Efficient gold(I)-catalyzed direct intramolecular hydroalkylation of unactivated alkenes with α-ketones

Article abstract of DOI:10.1002/anie.201100044

Easy access by gold: The Au^I-catalyzed title reaction provides simple and efficient access to highly substituted cyclic compounds with excellent yields and good diastereoselectivity. This transformation constitutes the first example of transition-metal-catalyzed direct hydroalkylation of unactivated alkenes with simple α-ketone groups in the absence of additive reagents. Bn=benzyl, Ts=tosyl. Copyright

Full text of DOI:10.1002/anie.201100044

DOI: 10.1002/anie.201100044
Gold Catalysis
Efficient Gold(I)-Catalyzed Direct Intramolecular Hydroalkylation of
Unactivated Alkenes with a-Ketones**
Ya-Ping Xiao, Xin-Yuan Liu, and Chi-Ming Che*
The direct addition of a stabilized carbon nucleophile to an
unactivated alkene (such as hydroalkylation) is one of the
most powerful and widely employed methods for the
formation of carbon–carbon bonds, often with concomitant
formation of rings and generation of stereocenters.[1] The
efficiency of this process can be greatly enhanced by
transition-metal catalysts, and broad substrate scope and
intriguing selectivity are observed under mild reaction con-
ditions,[2] which are advantageous relative to approaches
using free-radical[3] and Lewis acid catalysts.[4] These transi-
tion-metal-catalyzed hydroalkylation methodologies com-
monly involve the use of metal enolates and related stabilized
carbanions as the carbon nucleophile.[2] Despite the impor-
tance of these methods, they require synthesis of stabilized
carbon nucleophiles, resulting in the generation of toxic metal
salts as reaction by-products, often in stoichiometric
amounts.[2] To address this issue, much effort has been
devoted over the past decades to the development of direct
a-functionalization of a carbonyl group without the need for
enolate formation.[2,5] Through the use of such methodology,
these direct hydroalkylation reactions with carbonyl com-
pounds improve the overall atom economy of the reaction. In
the reported direct hydroalkylation reactions with carbonyl
compounds,[5] the carbon nucleophile substrates are limited
to those containing activated methylene units, such as
b-diketones or b-keto esters, which directly react with
unactivated alkenes through their corresponding enol form.
However, simple a-ketones remain a challenging class of
substrates for hydroalkylation of unactivated alkenes,
[6]
À
because they possess a less acidic C H bond and a
significantly lower enol/ketone equilibrium constant
(Kenol/ketone) than activated methylene compounds.[7] Indeed,
there have been a few reports on palladium-catalyzed intra-
molecular hydroalkylation of alkenes with a-aryl or alkyl
ketones by the 6-endo-trig cyclization pathway to build six-
membered rings,[8] but all of these palladium-catalyzed
reactions require substoichiometric or stoichiometric
amounts of CuCl2 and other external reagents, such as
trimethylsilylchloride (TMSCl)/H2O or the Brønsted acid
HCl, to facilitate the enolization of ketones.
