A mild access to γ- or δ-alkylidene lactones through gold catalysis

Article abstract of DOI:10.1016/j.tetlet.2006.06.129

ω-Acetylenic acids are efficiently and stereoselectively converted to the corresponding enol lactones in the presence of catalytic amounts of AuCl and K₂CO₃.

Full text of DOI:10.1016/j.tetlet.2006.06.129

Tetrahedron Letters 47 (2006) 6273–6276
A mild access to c- or d-alkylidene lactones through gold catalysis
Hassina Harkat, Jean-Marc Weibel and Patrick Pale*
`
´ ´ ´ ´
Laboratoire de Synthese et Reactivite Organique, Associe au CNRS, Institut de Chimie, Universite L. Pasteur, 67000 Strasbourg, France
Received 23 May 2006; revised 20 June 2006; accepted 23 June 2006
Available online 18 July 2006
Abstract—x-Acetylenic acids are efficiently and stereoselectively converted to the corresponding enol lactones in the presence of
catalytic amounts of AuCl and K2CO3.
Ó 2006 Elsevier Ltd. All rights reserved.
Although still its in infancy, gold catalysis is increasingly
gaining interest in organic chemistry due to the effi-
ciency, the mildness and the peculiar properties associ-
ated with such Lewis acids.1
pentynoic acid 1a to different gold salts in various con-
ditions (Table 1).
Without any catalyst, no cyclization was observed what-
ever the solvent (see entry 1 for an example). Gold chlo-
ride, alone or as its triphenylphosphine complex, did not
promote the expected cyclization, whatever the solvent
and the amount of catalyst (entries 4–6, 7 and 8). The
more electrophilic gold trichloride was not effective in
dichloromethane and acetonitrile (entries 2–3).12 The
solvent however seemed to play a critical role, since var-
ious products were formed in low yields in acetonitrile
while no conversion was observed in dichloromethane
(entries 2, 5, 7 vs 3, 6, 8). It is worth noting that both
gold chloride and trichloride were not readily soluble
in benzene and dichloromethane, although the latter is
the most often used solvent in Au-catalyzed reactions.1
Most of the reactions promoted by gold catalysts are
intramolecular or intermolecular additions to triple1e
or double bonds.1 Although the intramolecular versions
offer an interesting way to get heterocycles,1–8 only a few
possibilities have so far been explored. For example, no
cyclization of acetylenic acids is described,1e,9 despite of
the wide interest of the expected enol lactones,10 which
could be either exo- or endo-cyclic depending on the
exo-dig or endo-dig mode of cyclization.
In this context and due to our interest in such com-
pounds,11 we looked for a novel and mild access to enol
lactones based on the cyclization of acetylenic acids
mediated by gold species. Here we report our prelimin-
ary results in this area (Scheme 1).
We reasoned out that gold chloride could not be electro-
philic enough in this case to allow for an intramolecular
addition of the carboxylic function and that a gold car-
boxylate would better organize and/or place closer the
reacting functional groups (see Scheme 2). We thus
added bases into the reaction mixture to produce the
more nucleophilic carboxylate in situ. This addition
did not change much with gold trichloride (entries 9–
10 vs 2–3). Increasing the amount of either gold trichlo-
ride or of the base did not improved the reaction, and
only traces of the expected product were at best ob-
tained. However, potassium carbonate proved to be a
perfect choice with gold chloride (entries 13–16) and
with triphenylphosphinogold chloride (entries 11 and
12). Interestingly enough, in these cases, only a catalytic
amount of this base was required (entries 11–16). With
triphenylphosphinogold chloride as catalyst, the reac-
tion proved to be slower in acetonitrile (entry 12 vs
In order to find the appropriate conditions for this cycli-
zation, we submitted the commercially available 4-
R1
R1
HO
O
O
AuCl 10 %
O
K2CO3 10 %
MeCN
n
n
R2
R2
Scheme 1. Formation of enol lactones by AuI-catalyzed cyclization of
acetylenic acids.
*
Corresponding author. Tel./fax: +33 390 241 517; e-mail: ppale@
chimie.u-strasbg.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.129

