ESI) calcd. for
H O [M+H] 217.0859, found 217.0856.
13 13 3
+
In summary, an efficient and highly selective access to α-
functionnalized butenolide has been developed. Arylboronic
acids as well as potassium aryltrifluoroborates revealed efficient
cross-coupling partners allowing the exclusive access to the
corresponding endocyclic adducts in an average of moderate to
good yields. Variously substituted benzylic fragments bearing
electron withdrawing or donating group were successfully
installed at the unsaturated butyrolactone core. In addition, the
installation of a γ-vinylidene fragment on lactones 4 and 5 was
also achieved providing a short two-step sequence towards new
nostoclide analogues 21 and 22.
3-(Pyren-2-ylmethyl)furan-2(5H)-one 5. Light yellow solid; Mp: 151-
1
3
152 °C; Yield: (143 mg, 85%); H NMR (300 MHz, CDCl ): δ = 8.23-7.91
13
(
m, 9H), 6.59 (s, 1H), 4.68 (d, J = 1.8 Hz, 2H), 4.32 (s, 2H); C NMR (75
3
MHz, CDCl ): δ = 173.9, 146.2, 134.2, 131.3, 130.8, 130.7, 128.8, 128.0,
1
27.9, 127.4, 127.3, 126.1, 125.4, 125.2, 125.1, 123.2, 70.1, 29.2; HRMS
+
15 2
(ESI) calcd. for C21H O [M+H] 299.1072, found 299.1067.
1
3
-(2-Vinylbenzyl)furan-2(5H)-one 6. Yellow oil; Yield: (75 mg, 66%); H
): δ = 7.56 (d, J = 9.0 Hz, 1H), 7.30-7.19 (m, 3H),
.84 (dd, J = 11.1, 17.4 Hz, 1H), 6.76 (s, 1H), 5.67 (d, J = 17.4 Hz, 1H),
NMR (300 MHz, CDCl
6
5
3
13
.31 (d, J = 11.1 Hz, 1H), 4.74 (d, J = 1.8 Hz, 2H), 3.67 (s, 2H); C NMR
): δ = 173.8, 146.1, 136.7, 134.7, 134.1, 133.6, 130.3,
(75 MHz, CDCl
3
1
28.1, 127.5, 126.1, 116.3, 70.3, 29.4; HRMS (ESI) calcd. for C13
13
H O
2
+
[M+H] 201.0916, found 201.0914.
Experimental Section
1
3
-(3-Nitrobenzyl)furan-2(5H)-one 7. Grayish oil; Yield: (52 mg, 42%); H
General Methods. All experiments were conducted in dry reaction
NMR (300 MHz, CDCl
3
): δ = 8.15 (d, J = 9.0 Hz, 1H), 8.13 (s, 1H), 7.65
vessels under argon atmosphere. Solvents were purified by standard
1
(d, J = 9.0 Hz, 1H), 7.53 (t, J = 9.0 Hz, 1H), 7.11 (s, 1H), 4.85 (d, J = 1.5
procedures. H NMR spectra were obtained at 300 MHz in CDCl
3
with
1
3
Hz, 2H), 3.76 (s, 2H); C NMR (75 MHz, CDCl
3
): δ = 173.4, 148.5, 146.3,
CHCl
given in hertz (Hz) and chemical shifts in ppm. C NMR spectra were
recorded at 75 MHz in CDCl with CDCl (δ = 77.0 ppm) as an internal
3
(δ = 7.28 ppm) as an internal standard. Coupling constants are
13
139.3, 135.3, 132.8, 129.8, 123.8, 122.1, 70.4, 31.5; HRMS (ESI) calcd.
-
8
for C11H NO
4
[M-H] 218.0459, found 218.0469.
3
3
standard. All NMR spectra were acquired at room temperature.
Multiplicity of peaks is indicated by the following: s: singlet; d: doublet;
dd: doublet of doublet; t: triplet; q: quartet; br.: broad; m: multiplet. High
Resolution Mass spectroscopy data were recorded on an Autospec
Ultima (Waters/Micromass) device with a resolution of 5000 RP at 5%.
