[(NHC)AuI]-Catalyzed acid-free alkyne hydration at part-per-million catalyst loadings

Full text of DOI:10.1021/ja809403e

Published on Web 12/30/2008
[(NHC)AuI]-Catalyzed Acid-Free Alkyne Hydration at Part-per-Million Catalyst
Loadings
Nicolas Marion,‡ Rube´n S. Ramo´n,† and Steven P. Nolan*,†
Institute of Chemical Research of Catalonia (ICIQ), AV. Pa¨ısos Catalans 16, 43007 Tarragona, Spain
Received October 13, 2008; E-mail: sn17@st-andrews.ac.uk
Table 1. Optimization of the Hydration Conditions
The alkyne hydration reaction, leading to the formation of
carbonyl derivatives, is of prime interest considering the wide
availability of alkynyl substrates and the fundamental importance
of the carbonyl motif in modern organic synthesis.1 Advantageously,
this reaction, based on the incorporation of a water molecule, can
be considered as an outstanding example of both atom economy2
and environmentally friendly synthetic method. The alkyne hydra-
tion reaction possesses a long history, dating back to 1881 and
Kucherov’s observation3 that led to the development of a wide
variety of metal-based catalytic systems.4 Among these, gold
compounds have gradually taken a prominent place, beneficially
replacing toxic mercury(II) salts.5 Notably, Hayashi and Tanaka
reported the use of a [(Ph3P)AuMe]/H+ catalytic system allowing
for a high turnover frequency (TOF) in the hydration of 1-octyne.6
Despite its efficiency, this catalyst suffers from some drawbacks,
including the use of concentrated solutions of strong acids (H2SO4,
CF3SO3H) and high catalyst loadings.7
entry
changes from standard conditions
time (h)
GC convn
1
none
1.5
20
20
1.5
20
5
97%
NR
93%
95%
NR
<5%
<5%
67%
NR
2
IMes instead of IPr
3
ItBu instead of IPr
4
AgBF4 instead of AgSbF6
5
AgOAc instead of AgSbF6
6
7
8
toluene instead of 1,4-dioxane
DCE instead of 1,4-dioxane
1,4-dioxane/H2O (6:1) instead of (2:1)
neat water instead of 1,4-dioxane/H2O (2:1)
[Au] (0.1 mol %) instead of (2 mol %)
5
1.5
20
18
9
10b
77%
a GC conversions are average of at least two runs. NR ) no reaction.
T ) 120 °C.
b
To palliate these deficiencies, we set out to develop a [(L)AuI]-
based catalytic system allowing alkyne hydration under mild
conditions and at very low loadings. Regarding the critical choice
of the supporting ligand, we focused on N-heterocyclic carbenes
(NHCs)8 since (1) they have already proven successful in the rapidly
developing field of homogeneous gold catalysis9,10 and (2) they
have led, in the context of other organometallic transformations,
to the development of highly efficient systems at very low catalyst
loadings.11 Herein, we report a mild and general catalytic system
for alkyne hydration, using [(NHC)AuCl]/AgSbF6 in 1,4-dioxane
or MeOH, that displays high efficiency at part-per-million (ppm)
catalyst loadings.12
.
Keeping in mind our initial goal of developing a catalyst efficient
at low loadings, the amount of [(IPr)AuCl] used was decreased to
0.1 mol % (i.e., 1000 ppm) for the hydration of 1a and a promising
77% yield of ketone 2a (entry 10) was obtained at 120 °C. It should
be noted that the hydration of diphenylacetylene 1a has proven
difficult in the past, as for most internal alkynes, and that this result
already constitutes a notable improvement.14
We began the optimization studies on the hydration of diphe-
nylacetylene 1a, relying on our previous findings that [(NHC)AuCl]
complexes promote water addition-type reactions.13 Several pa-
rameters were examined, including temperature, concentration,
solvent, water/alkyne ratio, as well as the nature of the silver(I)
salt and the NHC ligand; most relevant results are presented in
Table 1. The equimolar combination of [(IPr)AuCl] and AgSbF6
was found particularly active (entry 1). Other NHCs led to poor
conversion or required extended reaction time (entries 2 and 3).
Most silver(I) salts, including AgPF6 (longer reaction time), AgOAc,
AgOTs, and AgTFA (no reaction) proved unsatisfactory, whereas
AgBF4 and AgClO4 were found as active as AgSbF6. Additionally,
only trace conversion to the ketone was observed in the presence
of the silver salts alone (i.e., without Au). The composition of the
reaction medium was critical, 1,4-dioxane being the best solvent
(entries 1, 6-7) when employed in a 2:1 ratio with water (entries
1 and 8). Trials in pure water proved unsuccessful (entry 9).
