Cycloisomerization versus hydration reactions in aqueous media: A Au(III)-NHC catalyst that makes the difference

Article abstract of DOI:10.1021/ol300811e

A novel water-soluble Au(III)-NHC complex has been synthesized and successfully applied in the intramolecular cyclization of γ-alkynoic acids into enol-lactones under biphasic toluene/water conditions, thus representing a rare example of an active and sel

Full text of DOI:10.1021/ol300811e

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2520–2523
Cycloisomerization versus Hydration
Reactions in Aqueous Media: A Au(III)-
NHC Catalyst That Makes the Difference
†
Eder Tomas-Mendivil, Patrick Y. Toullec, Josefina Dıez, Salvador Conejero,*
ꢀ
‡
†
,§
ꢀ
Veronique Michelet,* and Victorio Cadierno*
´
,‡
,†
ꢀ
ꢀ
Laboratorio de Compuestos Organometalicos y Catalisis (Unidad Asociada al CSIC),
Departamento de Quımica Organica e Inorganica, Universidad de Oviedo, Julian
´
ꢀ
ꢀ
ꢀ
´
Claverıa 8, E-33006 Oviedo, Spain, ChimieParisTech, Laboratoire Charles Friedel,
ENSCP, UMR 7223, 11 rue P. et M. Curie, F-75231, Paris Cedex 05, France, and
´
Departamento de Quımica Inorganica, Instituto de Investigaciones Quımicas (IIQ),
CSIC/Universidad de Sevilla, Avda. Americo Vespucio 49, E-41092, Sevilla, Spain
ꢀ
´
ꢀ
sconejero@iiq.csic.es; veronique-michelet@chimie-paristech.fr; vcm@uniovi.es
Received March 30, 2012
ABSTRACT
A novel water-soluble Au(III)-NHC complex has been synthesized and successfully applied in the intramolecular cyclization of γ-alkynoic acids
into enol-lactones under biphasic toluene/water conditions, thus representing a rare example of an active and selective catalyst for this
transformation in aqueous media. Remarkably, competing alkyne hydration processes were not observed, even during the desymmetrization
reaction of challenging 1,6-diyne substrates. In addition, after phase separation, the water-soluble Au(III) catalyst could be recycled 10 times
without loss of activity or selectivity.
After a long induction period, gold complexes have
emerged in recent years as versatile and powerful catalysts
for synthetic organic chemistry.1 The catalytic hydration
ofalkynes by Na[AuCl4] reported byFukuda and Utimoto
in 1991 initiated rapid development of the field.2 Since
then, gold complexes have been widely employed in many
organic transformations, with special focus on the electro-
philic π-activation of unsaturated carbonꢀcarbon bonds
(alkynes, enynes, alkenes, allenes, etc.) toward nucleophiles.1,3
Relativistic effects have been evoked to explain the supe-
rior effectiveness of gold as a π-activator compared to other
transition metals.4 In addition, it has also been largely
demonstrated that the stability and Lewis acidity of
Au(I) and Au(III) species can be easily modulated by the
surrounding ligands, thus enabling the fine tuning of the
activity and the chemo-, regio-, and/or stereoselectivity of
† Universidad de Oviedo.
‡ ChimieParisTech.
§ CSIC/Universidad de Sevilla.
(1) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006,
45, 7896–7936. (b) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180–3211.
(c) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239–3265. (d)
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Arcadi, A. Chem. Rev. 2008, 108, 3266–3325. (e) Furstner, A. Chem. Soc.
Rev. 2009, 38, 3208–3221. (f) Hashmi, A. S. K. Angew. Chem., Int. Ed.
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2010, 49, 5232–5241. (g) Corma, A.; Leyva-Perez, A.; Sabater, M. J.
Chem. Rev. 2011, 111, 1657–1712.
(2) Fukuda, Y.; Utimoto, K. J. Org. Chem. 1991, 56, 3729–3731.
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Int. Ed. 2007, 46, 3410–3449. (b) Shen, H. C. Tetrahedron 2008, 64, 3885–
3903. (c) Muzart, J. Tetrahedron 2008, 64, 5815–5849. (d) Shen, H. C.
