Copper-catalyzed preparation of γ-alkylidenebutenolides and isocoumarins under mild palladium-free conditions

Article abstract of DOI:10.1002/adsc.200800757

A general and efficient copper(I)-catalyzed cross-coupling and heterocyclization reaction of terminal alkynes and β-iodo-α,β- unsaturated acid derivatives has been developed under very mild conditions. This method provides easy access from good to excellent yields of a variety of 5-ylidenebutenolides and 3-substituted isocoumarins with excellent regio- and stereoselectivity. This procedure does not require the use of any expensive supplementary additives, and is palladium-free.

Full text of DOI:10.1002/adsc.200800757

FULL PAPERS
DOI: 10.1002/adsc.200800757
Copper-Catalyzed Preparation of g-Alkylidenebutenolides and
Isocoumarins under Mild Palladium-Free Conditions
Samuel Inack-Ngi,a Raphaꢀl Rahmani,b Laurent Commeiras,b Gaꢀlle Chouraqui,b
Jꢁrꢂme Thibonnet,a Alain DuchÞne,a Mohamed Abarbri,a,*
and Jean-Luc Parrainb,*
a
Laboratoire de Physicochimie des Matꢁriaux et de Biomolꢁcules, EA 4244, Facultꢁ des Sciences de Tours, Parc de
Grandmont, 37200 Tours, France
mohamed.abarbri@univ-tours.fr
Institut des Sciences Molꢁculaires de Marseille, iSm2 UMR CNRS 6263, Campus Scientifique de Saint Jꢁrꢂme,
b
Aix-Marseille Universitꢁ, 13397 Marseille, France
Fax : (+33)-4-9128-9187; e-mail: jl.parrain@univ-cezanne.fr
Received: December 5, 2008; Published online: March 20, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800757.
Abstract: A general and efficient copper(I)-catalyzed and stereoselectivity. This procedure does not re-
cross-coupling and heterocyclization reaction of ter- quire the use of any expensive supplementary addi-
minal alkynes and b-iodo-a,b-unsaturated acid deriv- tives, and is palladium-free.
atives has been developed under very mild condi-
tions. This method provides easy access from good to
excellent yields of a variety of 5-ylidenebutenolides Keywords: alkynes; copper; cross-coupling; homoge-
and 3-substituted isocoumarins with excellent regio- neous catalysis; lactones
Introduction
However, the synthesis often suffered from a lack
of stereoselectivity. Similarly, it has been found that
Butenolides and isocoumarins represent an important isocoumarins could be obtained under palladium cat-
class of naturally occurring lactones with a wide range alysis conditions[7] or in the presence of zinc chlo-
of biological and pharmacological uses such as anti- ride.[8] It is worthy of note that one-pot procedures
spasmodic, antifungal, herbicidal and pesticidal have also been reported and allow a direct access to
agents. Cytotoxic properties were also reported lead- g-alkylidenebutenolides starting from the correspond-
ing to a continued interest in the practical synthesis of ing b-iodopropenoic and ortho-halobenzoic acids, re-
this class of lactones, especially 5-ylidene-5H-furan-2- spectively. However, these pathways all bring into
ones and 3-substituted isocoumarins.[1,2,3]
play palladium-mediated reactions and Sonogashira
Transition metal-catalyzed cyclization of alkynes coupling is the most widely used method.[9] A major
possessing a nucleophile in close proximity to the drawback of this process in an industrial purpose is
triple bond is one of the most important processes in the use of two metal catalysts, making recovery of the
organic synthesis, and affords the title compounds. expensive and toxic palladium catalyst difficult.
Over the past decade a wide range of transition
In the past few years there has been a resurgence
metal-based catalysts (Ag, Hg, Rh, Pd, Zn, Au, etc.) of interest in copper(I)-catalyzed cross-coupling reac-
have been reported as effective catalysts to promote tions.[10] Many synthetic protocols for the formation of
the intramolecular addition of carboxylic acids to al-
kynes.[4,5]
Indeed, the lactonization of 4-alkynoic acids was
found to afford g-alkylidenebutenolide I through a 5-
exo pathway. In addition to the formation of I, six-
membered lactones II have been obtained resulting
from the 6-endo mode (Scheme 1).[6]
Scheme 1.
Adv. Synth. Catal. 2009, 351, 779 – 788
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
779

Samuel Inack-Ngi et al.
FULL PAPERS
Table 1. Optimization studies for the Cu-catalyzed coupling heterocyclization sequence.
Entry
Copper catalyst (%)
Base
Additive
Solvent
Time [h]
Temperature [8C]
Yield [%][a]
1
2
3
4
5
6
7
8
Cu2O (20%)
CuCN (20%)
CuCl (20%)
CuBr (20%)
CuI (20%)
CuBr2 (20%)
CuI (20%)
CuI (20%)
CuI (20%)
CuI (20%)
CuI (20%)
CuI (20%)
CuI (5%)
CuI (10%)
CuI (100%)
CuI (20%)
CuI (20%)
CuI (20%)
CuI (20%)
CuI (20%)
none
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
NaHCO3
Et3N
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
DMSO
THF
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
6
6
6
6
55
55
55
55
55
55
55
55
55
55
55
r.t.