Finally, during our optimization efforts, the use of alcohol
solvents, notably methanol, allowed us to uncover some interesting
aspects of the present gold-catalyzed hydration reaction. More
precisely, while alkyne 1a showed slower conversion to ketone 2a
in the presence of MeOH (20 h) when compared to dioxane (1.5
h), this relation was reversed when using phenylacetylene.15 This
dichotomy between internal and terminal alkynes, that was further
verified (vide infra), seems to point to two distinct mechanisms in
methanol and dioxane. This hypothesis was supported by the
observation that in methanol, the alkyne was readily converted to
the vinylether corresponding to the addition of methanol across the
Ct C bond,16 which in turn was converted into the ketone.17 This
clearly implies that methanol is not innocent in this reaction and
plays an active role in the catalytic cycle.18
With a fully optimized set of reaction conditions in hand, the
scope of the catalytic system was examined (Scheme 1). The
reactivity of several terminal alkynes was investigated. As men-
tioned above, we observed faster conversions with this type of
alkynes when the reactions were performed in methanol instead of
1,4-dioxane.19 Hence, phenylacetylene could be efficiently con-
verted to acetophenone 2b with only 50 ppm of the gold catalyst.
† Present address: School of Chemistry, University of St-Andrews, St-Andrews,
KY16 9ST U.K.
‡ Present address: Department of Chemistry, Massachusetts Institute of Technol-
ogy, Cambridge, MA 02139.
9
448 J. AM. CHEM. SOC. 2009, 131, 448–449
10.1021/ja809403e CCC: $40.75
2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Hydration of Alkynes at Low Catalyst Loadingsa
In conclusion, we have developed a highly efficient [(NHC)AuI]-
based catalytic system for the hydration of a wide array of alkynes
that operates under acid-free conditions and at very low catalyst
loadings (typically 50-100 ppm and as low as 10 ppm). Further
studies, notably aimed at shedding light onto the mechanism(s) of
this reaction, are ongoing in our laboratories.
Acknowledgment. We thank the Ministerio de Educacio´n y
Ciencia (Spain), the PRF administered by the ACS, the ICIQ
Foundation and the ICREA for financial support. SPN is an ICREA
Research Professor. NM (2007FI_A 01466) and RSR (2008FI
01047) thank the AGAUR for predoctoral fellowships. NM thanks
Umicore for a Ph.D. award.
Supporting Information Available: Full experimental procedures,
analysis of the hydration of diphenylacetylene in MeOH. This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim,
Germany, 2000.
(2) Trost, B. M. Science 1991, 254, 1471–1477.
(3) Kucherov, M. Chem. Ber. 1881, 14, 1540–1542.
(4) For an excellent review on alkyne hydration, see: Hintermann, L.; Labonne,
A. Synthesis 2007, 1121-1150.
(5) For selected reports on Au-catalyzed alkyne hydration, see: (a) Norman,
R. O. C.; Parr, W. J. E.; Thomas, C. B. J. Chem. Soc., Perkin Trans. 1
1976, 1983–1987. (b) Fukuda, Y.; Utimoto, K. J. Org. Chem. 1991, 56,
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(6) (a) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew. Chem., Int.
Ed. 2002, 41, 4563–4565. (b) Mizushima, E.; Cui, D.-M.; Nath, D. C. D.;
Hayashi, T.; Tanaka, M. Org. Synth. 2006, 83, 55–60.
a
1H NMR yields against benzaldehyde as internal standard. Yields are
b
average of at least two runs. Reaction performed with MeOH instead of
1,4-dioxane.
This result corresponds to a decrease in catalyst loading of nearly
2 orders of magnitude from previous studies.6,12c Similarly, p-OMe-
and m-F-acetophenones 2c and 2d were obtained in high yields,
with TONs of 8800 and 9700, respectively.20 Alkyl-substituted
terminal alkynes reacted equally well at 50 ppm (2e) and even the
very sterically hindered tert-butylmethyl ketone 2f was produced
in good yield at low catalyst loading (100 ppm). Remarkably, the
presence of an alkene moiety was well tolerated and conjugated
enone 2g was obtained with a high TON of 18200. A double
hydration was also efficiently performed at 100 ppm and yielded
diketone 2h in 76%.