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Tetrahedron 2008, 64, 7847–7870. (e) Jimenez-Nunez, E.; Echavarren,
A. M. Chem. Rev. 2008, 108, 3326–3350. (f) Patil, N.-T.; Yamamoto, Y.
(4) (a) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395–403. (b)
^
Chem. Rev. 2008, 108, 3395–3442. (g) Michelet, V.; Toullec, P. Y.; Genet,
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Leyva-Perez, A.; Corma, A. Angew. Chem., Int. Ed. 2012, 51, 614–635.
J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268–4315. (h) Belmont, P.;
Parker, E. Eur. J. Org. Chem. 2009, 6075–6089. (i) Wang, S.; Zhang,
G.; Zhang, L. Synlett 2010, 692–706. (j) Krause, N.; Winter, C. Chem.
Rev. 2011, 111, 1994–2009. (k) Pradal, A.; Toullec, P. Y.; Michelet, V.
Synthesis 2011, 1501–1514.
(5) (a) For a specific review on ligand effects in homogeneous Au
catalysis, see: Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008,
108, 3351–3378. (b) For a relevant recent example, see: Wang, W.;
Hammond, G. B.; Xu, B. J. Am. Chem. Soc. 2012, 134, 5697–5705.
r
10.1021/ol300811e
Published on Web 04/30/2012
2012 American Chemical Society

the catalytic processes in which gold is involved.5 In this
context, gold complexes with N-heterocyclic carbene
(NHC) ligands are gaining a great significance due to the
stability provided by the strong σ-donation and weaker
π-back-bonding ability of such ligands in comparison to
the more commonly used tertiary phosphines.6
Such a catalytic reaction constitutes nowadays the major
route for the construction of five-membered exocyclic
enol-lactones with complete atom economy. It is also
worthy of note that, although a plethora of transition-
metal catalysts including gold have been developed for this
synthetically useful transformation,16ꢀ18 efficient systems
able to operate in aqueous media are still rare.19
On the other hand, since the discoveries made by
Breslow and Grieco in the early 1980s on the positive
effect of water on the rate and endo/exo selectivity of
DielsꢀAlder reactions,7 the development of organic trans-
formations in aqueous media has become one of the major
cornerstones in modern chemistry.8 In addition, the use of
water as an alternative, available, safe, and cost-effective
solvent fullfills the principles of “Green Chemistry”,9
creating an answer to the growing concerns associated
with the environmental impact of chemical processes.10
Following this general trend, several Au-catalyzed reac-
tions conducted in aqueous media have been successfully
developed in recent years.1 However, concerning the use of
gold-NHC systems, studies in water have been scarce and
restricted to catalytic hydrations of alkynes11 and nitriles12
and MeyerꢀSchuster-type rearrangements.13
The route designed to synthesize the water-soluble Au-
(III)-NHC catalyst 3 is depicted in Scheme 1. First, the
novel zwitterionic imidazolium salt 2 was prepared by
reacting the known 2-(1H-imidazol-1-ylmethyl)pyridine
120 with 1,3-propane sultone.21 Then, sequential treatment
of 2 with Ag2O, [AuCl(SMe2)], and excess of PhICl2 led to
the clean formation of 3, via the corresponding Ag(I)- and
Au(I)-NHC intermediates.22 Complex 3, isolated as an air-
stable yellow solid in 63% yield, was characterized by
means of standard spectroscopic techniques as well as
elemental analysis. Inaddition, X-ray-quality crystals were
obtained by slow diffusion of toluene into a saturated
DMSO solution, allowing us to confirm unambiguously
the molecular structure of this new Au(III)-NHC deriva-
tive (see Supporting Information).
We wish therefore to describe herein that, despite the
high tendency of gold to promote the hydration of CtC
bonds,1ꢀ3,11,14 cycloisomerization reaction of γ-alkynoic
acids can be selectively performed in aqueous media in the
presence of a new water-soluble Au(III)-NHC complex.15
As expected, complex 3 readily dissolves in water at
room temperature. However, in this medium an equili-
brium is established between 3 and the zwitterionic deri-
vative 4, the latter resulting from the release of HCl and
concomitant coordination of the pyridyl unit to the gold
(6) For reviews on the catalytic uses of NHC-containing Au(I) and
Au(III) complexes, see: (a) Marion, N.; Nolan, S. P. Chem. Soc. Rev.
