Efficient silver-free gold(I)-catalyzed hydration of alkynes at low catalyst loading

Article abstract of DOI:10.1016/j.jorganchem.2010.08.052

The use of [(IPr)AuOH] as versatile, air- and moisture-stable pre-catalyst permits the in situ generation of the cationic gold(I) species [(IPr)Au]X after reaction with a Br?nsted acid. This catalytic system presents as a main advantage the lack of use of a silver salt activator or co-catalyst which is often air-, light- and moisture-sensitive. A general gold(I)-catalyzed procedure using this in situ activation at very low catalyst loading is reported for the hydration of a broad range of internal and terminal alkynes.

Full text of DOI:10.1016/j.jorganchem.2010.08.052

Journal of Organometallic Chemistry 696 (2011) 7e11
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Communication
Efficient silver-free gold(I)-catalyzed hydration of alkynes at low catalyst loading
*
Pierrick Nun, Rubén S. Ramón, Sylvain Gaillard, Steven P. Nolan
EaStCHEM School of Chemistry, University of Saint Andrews, North Haugh, KY16 9ST, St Andrews, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of [(IPr)AuOH] as versatile, air- and moisture-stable pre-catalyst permits the in situ generation of
the cationic gold(I) species [(IPr)Au]X after reaction with a Brønsted acid. This catalytic system presents
as a main advantage the lack of use of a silver salt activator or co-catalyst which is often air-, light- and
moisture-sensitive. A general gold(I)-catalyzed procedure using this in situ activation at very low catalyst
loading is reported for the hydration of a broad range of internal and terminal alkynes.
Ó 2010 Elsevier B.V. All rights reserved.
Received 5 August 2010
Received in revised form
25 August 2010
Accepted 27 August 2010
Available online 6 September 2010
Keywords:
Gold catalysis
Alkyne hydration
Acid activation
Ketones
1. Introduction
center [3b]. Nevertheless, a new (NHC)gold(I) (NHC ¼ N-heterocy-
clic carbene) pre-catalyst [(IPr)AuOH] (1) (IPr ¼ 1,3-bis(2,6-diiso-
Gold catalysis has emerged in the past five years as a powerful
tool enabling many useful synthetic transformations [1]. Among
these organic transformations, gold-catalyzed nucleophilic addi-
tions involving heteroatom-containing nucleophiles have been
frequently reported [2]. More specifically, the addition of a mole-
cule of water onto triple bonds of molecules such as alkynes [3] or
nitriles [4] is one of the simplest intermolecular and atom-
economical reactions performed by gold catalysis. Alkyne hydration
permits a simple access to the carbonyl function [5] and has
revealed to be a useful tool in total synthesis [6]. Since its first
discovery in 1881 by Kucherov [7], this reaction has been widely
used especially on industrial scale [8] in spite of the toxicity of the
more active catalytic systems, those comprising mercury(II) salts
and either Lewis or Brønsted acid [9]. Much effort has been focused
on the development of less toxic methods and among them the use
of organogold complexes has emerged as an attractive alternative
[10]. Tanaka first reported the use of concentrated solutions of
strong acids (H2SO3, H3PW12O40, CF3SO3H) in association with
[(PPh3)AuMe][3c,d]. Recently, Nolan et al. contributed to the area
by developing a method involving [(IPr)AuCl]/AgSbF6 as catalytic
system. This latter showed high efficiency even at part-per-million
(ppm) catalyst loadings and proved to be an advantageous alter-
native to the use of excess strong acid necessary to activate the gold
propylphenyl)imidazol-2-ylidene) [11,12] has recently emerged
and this complex has been employed to easily generate the ubiq-
uitous [(IPr)Au]þ catalytic active species by protonolysis in the
presence of a Brønsted acid (Scheme 1) [13]. The present study
focuses on the use of 1 as pre-catalyst in the hydration of various
alkynes. The minimum amount of Brønsted acid necessary to
activate the gold center in this system is closely examined.
This approach is devoid of any silver additive; the Reader will be
reminded that these air-, light- and moisture-sensitive silver salts of
type AgX (X ¼ BF4, SbF6, OTf, PF6, NTf2) are usually employed to
generate the cationic gold(I) species from [LAuCl] (L ¼ phosphine or
NHC). Moreover, this methodology removes any doubt about the
role of silver in the mechanism of this specific hydration reaction.
A second advantage of this activation type is that water is the only
co-product formed which is in any case a reagent or even the
reaction solvent in reactions of the type examined here. These initial
mechanistic studies into the acid activation of 1 led us to consider
a silver-free method for alkyne hydration using low loadings of 1 in
association with Brønsted acids as activator of the gold center,
providing very environmentally friendly and a very atom-econom-
ical method to generate ketones from alkynes.
