Carbonylation of alkynols catalyzed by Pd(II)/2-PyPPh2 dissolved in organic solvents and in ionic liquids: A facile entry to α-methylene γ- and δ-lactones

Article abstract of DOI:10.1016/S0040-4039(01)02309-7

The carbonylation of terminal 3-alkyn-1-ols and 1-alkyn-4-ols by Pd(OAc)₂ associated with 2-(diphenylphosphino)pyridine (2-PyPPh₂) dissolved in organic solvents or in 1-n-butyl-3-methyl imidazolium ionic liquids affords quantitatively and selectively exo-α-methylene γ- and δ-lactones, respectively. In the case of the reactions performed in ionic liquids (biphasic conditions), the lactones were isolated by simple distillation and the ionic catalyst solution can be reused.

Full text of DOI:10.1016/S0040-4039(01)02309-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 753–755
Carbonylation of alkynols catalyzed by Pd(II)/2-PyPPh2
dissolved in organic solvents and in ionic liquids: a facile entry
to a-methylene g- and d-lactones
Crestina S. Consorti, Gunter Ebeling and Ja¨ırton Dupont*
Laboratory of Molecular Catalysis, IQ-UFRGS. Av. Bento Gonc¸alves, 9500 Porto Alegre 91501-970 RS, Brazil
Received 14 November 2001; accepted 4 December 2001
Abstract—The carbonylation of terminal 3-alkyn-1-ols and 1-alkyn-4-ols by Pd(OAc)2 associated with 2-(diphenylphos-
phino)pyridine (2-PyPPh2) dissolved in organic solvents or in 1-n-butyl-3-methyl imidazolium ionic liquids affords quantitatively
and selectively exo-a-methylene g- and d-lactones, respectively. In the case of the reactions performed in ionic liquids (biphasic
conditions), the lactones were isolated by simple distillation and the ionic catalyst solution can be reused. © 2002 Elsevier Science
Ltd. All rights reserved.
exo-Methylene lactones are represented in many bio-
logically active natural products and are synthetically
versatile starting materials widely employed in organic
synthesis.1 This importance has spurred the develop-
ment of a plethora of methods for their preparation.2
Amongst these methods the Pd-catalyzed homogeneous
intramolecular alkoxy-carbonylation of propargyl or
homopropargyl alcohols is one of the most promising
and elegant approaches.3 However, in most of the cases
the yields and/or selectivity in methylene lactones are
low and/or the palladium catalyst cannot be recovered.
by simple distillation and the recovered catalytic solu-
tion could be reused.
The reaction conditions for the carbonylation reaction
were established after intense experimental work (sol-
vent, CO pressure, temperature and catalyst loading).
The catalytic solution was prepared by the addition of
toluene (3 mL) to a mixture of 2-PyPPh2 (0.1 mmol),
p-toluene sulfonic acid (0.1 mmol), Pd(OAc)2 (0.01
mmol) and hydroquinone (2–5 mg) at ambient tempera-
ture. This orange-red solution was transferred to an
autoclave containing 3-butyn-1-ol (10 mmol) and then
pressurized with CO (25 atm) and heated at 60°C. After
2 h the autoclave was depressurized at room tempera-
ture and the organic phase analyzed by GC, which
indicated complete conversion of the alkynol (using
methylbenzoate as internal standard). The a-methylene
butenolide (Scheme 1) was obtained exclusively (97%
yield) and the corresponding alternative six-membered
lactone was not detected by GC–MS. The exo-methyl-
ene lactone was isolated in 80% yield after distillation
under reduced pressure (0.1 bar) or extracted with
diethyl ether and purified by column chromatography
on basic alumina.
We wish to disclose herein our preliminarily results on
the establishment of a recyclable catalytic system for
palladium-catalyzed carbonylation reactions,4 in partic-
ular for the synthesis of a-methylene lactones. This
method is based on the use of Pd(II) compounds associ-
ated with 2-(diphenylphosphino)pyridine (2-PyPPh2).
The latter is one of the most efficient catalytic systems
for the intermolecular alkoxy-carbonylation of 1-alky-
nes and this is reflected by its industrial use in the
large-scale production of chemical intermediates includ-
ing methacrylates.5 This system dissolved in organic
solvents or in 1-n-butyl-3-methyl imidazolium ionic
liquids6 catalyzes the carbonylation of alkynols to yield
a-methylene-g or d-lactones. In the case of reactions
performed in the ionic liquid, the lactones were isolated
This protocol was successfully used for the generation
of other butenolides (Table 1). Moreover, it can also be
* Corresponding author. Tel.: +55 51 33166321; fax: +55 51
33167304; e-mail: dupont@iq.ufrgs.br
Scheme 1. Carbonylation of homo-propargylalcohol.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02309-7