Recently, gold complexes have been shown to be versatile
and efficient catalysts that promote a variety of organic
transformations.[9] In particular, gold catalysts have been
À
found to display an exceptional ability to activate C C
multiple bonds toward nucleophilic attack.[10] Based on this
mode of activation, several methods for gold-catalyzed inter-
and intramolecular addition of oxygen,[11] nitrogen,[12] or
active methylene nucleophiles[5g–i] to unactivated alkenes[5i,13]
have been reported. Moreover, gold complexes have been
demonstrated to be useful in catalyzing the addition of a
variety of enol equivalents such as electron-rich alkyl enol
ethers,[14] silyl enol ethers,[15] silyl ketene amides,[16] and
enamines[17] derived from ketones[18] to unactivated alkynes
and allenes. However, to our knowledge, gold-catalyzed
direct hydroalkylation of unactivated alkenes with simple a-
ketones has not been reported. Owing to the propensity of
gold complexes to promote the enolization of a-ketones,[19]
thus rendering a possible increase of their nucleophilicity to
react directly with gold-complexed alkenes, we envisioned
[*] Dr. Y.-P. Xiao,[+] Prof. Dr. C.-M. Che
Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis
Shanghai Institute of Organic Chemistry
The Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (P. R. China)
E-mail: cmche@hku.hk
À
that gold complexes might be able to catalyze direct C C
bond formation through hydroalkylation of unactivated
alkenes through attack by simple a-ketones. We describe
herein that gold(I) complexes, in the absence of additive
reagents, efficiently catalyze direct intramolecular hydro-
alkylation of unactivated alkenes with simple a-ketone
groups by exo-trig cyclization to build a variety of new five-
and six-membered rings in excellent yields (up to 99%) and
with good diastereoselectivity (Scheme 1).
Dr. X.-Y. Liu,[+] Prof. Dr. C.-M. Che
Department of Chemistry
State Key Laboratory on Synthetic Chemistry
and
Open Laboratory of Chemical Biology of the Institute of Molecular
Technology for Drug Discovery and Synthesis
The University of Hong Kong
Pokfulam Road, Hong Kong (P. R. China)
Fax: (+852)2857-1586
[+] These authors contributed equally to this work.
[**] We are thankful for the financial support of The University of Hong
Kong (University Development Fund), the Hong Kong Research
Grants Council, and the University Grants Committee of the Hong
Kong SAR of China (Area of Excellence Scheme, AoE/P-10/01). Y.-
P.X. thanks the Croucher Foundation of Hong Kong and the External
Cooperation Program of CAS (GJHZ200816).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100044.
Scheme 1. Synthesis of new cyclic compounds by gold-catalyzed hydro-
alkylation. Bn=benzyl, Ts=4-toluenesulfonyl.
Angew. Chem. Int. Ed. 2011, 50, 4937 –4941
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4937

Communications
Table 1: Scope of gold(I)-catalyzed intramolecular hydroalkylation of unactivated
alkenes with a-ketones.[a]
We first examined the cyclization reaction of
alkenyl alkyl ketone 1a using various electrophilic
transition metal catalysts in toluene at 1108C (see the
Supporting Information, Table S1; the structure of 1a
is shown in Table 1, entry 1). The metal salts Cu-
(OTf)2 (OTf = trifluoromethanesulfonate), AgOTf,
and PicAuCl2 (Pic = 2-picolinate) failed to catalyze
this cyclization (Table S1, entries 1–3). However, the
gold(I) cation derived from the reaction of [(tBu)2(o-
diphenyl)PAuCl], a catalyst previously reported by
Echavarren and co-workers,[20] with an equimolar
amount of AgOTf in toluene at 1108C for 15 hours
cleanly converted 1a to 2a by a 5-exo-trig cyclization
as a 7.9:1 mixture of diastereomers in 99% yield
(Table S1, entry 5). The relative trans configuration
of the substituents of the ketone and the methyl
groups of the product 2a was established by NOE
spectroscopy. Examination of other counteranions of
the cationic complex [(tBu)2(o-diphenyl)PAu]+
Entry Substrate
t [h] Product
Yield
[%][b]
d.r.[c]
1
4.5
99
97
8.6:1
2[d]
1a
16
2a
8.6:1
3
4
5
6
X=H: 1b
4-OMe: 1c
4-NO2: 1d
2-Br: 1e
9
6
10
9
X=H: 2b
4-OMe: 2c
4-NO2: 2d
2-Br: 2e
91
96
89
89
7.3:1
7.2:1
8.0:1
9.0:1
7
5
99
4.0:1.5:1
À
reveals that the non-coordinating anion ClO4 was
the best for the reaction, affording the product 2a in
99% yield with a diastereomeric ratio of 8.5:1 for a
reaction time of 3.5 hours (Table S1, entry 9). A
panel of AuI complexes with different ancillary
ligands were screened for activity and diastereomeric
induction in the cyclization reaction of 1a (Table S1,
entries 10–13). Among the complexes examined,
[IPrAuCl]/AgClO4 (molar ratio = 1:1, IPr= N,N’-
bis(2,6-diisopropylphenyl)-imidazol-2-ylidene),
8
9
13
5
99
91
10.3:1
2.1:1
which was reported by Nolan and co-workers to have
useful applications in gold catalysis,[21] gave the best
result (Table S1, entry 13). A further improvement in
diastereoselectivity was achieved by conducting the
reaction with a substrate concentration of 0.5m at
908C, thereby furnishing 2a with a diastereomeric
ratio of 8.6:1 in 99% yield (Table 1, entry 1). Further
screening of solvents showed that the nonpolar
solvent toluene gave the best result, while polar
solvents methanol, THF, and acetonitrile gave low
product yields and diastereoselectivities (see the
Supporting Information, Table S2). Notably, this
cyclization reaction was not catalyzed by trifluoro-
methanesulfonic acid (Table S1, entry 15).