2. Results and discussion
The investigations started with the determination of the best
catalytic system. Keeping in mind the previous work based on the
use of silver salts [3b], various Brønsted acids and HNTf2 in aqueous
* Corresponding author.
E-mail address: snolan@st-andrews.ac.uk (S.P. Nolan).
0022-328X/$ e see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.08.052

8
P. Nun et al. / Journal of Organometallic Chemistry 696 (2011) 7e11
N
N
N
N
+
HX
X
-H2O
Au
OH
Au
1
Scheme 1. Generation of [(IPr)Au][X] via acid activation of 1.
solutions were used to generate the active gold(I) species in
a mixture of MeOH/water (2:1) at 120 ꢀC during 24 h. In order to
develop a valuable alternative to silver salts, the amount of catalyst
was decreased to 1000 ppm (i.e., 0.1 mol%).
diphenylacetylene proceeds significantly slower and through an
intermediate product identified as the vinyl ether, which then
converts into the expected ketone. A kinetic profile of the reaction
is presented in Fig. 1.
Best results were obtained with HSbF6 and HNTf2 with average
conversions of 93% (Table 1, entries 1 and 2), whereas the use of
HBF4 led to irreproducible results, with conversions from 0% to 51%
under identical reaction conditions (Table 1, entry 3). These exper-
iments are in good agreement with the previously optimized reac-
tion conditions where [(IPr)Au][SbF6] generated after activation by
AgSbF6 showed the highest activity [3b]. A slight excess of acid is
necessary to ensure complete formation of the active species from 1
in the reaction medium. Due to the large amount of water in the
reaction medium, the absence of acid or the presence of exactly 1
equivalent can possibly result in an equilibrium involving 1 and [{Au
With a higher catalyst loading (4 mol%) (in order to obtain more
rapid conversions), diphenylacetylene is completely consumed
after 15 min and transformed into the corresponding vinylether
and ketone in a 71:29 ratio. This ratio evolves after 30 min to 46:54,
and the proportion of ketone rises continuously to obtain after 2 h
a complete conversion of vinylether into ketone. These results fit
those obtained by Leyva and Corma [16] concerning the hydration
of 1-octyne in alcohol solvents, showing that the attack of MeOH
onto the alkyne is faster compared to that of H2O. Corma postu-
lated that this vinyl ether could react with MeOH to give a diketal
that quickly evolves into the ketone in the presence of water.
Nevertheless, this diketal could not be observed. These observa-
tions have also been recently extended by Sahoo and co-workers to
the gold-catalyzed intermolecular hydrophenoxylation of internal
alkynes [17]. Fig. 1 clearly suggests that the conversion of vinyl-
ether into the desired ketone is the limiting step in the hydration of
internal alkynes. While the starting material is consumed within
15 min, the conversion of the intermediate requires 2 h to reach
completion. To avoid this vinylether formation and as consequence
accelerate the reaction rate, 1,4-dioxane was chosen as solvent
when internal alkynes were involved.
(IPr)}2(m-OH)][X] [13,14], which was found slightly less active in
alkyne hydration than [LAu]þ. Noteworthy, alkyne 2a did not lead to
the corresponding ketone 3a in the presence of the Brønsted acid
alone; gold is necessary (Table 1, entry 4), proving that the reaction
does not proceed via simple acid catalysis. Without any acid and in
the presence of a higher catalyst loading of 1 (Table 1, entry 5), the
conversion reached was only 12%. This low catalytic activity was
already reported in the previous NMR study of Gaillard, Nolan and
co-workers revealing the presence of an equilibrium between an
analogue of [{Au(IPr)}2(m-OH)][X] and complex 1 when complex 1 is
in an aqueous medium [13]. A similar equilibrium with phosphine-
gold hydroxonium was also proposed based on calculations by Toste
and co-workers [15].
Using the optimized conditions with HSbF6 as acid to activate
complex 1, a range of ketones was prepared from both terminal and
internal alkynes (Table 2).