2008, 37, 1776–1782. (b) Nolan, S. P. Acc. Chem. Res. 2011, 44, 91–100.
(c) Gaillard, S.; Cazin, C. S. J.; Nolan, S. P. Acc. Chem. Res. 2012,
published ASAP ahead of print; DOI: 10.1021/ar200188f).
(16) Representative examples published by some of us: (a) Genin, E.;
^
Toullec, P. Y.; Antoniotti, S.; Brancour, C.; Genet, J.-P.; Michelet, V.
J. Am. Chem. Soc. 2006, 128, 3112–3113. (b) Genin, E.; Toullec, P. Y.;
^
Antoniotti, S.; Brancour, C.; Genet, J.-P.; Michelet, V. ARKIVOC 2007,
^
67–78. (c) Toullec, P. Y.; Genin, E.; Antoniotti, S.; Genet, J.-P.;
(7) (a) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102,
7816–7817. (b) Grieco, P. A.; Yoshida, K.; Garner, P. J. Org. Chem.
1983, 48, 3137–3139.
Michelet, V. Synlett 2008, 707–711. (d) Nea-tu, F.; Li, Z.; Richards, R.;
^
€
Toullec, P. Y.; Genet, J.-P.; Dumbuya, K.; Gottfried, J. M.; Steinruck,
^
H.-P.; Parvulescu, V. I.; Michelet, V. Chem.;Eur. J. 2008, 14, 9412–
€
(8) See, for example: (a) Organic Reactions in Water; Lindstrom,
^
^
9418. (e) Nea-tu, F.; Parvulescu, V. I.; Michelet, V.; Genet, J.-P.; Goguet,
U. M., Ed.; Blackwell Publishing: Oxford, 2007. (b) Li, C.-J.; Chan, T. H. In
Comprehensive Organic Reactions in Aqueous Media; Wiley-VCH:
Weinheim, 2007. (c) Genin, E.; Leseurre, L.; Michelet, V. In Geꢀnie des
Proceꢀdeꢀs Verts et Durables: Outils et Meꢀthodes; Dunod: Paris, 2010. (d) Li,
C.-J. Chem. Rev. 2005, 105, 3095–3166. (e) Shaughnessy, K. H. Chem.
Rev. 2009, 109, 643–710 and references therein.
(9) (a) Anastas, P. T.; Warner, J. C. In Green Chemistry: Theory and
Practice; Oxford University Press: Oxford, 1998. (b) Sheldon, R. A.; Arends,
I.; Hanefeld, U. Green Chemistry and Catalysis; Wiley-VCH: Weinheim,
2007.
A.; Hardacre, C. New J. Chem. 2009, 33, 102–106. (f) Nea-tu, F.;
Protes-escu, L.; Florea, M.; Parvulescu, V. I.; Teodorescu, C. M.;
^
Apostol, N.; Toullec, P. Y.; Michelet, V. Green Chem. 2010, 12, 2145–
2149.
(17) For other cycloisomerization reactions based on Au catalysts,
see: (a) Harkat, H.; Weibel, J.-M.; Pale, P. Tetrahedron Lett. 2006, 47,
6273–6276. (b) Marchal, E.; Uriac, P.; Legouin, B.; Toupet, L.; van de
ꢀ
Weghe, P. Tetrahedron 2007, 63, 9979–9990. (c) Harkat, H.; Dembele,
A. Y.; Weibel, J.-M.; Blanc, A.; Pale, P. Tetrahedron 2009, 65, 1871–
1879. (d) Sperger, C. A.; Fiksdahl, A. J. Org. Chem. 2010, 75, 4542–4553.
(18) For reviews on catalytic additions of carboxylic acids to alkynes,
see: (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104,
3079–3160. (b) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104,
2127–2198. (c) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem.,
(10) Kerton, F. M. In Alternative Solvents for Green Chemistry; RSC
Publishing: Cambridge, 2009.