10
11
9
5
90
81
9.5:1
1.7:1
12
13
R=Me: 1k
Ph: 1l
17
13
R=Me: 2k
Ph: 2l
78
71
6.7:1
1.5:1
With the optimal reaction conditions, we set out
to explore the scope of this protocol with respect to
other alkenyl a-ketone substrates. As shown in
Table 1, changing the alkenyl alkyl ketone 1a to
14
3
71
86
3.0:1
6.0:1
alkenyl aryl ketones 1b–e did not have a significant 15[e]
influence on the product yield and diastereoselectiv-
ity. For example, treatment of 1b with a catalytic
amount of [IPrAuCl]/AgClO4 (5 mol%) at 908C for
16
16[e]
48
–
–
[f]
9 hours gave the expected product 2b in 91% yield
with a diastereomeric ratio of 7.3:1 (Table 1, entry 3).
In addition to substrate 1b, alkenyl aryl ketones with
electron-donating or electron-withdrawing substitu-
ents on the phenyl ring underwent gold(I)-catalyzed
direct intramolecular hydroalkylation to afford the
corresponding products in 89–96% yields (Table 1,
entries 4–6). In all cases, the trans diastereomer was
[a] Reaction conditions: substrate 1 (0.25 mmol), [IPrAuCl]/AgClO4 (5 mol%),
toluene (0.5 mL) at 908C. [b] Yield of isolated product. [c] Diastereomeric ratio
determined by 1H NMR spectroscopy; major isomer shown. [d] Reaction condi-
tions: substrate 1a (10 mmol), [IPrAuCl]/AgClO4 (0.5 mol%), toluene (5 mL) at
908C. [e] Reaction conditions: substrate
(10 mol%), toluene (0.5 mL) at 1108C. [f] No desired product was detected.
1 (0.25 mmol), [IPrAuCl]/AgClO4
4938 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 4937 –4941

favored with good to excellent selectivity (Table 1, entries 1–
6). This gold(I)-catalyzed hydroalkylation reaction also
allows rapid synthesis of bicyclic ring systems. Treatment of
cyclopentanone derivative 1 f in the presence of 5 mol%
[IPrAuCl]/AgClO4 gave the desired 5,5-bicyclic ketone 2 f in
99% yield, albeit with lower diastereoselectivity (Table 1,
entry 7). This process has also been applied to the synthesis of
6,5-bicyclic ketones in excellent yields and with modest to
good levels of diastereoselectivity by annealing a six-mem-
bered ring onto a cyclopentanone 1g (Table 1, entry 8) or a
five-membered ring onto a cyclohexanone 1h (Table 1,
entry 9). The 6,6-bicylic ketone 2i was obtained as a 9.5:1
mixture of two diastereomers in excellent yield (Table 1,
entry 10). The relative configuration of 2g and 2i was
determined by X-ray crystallographic analysis (Figure S1 in
the Supporting Information).[22] Notably, the gold(I)-cata-
lyzed cyclization reaction could also be used to furnish
spirocyclic ketone 2j in 81% yield (Table 1, entry 11).