Next, in the process of exploring the reaction scope, a diver-
gence between internal and terminal alkynes is observed in terms
of the optimum reaction medium. While the hydration of terminal
alkynes led to the rapid product formation without observation of
any intermediate species in MeOH, the same reaction with
The procedure proved to be gratifyingly efficient, since the study
of the reaction scope was performed using only 100 ppm of catalyst
with all substrates except diphenylacetylene 2j. Terminal alkynes
2aef were successfully converted in moderate to excellent yields
(Table 2, entries 1e6). Besides phenylacetylene 2a, aliphatic alkynes
2bee were hydrated with high conversions but volatility of
compounds 3b and 3c led to product isolation in moderate yields
Table 1
after work-up. The a,b-unsaturated ketone 3f was also efficiently
Optimization of the reaction conditionsa.
prepared (Table 2, entry 6) demonstrating complete compatibility
with conjugated double bonds. Internal alkynes, which have already
shown to be less reactive towards hydration, were also hydrated in
the same conditions with good yields (Table 2, entries 7e10). Both
aromatic and aliphatic alkynes could be converted under the given
conditions. Noteworthy, the presence of a hydroxy group was
tolerated with the quantitative hydration of 2h in ketone 3h
(Table 2, entry 8). As already observed, alkyne 2i led to the two
ketones 3i and 3i0 in, respectively, 15% and 50% yield. The selectivity
in this reaction might be improved by lowering the reaction
temperature and a concomitant use of a higher catalyst loading.
Diphenylacetylene 2j showed the lowest reactivity of all substrates
tested (Table 2, entry 9), requiring a higher catalyst loading
(1000 ppm) to enable the reaction and obtain product 3j with
a satisfying yield of 70%. The low reactivity of diphenylacetylene 2j
towards hydration has already been observed in other studies
[3bed,16].
1 (cat)
O
HX aq. (cat.)
MeOH/water (2:1)
120°C; 24h
2a
3a
Entry
1 (mol%)
HX (mol%)
GC conversion (%)b
1
2
3
4
5
0.1
0.1
0.1
e
HSbF6 (0.15)
HNTf2 (0.15)
HBF4 (0.15)
HSbF6 (0.15)
e
93
93
31
0
2
12
a
Reaction conditions: phenylacetylene 2a (2 mmol), complex 1 (solution 10 mg/
mL in MeOH) and Brønsted acid (solution 0.05 M in H2O) in 2 mL of a 2:1 MeOH/
water mixture.
b
GC conversions are average of at least two runs.

P. Nun et al. / Journal of Organometallic Chemistry 696 (2011) 7e11
9
Fig. 1. Kinetic follow of the hydration of diphenylacetylene in MeOH.
To further probe the mechanism of the reaction, attempts to
isolate a more stable dimethylketal were performed. Michelet,
Genêt and co-workers have already shown that cyclic diketals
could be prepared from bis-homopropargylic diols in the presence
of gold [18]. The reaction was conducted in ethylene glycol as
solvent and under anhydrous and acid-free conditions in order to
isolate the corresponding cyclic diketal (Scheme 2). The dinuclear
before use. Solvents and other reagents were purchased from
commercial sources and used without any further purification.
3.1. General procedure for the alkyne hydration at 100 ppm catalyst
loading
In a sealed reaction vial equipped with a magnetic stirring bar
complex [{Au(IPr)}2(m-OH)][BF4] (4) [14] was used as catalyst in this
reaction since no acid activation is required.
[(IPr)AuOH] (0.02
mmol, 12
mL of a 10 mg/mL solution in MeOH) is
added to an aqueous solution of HSbF6 (0.06
m
mol, 12 L of a 0.05 M
m
As expected and under non-optimized conditions, the ketal 5 is
obtained after 72 h at 120 ꢀC in the presence of 1.5 mol% of 4. This
diketal was then reacted with 1 (4 mol%) and HSbF6 (12 mol%) in
a dioxane/water (2:1) mixture and full conversion into the corre-
sponding ketone was observed. These experimental data support
the proposed mechanism, which can be written as illustrated in
Fig. 2. After activation of the triple bond by the gold center, ketals I
then II are formed, which then react with the other hydroxy
function to give the isolated diketal 5. In the presence of water, this
diketal leads to the corresponding ketone 3j.
solution in H2O) in 2 mL of a 2:1 MeOH/water or 1,4-dioxane/water
mixture. The alkyne (2 mmol) is added and the reaction mixture
stirred for 24 h at 120 ꢀC. Dichloromethane is then added and the
solution dried over MgSO4, concentrated under reduced pressure
and the yield determined by 1H NMR with 4-nitrobenzaldehyde as
internal standard (76 mg, 0.5 mmol).
3.2. 2-Benzyl-2-phenyl-1,3-dioxolane 5
In a sealed reaction vial equipped with a magnetic stirring bar
In conclusion, a new protocol for the hydration of alkynes involving
a Brønsted acid activation of the pre-catalyst [(IPr)AuOH] 1 was
developed. This catalytic system proved to be efficient even at low
catalyst loadings. Moreover, the use of the air and moisture-stable
complex 1 permits to circumvent the use of silver salts and permits the
generation in situ of the cationic gold(I) species after reaction with
strong acids. Thissystemwassuccessfullyapplied toa range of terminal
and internal alkynes variously substituted at a catalyst loading of only
100 ppm for most of substrates and with TON up to 9900.
