Synergistic Au/Ga catalysis in ambient nakamura reaction

Article abstract of DOI:10.1021/ol403337u

The gold-catalyzed intermolecular addition of 1,3-dicarbonyl compounds to unactivated 1-alkynes (Nakamura reaction) is achieved at room temperature for the first time through synergistic gold/gallium catalysis. The developed system is highly efficient wit

Full text of DOI:10.1021/ol403337u

Letter
pubs.acs.org/OrgLett
Synergistic Au/Ga Catalysis in Ambient Nakamura Reaction
Yumeng Xi, Dawei Wang, Xiaohan Ye, Novruz G. Akhmedov, Jeffrey L. Petersen, and Xiaodong Shi*
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506, United States
S
* Supporting Information
ABSTRACT: The gold-catalyzed intermolecular addition of 1,3-dicarbonyl compounds to unactivated 1-alkynes (Nakamura
reaction) is achieved at room temperature for the first time through synergistic gold/gallium catalysis. The developed system is
highly efficient with a gold catalyst loading that can be as low as 500 ppm.
Scheme 1. Ambient Nakamura Reaction
uring the past decade, the cationic gold complex has
Demerged as one of the most effective catalysts for alkyne
activation under mild conditions.1 However, recent develop-
ments revealed a plausibly more complicated mechanism
regarding the actual active catalysts in these processes.2 The
lack of mechanistic understanding hampered the developments
for new transformations.3 For example, the intermolecular
addition of 1,3-dicarbonyl compounds to unactivated alkynes
(Nakamura reaction)4 is of fundamental interest due to the
involvement of C−C bond formation from simple starting
materials. However, the original In(III) catalyzed conditions
required a high temperature (140 °C), which limited the
applications. The gold(I) catalyzed intramolecular version
(Conia-ene reaction) was reported back in 2004, where
excellent yields were observed at room temperature.5 In
contrast, the gold(I) catalyzed Nakamura reaction has not
been achieved to date. As indicated in Scheme 1, the [L−Au]+
catalysts (L = PPh3 or IPr) gave low yields of carbon-
nucleophilic addition products even at an elevated temperature
(<15% yield, 80 °C, 17 h). In addition, lowering the
temperature significantly decreased the In(III) catalyst
reactivity (<5% yield, 10% In(OTf)3, rt, 17 h). Herein, we
report the first successful gold-catalyzed Nakamura reaction
assisted by Ga(OTf)3. This new synergistic catalytic system6 is
highly efficient, promoting the reaction at room temperature
with typical gold loading and at 45 °C with 0.05% loading (500
ppm, up to 93% yield).
as effective catalysts for alkyne activation under mild conditions,
no desired products were observed for this transformation
using the typical LAuCl/AgX catalyst combinations. Raising the
reaction temperature to 80 °C caused significant gold complex
decomposition. In 2009, we reported the application of 1,2,3-
triazole gold complexes (TA-Au)8 as the “thermal-stable”
catalysts in promoting alkyne activation at higher temperature.
Unfortunately, these TA-Au catalysts failed to promote the
Nakamura reaction even at elevated temperature (<5% yield, 80
°C, 17h). In fact, the TA-Au catalysts were considered as a “less
effective” catalyst for alkyne activation due to the good stability.
This assumption was greatly challenged by the discovery
In 2003, Nakamura reported an In(OTf)3 catalyzed
intermolecular addition of 1,3-dicarbonyl compounds to
unactivated 1-alkynes (Nakamura reaction).4 Several groups
subsequently reported that this reaction could be achieved by
other metal catalysts, such as Re, Ir, Ru, etc.7 However, these
transformations often required high temperatures to be
successful. Although the gold(I) complexes have been reported
Received: November 19, 2013
Published: December 9, 2013
© 2013 American Chemical Society
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dx.doi.org/10.1021/ol403337u | Org. Lett. 2014, 16, 306−309

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Letter
regarding the TA-Au catalyzed enyne cyclization−isomer-
product observed in 90% yield (91% conversion, entry 5).