To further investigate the scope of application, we tested
the use of N-tethered a-ketones as substrates. Good yields
with moderate to good selectivity for the trans diastereomer
were observed when substrates with an alkyl or aryl group
attached to the ketone were used (Table 1, entries 12 and 13).
The relative trans configuration of 2k was established by
NOE spectroscopy and by X-ray crystallographic analysis
(Figure S1 in the Supporting Information).[22] The substrate
1m containing benzyl ether functional groups in the tether
was also cyclized to afford the corresponding product 2m as a
3.0:1 mixture of two diasteromers in 71% yield (Table 1,
entry 14). Furthermore, the a-ketone 1n with substitution at
the internal olefinic carbon atom was applicable to this AuI-
catalyzed system, giving 6,5-bicyclic ketone 2n with a
diastereomeric ratio of 6.0:1 and in 86% yield, although an
increased catalyst loading (10 mol%), a higher reaction
temperature (1108C), and a longer reaction time were
required for full substrate conversion (Table 1, entry 15).
However, the a-ketone 1o having an internal alkene group
did not yield the desired product 2o (Table 1, entry 16),
possibly owing to the large steric hindrance during the course
of intramolecular hydroalkylation. Notably, the gold-cata-
lyzed cyclization reaction could be scaled up (Table 1,
entry 2). For example, 2.4 g of cyclic product 2a was readily
obtained in 97% yield with a diastereomeric ratio of 8.6:1,
even using 0.5 mol% catalyst at 908C for 16 h.
Scheme 2. Proposed mechanism.
imately 70% deuterium incorporation at the a-position of the
ketone when alkyl ketone 3 was treated with a catalytic
amount of [IPrAuCl]/AgClO4 (5 mol%) in D2O/toluene at
908C for 7 hours [Eq. (1)].[25] No deuterium exchange
occurred in the absence of gold catalyst under the same
reaction conditions [Eq. (2)], thus indicating that the gold
catalyst might play a crucial role for the keto–enol tautome-
On the basis of the established reactivity of gold(I)-alkene
complexes toward nucleophiles,[23] a reaction mechanism for
the AuI-catalyzed addition of a-ketone to unactivated alkene
is proposed (Scheme 2). Coordination of the double bond of
1a to the gold(I) complex to form keto-I enhances the
electrophilicity of the alkene,[10] and the subsequent nucleo-
philic attack (as shown in enol-II) of the enol form of the
a-ketone to the gold-coordinated alkene affords the alkyl Au
intermediate III, which is protonated to give the final product
2a. Enolization of intermediate keto-I to generate the
reactive tautomer enol-II could be facilitated by the gold
complex in this catalytic system, and it should be noted that
the rate of enolization of simple a-ketone in the absence of an
acid catalyst is slow.[6,7,24] This hypothesis is supported by the
finding that [D5]-4 was obtained in 97% yield with approx-
rization between keto-I and enol-II in the proposed reaction
pathway in Scheme 2. Moreover, the gold(I)-catalyzed reac-
tion of 1a furnished [D5]-5 in 73% yield with 73% deuterium
incorporation at the newly formed methyl group in D2O/
toluene under the standard reaction conditions [Eq. (3)],
revealing that D atoms incorporated into the methyl group of
[D5]-5 mainly come from D2O through the protonolysis of
alkyl Au intermediate III depicted in Scheme 2. On the other
hand, an alternative dual catalyst mechanism, which proceeds
by the formation of a gold(I) enolate intermediate[5g,26] with
subsequent nucleophilic attack on a gold(I) alkene com-
plex,[23] would also be consistent with these observations.