55
55
55
55
55
55
55
55
55
55
55
55
62
19
24
80
0
9
4
55
8
0
9
10
11
12
13
14
15
16
17
18
19
21
22
23
24
none
none
0
7
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
23
98
2
79
18
9
73
<5
71
55
MeCN
MeCN
MeCN
MeCN
MeCN
Fe
Fe
Fe
Fe
G
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
CuI (2.5%)
CuI (2.5%)
[a]
Isolated yields.
carbon-carbon and carbon-heteroatom bonds based synthesis of dienoic acids and enynes bearing a car-
on copper(I) catalysts have been reported and they boxylic acid function from b-iodovinylic acids and vi-
have been the subject of growing attention.[11,12,13] Re- nyltin or alkynylzinc reagents.[21] This methodology
cently, the use of copper salts has also been shown to was then applied to the synthesis of 5-alkylidene-
mediate the synthesis of conjugated enynes.[14] In ad-
dition to being simple and mild, the newer copper-
ACHTUNGTRENNUNG
based methods accommodate substrates that are diffi- one-pot efficient and regioselective synthesis of 5-yli-
cult to couple by palladium reactions.[14e,15] Copper dene-5H-furan-2-ones and isocoumarins via the cross-
catalysts have the further advantage of having low coupling-heterocyclization reaction sequence of termi-
costs for use in large-scale industrial applications. The nal alkynes and (Z)-3-iodopropenoic acid derivatives
avoidance of expensive or air-sensitive ligands makes mediated by a simple salt. Herein we present a full
copper-based protocols very attractive from a synthet- account of our studies, including extensive investiga-
ic point of view.
tions of the reaction scope.
To the best of our knowledge, the one-pot palladi-
um-free catalyzed synthesis of 5-ylidenebutenolides
and isocoumarins from alkynes and b-iodopropenoic Results and Discussion
acid derivatives has never previously been reported.
In all cases described in the literature, the synthesis of As a starting point for the development of our transi-
butenolides, pyran-2-ones, phthalides and isocoumar- tion metal-free methodology we chose to study the
ins starting from b-iodopropenoic acid derivatives and coupling of (Z)-3-iodobut-2-enoic acid with phenyla-
alkynes using copper as catalyst has been performed cetylene. To optimize the reaction protocol, we exam-
in two separate steps: (i) coupling of (Z)-3-iodoprop- ined a range of copper(I) salts, additives, solvents and
ACHTUNGTRENNUNGenoic acid derivatives with terminal alkynes, typically bases (Table 1 and Scheme 2).
by a Sonogashira-type reaction, and (ii) cyclization
mediated by metal complexes,[16] bases,[17] and halo-
gen.[18]
Determination of the Best Catalytic System
In addition, our interest in the field[19] has focused
on an intramolecular addition of carboxylic acids to In comparison with the corresponding palladium-cata-
allenylstannanes for the construction of 3-substituted lyzed cross-coupling reactions, the copper-catalyzed
isocoumarins and a-pyrones.[20] We also described the version seemed to be less sensitive to the choice of
780
asc.wiley-vch.de
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 779 – 788

Copper-Catalyzed Preparation of g-Alkylidenebutenolides and Isocoumarins
FULL PAPERS
Figure 1.
Scheme 2.
the metal source. We examined the efficiency of cop- amount of copper catalyst (less than 20%) we have
À
per(I) salts as catalyst for the tandem C C coupling- evaluated the possibility to use a ligand on metal or
heterocyclization reaction. We then studied the effects to co-catalyze the reaction. Because 1,3-diketones
of different simple copper salts and the amount re- III[23] or 2-pyridylimine IV[24] (Figure 1) were recently
quired for the coupling of (Z)-3-iodobut-2-enoic acid reported in Sonogashira or Ullmann-type reactions,
1a with phenylacetylene. All the copper (I) salts (CuI, we decided to test them in our transformation but no
CuBr, CuCl, Cu2O, CuCN, etc.) tested and used with beneficial effects were observed.
a base provided poor to good yields of the lactone 2a
It should be noted that the reaction temperature
(entries 1–5, Table 1). Upon optimization, we found was kept under 708C in order to preserve the temper-
that CuI was the most effective catalyst for the cou- ature-sensitive arylidenebutenolides. More interest-
pling of (Z)-3-iodobut-2-enoic acid 1a with phenylace- ingly, we also examined the influence of an iron co-
tylene (entry 5, Table 1). It should be noted that when catalyst which was recently described by Taillefer
copper(II) salts such as CuBr2 were used as a catalyst et al. in the co-catalyzed arylation of nitrogen nucleo-
instead of copper(I) salts, no reaction was observed philes.[25] Using copper iodide and iron acetylaceto-
(entry 6, Table 1).