(11) (a) Schneider, S. K.; Herrmann, W. A.; Herdtweck, E. Z. Anorg.
ꢀ
All. Chem. 2003, 629, 2363–2370. (b) de Fremont, P.; Singh, R.; Stevens,
ꢀ
~
E. D.; Petersen, J. L.; Nolan, S. P. Organometallics 2007, 26, 1376–1385.
Int. Ed. 2004, 43, 3368–3398. (d) Jimenez- Nunez, E.; Echavarren, A. M.
Chem. Commun. 2007, 333–346. (e) Bruneau, C.; Dixneuf, P. H. Acc.
Chem. Res. 1999, 32, 311–323.
ꢀ
(c) Marion, N.; Ramon, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009, 131,
ꢀ
ꢀ
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448–449. (d) Almassy, A.; Nagy, C. E.; Benyei, A. C.; Joo, F. Organo-
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
metallics 2010, 29, 2484–2490. (e) Czegeni, C. E.; Papp, G.; Katho, A.;
Joo, F. J. Mol. Catal. A: Chem. 2011, 340, 1–8.
(19) Only two catalytic systems, involving Pt and Cu complexes,
active in aqueous media have been previously described: (a) Mindt,
ꢀ
ꢀ
(12) Ramon, R. S.; Marion, N.; Nolan, S. P. Chem.;Eur. J. 2009, 15,
8695–8697.
T. L.; Schibli, R. J. Org. Chem. 2007, 72, 10247–10250. (b) Aleman, J.;
del Solar, V.; Navarro-Ranninger, C. Chem. Commun. 2010, 46, 454–
456. (c) The presence of water was tolerated in ref 16c.
(20) Chiu, P. L.; Lai, C.-L.; Chang, C.-F.; Hu, C.-H.; Lee, H. M.
Organometallics 2005, 24, 6169–6178.
(21) Related zwitterionic imidazolium salts have been previously
synthesized following this route: Moore, L. R.; Cooks, S. M.; Anderson,
M. S.; Schanz, H.-J.; Griffin, S. T.; Rogers, R. D.; Kirk, M. C.;
Shaughnessy, K. H. Organometallics 2006, 25, 5151–5158.
(22) Trace amounts of HCl in the dichloromethane employed is
probably responsible for the protonation of the sulfonate group. In
addition, HCl may also be present in the iodobenzene dichloride
employed as oxidant, since it was synthesized by chlorination of
iodobenzene with NaClO2 in hydrochloric acid solution as described
in Zhao, X.-F.; Zhang, C. Synthesis 2007, 4, 551–557.
ꢀ
(13) (a) Ramon, R. S.; Marion, N.; Nolan, S. P. Tetrahedron 2009, 65,
1767–1773. (b) Ramon, R. S.; Gaillard, S.; Slawin, A. M. Z.; Porta, A.;
ꢀ
D’Alfonso, A.; Zanoni, G.; Nolan, S. P. Organometallics 2010, 29, 3665–
3668. (c) Merlini, V.; Gaillard, S.; Porta, A.; Zanoni, G.; Vidari, G.;
Nolan, S. P. Tetrahedron Lett. 2011, 52, 1124–1127.
(14) For leading references using Au(III) catalysts, see: (a) Casado,
R.; Contel, M.; Laguna, M.; Romero, P.; Sanz, S. J. Am. Chem. Soc.
2003, 125, 11925–11935. (b) Wang, W.; Xu, B.; Hammond, G. B. J. Org.
Chem. 2009, 74, 1640–1643.
(15) Competitive hydration of the substrates is probably the major
limitation when catalytic transformations of alkynes are performed in
water: (a) Chen, L.; Li, C.-J. Adv. Synth. Catal. 2006, 348, 1459–1484.
(b) Li, C.-J. Acc. Chem. Res. 2010, 43, 581–590.