It is interesting to note that the protocol for the synthesis
of highly substituted cyclic compounds could be extended to a
Angew. Chem. Int. Ed. 2011, 50, 4937 –4941
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 4939

Communications
11291; b) T. Pei, X. Wang, R. A. Widenhoefer, J. Am. Chem.
Soc. 2003, 125, 648 – 649; c) H. Qian, R. A. Widenhoefer, J. Am.
Chem. Soc. 2003, 125, 2056 – 2057; d) H. Qian, T. Pei, R. A.
Widenhoefer, Organometallics 2005, 24, 287 – 301; Pt-mediated
reactions: e) X. Wang, R. A. Widenhoefer, Chem. Commun.
2004, 660 – 661; f) C. Liu, R. A. Widenhoefer, Tetrahedron Lett.
2005, 46, 285 – 287; Au-mediated reactions: g) X. Yao, C.-J. Li, J.
Am. Chem. Soc. 2004, 126, 6884 – 6885; h) R.-V. Nguyen, X.-Q.
Yao, D. S. Bohle, C.-J. Li, Org. Lett. 2005, 7, 673 – 675; i) C.-Y.
Zhou, C.-M. Che, J. Am. Chem. Soc. 2007, 129, 5828 – 5929; Ag-
mediated reactions: j) X. Yao, C.-J. Li, J. Org. Chem. 2005, 70,
5752 – 5755; Cu-mediated reactions: k) Y. Li, Z. Yu, S. Wu, J.
Org. Chem. 2008, 73, 5647 – 5650; In-mediated reactions: l) Y.
Yuan, Z. Shi, Synlett 2007, 3219 – 3223; Fe-mediated reactions:
m) J. Kischel, D. Michalik, A. Zapf, M. Beller, Chem. Asian J.
2007, 2, 909 – 914; n) Z. Duan, X. Xuan, Y. Wu, Tetrahedron Lett.
2007, 48, 5157 – 5159; Bi-mediated reactions: o) M. Rueping,
B. J. Nachtsheim, A. Kuenkel, Synlett 2007, 1391 – 1394; Sn-
mediated reactions: p) O. Kitagawa, H. Fujiwara, T. Suzuki, T.
Taguchi, M. Shiro, J. Org. Chem. 2000, 65, 6819 – 6825.
[6] The values of pKa for 2,4-pentanedione, ethyl acetoacetate,
benzyl methyl ketone, ethyl methyl ketone, and cyclohexanone
in DMSO are 13.3, 14.2, 19.9, 24.8 and 26.4, respectively. F. G.
Bordwell, Acc. Chem. Res. 1988, 21, 456 – 463.
gold(I)-catalyzed cascade intermolecular N-Michael addition/
intramolecular hydroalkylation reaction. Thus, when a,b-
unsaturated ketone 6 was treated with N-tosyl allylic amine
(7) in the presence of 5 mol% [(tBu)2(o-diphenyl)PAuCl] and
15 mol% AgClO4 in toluene at 908C for 20 h, the cascade
product 2l was isolated in 76% yield as a 4.1:1 mixture of
trans/cis isomers [Eq. (4)].
[7] The values of Kenol/ketone for 2,4-pentanedione, ethyl acetoacetate,
benzyl methyl ketone, cyclohexanone, and ethyl methyl ketone
are 5.1, 0.09, 8 ꢂ 10À5, 3 ꢂ 10À7, and 5 ꢂ 10À9, respectively; a) J. P.
Guthrie, P. A. Cullimore, Can. J. Chem. 1979, 57, 240 – 248;
b) J. P. Guthrie, Can. J. Chem. 1979, 57, 1177 – 1185; c) M.
Bassetti, G. Cerichelli, B. Floris, Tetrahedron 1988, 44, 2997 –
3004.