[{(IPr)Au}2(m-OH)][BF4] (0.03 mmol, 38 mg) is diluted in 2 mL of
ethylene glycol. Diphenylacetylene (2 mmol) is added and the
reaction mixture stirred for 72 h at 120 ꢀC then allowed to cool at rt
and concentrated under reduced pressure. The crude mixture was
purified by silica gel column chromatography (EtOAc/pentane,
2:98) to afford 331 mg of 5 (69%).
1H NMR (300 MHz, CD2Cl2):
d
7.42e7.24 (m, 5H), 7.23e7.06 (m,
5H), 3.86e3.77 (m, 2H), 3.77e3.67 (m, 2H), 3.16 (s, 2H). 13C NMR
(126 MHz, CD2Cl2): 143.0, 136.6, 131.2, 128.2, 128.1, 128.0, 126.7,
126.3, 110.3, 65.1, 47.2.
d
3. Experimental
3.3. 1,2-Diphenylethanone 3j
All reactions were carried out in air. [(IPr)AuOH] and [{(IPr)
Au}2(
m
-OH)][BF4] were prepared according to literature procedure
In a sealed reaction vial equipped with a magnetic stirring bar
[(IPr)AuOH] (0.08 mmol, 48 mg) is added to a aqueous solution of
[11,13]. Phenylacetylene was purified via Kugelrohr distillation

10
P. Nun et al. / Journal of Organometallic Chemistry 696 (2011) 7e11
Table 2
Alkyne hydration with in situ generated cationic gold(I) speciesa.
[(IPr)AuOH] cat.
HSbF6 aq. cat.
O
R
R'
R'
R
MeOH/water (2:1)
or
2a-j
3a-j
1,4-dioxane/water (2:1)
120°C, 24h
Entry
1
Alkyne
Catalyst loading (ppm)
100
Product
Yield (%)b
81
TON
8100
O
2a
2b
3a
2
3
100
100
40
41
4000
4100
O
3b
O
2c
3c
4
100
90
9000
O
2d
O
3d
5
6
100
100
94
76
9400
7600
O
2e
3e
O
2f
3f
7
8
100
100
56
99
5600
9900
O
2g
2h
3g
OH
O
OH
3h
9
100
15
6500
O
2i
3i
50
70
O
3i’
10
1000
700
O
3j
2j
a
Reaction conditions: alkyne 2a (2 mmol), complex 1 (0.02 mmol, 12 mL of a 10 mg/mL solution in MeOH) and acid (0.06 mmol, 12 mL of a 0.05 M solution in water) in 2 mL
of a 2:1 MeOH/water or 1,4-dioxane/water mixture at 120 ꢀC during 24 h.
b
NMR yields determined with 4-nitrobenzaldehyde as internal standard.

P. Nun et al. / Journal of Organometallic Chemistry 696 (2011) 7e11
11
1 (4 mol %)
O
[{Au(IPr)}2(µ-OH)][BF4] (4) (1.5 mol %)
HSbF6 aq (12 mol %)
O
Ph
O
Ph
Ph
Ph
Ph
HOCH2CH2OH
1,4-dioxane/water
120°C; 24h
Ph
120°C; 72h
2j
5
3j
Scheme 2. Formation of ketal 5 in ethylene glycol and subsequent conversion in 3j.
Ph
[Au]
HO
OH
H+
Ph
Ph
Ph
2j
OH
[Au]
Ph
O
Ph
[(IPr)Au][BF4]
4
I
- 1
Ph
O
H+
Ph
O
5
OH
H+
[Au]
O
O
[Au]
Ph
O
Ph
Ph
Ph
H+; H2O
II
III
H+
O
Ph
Ph
3j
Fig. 2. Proposed mechanism for the alkyne hydration with ethylene glycol.
(d) E. Mizushima, K. Sato, T. Hayashi, M. Tanaka, Angew. Chem. Int. Ed. 41
(2002) 4563e4565.
[4] R.S. Ramón, N. Marion, S.P. Nolan, Chem. Eur. J. 15 (2009) 8695e8697.
[5] J. Otera, Modern Carbonyl Chemistry. Wiley-VCH, Weinheim, Germany, 2000.
[6] A.S.K. Hashmi, M. Rudolph, Chem. Soc. Rev. 37 (2008) 1766e1775.
