AuPPh3Cl/AgOTf-catalyzed reaction of terminal alkynes: nucleophilic addition to activated C{double bond, long}O bond

Article abstract of DOI:10.1016/j.tetlet.2009.08.049

Terminal alkynes, under Au-catalyzed conditions, react with aromatic aldehyde diethyl acetals, affording propargylation products through C{double bond, long}O bond addition. Furthermore, AuPPh₃Cl/AgOTf-catalyzed three-component reaction of alde

Full text of DOI:10.1016/j.tetlet.2009.08.049

Tetrahedron Letters 50 (2009) 6053–6056
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Tetrahedron Letters
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AuPPh3Cl/AgOTf-catalyzed reaction of terminal alkynes: nucleophilic
addition to activated C@O bond
*
Changkun Li, Fanyang Mo, Weibin Li, Jianbo Wang
Beijing National Laboratory of Molecular Sciences (BNLMS), and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry, Peking University, Beijing 100871, China
The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Terminal alkynes, under Au-catalyzed conditions, react with aromatic aldehyde diethyl acetals, affording
propargylation products through C@O bond addition. Furthermore, AuPPh3Cl/AgOTf-catalyzed three-
component reaction of aldehydes, alkynes, and triethyl orthoformate is developed. Gold alkynilides are
supposed to be reactive intermediates in these reactions.
Received 28 July 2009
Revised 14 August 2009
Accepted 18 August 2009
Available online 20 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Au-catalyzed reaction
Three-component reaction
Terminal alkyne
Propargyl ether
Development of catalytic reactions that lead to C–C bond forma-
tion is of fundamental importance in modern synthetic organic
chemistry. In this regard, metalated terminal alkynes are versatile
nucleophiles that can react with a wide variety of electrophiles.1
Traditionally, metalated terminal alkynes are generated by the
reaction with organolithium or organomagnesium reagents
through deprotonation. In these cases, the metalated terminal al-
kynes must be generated in a separate step due to the strong
nucleophilicity of organolithium or organomagnesium reagents.
Obviously, catalytic processes that can lead to the generation of
metal alkynilides under mild conditions are highly desirable. Car-
reira and co-workers have reported an efficient catalytic in situ
generation of Zn(II)-alkynilides that add to C@N bond efficiently.
The catalytic asymmetric version has also been subsequently
developed by the same group.1c,2 Terminal alkyne additions that
are catalyzed by In,3 Ru,4 Rh,5 Ir,6 Cu,7 Fe,8 Ag,9 Hg,10 and Au11 com-
plexes have appeared subsequently. In most of these reactions, me-
tal alkynilides are suggested as reactive intermediates (Scheme 1).
Among these reactions, Au-catalyzed nucleophilic additions
have attracted attentions. Recently, Au complexes have emerged
as efficient catalysts for a wide variety of transformations involving
alkynes, allenes, and alkenes.12 The research activities in this field
so far have been mostly concentrated on the reaction of gold-acti-
vated alkynes functioning as electron-deficient species to accept
nucleophilic attack. The process that gold-alkyne species function
as nucleophile has been much less developed except simple pro-
tonation or elimination. Wei and Li have reported a gold-catalyzed
three-component coupling reaction of aldehydes, alkynes, and
amines. A gold acetylide species, which adds to C@N bond of imin-
ium ion, is proposed as the reactive intermediate.11a Wang and
Zhang have reported a Au(III)-catalyzed acyl migration of propar-
gylic esters in which the intramolecular attack of nucleophilic
Au(III)–C(sp2) to C@O bond is supposed as the key step in the reac-
tion mechanism.11d,13 These results indicate that the nucleophilic-
ity of Au–C bond can be exploited in the formation of C–C bond.
In this context, we have reported a AuCl3/CuBr-catalyzed three-
component reaction of aldehydes, amines, and alkynes. The reac-
tion gives quinoline derivatives through a sequential catalytic pro-
cess, involving initial formation of propargyl amine via
nucleophilic addition of gold alkynilide intermediate to C@N bond
(Eq. 1).11f Furthermore, we have recently reported Au-catalyzed
reaction of terminal alkynes and benzyl trichloroacetimidates,
which leads to benzylacetylene products through nucleophilic sub-
stitution by gold acetylide (Eq. 2).14 As a continuation of our re-
-H
R
H
R
MLn
MLn
N
M = In, Ru, Rh, Ir, Cu, Fe, Ag, Hg, Au
* Corresponding author.
E-mail address: wangjb@pku.edu.cn (J. Wang).
Scheme 1. Metal-catalyzed reaction of terminal alkyne.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.049