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C. S. Consorti et al. / Tetrahedron Letters 43 (2002) 753–755
extended to the synthesis of exo-methylene six-mem-
bered lactones (Table 1).8 In all cases almost complete
conversion of the alkynol was achieved and the exo-
cyclic methylene lactones were isolated in moderate to
good yields. The products were characterized by GC–
1
MS, IR, H and 13C NMR spectroscopy.9
These intramolecular carbonylation reactions are highly
selective since in all cases, a single lactone isomer was
detected in the crude reaction mixture (GC–MS). This
high degree of selectivity can be explained on the basis
of the mechanism(s) generally accepted for the carbony-
lation of non-functionalized 1-alkynes promoted by
cationic Pd(2-PyPPh2) complexes. Although there
remains some controversy as to whether the reaction
proceeds through a Pd–H or Pd–CO2R intermediate, in
both cases the regioselectivity is determined during the
alkyne insertion–migration step.5,10 Therefore, the
regioselectivity can be attributed to the steric control
imposed by the 2-PyPPh2 ligand, on the elementary
alkyne insertion step into the Pd–H of PdꢀC(O)OMe
bond (Fig. 1), similar to that proposed earlier for the
intermolecular alkoxy-carbonylation of 1-alkynes.10
Figure 1. Steric control on the alkyne insertion step during
the carbonylation reaction.
Although more than 60% alkynol conversion was
observed for the carbonylation of propargyl alcohols,
such as 1-methyl-2-butyn-1-ol, the desired exo-methyl-
ene-b-lactone was obtained in only 5% yield (Scheme
3). The side products are probably polymeric esters
resulting from the successive intermolecular alkoxy-car-
bonylation reaction, similar to those already observed
in analogous palladium-catalyzed carbonylation
reactions.11
Moreover, attempts to perform the intramolecular
alkoxy-carbonylation of long chain alkynols, such as
8-nonyn-1-ol and 7-octyn-2-ol, have failed and the sub-
strates were recovered almost quantitatively (>90%)
after catalysis. In these cases, again, the side products
are probably polymeric esters resulting from the inter-
molecular alkoxy-carbonylation reaction. These results
are a strong indication that the intramolecular alkoxy-
carbonylation reaction is under thermodynamic con-
trol, i.e. the formation of five- and six-membered
lactones is favored. In opposition, the intermolecular
alkoxy-carbonylation process is predominant and over-
rides the formation of four-, seven-membered or higher
lactones.
This steric effect is more pronounced in the intramolec-
ular alkoxycarbonylation of internal alkynes such as 7
and 8 (Scheme 2) that react only sluggishly to afford
the corresponding lactones 7a and 8a in low yields.
Table 1. Intramolecular alkoxy-carbonylation of alkynols
catalyzed by Pd/2-PyPPh2/CH3PhSO3H a
Once the carbonylation method and its scope were
established we turned our attention to the generation of
a recyclable liquid–liquid biphasic catalytic system. We
selected imidazolium ionic liquids (Fig. 2) as the mobile
phase since this medium allows the direct transposition
of homogeneous catalyzed reactions to liquid–liquid
biphasic conditions without the need for ligand or
metal-complex modifications.6
Scheme 2. Carbonylation of internal alkynols.
Scheme 3. Carbonylation of a propargyl alcohol.