nate in a 1/3 ratio, good yields were obtained while in
The effects of the amount of copper required were the absence of copper salt, the reaction failed. Finally,
investigated in the optimization process, and further using 2.5 mol% of copper iodide and 7.5 mol% of
experiments showed that the reaction was complete iron acetylacetonate, the lactone 2a was obtained in
within 4 h in 80% yield using 20 mol% of CuI 71% (entry 23, Table 1). With an equimolar amount
(entry 5, Table 1). Lowering the amount of catalyst to of the two salts, we observed a slight decrease of yield
5 or 10 mol%, provided unsatisfactory yields of the (entry 24, Table 1). Comparison between the entries 1
desired product (<30%) (entries 13 and 14, Table 1). and 23 (Table 1) clearly shows the beneficial effect of
Moreover, a stoichiometric amount of CuI improved the co-catalytic system. Unfortunately, this observa-
the yield to 98% (entry 15, Table 1). At room temper- tion was only valid for this particular alkyne and acid
ature, no reaction occurred, and the starting material pair. Indeed, the reaction with octyne in place of phe-
was completely recovered (entry 12, Table 1). There- nylacetylene in the conditions of the entry 23, Table 1
after, different solvents were tested and we reached failed to give the corresponding lactone. Identically,
the conclusion that solvents with Lewis basicity prop- (Z)-3-iodopropenoic acid did not led to the 3-unsub-
erties were necessary. Indeed, the use of DMF or stituted g-alkylidenelactone. For these reasons and
DMSO as a solvent could lead to the formation of after a careful analysis of our results, the best set of
good yields of heterocyclized product 2a (entries 5 reaction conditions has been established : 20 mol% of
and 17, Table 1), whereas none of the desired prod- copper iodide (or CuI 1 equivalent in (Z)-3-iodoal-
ucts or unsatisfactory yields of the desired adducts
ACHTUNGTRENkNGNU enoic acid case), 2.0 equivalents of potassium car-
were obtained in toluene, THF and CH3CN (en- bonate in DMF at 558C for 4 h.[26]
tries 16, 18 and 19, Table 1). Our attention was next
turned to the screening of different bases. Gratifying-
ly, potassium carbonate (K2CO3), an inexpensive base, Scope of the Method: Preparation of (Z)-5-
was found to be highly effective and resulted in 80% Ylidenefuran-2(5H)-ones
yield of the coupled and cyclized product (entry 5,
Table 1). On the other hand, Cs2CO3, K3PO4, To investigate the scope of the copper-catalyzed
NaHCO3 and Et3N, proved to give unsatisfactory tandem coupling-heterocyclization reaction, a variety
yields (entries 7–10, Table 1). In addition, when the of commercially available terminal alkynes and (Z)-3-
reaction was performed in the absence of base iodoacrylic acids was tested.[27]
(entry 11, Table 1), the starting material was recov-
The reaction described is extremely versatile and
ered unchanged. Lowering the amount of base to provides a convenient method for the synthesis of var-
1.5 equivalents resulted in poor yields and minor sec- ious 5-ylidene-5H-furan-2-ones with the (Z)-configu-
ondary by-products such as phenylacetylene dimer ration exclusively, demonstrating that our strategy is
were detected (<10%). In order to decrease the very effective to prepare 5-ylidenebutenolides without
Adv. Synth. Catal. 2009, 351, 779 – 788
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
781

Samuel Inack-Ngi et al.
FULL PAPERS
Scheme 3.
any trace of pyran-2-ones, giving a regio- and stereo- regioselectivity of the coupling-cyclization process
selective character to the cyclization process (entries 13 and 14, Table 2), providing good yields of
(Scheme 3).
the corresponding butenolides 15a and 16a without
For example, alkynes bearing alkyl, alkenyl, aryl, formation of pyran-2-ones. However, in these cases,
heteroaryl, silyl and methoxy groups are tolerated we found that the temperature (<558C) was a crucial
(Table 2, entries 1–24). The presence of a long-chain parameter to obtain the expected butenolides as a
alkyl group in the terminal alkyne did not affect the single isomer. When the reaction temperature was in-
Table 2. Copper-catalyzed coupling-heterocylization reaction of b-iodopropenoic acid derivatives with terminal alkynes.
Entry
R
R1
CuI [mol%]
Product
Yield [%][a]
1
Me
Ph
20
2a
3a
4a
80
2
3
4
Me
o-Tol
Ph
20
20
20
82
86
84
CH3OCH2
CH3OCH2
o-Tol
5a
5
6
Me
H
2-Pyridinyl
2-Pyridinyl
20
20
6a
7a
62
40
7
n-Pent
Ph
20
8a
75
782
asc.wiley-vch.de
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 779 – 788

Copper-Catalyzed Preparation of g-Alkylidenebutenolides and Isocoumarins
Table 2. (Continued)
FULL PAPERS
Entry
R
R1
CuI [mol%]
Product
Yield [%][a]
8
H
Ph
100
9a
72
9
Me
H
CH
G
20
10a
11a
85
65
10
CH
G
100
11
12
H
H
CH2OTHP
CH2OPMB
100
100
12a
13a
63
52
13
14
Me
Me
CH2CH
(OEt)2
100
100
14a
15a
70
40
n-Bu
15
16
Me
Me
n-Hex
100
100
16a
–
40
0
CO2Et
17[b]
18[b]
H
SiMe3
SiMe3
100
20
17a
18a
<5
<5
Me
19[b]
20[b]
CH3OCH2
Ph
SiMe3
SiMe3
20
20
19a
20a
<5
<5
21
22
H
H
20
20
21a
22a
62
63
Adv. Synth. Catal. 2009, 351, 779 – 788
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
783

Samuel Inack-Ngi et al.
Yield [%][a]
FULL PAPERS
Table 2. (Continued)
Entry
R
R1
CuI [mol%]
20
Product
23
CH3
23a
24a
69
66
24
CH3
20
[a]
Isolated yields.