Org. Lett., Vol. 14, No. 10, 2012
2521

center (Scheme 1). Complex 4 is the major species present
in solution at rt, and its structure was also determined by
X-ray crystallography (see Supporting Information). Che-
lation of the NHC ligand in water is readily evidenced by
1H NMR spectroscopy, where the singlet signal corre-
sponding to the methylenic protons of the picolyl moiety
in 3 (δ 5.63 ppm) undergoes an AB splitting (δ 5.65 and
5.81 ppm; J = 16.0 Hz) as a consequence of the conforma-
tional rigidity of the six-membered metallacycle in 4.23
be ruled out, as demonstrated by the result shown in entry
6.26 The use of a base (KOH, entry 7) associated with the
catalyst allowed the formation of the desired lactone.17a
Conversely, no catalytic activity was observed in the
presence of the free ligand 2 alone (entry 8). These results
fully support that the intramolecular nucleophilic attack of
the carboxylic unit is taking place upon coordination of the
alkyne to the metal center. The required vacant site is most
probably generated by decoordination of the picolyl moi-
ety in the in situ formed complex 4, owing to the well-
known hemilabile character of this group.27 As shown in
entries 9 and 10, simple Au(III) and Au(I) sources were
comparatively much less effective and selective, thus high-
lighting the synthetic potential of complex 3.
Scheme 1. Synthesis of Complex 3 and Its Behavior in Water
Table 1. Catalytic Cycloisomerization of 5a in Aqueous Mediaa
entry
conditions
time (h) yield (%)e
1b
3 (2.5 mol %), MeCN/H2O
3 (2.5 mol %), Et2O/H2O
6
5
2
1
1
1
1
1
4
6
>99
>99
>99
>99 (81)
50f
2b
3b
3 (2.5 mol %), CH2Cl2/H2O
3 (2.5 mol %), toluene/H2O
3 (2.5 mol %), H2O
4b
5c
As shown in Table 1, complex 3 turned out to be an
efficient and selective catalyst for the cycloisomerization of
model 4-pentynoic acid 5a in different mono- and biphasic
water/organic solvent mixtures (entries 1ꢀ4). Reactions,
performed at rt under aerobic conditions with a metal
loading of 2.5 mol %, led to the quantitative transforma-
tion of 5a into enol-lactone 6a, with no byproduct resulting
from the hydration of the CtC bond of 5a being detected
by 1H NMR spectroscopy in the crude reaction mixtures.
Best results in terms of activity were obtained using a
biphasic toluene/water solvent system,24 where total con-
sumption of 5a was observed after only 1 h, thus allowing
the isolation of 6a in high yield (81%; entry 4). The process
is also operative in pure water (entry 5). However, both the
activity and selectivity of 3 in this medium were lower, the
latter due to the partial hydrolysis of 6a to form 3-
acetylpropanoic acid.25 Brønsted acid catalysis mediated
by the HCl released after dissolving complex 3 in water can
6b
HCl (2.5 mol %), toluene/H2O
3 þ KOH (2.5 mol %), toluene/H2O
2 (2.5 mol %), toluene/H2O
AuCl3 (2.5 mol %), toluene/H2O
AuCl (2.5 mol %), toluene/H2O
1
7b,d
8b
>99
0
90g
70f
9b
10b
a Reactions were performed at rt under aerobic conditions starting
from 0.3 mmol of 5a. b 1 mL of the corresponding organic solvent and
1 mL of distilled water were employed. c 2 mL of distilled water were
employed. d 2.5 mol % of each reagent was employed. e Determined by
1H NMR. Isolated yields are given in brackets. f A mixture of 6a and
3-acetylpropanoic acid in ca. 3:1 ratio is formed. g A mixture of 6a and
3-acetylpropanoic acid in ca. 5:1 ratio is formed.
The scope of the reaction was then studied for various
γ-alkynoic acids in a biphasic toluene/water mixture
(Table 2).28 Complete conversions were observed for sub-
strates 5bꢀh, all bearing a terminal alkyne unitand alkyl or
alkenyl side chains, after 2ꢀ4 h of stirring at rt in the
presence of 2.5 mol % of 3 (entries 1ꢀ7). The reactions led
to the selective formation of lactones 6bꢀh, which could be
isolated in good yields (66ꢀ97%), without detection of
any byproduct by 1H NMR in the crude reaction mixtures.