All reactions were monitored by TLC on silica gel plates (Fluka Kiesel gel
3
4
1
-(2,3,4-Trimethoxybenzyl)furan-2(5H)-one 8. Brown oil; Yield: (67 mg,
1
5%); H NMR (300 MHz, CDCl
3
): δ = 6.93 (s, 1H), 6.90 (d, J = 8.4 Hz,
H), 6.64 (d, J = 8.4 Hz, 1H), 4.76 (d, J = 2.1 Hz, 2H), 3.89 (s, 3H), 3.88
13
(s, 3H), 3.87 (s, 3H), 3.55 (s, 2H); C NMR (75 MHz, CDCl
3
): δ = 174.1,
1
5
2
52.7, 151.5, 144.9, 142.6, 134.2, 124.3, 123.1, 106.7, 70.0, 60.9, 60.6,
5.7, 25.6; HRMS (ESI) calcd. for C14
65.1075.
+
17 5
H O [M+H] 265.1076, found
6
0 F254, Merck) and visualized by a 254 nm UV lamp and potassium
permanganate aqueous solution. Melting points (Mp) were determined on
System Kofler type WME apparatus. Column chromatography
a
separations were performed using silica gel (0.040-0.060 mm).
3-(4-Methoxybenzyl)furan-2(5H)-one 9. Yellow oil; Yield: (91 mg, 79%);
1
H NMR (300 MHz, CDCl
3
): δ = 7.17 (d, J = 9.0 Hz, 2H), 6.94 (s, 1H),
6
.88 (d, J = 9.0 Hz, 2H), 4.76 (d, J = 1.5 Hz, 2H), 3.81 (s, 3H), 3.56 (s,
General procedure for cross-coupling reaction of arylboronic acids.
13
2
1
2
H); C NMR (75 MHz, CDCl
29.4, 114.1, 70.3, 55.3, 31.9; HRMS (ESI) calcd. for C12
05.0865, found 205.0865. Physical data are in accordance with
3
): δ = 174.0, 158.5, 145.5, 134.5, 129.9,
+
13 3
H O [M+H]
To a solution of 3-(bromomethyl)furan-2(5H)-one 1 (100 mg, 0.56 mmol)
in THF (3 mL) at ambient temperature was added arylboronic acids
10a
literature.
2
(0.67 mmol, 1.2 eq.), Pd(dppf)Cl (29 mg, 0.04 mmol) and cesium
fluoride (215 mg, 1.40 mmol). After addition was completed, the mixture
was heated to 65 °C and stirred until complete conversion of the starting
material 1. After cooling to room temperature, the reaction was quenched
3
-(2-(Hydroxymethyl)benzyl)furan-2(5H)-one 11. Brown oil; Yield: (90
1
3
mg, 78%); H NMR (300 MHz, CDCl ): δ = 7.43 (d, J = 9.0 Hz, 1H), 7.31
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700895
FULL PAPER
(
m, 2H), 7.22 (d, J = 9.0 Hz, 1H), 7.02 (s, 1H), 4.79 (d, J = 1.8 Hz, 2H),
purified by chromatography on silica gel with (CH
8:2) as eluent.
2 2
Cl /petroleum ether,
13
4
1
2
2
.73 (s, 2H), 3.74 (s, 2H), 1.96 (brs 1H); C NMR (75 MHz, CDCl
3
): δ =
74.2, 145.9, 138.7, 135.4, 133.9, 130.2, 129.2, 128.3, 127.4, 70.4, 63.2,
+
8.3; HRMS (ESI) calcd. for C12
12 3
H O Na [M+Na] 227.0684, found
3-((2,3-Dihydrobenzofuran-5-yl)methyl)-5-(4-methoxybenzylidene)
27.0679.