Increasing the Au/Ga ratio to 1:2 led to the full conversion, and
5a was obtained in excellent yield (98%, entry 6). This was
likely due to the improved nucleophilicity of diketone through
Ga(III) chelation (formation of gallium enolate). The
combination of the Au/Ag system with Ga(OTf)3 (instead of
the TA-Au complex) gave a lower yield and slightly messier
reaction (entries 7 and 8, unidentified side products),
presumably due to the greater stability of triazole−gold
complexes over the simple [L−Au]+. Notably, Ga(OTf)3
alone could not promote this reaction at all either at rt or at
45 oC (entry 10), which confirmed the important role of Au in
this transformation.12 Other acids, such as TfOH,13 triflate salts
of Zn(II), Ni(II), and Ag(I), were also tested as additives
(entries 12−15). Much worse performances were observed,
highlighting the special role of Ga(III) in this catalytic system.
With the optimal conditions in hand, we embarked on the
evaluation of the substrate scope. As shown in Figure 1, a
ization9 shown in Scheme 2.
Scheme 2. Ga(OTf)3-Assisted TA-Au Catalysis
These results were surprising and encouraging since they
suggested the application of a Au(I) and Ga(III) mixture as a
new catalytic system for alkyne activation.10 Thus, we decided
to explore the reactivity of this bimetallic concept11 in the
Nakamura reaction. Our general hypothesis was that (A) as
hard Lewis acid, the Ga(III) could activate the dicarbonyl
compounds, making them better nucleophiles, and (B)
potential formation of new active catalysts upon mixing Au(I)
and Ga(III) might provide the needed reactivity to promote the
challenging intermolecular carbon nucleophilic addition that
simple gold systems could not achieve.
Diketone 3a and alkyne 4a were selected to evaluate the
reaction conditions. As indicated in Table 1, the typical LAuCl/
AgOTf conditions gave no reactions (entries 1−3) except when
L = XPhos (entry 4), which gave the desired product in 28%
NMR yield. Notably, no further conversion was obtained after
17 h. As expected, the combination of 5% Ga(OTf)3 and 5%
XPhosAu(TA)OTf gave a very clean reaction with the desired
Table 1. Optimization of Gold(I)-Catalyzed Nakamura
a
Reaction
a
Figure 1. Scope of Alkynesa,b General reaction conditions: 3a (0.4
mmol), alkynes (2.0 equiv), 2.5 mol % XPhosAu(TA)OTf, and 5 mol
% Ga(OTf)3 in dry DCM (0.8 mL), rt. b Isolated yield. c Trace amount
b
c
d
entry
gold catalyst
additive
yield (%)
of direct adduct could be detected. 4 equiv of alkyne, 5 mol %
1
2
3
4
5
6
7
8
9
5% Ph3PAuCl, 5% AgOTf
5% IPrAuCl, 5% AgOTf
5% XPhosAuCl, 5% AgOTf
5% XPhosAu(TA)OTf
5% XPhosAu(TA)OTf
5% XPhosAu(TA)OTf
5% XPhosAuCl, 5% AgOTf
5% Ph3PAuCl, 5% AgOTf
5% Ph3PAu(TA)OTf
−
−
−
−
−
<5
<5
28
<5
XPhosAu(TA)OTf, and 10 mol % Ga(OTf)3 were used. e 1.2 equiv of
alkyne was used.
variety of aromatic alkynes were tested. Generally, over 90%
yields were achieved. The electronic effect of substituent groups
on the para-position of phenylacetylene was evaluated (5a−
5d). Aromatic alkynes with substituents on meta and ortho
positions (5f−5h) also gave very promising yields. Alkyne
derivatives of the electron-rich heterocycle could proceed
smoothly through this transformation (5i), as well as aliphatic
alkynes, though with a lower yield (5j).14 Unfortunately,
internal alkynes, such as 1-phenylhexyne and diphenylacetylene,
gave no reactions even at elevated temperature (45 °C).