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H. Harkat et al. / Tetrahedron Letters 47 (2006) 6273–6276
Table 1. Formation of methylene butenolide 2a from 4-pentynoic acid
1a in the presence of gold salts in various conditions
Therefore, these conditions promoted the exclusive for-
mation of the exo-dig product.
O
OH
Au catalyst
O
In order to study the scope of this new formation of enol
lactones, various representative acetylenic acids were
then submitted to the above conditions (Table 2).
O
1a
2a
Catalysta
—
Solvent T (°C) Time (h) Yieldb
1
CH2Cl2 40
5
0c
The chain length between the acetylenic and the carbox-
ylic parts was first varied in order to check the exo/endo-
selectivity of this cyclization. As for 4-pentynoic acid 1a,
5-hexynoic acid 3a exclusively gave the exo-dig product
(entry 6 vs 1). Both acetylenic acids exhibited the same
reactivity and gave the corresponding methylene lac-
tones 2a, 4a with the same yield. However, the longer
6-heptynoic acid 5a reacted in a much slower way but
still gave the exo-products 6a, although in a much lower
yield and in a less cleaner reaction (entry 10 vs 6 vs 1).
2
3
AuCl3
AuCl
CH2Cl2 20
MeCN 20
6
5
0c
Traced
4
5
6
PhH
80
6
5
5
Traced
0c
Traced
CH2Cl2 40
MeCN 20
7
8
AuCl(PPh3)
CH2Cl2 40
MeCN 20
6
5
0c
Traced
9
10
AuCl3, K2CO3
CH2Cl2 40
MeCN 20
6
5
0c
Using conventional methods, we then prepared substi-
tuted acetylenic acids to look at the stereoselectivity of
this cyclization. The brominated 4-pentynoic and 5-
hexynoic acids 1b, 3b were easily obtained from the cor-
responding acetylenic acids 1a, 3a by NBS treatment in
the presence of catalytic amounts of silver nitrate.15
Placed in the presence of gold chloride and potassium
carbonate, these bromoacetylenic acids were exclusively
again converted to the exo-products 2b, 4b as single ste-
reoisomers (entries 2 and 7). The Z stereochemistry of
these compounds was assigned from the chemical shift
of their vinylic protons (5.34 and 5.37 ppm, respectively)
and by comparison with known products.16,17
Traced
11 AuCl(PPh3), K2CO3 CH2Cl2 20
12
3
3
95
96
MeCN 20
13 AuCl, K2CO3
PhH 80
CH2Cl2 20
MeCN 20
3
3
1
1
<10d
Traced
96
14
15
16
THF
20
95
a 0.1 equiv.
b Yield of isolated pure product.
c The starting material was recovered.
d Several products were formed in low yields (<5%).
The phenyl substituted 4-pentynoic and 5-hexynoic
acids 1c, 3c were easily obtained by coupling the butyl
4-pentynoate and 5-hexynoate with phenyl iodide,18 fol-
lowed by saponification. Again, gold chloride in the
presence of potassium carbonate promoted the exclusive
formation of the exo-products 2c, 4c as single stereoiso-
mers (entries 3 and 8). The Z stereochemistry was again
proved by spectroscopic comparison with known
compounds.19
O
O
_
O
O
Au
or
R
n
n
R
I2
Au+
I1
O
_
O
O
K2CO3
OH
O
O
Au+
n
R
n
R
R
KHCO3
The corresponding alkyl substituted acetylenic acids 1d,
3d, exclusively led to the exo-products 2d, 4d. Surpris-
ingly, a 1:1 mixture of Z and E stereoisomers20 was ob-
tained from 1d (entry 4), but only the Z stereoisomer
was isolated from 3d although in a modest yield (entry
9). In the latter case, it seems that one of the stereoiso-
mers formed decomposed.
Au
I3
O
R
OH
O
n
O
n
R
Scheme 2. Proposed mechanism for the gold catalyzed cyclization of
x-acetylenic acids.
The 5-tri-iso-propylsilyl-4-pentynoic acid 1e did not
cyclize in these conditions, even after prolonged reaction
time (entry 5). It seems that a silyl atom adjacent to the
p-system withdraws electron density by d–p conjuga-
tion, thus lowering the coordination ability of the acet-
ylenic moiety towards AuI.
15) but faster in dichloromethane (entry 11 vs 14). With
gold chloride, acetonitrile and tetrahydrofuran were the
solvents in which the best yields and rapid reactions
were achieved (entries 12, 15–16 vs 13–14). It is worth
noting that although acetonitrile has been applied in a
few Au-catalyzed reactions,5,13 no report of the use of
THF was so far mentioned.
In contrast to other Au-catalyzed reactions,1 the cycliza-
tion of x-acetylenic acids described here can only be
catalyzed by AuI. These results rule out redox processes
(disproportionation)1a and suggest an electrophilic acti-
vation of the acetylenic moiety by AuI. The fact that a
mild base (K2CO3) is required also suggests a deproto-
Interestingly, a single compound was formed in these
conditions, the spectroscopic data of which corre-
sponded to the known c-methylene butenolide 2a.14