furan-2(5H)-one 21. Dark yellow solid; Mp: 163.8-164.8 °C; Yield: (30
1
mg, 48%); H NMR (300 MHz, CDCl
3
): δ = 7.72 (d, J = 9.0 Hz, 2H), 7.11
3
-((Phenylamino)methyl)furan-2(5H)-one 16. Yellow oil; Yield: (65 mg,
(s, 1H), 7.02-6.89 (m, 4H), 6.76 (d, J = 9.0 Hz, 1H), 5.85 (s, 1H), 4.59 (t,
1
13
60%); H NMR (300 MHz, CDCl
3
): δ = 7.30 (s, 1H), 7.20 (t, J = 9.0 Hz,
J = 9.0 Hz, 2H), 3.85 (s, 3H), 3.66 (s, 2H), 3.22 (t, J = 9.0 Hz, 2H);
NMR (75 MHz, CDCl ): δ = 170.7, 160.2, 159.1, 146.1, 139.5, 132.1,
131.8, 129.3, 128.4, 127.6, 126.0, 125.5, 114.3, 112.5, 109.3, 71.3, 55.3,
C
2H), 6.76 (t, J = 9.0 Hz, 1H), 6.63 (d, J = 9.0 Hz, 2H), 4.79 (d, J = 2.4 Hz,
3
13
2H), 4.18 (brs, 1H), 4.09 (s, 2H); C NMR (75 MHz, CDCl
3
): δ = 173.5 ,
+
147.1, 146.5, 131.8, 129.4, 118.3, 113.2, 70.6, 39.6; HRMS (ESI) calcd.
31.1, 29.7; HRMS (ESI) calcd. for C21
19 4
H O [M+H] 335.1278, found
+
13
2
for C11H12NO [M+H] 190.0863, found 190.0860.
335.1270.
Representative procedure for cross-coupling reaction of potassium
aryltrifluoroborates.
5-(4-Methoxybenzylidene)-3-(pyren-2-ylmethyl)furan-2(5H)-one
This compound was prepared using the same procedure as compound
1, from 3-(pyren-2-ylmethyl)furan-2(5H)-one 5 (40 mg, 0.13 mmol),
22.
2
TBDMSOTf (41 μL, 0.18 mmol), diisopropylethyl amine (49.7 μL, 0.28
mmol), 4-methoxybenzaldehyde (39.5 mg, 0.28 mmol), DBU (42.25 μL,
To a stirred mixture of bromomethylbutenolide 1 (50 mg, 0.28 mmol) and
potassium aryltrifluoroborates (0.33 mmol, 1.2 eq.) in Toluene-H
2
O (10:1,
0.28 mmol) and anhydrous dichloromethane (2 mL). After
3
mL), K CO (117 mg, 0.85 mmol) and Pd(dppf)Cl (10 mg, 0.015 mmol)
2
3
2
chromatography, the desired product was obtained as a yellow solid; Mp:
were rapidly added. The solution was heated at 110 °C until total
consumption of the starting material 1. After cooling to room temperature,
the reaction was quenched by addition of water (5 mL), the organic layer
1
186.3-187.3 °C; Yield: (29 mg, 52%); H NMR (300 MHz, CDCl
3
): δ =
8
.23-7.96 (m, 9H), 7.65 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 6.62
13
(
s, 1H), 5.65 (s, 1H), 4.45 (s, 2H), 3.80 (s, 3H); C NMR (75 MHz,
CDCl ): δ = 170.7, 160.2, 146.1, 140.3, 132.1, 131.3, 131.2, 131.1, 130.8,
30.7, 128.9, 128.1, 127.9, 127.4, 127.3, 126.1, 125.9, 125.4, 125.2,
25.1, 124.8, 123.2, 114.3, 112.8, 55.3, 29.5; HRMS (ESI) calcd. for
was separated and the aqueous phase was extracted twice with CH
Cl
2 2
(10 mL for each extraction), the combined organic extracts were then
3
1
1
4
washed with brine (5 mL), dried over anhydrous MgSO , filtered, and
concentrated under reduced pressure. The crude residue was purified by
column chromatography on silica gel, using petroleum ether/AcOEt
mixtures of increasing polarity as eluent.
+
29 21 3
C H O [M+H] 417.1485, found 417.1472.
3
-(4-Fluorobenzyl)furan-2(5H)-one 17. Light yellow solid; Mp: 92-94 °C;
1
Yield: (30 mg, 55%); H NMR (300 MHz, CDCl
3
): δ = 7.22 (dd, J = 9.0,
6
3
.0 Hz, 2H), 7.09 (t, J = 9.0 Hz, 2H), 6.96 (s, 1H), 4.79 (d, J = 1.8 Hz, 2H),
.60 (s, 2H); C NMR (75 MHz, CDCl ): δ = 173.8, 161.8 (d, J = 250.2
3
Acknowledgements
13
Hz), 145.5, 134.2, 133.0, 130.4 (d, J = 8.5 Hz), 115.6 (d, J = 28.5 Hz),
+
This work was supported by the Tunisian Ministry of Higher
Education and Scientific Research, the University of Versailles
St-Quentin and CNRS.