To demonstrate the broad versatility of this transformation,
the scope of 1,3-dicarbonyl nucleophiles was also evaluated as
shown in Figure 2. Although, in some cases, slightly harsher
conditions (condition B, 45 °C) were required for the optimal
results, this Au/Ga bimetallic system worked well with both
cyclic and acyclic 1,3-dicorbonyl compounds. The cyclic β-
ketoesters containing ring systems could successfully undergo
this transformation (6a−6i). Remarkably, the addition to the
d
5% Ga(OTf)3
10% Ga(OTf)3
10% Ga(OTf)3
10% Ga(OTf)3
10% Ga(OTf)3
10% Ga(OTf)3
10% Ga(OTf)3
10% Ni(OTf)2
10% Zn(OTf)2
10% AgOTf
90(91)
d
98 (100)
d
79 (88)
40
38
<5
<5
8
e
10
11
12
13
14
15
5% XPhosAuCl
5% XPhosAu(TA)OTf
5% XPhosAu(TA)OTf
5% XPhosAu(TA)OTf
5% XPhosAu(TA)OTf
−
6
<5
35
<6%
10% HOTf
e
f
16
10% M(OTf)3
a
Reaction conditions: 3a (0.2 mmol), phenylacetylene (2.0 equiv),
catalyst and additives in CDCl3 (0.4 mL), rt, 17 h. TA = 1H-
benzotriazole. Determined by H NMR using 1,3,5-trimethoxyben-
zene as internal standard. Conversion in parentheses. Both rt and 45
b
c
1
d
e
f
°C, 17 h. M = Sc, Yb, In, Bi.
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Organic Letters
Letter
Scheme 3. Proposed Mechanism
low as 100 ppm could promote the reaction (5b), albeit with a
low yield (TON = 3600).
a
Figure 2. Scope of 1,3-Dicarbonyl Nucleophilesa General reaction
conditions: 3a (0.4 mmol), 3.3 mol % XPhosAu(TA)OTf and 10 mol
% Ga(OTf)3 in dry DCM (0.8 mL), and Condition A: alkynes (2.0
equiv), rt; Condition B: alkynes (4.0 equiv), 45 °C; isolated yield. b
mol % XPhosAu(TA)OTf and 15 mol % Ga(OTf)3, 12 h. Obtained
as a mixture of three known compounds and yield was determined by
1H NMR.
5
c
ethynyl ferrocene gave a good yield, which highlighted the mild
reaction conditions of this method. The acyclic α-alkyl-β-
ketoester could also undergo this transformation, as well as 3-
methyl-2,4-pentadione, dibenzoyl methane, and dimethyl
malonate (6j, 6k, 6m−6o). The products of the latter two
were the thermodynamically stable α,β-conjugated carbonyl
compounds through olefin isomerization. Interestingly, the
enamine derivative of 2,4-pentadione could also serve as an
effective nucleophile in this transformation (6l), which
provided the possibility for other carbon nucleophiles with
broader synthetic applications. Notably, in most cases, an all-
carbon quaternary center was efficiently generated.
It is too early to “call” the exact mechanism or the actual
catalytic species in this transformation. However, based on the
experimental results, it is highly likely that the Ga(III)
interacted with the triazole-gold and helped the formation of
catalytic active species. Based on the current results, a tentative
mechanism is proposed in Scheme 3. We are currently
investigating the actual catalytic components in this Au/Ga
catalytic system.