H. Harkat et al. / Tetrahedron Letters 47 (2006) 6273–6276
Table 2. Formation of alkylidene lactones from various acetylenic acidsa
Acetylenic acid
6275
Lactone
Yieldb
OH
O
O
1
2
1a
1b
2a
2b
96
96
O
Br
Br
OH
OH
O
O
O
Ph
Ph
O
3
4
1c
1d
2c
2d
96
O
O
nBu
nBu
O
88d
O
OH
O
i
Pr3Si
iPr3Si
OH
OH
5
6
1e
3a
2e
4a
0c
O
O
O
O
O
97
OH
Br
Br
O
O
O
O
O
O
7
8
3b
3c
4b
4c
98
97
OH
Ph
Ph
OH
nBu
nBu
O
O
O
9
3d
4d
6a
50–60e
OH
O
O
OH
10
5a
25f
O
a 0.1 equiv of AuCl and 0.1 equiv of K2CO3 in acetonitrile at 20 °C for 2 h unless otherwise stated.
b Yield of the pure product after column chromatography.
c The starting material was recovered.
d Isolated as a 1:1 Z/E mixture.
e One of the stereoisomers formed seemed unstable.
f The reaction required longer time (48 h) and by-products were also formed (<10%).
nation of the acid group. Whatever their order, these
events would lead to an intermediate like I1 or I2 in
Scheme 2. The latter, analog to intermediates calculated
for methanol addition to alkynes,21 does not account for
the observed stereochemistry, since it should lead to syn
auration and thus to E isomers. The former however
would be perfectly oriented for a nucleophilic addition
of the carboxylate moiety to the gold-activated acetyl-
enic group (anti auration).8 The organogold intermedi-
ate I3 would thus be produced through an exo-dig
process. In contrast to other known Au-catalyzed cycli-
zations,1,4,5 the exo-dig cyclization seems to be always
preferred here, even when both exo- or endo-dig path-
ways are possible (Table 2, entries 1–4). It is nevertheless
worth noting that a few other Au-catalyzed exo-dig
cyclizations have been described.2b,3,8,22 Hydrolysis of
the carbon–gold bond would then liberate the enol lac-
tone and regenerate the gold catalyst. The fact that only
catalytic amount of potassium carbonate is necessary
suggests that the proton source in the later step is the
starting acid itself (Scheme 2).
These hypotheses could account for the observed stereo-
chemistry of the cyclized products in the case of the bro-
mo- and phenyl-substituted c- and d-acetylenic acids
(2b, 2c and 4b, 4c, respectively) but not in the case of
the butyl analogs (2d). The reasons for this discrepancy
are still unknown. Equilibration does not occur in the
present conditions, since the E/Z equilibrium ratio is
known for the bromomethylene lactones 2b, 4b (1/1.2,