7
0.1, 30.8; HRMS (ESI) calcd. for C11
2
H10FO [M+H] 193.0665, found
10e
193.0659. Physical data are in accordance with literature.
3
-(4-(Trifluoromethyl)benzyl)furan-2(5H)-one 18. Yellow oil; Yield: (28
1
mg, 40%); H NMR (300 MHz, CDCl
3
): δ = 7.61 (d, J = 7.8 Hz , 2H), 7.39
(
d, J = 7.8 Hz, 2H), 7.01 (s, 1H), 4.81 (d, J = 1.5 Hz, 2H), 3.70 (s, 2H);
1
3
C NMR (75 MHz, CDCl
3
): δ = 173.6, 145.9, 141.4, 133.4, 129.3, 125.7
Keywords: unsaturated butyrolactones • palladium • Suzuki-
(
C
q, J = 7.7 Hz), 124.1 (q, J = 272 Hz), 70.3, 31.7; HRMS (ESI) calcd. for
+
12 10 3
H F O
2
[M+H] 243.0633, found 243.0639.
Miyaura • Nostoclides analogues
3
-(2-Methylbenzyl)furan-2(5H)-one 19. Yellow oil; Yield: (35 mg, 65%);
[1]
a) R. R. Teixeira, L. C. A. Barbosa, C. R. A. Maltha, M. E. Rocha, D. P.
Bezzerra, L. V. Costa-Lotufo, C. Pessoa, M. O. Moraes, Molecules
2007, 12, 1101-1116; b) A. Kar, S. Gogoi, N. P. Argade, Tetrahedron
2005, 61, 5297-5302; c) E. Negishi, M. Kotora, Tetrahedron 1997, 53,
6707-6738.
1
3
H NMR (300 MHz, CDCl ): 7.22-7.18 (m, 4H), 6.78 (s, 1H), 4.77 (d, J =
13
1
1
1
.8 Hz, 2H), 3.61 (s, 2H), 2.28 (s, 3H); C NMR (75 MHz, CDCl
73.9, 145.5, 136.2, 135.7, 133.6, 130.6, 129.8, 127.2, 126.4, 70.4, 29.5,
9.1; HRMS (ESI) calcd. for C12H O [M+H] 189.0916, found 189.0910.
13 2
3
): δ =
+
[
2]
3]
a) S.-C. Lee, G. D. Brown, J. Nat. Prod. 1998, 61, 29–33; b) W.-Y. Tsui,
G. A. Williams, G. D. Brown, Phytochemistry 1996, 43, 1083-1095.
a) L. C. A. Barbosa, J. O. S. Varejao, D. Petrollino, P. F. Pinheiro, A. J.
Demuner, C. R. A. Maltha, G. Forlani, Arkivoc 2012, iv, 15-32; b) R. R.
Teixeira, L. C. A. Barbosa, J. W. M. Carneiro, R. S. Correa, J. Ellena, A.
C. Doriguetto, J. Mol. Struct. 2009, 917, 1-9; c) R. R. Teixeira, L. C. A.
Barbosa, G. Forlani, D. Pilo-Veloso, J. W. M. Carneiro, J. Agric. Food.
Chem. 2008, 56, 2321-2329; d) R. R. Teixeira, L. C. A. Barbosa, J. O.
Santan, D. P. Veloso, J. Ellena, A. C. Doriguetto, M. G. B. Brew, F. M.
D. Ismail, J. Mol. Struct. 2007, 837, 197-205. e) ; C. J. G. Duncan, M.
Cuendet, F. R. Fronczek, J. M. Pezzuto, R. G. Mehta, M. T. Hamann, S.
A. Ross, J. Nat. Prod. 2003, 66, 103-107.
Representative procedure for new nostoclide analogues.