As shown in entries 8 and 9, the process is also operative
with the internal alkynes 5iꢀj. Nevertheless, longer reac-
tion times or higher temperatures were required. In addi-
tion, traces of the corresponding six-membered ring
lactones, resulting from an endo instead of an exo
(23) Related Au(III) complexes containing chelating picolyl-NHC
ꢁ
ligands have been described. See, for example: (a) Pazicky, M.; Loos, A.;
Ferreira, M. J.; Serra, D.; Vinokurov, N.; Rominger, F.; Jakel, C.;
ꢀ
€
Hashmi, A. S. K.; Limbach, M. Organometallics 2010, 29, 4448–4458.
(b) Topf, C.; Hirtenlehner, C.; Fleck, M.; List, M.; Monkowius, U. Z.
Anorg. Allg. Chem. 2011, 637, 2129–2134. (c) See also ref 20.
(24) For examples of improved selectivity when biphasic toluene/
^
water systems are employed, see: (a) Genin, E.; Michelet, V.; Genet,
J.-P. Tetrahedron Lett. 2004, 45, 4157–4161. (b) Genin, E.; Michelet, V.;
^
Genet, J.-P. J. Organomet. Chem. 2004, 689, 3820–3830 and references
therein.
(25) Formation of 3-acetylpropanoic acid by direct hydration 5a was
discarded since, under the same reaction conditions, complex 3 is not
able to hydrate terminal alkynes, such as 1-pentyne or 1-hexyne (only at
100 °C hydration could be observed). Note also that hydrolysis of
lactones is a well-known process: Olson, A. R.; Hyde, J. L. J. Am. Chem.
Soc. 1941, 63, 2459–2461.
(26) For a review on π-activation of alkynes by Brønsted acids, see:
Yamamoto, Y.; Gridner, I. D.; Patil, N. T.; Jin, T. Chem. Commun. 2009,
5075–5087.
(27) Slone, C. S.; Weinberger, D. A.; Mirkin, C. A. Prog. Inorg.
Chem. 1999, 48, 233–350 and references therein.
2522
Org. Lett., Vol. 14, No. 10, 2012

Table 2. Au(III)-Catalyzed Cycloisomerization of γ-Alkynoic
Acids 5bꢀj in a Biphasic Toluene/Water Mediuma
Table 3. Au(III)-Catalyzed Cycloisomerization of Bispro-
pargylic Carboxylic Acids 7aꢀh in a Biphasic Toluene/Water
Mediuma
time
(h)
yield
(%)b
entry
substrate
time
(h)
yield
R1 = R2 = Me; R3 = H (5b)
2
2
2
2
2
2
4
84
96
80
97
92
84
66
entry
substrate
temp
(%)b
1
2
3
4
5
6
7
R1 = CO2Me; R2 = R3 = H (5c)
R1 = CO2Me; R2 = Me; R3 = H (5d)
R1 = CO2Me; R2 = Et; R3 = H (5e)
R1 = CO2Et; R2 = Bn; R3 = H (5f)
R1 = CO2Me; R2 = CH2CHdCH2; R3 = H (5g)
R1 = CO2Me; R2 = CH2CHdCHPh; R3 = H
(5h)
1
2
3
4
5
6
7
8
R1 = R2 = R3 = H (7a)
rt
2
2
2
2
1
1
2
6
94
84
88
84c
90d
40
80
86
R1 = CO2Me; R2 = R3 = H (7b)
R1 = Ph; R2 = R3 = H (7c)
R1 = H; R2 = R3 = Me (7d)
R1 = CO2Me; R2 = R3 = Me (7e)
R1 = CO2Me; R2 = R3 = Ph (7f)
rt
rt
80 °C
80 °C
80 °C
R1 = CO2Me; R2 = H; R3 = Me (7g) rt
R1 = CO2Me; R2 = H; R3 = Ph (7h) rt
8
R1 = CO2Me; R2 = Et; R3 = Me (5i)
24
2
94c
28c
9d R1 = CO2Me; R2 = H; R3 = Ph (5j)
a Reactions were performed as described in ref 28. b Isolated yields.
c A mixture of 8d and the corresponding six-membered ring lactone is
formed in ca. 6:1 ratio. d A mixture of 8e and the corresponding six-
membered ring lactone is formed in ca. 3:1 ratio.
a Reactions were performed as described in ref 28. b Isolated yields.
c Traces of the six-membered ring lactone were detected by 1H NMR in
the crude reaction mixture. d Reaction performed at 80 °C.
cyclization, were now detected in the 1H NMR spectra of
the crude mixtures.
these desymmetrization processes were hydration bypro-
ducts detected.