6276
H. Harkat et al. / Tetrahedron Letters 47 (2006) 6273–6276
1/6.5, respectively)17 and is far from what is observed
here (Table 2, entries 2 and 7).
4. Yao, T.; Zhang, X.; Larock, C. K. J. Org. Chem. 2005, 70,
7679–7685.
5. Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M.
Angew. Chem., Int. Ed. 2000, 39, 2285–2287.
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2005, 127, 11260–11261.
7. Arcadi, A.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. Adv.
Synth. Catal. 2001, 343, 443–446.
In conclusion, we have developed a simple and very effi-
cient method for the synthesis of c- and d-alkylidene lac-
tones by intramolecular cyclization of x-acetylenic acids
catalyzed by AuCl and K2CO3. Moreover, a single Z
stereoisomer was formed with bromo- and phenyl
substituted derivatives.
8. Hashmi, A. S. K.; Weyrauch, J. P.; Frew, W.; Bats, J. W.
Org. Lett. 2004, 6, 4391–4394.
9. While submitted, a paper describing a similar cyclization
appeared, taking benefit of the Thorpe–Ingold effect, see:
Genin, E.; Toullec, P. Y.; Antoniotti, S.; Brancour, C.;
Genet, J. P.; Michelet, V. J. Am. Chem. Soc. 2006, 128,
3112–3113.
10. For a review on the synthesis of c-alkylidenebutenolides,
see: (a) Negishi, E.-i.; Kotora, M. Tetrahedron 1997, 53,
6707–6738; For a review on this family of natural
products, see: (b) Knight, D. M. Contemp. Org. Synth.
1994, 1, 287.
11. (a) Pale, P.; Chuche, J. Tetrahedron Lett. 1987, 51, 6447–
6448; (b) Chuche, J.; Grandjean, D.; Pale, P. Bull. Soc.
Chim. Belg. 1992, 101, 415–431; (c) Dalla, V.; Pale, P.
Tetrahedron Lett. 1994, 35, 3525–3528; (d) Dalla, V.; Pale,
P. New J. Chem. 1999, 803–805.
12. AuCl3 is known to react with benzene, see: Kharash, M.
S.; Isbell, H. S. J. Am. Chem. Soc. 1931, 53, 3053–3059,
and indeed, gave here complex mixture of products in
benzene in low yields.
Further works are now underway to expand and better
understand this cyclization of x-acetylenic acids.
Typical procedure for the formation of enol lactones from
x-acetylenic acids: To a solution of x-acetylenic acid
(1 equiv) in acetonitrile (3 ml/mmol) at room tempera-
ture, was added gold chloride (0.1 equiv) and then
K2CO3 (0.1 equiv). The reaction mixture, initially a white
suspension, turned to a dark brown solution within min-
utes. After the disappearance of the starting material
(TLC monitoring, usually 2 h), water was added to the
reaction mixture and the resulting two layers were
separated. After extraction with dichloromethane, the
combined organic layers were dried over MgSO4. After
filtration and solvent evaporation, the crude product
was purified by column chromatography when necessary.
13. (a) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc.
2005, 127, 5802–5803; (b) Zhang, L.; Kozmin, S. A. J. Am.
Chem. Soc. 2005, 127, 6962–6963.
Acknowledgements
14. The 1H NMR spectra of the crude reaction mixtures
exhibited only one set of peaks in the vinylic region (two
broad singlets at 3.75 and 4.49 ppm in C6D6).
15. Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, H.
Angew. Chem., Int. Ed. 1984, 23, 727–729.
H.H. thanks the Algerian government for a Ph.D. fel-
lowship. P.P. and J.-M.W. thank the ‘CNRS’ and the
French Ministry of Research for financial support.
16. Z and E isomers of 2b, E isomers of 4b: Krafft, G. A.;
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