6054
C. Li et al. / Tetrahedron Letters 50 (2009) 6053–6056
Table 1
search program aiming at C–H activation of terminal alkynes with
transition metal catalysis, we proceeded to study the nucleophilic
addition of gold acetylide to C@O bond in similar catalytic system
(Eq. 3). Herein we report a Au-catalyzed three-component reaction
of aldehyde, alkyne, and triethyl orthoformate, which affords prop-
argylation products in good yields.
Reactions of 1a and 2a under various catalytic conditionsa
Entry
Cat. (5 mol %)
t (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
AuCl3/AgOTf
AuPPh3Cl
AuCl3
6
12
48
24
24
24
18
24
24
66
Trace
9
59
0
Trace
Trace
Trace
Trace
AgOTf
AuCl3/AgOTf/DIPEAc
PtCl2
NR'
NHR'
R
R
[Au]
[Au]
ð1Þ
ð2Þ
ð3Þ
Ar
Ar
Ar
H
CuI
R'
R
H
Cu(CH3CN)4PF6
Zn(OTf)2
ref. 11
NH2
CCl3
a
b
c
Ar
Reaction was carried out in refluxing DCE.
Isolated yield.
DIPEA: Diisopropylethylamine.
O
ref. 14
OEt
R
OEt
Table 2
R
[Au]
H
Three-component reactions under various catalytic conditions
Ar
R
H
This work
OEt
On the outset of this investigation, we have attempted the
O
cat.(5 mol%)
DCE, 83 oC
nucleophilic addition of terminal alkyne to aldehyde by gold cata-
lyst. The reaction failed to give any C@O bond addition products.
The failure might be attributed to the low reactivity of aldehyde
carbonyl group toward nucleophiles. We then examined the
oxocarbenium ion, which can be generated from benzaldehyde
diethyl acetal.15 We were delighted to find that addition of termi-
nal alkyne occurs with AuPPh3Cl/AgOTf catalyst (Scheme 2).
Several other metal complexes have also been examined and
the results are summarized in Table 1. AuCl3/AgOTf was less effec-
tive to afford 3a in 66% yield (entry 1). Without AgOTf as co-cata-
lyst, AuPPh3Cl or AuCl3 gave very low yields of 3a (entries 2 and 3).
However, AgOTf alone afforded the product in the yield similar to
the reaction with AuCl3/AgOTf (entry 4). It was also noted that base
additive completely shut down the reaction (entry 5). Other metal
catalysts, such as PtCl2, CuI, Cu(CH3CN)4PF6, and Zn(OTf)2, all failed
to catalyze this reaction.
+ HC(OEt)3 +
Ph
Ph
Ph
H
Ph
3a
4a
2a
Entry
Cat. (5 mol %)
t (h)
Yielda (%)
1
2
3
4
5
AuPPh3Cl/AgOTf
AuPPh3Cl
AuCl/AgOTf
AuCl3/AgOTfb
AuCl3
1
24
24
1
24
24
2
87
0
31
32
0
Trace
84
0
6
AgOTf
7c
8d
9
AuPPh3Cl/AgOTf
AuPPh3Cl/AgOTf
PtCl2
2
12
12
12
12
12
3
0
0
10
11
12
13
14
CuI
Cu(CH3CN)4PF6
ZnI2
Zn(OTf)2
Trace
Trace
0
TfOH
24
During the course of this investigation, we observed that
AuPPh3Cl/AgOTf could efficiently catalyze the formation of benzal-
dehyde diethyl acetal from benzaldehyde and triethyl orthofor-
mate. This observation led us to conceive that a three-component
reaction of aldehydes, alkynes, and triethyl orthoformate might
be catalyzed by the same catalytic system. To test this hypothesis,
benzaldehyde, phenylacetylene, and triethyl orthoformate were
subjected to the reaction with catalytic AuPPh3Cl/AgOTf. Upon
refluxing in 1,2-dichloroethane (DCE) for 1 h, product 3a could be
isolated in 87% yield (Table 2, entry 1). Other catalytic systems
were also examined. For the gold catalyst, co-catalyst AgOTf was