[8] a) X. Wang, T. Pei, X. Han, R. A. Widenhoefer, Org. Lett. 2003,
5, 2699 – 2701; b) X. Han, X. Wang, T. Pei, R. A. Widenhoefer,
Chem. Eur. J. 2004, 10, 6333 – 6342.
[9] For selected reviews on gold-catalyzed reactions, see: a) D. J.
Gorin, F. D. Toste, Nature 2007, 446, 395 – 403; b) A. S. K.
Hashmi, Chem. Rev. 2007, 107, 3180 – 3211; c) Z. Li, C. Brouwer,
C. He, Chem. Rev. 2008, 108, 3239 – 3265; d) E. Jimꢀnez-Nfflæez,
A. M. Echavarren, Chem. Rev. 2008, 108, 3326 – 3350; e) D. J.
Gorin, B. D. Sherry, F. D. Toste, Chem. Rev. 2008, 108, 3351 –
3378; f) A. S. K. Hashmi, Angew. Chem. 2010, 122, 5360 – 5369;
Angew. Chem. Int. Ed. 2010, 49, 5232 – 5241.
[10] For selected reviews, see: a) C. Bruneau, Angew. Chem. 2005,
117, 2380 – 2386; Angew. Chem. Int. Ed. 2005, 44, 2328 – 2334;
b) L. Zhang, J. Sun, S. A. Kozmin, Adv. Synth. Catal. 2006, 348,
2271 – 2296; c) V. Michelet, P. Y. Toullec, J.-P. GenÞt, Angew.
Chem. 2008, 120, 4338 – 4386; Angew. Chem. Int. Ed. 2008, 47,
4268 – 4315.
[11] For selected examples, see: a) C.-G. Yang, C. He, J. Am. Chem.
Soc. 2005, 127, 6966 – 6967; b) R.-V. Nguyen, X. Yao, C.-J. Li,
Org. Lett. 2006, 8, 2397 – 2399; c) A. S. K. Hashmi, S. Schäfer, M.
Wölfle, C. Diez Gil, P. Fischer, A. Laguna, M. C. Blanco, M. C.
Gimeno, Angew. Chem. 2007, 119, 6297 – 6300; Angew. Chem.
Int. Ed. 2007, 46, 6184 – 6187; d) X. Zhang, A. Corma, Chem.
Commun. 2007, 3080 – 3082; e) A. Aponick, C.-Y. Li, B. Biannic,
Org. Lett. 2008, 10, 669 – 671.
[12] For recent reviews on gold-catalyzed hydroamination, see:
a) R. A. Widenhoefer, X. Han, Eur. J. Org. Chem. 2006, 4555 –
4563; b) R. A. Widenhoefer, Chem. Eur. J. 2008, 14, 5382 – 5391;
c) N. Krause, V. Belting, C. Deutsch, J. Erdsack, H.-T. Fan, B.
Gockel, A. Hoffmann-Röder, N. Morita, F. Volz, Pure Appl.
Chem. 2008, 80, 1063 – 1069.
In summary, we have developed the first protocol for
direct hydroalkylation of unactivated alkenes with simple
a-ketone groups that can be performed with gold(I) com-
plexes as catalysts in the absence of additive reagents. The
protocol provides a highly efficient method for the synthesis
of highly substituted cyclic compounds with excellent yields
and good diastereoselectivity from simple starting materials.
This operationally simple procedure not only provides a more
straightforward alternative to the existing transition-metal-
catalyzed hydroalkylation methods but also has the potential
to open the door to novel gold(I)-catalyzed organic trans-
formation.
Received: January 4, 2011
Published online: April 28, 2011
Keywords: cyclic compounds · gold · homogeneous catalysis ·
.
hydroalkylation · unactivated alkenes
[1] D. Caine in Comprehensive Organic Synthesis, Vol. 3 (Eds.: B. M.
Trost, I. Fleming), Pergamon, New York, 1991, pp. 1 – 63.