One of the major advantages of biphasic catalysis is that
it is associated with the recycling of the catalytic species.31
In this context, we have found that, after separation of the
toluene layer in which the lactone is soluble, the aqueous
phase containing the catalytically active gold species
can be reused. Thus, using the 1,6-diyne 7a as model
substrate, 10 consecutive reactions could be performed
without any loss of activity or selectivity (quantitative
yield over the 10 cycles).
In summary, we have demonstrated that non-hydrative
transformations of functionalized alkynes can be effi-
ciently and selectively performed in aqueous media by
means of NHC-gold catalysis. This unprecedented fact,
together with the possibility of an effective recycling, opens
new research directions to expand the applications of
NHC-gold complexes in synthetic organic chemistry.
Complex 3 proved also selective in the cyclization
of more challenging bispropargylic carboxylic acids
(Table 3).29 Thus, starting from the symmetrical terminal
1,6-diynes 7aꢀc (entries 1ꢀ3), enol-lactones 8aꢀc contain-
ing a propargylic side arm intact could be generated in
excellent yields (84ꢀ94%) under mild conditions. In con-
trast, desymmetrization of diynes 7dꢀf containing internal
CtC bonds proved more difficult, and a higher tempera-
ture (80 °C) was required (entries 4ꢀ6). As in the case of
5iꢀj, competitive formation of the corresponding six-
membered ring lactones was again observed. The remark-
able higher reactivity of terminal versus internal CtC
bonds was clearly evidenced in the reactions of the non-
symmetrical 1,6-diynes 7gꢀh (entries 7 and 8), where only
theformerparticipatedinthe cyclization processleading to
the exclusive formation of lactones 8gꢀh.30 In none of
(28) General procedure for the catalytic reactions. To a biphasic
system composed of 1 mL of toluene and 1 mL of distilled water were
added 0.3 mmol of the corresponding alkynoic acid and 4.4 mg of
complex 3 (0.0075 mmol; 2.5 mol %). The resulting mixture was stirred
under air, at rt or 80 °C (see Tables 1ꢀ3), until complete consumption of
the alkynoic acid was observed by TLC. The organic phase was then
separated, the aqueous one was extracted with diethyl ether (2 ꢁ 2 mL),
and the combined organic extracts were dried over anhydrous MgSO4
and filtered over a short pad of silica gel using CH2Cl2 as eluent. The
volatiles were removed under vacuum to yield the corresponding lactone
in high yield and purity. When required, lactones were further purified
by column chromatography over silica gel using hexane/EtOAc (9:1) as
eluent.
Acknowledgment. This work was financially supported
by MICINN (projects CTQ2010-14796/BQU, CTQ2010-
17476/BQU, and CSD2007-00006) and Junta de Andalucia
(project FQM-3151) of Spain and CNRS of France. E.T.-M.
thanks MECD of Spain and the European Social Fund for
the award of a FPU grant.
Supporting Information Available. Experimental details,
characterization data, and crystallographic data for com-
pounds 3 and 4 in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org.
(29) For related transformations catalyzed by NHC-gold complexes
in organic media see ref 17d.
(30) From a mechanistic point of view, the cyclization processes
reported herein proceed via an anti-addition of the carboxylic unit to
the π-coordinated alkyne. This was inferred by performing the cycliza-
tion of 7a into lactone 8a in a biphasic toluene/D2O mixture, reaction
that led to the major incorporation of deuterium in E position of the
exocyclic CdC bond of 8a (details are given in the Supporting
Information).
(31) Aqueous-Phase Organometallic Catalysis: Concepts and Applica-
tions; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: Weinheim, Germany,
1998.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
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