[7] M. Kucherov, Chem. Ber. 14 (1881) 1540e1542.
HSbF6 (0.24 mmol, 87.4 mg of a 65% solution in H2O) in 2 mL of
a 2:11,4-dioxane/water mixture. The ketal 5 (2 mmol) is added and
the reaction mixture stirred for 24 h at 120 ꢀC. Dichloromethane is
then added and the solution dried over MgSO4, concentrated under
reduced pressure to afford 3j.
[8] Ullmann’s Encyclopedia of Industrial Chemistry, seventh ed. Wiley-VCH,
Weinheim, Germany, 2006.
[9] (a) G.F. Hennion, D.B. Killian, V.T.H., J.A. Nieuwland, J. Am. Chem. Soc. 56
(1934) 1130e1132;
Acknowledgments
(b) J.A. Nieuwland, R.R. Vogt, W.L. Foohey, J. Am. Chem. Soc. 52 (1930)
1018e1024.
[10] (a) J.H. Teles, S. Brode, M. Chabanas, Angew. Chem. Int. Ed. 37 (1998) 1415e1418;
(b) R. Casado, M. Contel, M. Laguna, P. Romero, S. Sanz, J. Am. Chem. Soc. 125
(2003) 11925e11935;
The ERC (FUNCAT e Advanced Investigator Award to SPN) and
the EPSRC are gratefully acknowledged for support of this work.
Umicore AG and Johnson Matthey are thanked for their generous
gifts of materials. SPN is a Royal Society-Wolfson Research Merit
Award holder.
(c) R.O.C. Norman, W.J.E. Parr, C.B. Thomas, J. Chem. Soc. Perkin Trans. 1 (1976)
811e817;
(d) Y. Fukuda, K. Utimoto, J. Org. Chem. 56 (1991) 3729e3731;
(e) P. Roembke, H. Schmidbaur, S. Cronje, H. Raubenheimer, J. Mol. Cat. A: Chem.
212 (2004) 35e42;
References
(f) A. Almássy, C.E. Nagy, A.C. Bényei, F. Joó, Organometallics 29 (2010)
2484e2490.
[1] For selected review on gold catalysis, see: (a) A. Arcadi, Chem. Rev. 108 (2008)
3266e3325;
[11] S. Gaillard, A.M.Z. Slawin, P. Nolan, Chem. Commun. 46 (2010) 2742e2744.
[12] For the use of NHC in Late Transition Metal Catalysis see: S. Díez-González,
N. Marion, S.P. Nolan Chem. Rev. 109 (2009) 3612e3676.
[13] S. Gaillard, J. Bosson, R.S. Ramón, P. Nun, A.M.Z. Slawin, S.P. Nolan, Chem. Eur.
J. (2010). doi:10.1021/om100733n.
[14] R.S. Ramón, S. Gaillard, A.M.Z. Slawin, A. Porta, A. D’Alfonso, G. Zanoni,
S.P. Nolan, Organometallics 29 (2010) 3665e3668.
[15] P.H.-Y. Cheong, P. Morganelli, M.R. Luzung, K.N. Houk, F.D. Toste, J. Am. Chem.
Soc. 130 (2008) 4517e4526.
(b) A. Fürstner, Chem. Soc. Rev. 38 (2009) 3208e3221;
(c) D.J. Gorin, F.D. Sherry, F.D. Toste, Chem. Rev. 108 (2008) 3351e3378;
(d) A.S.K. Hashmi, Chem. Rev. 107 (2007) 3180e3211;
(e) E. Jiménez-Núñez, A.M. Echavarren, Chem. Rev. (2008) 3326e3350;
(f) R. Skouta, C.-J. Li, Tetrahedron (2008) 4917e4938.
[2] Z. Li, C. Brouwner, C. He, Chem. Rev. 108 (2008) 3239e3265.
[3] For
a review on alkyne hydration, see: (a) L. Hintermann, A. Labonne,
Synthesis (2007) 1121e1150;
[16] A. Leyva, A. Corma, J. Org. Chem. 74 (2009) 2067e2074.
[17] M.R. Kuram, M. Bhanuchandra, A.K. Sahoo, J. Org. Chem. 75 (2010) 2247e2258.
[18] S.A. Antoniotti, E. Genin, V. Michelet, J.-P. Genêt, J. Am. Chem. Soc. 127 (2005)
9976e9977.
(b) N. Marion, R.S. Ramón, S.P. Nolan, J. Am. Chem. Soc. 131 (2009) 448e449;
(c) E. Mizushima, D.-M. Cui, D.C.D. Nath, T. Hayashi, M. Tanaka, Org. Synth. 83
(2006) 55e60;