[
A 25 mL round bottom flask, under argon atmosphere, were added 3-
((2,3-dihydrobenzofuran-5-yl)methyl)furan-2(5H)-one 4 (40 mg, 0.18
mmol), anhydrous dichloromethane (1 mL), TBDMSOTf (56 μL, 0.24
mmol), diisopropylethyl amine (66 μL, 0.38 mmol) and 4-
methoxybenzaldehyde (47 mg, 0.38 mmol). The resulting mixture was
stirred at room temperature for 1h. After adding DBU (57 μL, 0.38 mmol),
the reaction mixture was refluxed for an additional for 16h and anhydrous
dichloromethane (1 mL) was added. The resulting organic layer was
-1
washed with 2 mol.L HCl aqueous solution (2 x 10 mL) and brine (10
mL). After separation, the organic layer was dried over MgSO , filtered,
and concentrated under reduced pressure. The crude residue was
4
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700895
FULL PAPER
[
4]
L. C. A. Barbosa, C. R. A. Maltha, M. R. Lage, R. C. Barcelos, A. Dona,
Colby, J. Org. Chem. 2009, 74, 7176-7179; e) A. Arcadi, M. Chiarini, F.
Marinelli, Z. Berente, L. Kollar, Eur. J. Org. Chem. 2001, 3165-3173; f)
A. Arcadi, M. Chiarini, F. Marinelli, Z. Berente, L. Kollar, Org. Lett. 2000,
2, 3165-3173; g) H. Brunner, N. L. C. de Courcy, J.-P. Genet,
Tetrahedron Lett. 1999, 40, 4815-4818.
J. W. M. Carneiro, G. Forlani, J. Agric. Food. Chem. 2012, 60, 10555-
10563;
[
5]
6]
see for example D. Prim, A. Fuss, G. Kirsch, A. M. S. Silva, J. Chem.
Soc., Perkin Trans. 2 1999, 1175-1180.
[
a) for iterative functionalisation and selective reduction process from
maleic anhydride derivatives see ref 4. b) for flash vacuum pyrolysis of
anthracene Diels-Alder adducts see S. Jones, I. Wilson, Tetrahedron
Lett. 2006, 47, 4377-4380. c) for ring expansion of four-membered ring
lactones see T. H. Black, J. Huang, Tetrahedron Lett. 1993, 34, 1411-
[8]
[9]
The synthesis of compound 1 was previously prepared in six steps from
γ-butyrolactone. See (a) A. Calderón, P. de March, M. el Arrad, J. Font,
Tetrahedron 1994, 50, 4201-4214; b) C. B. Chapleo, K. L. Svanholt, R.
Martin, A. S. Dreiding, Helv. Chim. Acta. 1976, 59, 100-107. We found
that the use of acetone as the solvent allowed cleaner transformation
and easier purification step in the preparation of starting material 1.
T. Jeffery, Tetrahedron 1996, 52, 10113-10130.
1412. d) for oxidation and elimination of selenoethers see E. Bosch, J.
K. Kochi, J. Chem. Soc., Perkin Trans. 1 1996, 2731-2738. e) for
nucleophilic addition and substitution followed by dearomatisation of
furanes see . Boukouvalas, R. P. Loach, J. Org. Chem. 2008, 73, 8109-
[10] A. Talbi, A. Arfaoui, T. Bsaibess, M. L. Efrit, A. Gaucher, D. Prim, H.
M’Rabet, Org. Biomol. Chem. 2017, 15, 3298-3303.
8
112.
[11] G. A. Molander, N. Ellis, Acc. Chem. Res. 2007, 40, 275-286.
[12] Following the procedure developed by Argade (see ref 1b) or Teixeira
(see ref 3).
[7]
a) B. Schmidt, F. Wolf, C. Ehlert, J. Org. Chem. 2016, 81, 11235-
11249; b) S. H. Kim, K. H. Kim, H. J. Lee, J. N. Kim, Tetrahedron Lett.
2013, 54, 329-334; c) A. V. Belovodskii, E. E. Shults, M. M. Shakirov, I.
Yu. Bagryanskaya, Yu. V. Gatilov, G. A. Tolstikov, Russ. J. Org. Chem.
010, 46, 1719−1734; d) C. Han, F. J. Barrios, M. V. Riofski, D. A.
2
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European Journal of Organic Chemistry
10.1002/ejoc.201700895
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
Selective palladium-promoted access
to α-functionnalized butenolides has
been developed from arylboron
α-Benzyl unsaturated butyrolactones
A. Talbi, T. Bsaibess, M. L. Efrit, H.
M’Rabet,* A. Gaucher and D. Prim*
derivatives
and
α-bromomethyl-
butenolide. In addition a short two
step new route towards nostoclide
analogues is also described.
Page No. – Page No.
Title
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