[b]
Compounds were only detected by GC/MS and were present in mixture with numerous by products.
creased to 658C, a mixture of butenolide and pyra- Scope of the Method: Preparation of Isocoumarins
none was obtained in a 1/1 ratio. The coupling-hetero-
cyclization reaction of (Z)-1a with (7E)-1-(but-3-en-1- With the reaction conditions thus optimized, and in
yn-4-yl)-2,6,6-trimethylcyclohex-1-ene
tries 21–23, Table 2) or (7E)-1-(but-3-en-1-yn-4-yl)- tention was next directed toward the synthesis of new
2,6,6-trimethylcyclohex-2-ene (b) (entries 22–24, heterocycles from o-iodobenzoic acids and terminal
(a)[28]
(en- order to explore the generalization of our method, at-
Table 2) under the same conditions as described alkynes by using the same strategy. Indeed, compound
above provided reasonable yields of the desired trien- 1f underwent the domino sequence to provide reac-
ylbutenolides 21a–24a. A NOESY NMR experiment tion mixtures in which 3-substituted isocoumarins
on 21a confirmed the retention of the configuration 25a–32a were the major products and (Z)-5-ylidene
of the double bonds of the starting materials, and a phthalides 25b–32b the minor ones (Scheme 4). How-
clean Z configuration of the exocyclic double bond of ever, in the cases of phenylacetylene and 3,3-dieth-
the butenolide is observed. No significant electronic
ACHTUNGTRENoNGNU xypropyne, mixtures of the five- and six-membered
effects were observed for an electron-donating sub- rings were respectively obtained in 50/50 and 95/5
stituent group at the ortho-position of the terminal ar- ratios (entries 1 and 3, Table 3) (combined yield=
omatic ring (entries 2 and 4, Table 2). In contrast, the 45%). These heterocyclic compounds have previously
introduction of an electron-withdrawing group at the been prepared by the palladium-catalyzed coupling of
ortho-position of the terminal aromatic ring markedly 2-halobenzoate esters or 2-halobenzonitriles with al-
diminished the yield of the coupling-heterocyclization kenes,[29] vinylic stannanes[30] or terminal alkynes,[9a,31]
sequence, presumably due to the reduced electron with subsequent cyclization or p-allylnickel cross-cou-
density on the triple bond (entry 8, Table 2). In anoth- pling and palladium-catalyzed cyclization,[32] or by
er case, trimethylsilylacetylene afforded with a very palladium-catalyzed annulation of terminal alkynes
low conversion rate the very sensitive five-membered and 2-iodophenols.[33] Isocoumarins have also been
ring product exclusively, in which a desilylation reac- prepared by the palladium-catalyzed annulation of in-
tion certainly occurs in these experimental conditions ternal alkynes.[34] The cross-coupling of o-iodobenzoic
(entries 17–20, Table 2). Attempts to improve the acid and terminal alkynes produces either unsaturated
yield by increasing the amount of copper catalyst phthalides[35,36] or 3-substituted isocoumarins as major
were unsuccessful.
products.[7,37]
For the coupling-intramolecular cyclization se-
quence, “5-exo-dig” or “6-endo-dig” closure is al-
lowed according to Baldwinꢄs rules.[38] However, the
reasons for the regioselectivity observed associated
Scheme 4.
784
asc.wiley-vch.de
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 779 – 788

Copper-Catalyzed Preparation of g-Alkylidenebutenolides and Isocoumarins
Table 3. Copper-catalyzed reaction of ortho-iodobenzoic acid with alkynes.
FULL PAPERS
Entry
R1
Product
a/b
Yield [%][a]
1
Ph
50/50
45
2
55/45
54
3
4
U
5/95
70
64
65/35
5
6
n-Bu
70/30
72/28
65
58
n-Pent
7
CH3OCH2
HOCH2
75/25
100/0
43
24
8
[a]
Isolated yields of isocoumarins.
with the use of CuI (20 mol%) as catalyst system are ing from the 6-endo-dig and 5-exo-dig cyclization
not yet clear at this stage. Despite their well-known mode. Surprisingly, the alkyne bearing propargyl
role in the formation of phthalides, Cu(I) salts are acetal or alcohol functions resulted from an opposite
also known to catalyze the intramolecular cyclization cyclization mode (entries 3 and 8, Table 3). In the
of 2-(1-alkynyl)benzoic acid or its derivative to the case of a terminal alkyne substituted with a long-
six-membered lactone ring.[12e,39] In our case, the reac- chain alkyl group, a six-membered heterocycle was
tion of 2-iodobenzoic acids and terminal alkynes also formed as major product with moderate isolated
under regio- and stereocontrol gave reasonable yields yield (entries 5 and 6, Table 3). It should be noted
of mixtures of the six- and five-membered ring result- that 3-pentylisocoumarin 30a is a precursor for a nat-
Adv. Synth. Catal. 2009, 351, 779 – 788
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
785

Samuel Inack-Ngi et al.
FULL PAPERS
urally occurring isocoumarin (artemidin) and there- Experimental Section
fore a compound of biological interest.[40] In another
All reactions were carried out under inert atmosphere (Ar
or N2). DMF was dried by distillation over CaH2. The petro-
leum ether (PE) used was the fraction boiling in the range
40–608C. Flash chromatography was carried out with Merck
case an alkyne bearing a methoxy group furnished a
mixture of six-membered ring product 31a and five-
membered ring 31b in a 75:25 ratio. For the coupling
of iodobenzoic acid with phenylacetylene, a mixture
of isocoumarin and phthalide was formed in similar
proportions with 45% yield. When 2-iodo-5-nitroben-
zoic acid was reacted with phenylacetylene under the
conditions given, only trace amounts of the isocou-
marin could be obtained. This result indicates that the
electron-withdrawing groups on the aromatic ring
must play an important role in the reaction. Attempts
to improve the yield by increasing the amount of
copper catalyst met with no success.
As shown in Table 2 and Table 3, better yields were
obtained with (Z)-3-iodoalkenoic acids 1a–e than
with 2-iodobenzoic acid 1f. Extension of this cou-
pling-heterocyclization sequence using copper catalyst
to other classes of functionalized b-iodopropenoic
acid derivatives is currently being studied in our labo-
ratory.