C. S. Consorti et al. / Tetrahedron Letters 43 (2002) 753–755
755
3233; (c) Matsuda, H.; Shimoda, H.; Uemura, T.;
Yoshikawa, M. Bioorg. Med. Chem. Lett. 1999, 9, 2647;
(d) Fardella, G.; Barbetti, P.; Grandolini, G.; Chiappini,
I.; Ambrogi, V.; Scarcia, V.; Candiani, A. F. Eur. J. Med.
Chem. 1999, 34, 515.
Figure 2. Imidazolium-based ionic liquids.
2. (a) Petragnani, N.; Ferraz, H. M. C.; Silva, G. V. J.
Synthesis 1986, 157; (b) Hoffmann, H. M. R.; Rabe, J.
Angew. Chem., Int. Ed. 1985, 24, 94; (c) Dupont, J.;
Donato, A. J. Tetrahedron: Asymmetry 1998, 9, 949; (d)
Leroy, B.; Dumeunier, R.; Marko, I. E. Tetrahedron Lett.
2000, 41, 10215.
3. (a) El Ali, B.; Alper, H. Synlett 2000, 161; (b) Hosokawa,
T.; Murahashi, S. I. Heterocycles 1992, 33, 1079; (c)
Reetz, M. T.; Demuth, R.; Goddard, R. Tetrahedron
Lett. 1998, 39, 7089; (d) Gabriele, B.; Costa, M.; Salerno,
G.; Chiusoli, G. P. J. Chem. Soc., Chem. Commun. 1994,
1429; (e) Scrivanti, A.; Beghetto, V.; Campagna, E.;
Matteoli, U. J. Mol. Catal. A: Chem. 2001, 168, 75; (f) El
Ali, B.; Alper, H. J. Org. Chem. 1991, 56, 5357.
4. Zim, D.; de Souza, R. F.; Dupont, J.; Monteiro, A. L.
Tetrahedron Lett. 1998, 39, 7071.
5. (a) Drent, E.; Arnoldy, P.; Budzelaar, P. H. M. J.
Organomet. Chem. 1994, 475, 57; (b) Drent, E.; Arnoldy,
P.; Budzelaar, P. H. M. J. Organomet. Chem. 1993, 455,
247; (c) Drent, E.; Budzelaar, P. H. M.; Jager, W. W. US
Patent 5 099 062, 1992.
6. (a) Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed.
2000, 39, 3773; (b) Dupont, J.; Consorti, C. S.; Spencer,
J. J. Braz. Chem. Soc. 2000, 11, 337; (c) Welton, T. Chem.
Rev. 1999, 99, 2071.
The ionic liquid catalytic solution was prepared by the
addition of Pd(OAc)2, p-tolSO3H and 2-PyPPh2 to 3
mL of 1-n-butyl-3-methylimidazolium tetrafluoroborate
(BMI·BF4) or 1-n-butyl-3-methylimidazolium hex-
afluoro phosphate ionic liquids (BMI·PF6).7 The car-
bonylation reaction of 3-butyn-1-ol (10 mmol) was
performed using the reaction conditions employed
under homogeneous conditions (toluene). The alkynol
conversion was determined by GC using methyl ben-
zoate as internal standard. In both cases (reactions
performed in BMI·BF4 and BMI·PF6) complete alkyne
conversion was observed and the exo-methylene
butenolide was the sole product. The lactone was iso-
lated in good yields (>80%) by distillation under
reduced pressure or by extraction with diethyl ether. In
both cases the recovered ionic catalytic solution can be
reused for further alkoxy-carbonylation reactions.
However, a significant drop in the lactone yield was
observed (from 99% on the first run to 85 and 37% on
the first and second recharges using the same BMI·BF4
or BMI·PF6 ionic liquid catalytic solutions). This
strongly suggests that the isolation procedures are pos-
sibly decomposing the palladium-containing catalyti-
cally active species. Work is in progress in order to
avoid the ionic catalytic solution deactivation.
7. Suarez, P. A. Z.; Dullius, J. E. L.; Einloft, S.; de Souza,
R. F.; Dupont, J. Polyhedron 1996, 15, 1217.
8. The alkynols 3 and 5 are easily prepared by an epoxide
ring-opening reaction with a lithium acetylide or propar-
gylmagnesium bromide reagent following classical proce-
dures: Brandsma, L.; Verkruijsse, H. D. Synthesis of
Acetylenes, Allenes and Cumulenes; Elsevier: Amsterdam,
1981. Alkynol 6 was prepared by a known procedure:
Arcadi, A.; Cachi, S.; Delrosario, M.; Fabrizi, G.;
Marinelli, F. J. Org. Chem. 1996, 61, 9280. All other
alkynols are commercially available.
In summary Pd(OAc)2/2-PyPPh2 dissolved in toluene
(homogeneous conditions) is a simple and efficient
method for the intramolecular alkoxycarbonylation of
alkynols, leading exclusively to five- or six-membered
exo-methylene lactones. This catalytic system can also
be immobilized in ionic liquids such as BMI·BF4 and
BMI·PF6 (liquid–liquid biphasic conditions) without
any changes in catalytic activity or selectivity.
9. The five- and six-membered lactones reported in this
work are known and have spectroscopic data in accord
with those reported: 1a, 3a, 4a and 5a;11 2a;12 9a.13 7a
and 8a: Murray, T. F.; Norton, J. R. J. Am. Chem. Soc.
1979, 101, 4107.
Acknowledgements
This work was partially supported by grants from the
CNPq and FAPERGS (Brazil). C.S.C. thanks CAPES
for a PhD grant (PGCIMAT-UFRGS).
10. Scrivanti, A.; Beghetto, V.; Campagna, E.; Zanato, M.;
Matteoli, U. Organometallics 1998, 17, 630.
11. Murray, T. F.; Samsel, E. G.; Varma, V.; Norton, J. R.
J. Am. Chem. Soc. 1981, 103, 7520.
12. Tezuka, K.; Ishizaki, Y.; Inoue, Y. J. Mol. Cat. A: Chem.
References
1998, 129, 199.
13. Adam, W.; Albert, R.; Grau, N. D.; Hasemann, L.;
Nestler, B.; Peters, E. M.; Peters, K.; Prechtl, F.; von
Schnegring, H. G. J. Org. Chem. 1991, 56, 5778.
1. (a) Ogliaruso, M. A.; Wolfe, J. F. In Synthesis of Lac-
tones and Lactams; Patai, S.; Rappoport, Z., Eds.; Wiley:
New York, 1993; (b) Mori, K. Tetrahedron 1989, 45,