[2] For a recent review on hydroalkylation reactions, see: F. Dꢀnꢁs,
A. Pꢀrez-Luna, F. Chemla, Chem. Rev. 2010, 110, 2366 – 2447.
[3] a) M. Julia, Acc. Chem. Res. 1971, 4, 386 – 392; b) D. P. Curran,
Synthesis 1988, 489 – 513; c) B. Giese, Radicals in Organic
Synthesis: Formation of Carbon–Carbon Bonds, Pergamon,
New York, 1986; d) C. P. Jasperse, D. P. Curran, T. L. Fevig,
Chem. Rev. 1991, 91, 1237 – 1286; e) B. B. Snider, Chem. Rev.
1996, 96, 339 – 364.
[4] M. T. Reetz, I. Chatziiosifidis, K. Schwellnus, Angew. Chem.
1981, 93, 716 – 717; Angew. Chem. Int. Ed. Engl. 1981, 20, 687 –
689.
[5] For selected recent examples, see: Pd-mediated reactions: a) T.
Pei, R. A. Widenhoefer, J. Am. Chem. Soc. 2001, 123, 11290 –
[13] a) X.-Y. Liu, C.-H. Li, C.-M. Che, Org. Lett. 2006, 8, 2707 – 2710;
b) M.-Z. Wang, M.-K. Wong, C.-M. Che, Chem. Eur. J. 2008, 14,
8353 – 8364; c) Y.-P. Xiao, X.-Y. Liu, C.-M. Che, J. Organomet.
Chem. 2009, 694, 494 – 501.
4940 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 4937 –4941

[14] C. Nevado, D. J. Cµrdenas, A. M. Echavarren, Chem. Eur. J.
2003, 9, 2627 – 2635.
8482 – 8484; c) Y. Yamamoto, J. Org. Chem. 2007, 72, 7817 –
7831.
[20] C. Nieto-Oberhuber, S. López, A. M. Echavarren, J. Am. Chem.
Soc. 2005, 127, 6178 – 6179.
[21] For recent reviews on catalytic applications of NHC Au
complexes, see: a) N. Marion, S. P. Nolan, Chem. Soc. Rev.
2008, 37, 1776 – 1782; b) S. P. Nolan, Acc. Chem. Res. 2011, 44,
91 – 100.
[15] a) J. W. Dankwardt, Tetrahedron Lett. 2001, 42, 5809 – 5812;
b) S. T. Staben, J. J. Kennedy-Smith, D. Huang, B. K. Corkey,
R. L. LaLonde, F. D. Toste, Angew. Chem. 2006, 118, 6137 –
6140; Angew. Chem. Int. Ed. 2006, 45, 5991 – 5994; c) K. Lee,
P. H. Lee, Adv. Synth. Catal. 2007, 349, 2092 – 2096.
[16] E. C. Minnihan, S. L. Colletti, F. D. Toste, H. C. Shen, J. Org.
Chem. 2007, 72, 6287 – 6289.
[22] CCDC 806093 (2g), 806092 (2k), and 812576 (2i) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[23] a) N. D. Shapiro, F. D. Toste, Proc. Natl. Acad. Sci. USA 2008,
105, 2779 – 2782; b) T. J. Brown, M. G. Dickens, R. A. Widen-
hoefer, J. Am. Chem. Soc. 2009, 131, 6350 – 6351; c) T. N.
Hooper, M. Green, J. E. McGrady, J. R. Patel, C. A. Russell,
Chem. Commun. 2009, 3877 – 3879; d) T. J. Brown, M. G. Dick-
ens, R. A. Widenhoefer, Chem. Commun. 2009, 6451 – 6453;
e) T. N. Hooper, C. P. Butts, M. Green, M. F. Haddow, J. E.
McGrady, C. A. Russell, Chem. Eur. J. 2009, 15, 12196 – 12200;
f) R. L. LaLonde, W. E. Brenzovich, Jr., D. Benitez, E. Tkatch-
ouk, K. Kelley, W. A. Goddard III, F. D. Toste, Chem. Sci. 2010,
1, 226 – 233.