1
silica gel (silica gel, 230–400 mesh). H NMR spectra were
recorded at 200 or 300 MHz using CDCl3 as solvent. Find-
ings, reported using the residual solvent proton resonance of
CDCl3 (dH =7.25 ppm) as internal reference, were as follows
(in order): chemical shift (d in ppm in relation to Me4Si),
multiplicity (s, d, t, q, m, b for singlet, doublet, triplet, quar-
tet, multiplet, broad) and coupling constants (J in Hz).
13C NMR sopectra were recorded at 50.3 MHz using the
CDCl3 solvent peak at dC =77.0 ppm as reference. Mass
spectra were recorded on a Applied Biosystems QSTAR
Elite spectrometer. Melting points were uncorrected.
General Procedure for the Synthesis of g-
Alkylidenebutenolides
A dry Schlenk tube equipped with a Teflon-coated magnetic
stirrer was charged with K2CO3 (2.8 g, 20.0 mmol, 2 equiv.)
and (Z)-3-iodobut-2-enoic acid (2.1 g, 10.0 mmol, 1 equiv.).
The mixture vessel was evacuated and backfilled with argon.
Anhydrous DMF (40 mL) was added and the suspension
was stirred for 15 min. Then, the mixture was degassed at
À808C for 10 min and backfilled with argon. After reaching
room temperature, the alkyne (20.2 mmol, 2 equiv.) was
added and finally CuI (0.384 g, 2.02 mmol, 20 mol%). The
Schlenk tube was sealed and then placed in a preheated oil
bath at 658C and the mixture stirred overnight. The reaction
mixture was allowed to reach room temperature and was
partitioned between diethyl ether (40 mLꢅ3) and saturated
aqueous NH4Cl (30 mL). The organic portions were dried
over Na2SO4, filtered and concentrated by rotary evapora-
tion. The material thus obtained was purified by flash chro-
matography on silica gel to give the desired g-alkylidene-
Conclusions
The aim of this research was to develop an efficient
and cheaper method for the synthesis of a (Z)-5-yli-
dene-5H-furan-2-one library under mild and more en-
vironmentally friendly conditions. These issues were
addressed by replacing the expensive palladium cata-
lysts with less expensive 20 mol% CuI. In summary,
we have developed a practical and general catalytic
system [Cu(I) salts in DMF] for the efficient tandem
coupling-heterocyclization reaction of (Z)-3-iodopro-
penoic acid derivatives with terminal alkynes, leading
to the easy formation of an important range of (Z)-5-
alkylidene- or arylidene-5H-furan-2-ones that can also
be extended to the preparation of 3-substituted iso-
coumarins. Compared to other copper-catalyzed So-
nogashira-type reactions, we found that the reaction
temperature is significantly lower (90–1408C vs.
508C) indicating a strong effect of the close carboxyl-
ate function. As a possible explanation we thought
that the oxidative addition step of copper into the
carbon/iodine bond would be favored through an in-
tramolecular process from a copper carboxylate. In
AHCTUNGTRENNUNG
;
1H NMR (CDCl3, 200 MHz): d=7.83–7.14 (5H, m), 6.49
(1H, s), 6.04 (1H, s), 2.20 (3H, s); 13C NMR (CDCl3,
50 MHz): d=22.2, 104.6, 112.3, 126.2, 127.8, 129.4, 132.0,
156.7, 161.5, 168.6; MS (EI): m/z (%)=186 (M+, 100), 158
(25), 157 (17), 130 (23), 129 (42), 128 (10), 118 (22), 115
(32), 90 (46), 89 (39), 64 (13), 63 (24), 51 (14), 40 (17), 39
(42); HR-MS (EI): m/z=187.0688, calcd. for C12H10O2 (M+):
187.0681.
order to confirm this point, we have realized experi- Acknowledgements
ments with (E)-3-iodopropenoic acid under the same
We thank MESR and CNRS for a PhD grant and financial
support. We also thank Dr Marc Taillefer (University of
Montpellier) for fruitful discussions.
experimental conditions which were unsuccessful in
leading to the corresponding enynoic acids. Finally,
the present methodology does not involve the use of
an expensive, air-sensitive palladium(0) catalyst or
any additive ligand. Further applications of this cata-
lytic system to generate butenolide- and isocoumarin-
based chemical libraries of potential pharmacological
interest are under investigation in our laboratory.
786
asc.wiley-vch.de
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 779 – 788

Copper-Catalyzed Preparation of g-Alkylidenebutenolides and Isocoumarins
FULL PAPERS
References
[10] G. Evano, N. Blanchard, M. Toumi Chem. Rev. 2008,
3054–3131.
À
[1] a) L. Pochet, F. Raphael, B. Masereel, Curr. Pharm.
Des. 2004, 10, 3781–3796; b) T.-J. Hsieh, F.-R. Chang,
Y.-C. Chia, C.-Y. Chen, H.-C. Lin, H.-F. Chiu, Y.-C.
Wu, J. Nat. Prod. 2001, 64, 1157- 1161; c) D. Kuhnt, T.
Anke, H. Besl, M. Bross, R. Herrmann, U. Mocek, B.
Steffan, W. Steglich, J. Antibiot. 1990, 43, 1413–1420.
[2] For two examples of new bioactive isocoumarins see
a) M. Azumi, K.-i. Ogawa, T. Fujita, M. Takeshita, R.
Yoshida, T. Furumai, Y. Igarashi, Tetrahedron 2008, 64,
6420–6425; b) W. Zhang, K. Krohn, S. Draeger, B.
Schulz, J. Nat. Prod. 2008, 71, 1078–1081.