The fact that the Nakamura reaction is successfully achieved
at room temperature highlights the high efficiency of this new
bimetallic catalyst. To test the limits of the gold catalyst in this
bimetallic system, reactions were performed with a decreased
gold loading while keeping the Ga(OTf)3 at a similar amount as
shown in Table 1. To our great delight, after some
optimizations (see Table S6), we discovered that 0.05 mol %
(500 ppm) was sufficient to promote this transformation if
Ga(OTf)3 was kept at the 5% level (at 45 °C). The scope at
low Au loading is summarized in Figure 3. Notably, a loading as
Figure 3. Nakamura reaction at low Au loading. The yields are
determined by H NMR and are the average of two runs.
1
For most cases in gold(I) homogeneous catalysis, the catalyst
loadings are usually 1−5 mol %.15 The high catalytic efficiency
of the small gold cluster reported by Corma provided an
alternative approach in reaching active gold catalysts with a low
loading. Meanwhile, very recently, Hashmi reported a highly
active mononuclear gold(I) catalyst which could promote the
alkyne activation at a 0.01 ppm loading.16 Thus, at this time, it
is uncertain whether the gold cluster or the ‘genuine’ gold(I)
cation serves as the active catalytic species in this Nakamura
reaction.
In conclusion, we have unveiled synergistic gold/gallium
catalysis in promoting an ambient Nakamura reaction. This is
the first general protocol for an intermolecular reaction
between 1,3-dicarbonyl compounds and unactivated alkynes
at room temperature. Combining the low Au loading (500 ppm
and as low as 100 ppm), the reported Au/Ga system provided a
new practical approach to achieve a highly active catalytic
system for alkyne activation. New reactivity with this bimetallic
system for other challenging transformations (if using typical
[L−Au]+) is expected. A detailed mechanistic investigation is
currently underway in our group.
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Organic Letters
Letter
(11) For a dual catalytic system involving gold and a second metal,
see: (a) Shi, Y.; Peterson, S. M.; Haberaecker, W. W., III; Blum, S. A. J.
Am. Chem. Soc. 2008, 130, 2168. (b) Lauterbach, T.; Livendahl, M.;
ASSOCIATED CONTENT
* Supporting Information
■
S
́
Rosellon, A.; Espinet, P.; Echavarren, A. M. Org. Lett. 2010, 12, 3006.
Experimental details, NMR data, and crystal data CCDC
933135. This material is available free of charge via the Internet
at http://pubs.acs.org.
(c) Panda, B.; Sarkar, T. K. Chem. Commun. 2010, 46, 3131.
(d) Hirner, J. J.; Shi, Y.; Blum, S. A. Acc. Chem. Res. 2011, 44, 603.
(e) Weber, D.; Gagne,
(f) Hashmi, A. S. K.; Lothschutz, C.; Dopp, R.; Ackermann, M.;
́
M. R. Chem. Commun. 2011, 47, 5172.
̈
̈
AUTHOR INFORMATION
Corresponding Author
■
Becker, J. B.; Rudolph, M.; Scholz, C.; Rominger, F. Adv. Synth. Catal.
2012, 354, 133. For a conceptually novel use of a bimetallic system in
Conia-ene reaction, see: (g) Gao, Q.; Zheng, B.-F.; Li, J.-H.; Yang, D.
Org. Lett. 2005, 7, 2185.
*E-mail: Xiaodong.Shi@mail.wvu.edu.
Notes
(12) (a) Although gallium(III) halides (Cl, Br, and I) can serve as a
π-acid in promoting alkyne-participating transformations, there have
been no reports using Ga(OTf)3 as a π-acid toward alkyne activation.
Gandon reported a GaCl3-catalyzed cycloisomerization/Friedel−
Crafts tandem reaction: Li, H.-J.; Guillot, R.; Gandon, V. J. Org.
Chem. 2010, 75, 8435. (b) However, this reaction cannot be catalyzed
by Ga(OTf)3. For a recent review on Ga(OTf)3, see: Prakash, G. K.
S.; Mathew, T.; Olah, G. A. Acc. Chem. Res. 2012, 45, 565.
(13) Low yield (<5%) was obtained with 1% HOTf.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSF (CHE-0844602) and NSFC (No.
21228204) for financial support.
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