[17] For a recent review, see: a) A. Duschek, S. F. Kirsch, Angew.
Chem. 2008, 120, 5787 – 5789; Angew. Chem. Int. Ed. 2008, 47,
5703 – 5705; for selected examples, see: b) T. J. Harrison, B. O.
Patrick, G. R. Dake, Org. Lett. 2007, 9, 367 – 370; c) P. Belmont,
T. Belhadj, Org. Lett. 2005, 7, 1793 – 1795; d) T. J. Harrison, G. R.
Dake, Org. Lett. 2004, 6, 5023 – 5026; e) G. Abbiati, A. Arcadi,
G. Bianchi, S. Di Giuseppe, F. Marinelli, E. Rossi, J. Org. Chem.
2003, 68, 6959 – 6966; f) J. T. Binder, B. Crone, T. T. Haug, H.
Menz, S. F. Kirsch, Org. Lett. 2008, 10, 1025 – 1028; g) T. Yang,
A. Ferrali, L. Campbell, D. J. Dixon, Chem. Commun. 2008,
2923 – 2925; h) B. Montaignac, M. R. Vitale, V. Michelet, V.
Ratovelomanana-Vidal, Org. Lett. 2010, 12, 2582 – 2585; i) B.
Montaignac, M. R. Vitale, V. Ratovelomanana-Vidal, V.
Michelet, J. Org. Chem. 2010, 75, 8322 – 8325.
[18] For the addition of b-diketones or b-keto esters to unactivated
alkynes, see: a) J. J. Kennedy-Smith, S. T. Staben, F. D. Toste, J.
Am. Chem. Soc. 2004, 126, 4526 – 4527; b) S. T. Staben, J. J.
Kennedy-Smith, F. D. Toste, Angew. Chem. 2004, 116, 5464 –
5466; Angew. Chem. Int. Ed. 2004, 43, 5350 – 5352; for the
addition of b-keto esters to unactivated allenes, see: c) X. Jiang,
X. Ma, Z. Zheng, S. Ma, Chem. Eur. J. 2008, 14, 8572 – 8578; for
the addition of simple ketones to unactivated alkynes, see:
d) P. W. Davies, C. Detty-Mambo, Org. Biomol. Chem. 2010, 8,
2918 – 2922.
[24] J. R. Keefe, A. J. Kresge in The Chemistry of Enols (Ed.: Z.
Rappoport), Wiley, New York, 1990, pp. 451 – 453.
[25] This result is also consistent with the literature, in that hydrogen
atoms in a-positions to the carbonyl group can be exchanged
with D2O; a) J. Barluenga, A. Diꢀguez, A. Fernµndez, F.
Rodríguez, F. J. Faæanµs, Angew. Chem. 2006, 118, 2145 – 2147;
Angew. Chem. Int. Ed. 2006, 45, 2091 – 2093; b) X.-Y. Liu, C.-M.
Che, Angew. Chem. 2008, 120, 3865 – 3870; Angew. Chem. Int.
Ed. 2008, 47, 3805 – 3810.
[26] Au-mediated organic reactions through Au enolate intermedi-
ates: a) Y. Ito, M. Inouye, M. Suginome, M. Murakami, J.
Organomet. Chem. 1988, 342, C41-C44; b) M. Murakami, M.
Inouye, M. Suginome, Y. Ito, Bull. Chem. Soc. Jpn. 1988, 61,
3649 – 3652.
[19] a) G. Dyker, D. Hildebrandt, J. Liu, K. Merz, Angew. Chem.
2003, 115, 4536 – 4538; Angew. Chem. Int. Ed. 2003, 42, 4399 –
4402; b) L.-W. Xu, C.-G. Xia, L. Li, J. Org. Chem. 2004, 69,
Angew. Chem. Int. Ed. 2011, 50, 4937 –4941
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4941