[3] For reviews on butenolides, see: a) Y. S. Rao, Chem.
Rev. 1976, 76, 625–694; b) D. W. Knight, Contemp.
Org. Synth. 1994, 1, 287–315; c) R. Rossi, F. Bellina,
Targets Heterocycl. Syst. 2001, 5, 169–198; d) R. Brꢆck-
ner, Chem. Commun. 2001, 141–152; e) R. Brꢆckner,
Curr. Org. Chem. 2001, 5, 679–718. For two recent
publications in the field, see: f) G. Le Bras, A. Hamze,
S. Messaoudi, O. Provot, P.-B. Le Calvez, J.-D. Brion,
M. Alami, Synthesis 2008, 1607–1611; g) H.-W. Xu, J.-
F. Wang, G.-Z. Liu, G.-F. Hong, H.-M. Liu, Org.
Biomol. Chem. 2007, 5, 1247–1250.
[4] For recent synthesis using Pd or Ag catalysts, see: a) C.
Xu, E. Negishi, Tetrahedron Lett. 1999, 40, 431–434;
b) S. Ma, Z. Shi, J. Org. Chem. 1998, 63, 6387–6389;
c) R. Rossi, F. Bellina, M. Biagetti, L. Mannina, Tetra-
hedron Lett. 1998, 39, 7799–7802; d) R. Rossi, F. Belli-
na, M. Biagetti, L. Mannina, Tetrahedron Lett. 1998, 39,
7599–7602; e) R. Rossi, F. Bellina, L. Mannina, Tetra-
hedron Lett. 1998, 39, 3017–3020; f) R. Rossi, F. Belli-
na; C. Bechini, L. Mannina, P. Vergamini, Tetrahedron
1998, 54, 135–156; g) J. A. Marshall, M. A. Wolf, E. M.
Wallace, J. Org. Chem. 1997, 62, 367–371; h) J. A. Mar-
shall, M. A. Wolf, E. M. Wallace, J. Org. Chem. 1995,
60, 796–797; i) J. A. Marshall, M. A. Wolf, E. M. Wal-
lace, J. Org. Chem. 1996, 61, 3238–3239; j) Y. Ogawa,
M. Maruno, T. Wakamatsu, Synlett 1995, 871–872.
[5] Reactions catalyzed by other metal complexes, see:
a) T. Sakamoto, M. Annaka, Y. Kondo, H. Yamanaka,
Chem. Pharm. Bull. 1986, 34, 2754–2759; b) N. Me-
nashe, Y. Shvo, Heterocycles 1993, 35, 611–613.
[11] For copper salt-catalyzed C X bond formation, see:
a) D. Ma, Y.; Zhang, J.; Yao, S. Wu, F. Tao, J. Am.
Chem. Soc. 1998, 120, 12459–12467; b) D. Ma, C. Xia,
Org. Lett. 2001, 3, 2583–2586; c) A. Klapars, J. C. Anti-
lla, X. Huang, S. L. Buchwald, J. Am. Chem. Soc. 2001,
123, 7727–7729; d) J. C. Antilla, A. Klapars, S. L. Buch-
wald, J. Am. Chem. Soc. 2002, 124, 11684–11688;
e) F. Y. Kwong, A. Klapars, S. L. Buchwald, Org. Lett.
2002, 4, 581–584; f) F. Y. Kwong, S. L. Buchwald, Org.
Lett. 2003, 5, 793–796; g) R. Shen, C. T. Lin, E. J.
Bowman, B. J. Bowman, J. A. Porco, Jr., J. Am. Chem.
Soc. 2003, 125, 7889–7901; h) H.-J. Cristau, P. P. Cellier,
J.-F. Spindler, M. Taillefer, Chem. Eur. J. 2004, 10,
5607–5622; i) D. Ma, Q. Cai, Synlett 2004, 128–130;
j) X. Pan, Q. Cai, D. Ma, Org. Lett. 2004, 6, 1809–
1812; k) Q. Cai, W. Zhu, H. Zhang, Y. Zhang, D. Ma,
Synthesis 2005, 496–499; l) B. M. Trost, D. T. Stiles,
Org. Lett. 2005, 7, 2117–2120; m) A. Shafir, S. L. Buch-
wald, J. Am. Chem. Soc. 2006, 128, 8742–8743; n) Z.
Zhang, J. Mao, D. Zhu, F. Wu, H. Chen, B. Wan, Tetra-
hedron 2006, 62, 4435–4444; o) B. Zou, Q. Yuan, D.
Ma, Angew. Chem. 2007, 119, 2652–2655; Angew.
Chem. Int. Ed. 2007, 46, 2598–2601; p) H.-J. Cristau,
P. P. Cellier, S. Hamada, J.-F. Spindler, M. Taillefer,
Org. Lett. 2004, 6, 913–916; q) H.-J. Cristau, P. P. Celli-
er, J.-F. Spindler, M. Taillefer, Eur. J. Org. Chem. 2004,
695–709; r) H. Kaddouri, V. Vicente, A. Ouali, F.
Ouazzani, M. Taillefer, Angew. Chem. 2009, 121, 339–
342; Angew. Chem. Int. Ed. 2009, 48, 333–336; s) N.
Xia, M. Taillefer, Angew. Chem. 2009, 121, 343–346;
Angew. Chem. Int. Ed. 2009, 48, 337–339.
[12] For special reviews on copper-catalyzed cross-cou-
plings, see: a) P. Siemsen, R. C. Livingston, F. Dieder-
ich, Angew. Chem. 2000, 112, 2740–2767; Angew.