(7) Hayashi and Tanaka (see ref 6) reported low catalyst loadings (100 ppm)
and low amounts of acid promoter (4 mol %) only for the hydration of
1-octyne. For all other alkynes, catalyst loadings typically range from 0.2
to 1 mol % and acid loadings from 25 to 50 mol %.
(8) For the most recent reviews on NHCs, see: (a) de Fre´mont, P.; Marion,
N.; Nolan, S. P. Coord. Chem. ReV., DOI: 10.1016/j.ccr.2008.05.018. (b)
Hahn, F. E.; Jahnke, M. C. Angew. Chem., Int. Ed. 2008, 47, 3122–3172.
(9) For recent reviews on homogeneous gold catalysis, see: (a) Gorin, D. J.;
Sherry, B. D.; Toste, F. D. Chem. ReV. 2008, 108, 3351-3378. (b) Arcadi,
A. Chem. ReV. 2008, 108, 3266-3325. (c) Li, Z.; Brouwer, C.; He, C.
Chem. ReV. 2008, 108, 3239-3265.
(10) For a review focused on catalytic applications of NHC-Au complexes,
see: Marion, N.; Nolan, S. P. Chem. Soc. ReV. 2008, 37, 1776–1782.
(11) Selected examples: (a) Albrecht, M.; Crabtree, R. H.; Mata, J.; Peris, E.
Chem. Commun. 2002, 32–34. (b) Marko´, I. E.; Ste´rin, S.; Buisine, O.;
Mignani, G.; Branlard, P.; Tinant, B.; Declercq, J.-P. Science 2002, 298,
204–206. (c) Díez-Gonza´lez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2008,
47, 8881–8884.
Internal alkynes, as observed by Hayashi and Tanaka,6 are usually
more reluctant participants than their terminal counterparts toward
hydration. Nevertheless, encouraged by our preliminary results with
diphenylacetylene 1a, we examined the reactivity of both sym-
metrical and unsymmetrical disubstituted alkynes (Scheme 1). We
were then pleased to observe the high yield conversion of 4-octyne
into 2i with a TON of 9500; a reaction that could be scaled up to
20 mmol without loss of activity.17 Similarly, we obtained
3-hexanone 2j in high yield. In this case, the reaction could be
performed with only 10 ppm of [(IPr)AuCl] precatalyst, leading to
an unprecedented high TON value of 84000. Finally, two unsym-
metrical alkynes were efficiently hydrated, yielding 2k and 2l, albeit
with moderate selectivity, as previously reported with other catalytic
systems.4 At this point, it should be noted that terminal and internal
alkynes possessing any combination of alkyl and aryl substituents
(alkyl/H, aryl/H, alkyl/alkyl, alkyl/aryl, and aryl/aryl) were found
suitable substrates in the present catalytic system. To the best of
our knowledge, this versatility is unprecedented, especially at such
low loadings.
(12) For other, rare Au-based catalytic systems displaying high TONs, see: (a)
Teles, J. H.; Brode, S.; Chabanas, M. Angew. Chem., Int. Ed. 1998, 37,
1415–1418. (b) Comotti, M.; Della Pina, C.; Matarrese, R.; Rossi, M.
Angew. Chem., Int. Ed. 2004, 43, 5812–5815. (c) Sanz, S.; Jones, L. A.;
Mohr, F.; Laguna, M. Organometallics 2007, 26, 952–957.
(13) (a) Marion, N.; Carlqvist, P.; Gealageas, R.; de Fre´mont, P.; Maseras, F.;
Nolan, S. P. Chem.sEur. J. 2007, 13, 6437–6451. (b) Ramón, R. S.;
Marion, N.; Nolan, S. P. Tetrahedron, in press.
(14) The best result we are aware of was reported by Hayashi and Tanaka (ref
6): 53% with 1 mol % [Au], TON ) 53.
(15) For reactions carried out at 65 °C for 18 h, conversion of phenylacetylene
into acetophenone: MeOH (100%), 1,4-dioxane (29%).
(16) For a seminal study on the Au-catalyzed alcohol addition to alkyne, see
ref 12a.
(17) For details, see the Supporting Information.
(18) We are currently investigating, both experimentally and theoretically, several
mechanistic hypotheses that would account for these observations and allow
for a more complete understanding of the present reaction.
(19) It should be noted that, unlike in 1,4-dioxane, silver salts alone catalyze
the hydration reaction in MeOH, but only to a minor extent.
(20) Of note, the similar behavior of 1c and 1d with the present catalytic system
contrasts with Hayashi and Tanaka’s observation that electron-deficient
phenylacetylenes are less reactive than electron-rich ones, see ref 6.
JA809403E
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