Chem. Int. Ed. 2000, 39, 2632–2657; b) J. Hassan, M.
Sevignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev.
2002, 102, 1359–1470; c) S. V. Ley, A. W. Thomas,
Angew. Chem. 2003, 115, 5558–5607; Angew. Chem.
Int. Ed. 2003, 42, 5400–5449; d) I. P. Beletskaya, A. V.
Cheprakov, Coord. Chem. Rev. 2004, 248, 2337–2364;
e) F. Monnier, M. Taillefer, Angew. Chem. 2008, 120,
3140–3143; Angew. Chem. Int. Ed. 2008, 47, 3096–
3099.
[6] M. Uchiyama, H. Ozawa, K. Takuma, Y. Matsumoto,
M. Yonehara, K. Hiroya, T. Sakamoto Org. Lett. 2006,
8, 5517–5520.
[7] a) R. Rossi, F. Bellina, M. Biagetti, A. Catanese, L.
Mannina, Tetrahedron Lett. 2000, 41, 5281–5286; b) F.
Bellina, D. Ciucci, P. Vergamini, R. Rossi, Tetrahedron
2000, 56, 2533–2545; c) N. G. Kundu, M. Pal, B. Nandi,
J. Chem. Soc. Perkin Trans. 1 1998, 561–568, and refer-
ences cited therein.
À
[13] For some selected papers on copper salt-catalyzed C C
bond formation, see: a) J.-H. Li, D.-P. Wang, Y.-X. Xie,
Tetrahedron Lett. 2005, 46, 4941–4944; b) D.-W. Ma, F.
Liu, Chem. Commun. 2004, 1934–1935; c) J. Zanon, A.
Klapars, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125,
2890–2891; d) M. Hoshi, K. Shirakawa, Synlett 2002,
1101–1104; e) J.-H. Li, B.-X. Tang, L.-M. Tao, Y.-X.
Xie, Y. Liang, M.-B. Zhang, J. Org. Chem. 2006, 71,
7488–7490; f) T. Schareina, A. Zapf, W. Mꢈgerlein, N.
Mꢆller, M. Beller, Chem. Eur. J. 2007, 13, 6249–6254;
g) H.-J. Cristau, A. Ouali, J.-F. Spindler, M. Taillefer,
Chem. Eur. J. 2007, 13, 2483–2492.
[8] H.-Y Liao, C.-H. Cheng, J. Org. Chem. 1995, 60, 3711–
3716.
[9] a) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron
Lett. 1975, 4467–4470; b) K. Sonogashira, in: Compre-
hensive Organic Synthesis, (Ed.: B. M. Trost), Perga-
mon Press, Oxford, UK, 1999, Vol. 3, p 521; c) H.
Doucet, J.-C. Hierso, Angew. Chem. 2007, 119, 850–
888; Angew. Chem. Int. Ed. 2007, 46, 834–871; d) R.
Chinchilla, C. Nꢇjera, Chem. Rev. 2007, 107, 874–892.
[14] a) G. Batu, R. Stevenson, J. Org. Chem. 1980, 45,
1532–1534; b) K. Okuro, M. Furune, M. Enna, M.
Miura, M. Nomura, J. Org. Chem. 1993, 58, 4716–4721;
c) J.-X. Wang, Z. Liu, Y. Hu, B. Wei, L. Kang, Synth.
Commun. 2002, 32, 1937–1945; d) R. K. Gujadhur,
Adv. Synth. Catal. 2009, 351, 779 – 788
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
787

Samuel Inack-Ngi et al.
FULL PAPERS
C. G. Bates, D. Venkataraman, Org. Lett. 2001, 3,
4315–4318; e) A.-Y. Peng, Y.-X. Ding, J. Am. Chem.
Soc. 2003, 125, 15006–15007; f) P. Saejueng, C. G.
Bates, D. Venkataraman, Synthesis 2005, 1706–1712;
g) L.-X. Shao, M. Shi, Tetrahedron 2007, 63, 11938–
11942.
Thibonnet, A. DuchÞne, J.-L. Parrain, M. Abarbri, Tet-
rahedron Lett. 2004, 45, 2063–2066.
[23] F. Monnier, F. Tutault, L. Duroure, M. Taillefer, Org.
Lett. 2008, 10, 3203–3206.
[24] A. Ouali, J.-F. Spindler, H.-J. Cristau, M. Taillefer, Adv.
Synth. Catal. 2006, 348, 499–505.
[25] M. Taillefer, N. Xia, A. Oualli, Angew. Chem. 2007,
119, 952–954; Angew. Chem. Int. Ed. 2007, 46, 934–
936.
[26] In the case of 2-alkylalkynes, from any b-iodoacrylic
acids, best yields are obtained using one equivalent of
copper iodide in similar other conditions (K2CO3,
DMF).
[27] J. C. Chalcat, F. Thꢁron, R. Vessiꢉre, C. R. Acad. Sci.
Sꢀrie C 1971, 273, 763–765.
[28] The dienyne (a) and (b) were obtained from a- or b-
ionone according to the procedure described by E.-I.
Negishi, A. O. King, W. L. Klima, J. Org. Chem. 1980,
45, 2526–2528.
[15] Y.-J. Chen, H.-H. Chen, Org. Lett. 2006, 8, 5609–5612.
[16] a) B. Doroh, G. A. Sulikowski, Org. Lett. 2006, 8, 903–
906; b) H. H. Noriyuki; T. Osaki, M. Nakano, H. Mori,
S. Katsumura J. Org. Chem. 2004, 69, 7949–7959; c) L.
Anastasia, C. Xu, E. Negishi, Tetrahedron Lett. 2002,
43, 5673–5676; d) N. Furuichi, H. Hara, T. Osaki, H.
Mori, S. Katsumura, Angew. Chem. 2002, 114, 1065–
1068; Angew. Chem. Int. Ed. 2002, 41, 1023–1026; e) F.
Rossi, A. Bellina, L. Catanese, L. Mannina, D. Valen-
sin, Tetrahedron 2000, 56, 479–487; f) C. Xu; E. Negishi
Tetrahedron Lett. 1999, 40, 431–434; g) M. Kotora, E.
Negishi, Synthesis 1997, 121–128.
[17] a) M. Biagetti, F. Bellina, A. Carpita, S. Viel, L. Manni-
na, R. Rossi, Eur. J. Org. Chem. 2002, 1063–1076;
b) R. Rossi, F. Bellina, L. Mannina, Tetrahedron Lett.
1998, 39, 3017–3020; c) H. Mori, H. Kubo, H. Hara, S.
Katsumura, Tetrahedron Lett. 1997, 38, 5311–5314;
d) N. G. Clemo, G. Pattenden, J. Chem. Soc. Perkin
Trans. 1 1986, 2133–2136.
[29] a) T. Izumi, Y. Nishimoto, K. Kohei, A. Kasahara, J.
Heterocycl. Chem. 1990, 27, 1419–1424; b) T. Sakamo-
to, Y. Kondo, H. Yamanaka, Heterocycles 1988, 27,
453–456.
[30] T. Sakamoto, Y. Kondo, A. Yasuhara, H. Yamanaka,
Tetrahedron 1991, 47, 1877–1886.
[31] T. Sakamoto, Y. Kondo, H. Yamanaka, Heterocycles
1988, 27, 2225–2249.
[18] a) M. Biagetti, F. Bellina, A. Carpita, P. Stabile, R.
Rossi, Tetrahedron 2002, 58, 5023–5036; b) F. Bellina,
M. Biagetti, A. Carpita, R. Rossi, Tetrahedron 2001, 57,
2857–2870; c) M. J. Sofia, J. A. Katzenellenbogen, J.
Med. Chem. 1986, 29, 230–238.
[32] D. E. Korte, L. S. Hegedus, R. K. Wirth, J. Org. Chem.
1977, 42, 1329–1336.
[33] D. V. Kadnikov, R. C. Larock, J. Organomet. Chem.
2003, 687, 425–435.
[19] a) K. Cherry, M. Abarbri, J.-L. Parrain, A. DuchÞne,
Tetrahedron Lett. 2003, 44, 5791–5794; b) K. Cherry,
A. DuchÞne, J. Thibonnet, J.-L. Parrain, M. Abarbri,
Synthesis 2005, 2349–2356; c) S. Rousset, M. Abarbri,
J. Thibonnet, J.-L. Parrain, A. DuchÞne, Tetrahedron
Lett. 2003, 44, 7633–7636; d) S. Rousset, M. Abarbri, J.
Thibonnet, A. DuchÞne, J.-L. Parrain, Org. Lett. 1999,
1, 701–703.
[20] a) S. Rousset, M. Abarbri, J. Thibonnet, A. DuchÞne,
J.-L. Parrain, Chem. Commun. 2000, 1987–1988; b) K.
Cherry, M. Abarbri, J.-L. Parrain, A. DuchÞne, Tetrahe-
dron Lett. 2003, 44, 5791–5794.
[21] a) M. Abarbri, J.-L. Parrain, M. Kitamura, R. Noyori,
A. DuchÞne, J. Org. Chem. 2000, 65, 7475–7478; b) J.
Thibonnet, M. Abarbri, A. DuchÞne, J.-L. Parrain, Syn-
lett 1999, 141–143; c) M. Abarbri, J.-L. Parrain, J.-C.
Cintrat, A. DuchÞne, Synthesis 1996, 82–86.
[34] a) R. C. Larock, M. J. Doty, X. Han, J. Org. Chem.
1999, 64, 8770–8779; b) L. Wang, W. Shen, Tetrahedron
Lett. 1998, 39, 7625–7628.
[35] N. G. Kundu, M. Pal, B. Nandi, J. Chem. Soc. Perkin
Trans. 1 1998, 561–568.
[36] N. G. Kundu, M. Pal, J. Chem. Soc. Chem. Commun.
1993, 86–87.
[37] H. Sashida, A. Kawamukai, Synthesis 1999, 1145–1148.
[38] a) J. E. Baldwin, J. Chem. Soc. Chem. Commun. 1976,
734–736; b) C. D. Johnson, Acc. Chem. Res. 1993, 26,
476–482.
[39] a) G. Batu, R. Stevenson, J. Org. Chem. 1980, 45,
1532–1534; b) K. Okuro, M. Furuune, M. Enna, M.
Miura, M. Nomura, J. Org. Chem. 1993, 58, 4716–4721;
c) J.-X. Wang, Z. Liu, Y. Hu, B. Wei, L. Kang Synth.
Commun. 2002, 32, 1937–1945.
[40] D. Engelmeier, F. Hadacek, O. Hofer, G. Lutz-Kut-
schera, M. Nagl, G. Wurz, H. Greger, J. Nat. Prod.
2004, 67, 19–25.
[22] a) S. Rousset, J. Thibonnet, M. Abarbri, A. DuchÞne,
J.-L. Parrain, Synlett 2000, 260–262; b) K. Cherry, J.
788
asc.wiley-vch.de
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 779 – 788