found necessary (entries 2 and 5). AuCl3 and AuCl were also found
to catalyze the formation of 3a when AgOTf was used as co-cata-
lyst, albeit in much lower yields (entries 3 and 4). Control experi-
ment showed that AgOTf alone failed to catalyze the reaction
(entry 6). Solvent has marginal effect, as seen by the similar result
obtained with benzene (entry 7). However, water can completely
shut down the reaction (entry 8).
a
b
c
Isolated yield.
15 mol % AgOTf.
Benzene as solvent.
Water as solvent.
d
albeit in low yield (entry 14). Very recently, highly efficient
TfOH-catalyzed reaction of alkenes and alkynes has been docu-
mented.16 Thus, for the current Au-catalyzed reaction the possibil-
ity existed that small amount of TfOH could be generated in situ,
which catalyzed the three-component reaction. However, this
should not be the major reaction pathway in view of the fact that
TfOH-catalyzed reaction gave much lower yield of the product as
compared with AuPPh3Cl/AgOTf-catalyzed reaction.
With AuPPh3Cl/AgOTf catalytic system, the scope of the three-
component reaction was examined by a series of aldehydes and al-
kynes, and triethyl orthoformate. The results are summarized in
Table 3. For a wide range of aromatic aldehydes and alkynes, the
reaction afforded the addition products in moderate to good yields.
1-Naphthaldehyde and 2-naphthaldehyde gave similar results (en-
tries 10 and 11). Secondary cyclohexanecarbaldehyde could react
with aromatic alkyne smoothly and give moderate yield (entry
16). The electron-donating group makes the reaction faster than
the electron-withdrawing groups. p-Nitrobenzaldehyde and basic
pyridinecarbaldehyde failed to react.
Other metal complexes, such as PtCl2, CuI, Cu(CH3CN)4PF6, ZnI2,
and Zn(OTf)2, all failed to catalyze the reaction (entries 9–13).
Interestingly, strong protic acid TfOH could catalyze the reaction,
5 mol% AgOTf
5 mol% AuPPh3Cl
OEt
OEt
OEt
1a
+ Ph
Ph
Ph
DCE, reflux, 2h
88%
To account for the three-component reaction, two possible
reaction mechanisms are considered (Scheme 3). The first mecha-
nism (path a) involves the generation of gold alkynilide B, which
adds to the C@O bond of oxocarbenium ion D, as proposed previ-
Ph
2a
3a
Scheme 2. Au-catalyzed reaction of 1a and 2a.

C. Li et al. / Tetrahedron Letters 50 (2009) 6053–6056
6055
Table 3
possible Friedel–Crafts reaction with benzene was not detected,
and the reaction gave three-component reaction product in similar
yield. All these observations were not in favor of the Prins-type
reaction mechanism (path b).
Gold alkynilide species has been previously synthesized and
characterized in stoichiometric reaction.17 These species have also
been suggested in the reaction mechanism of Au-catalyzed reac-
tions of terminal alkynes.11,14 Based on these reports and our
own observation in this study, we consider that the mechanism
path a, which involves nucleophilic addition of gold alkynilide B,
is most plausible.
In summary, we have developed an AuPPh3Cl/AgOTf-catalyzed
three-component reaction of terminal alkyne, aldehyde, and
amine. The three-component reaction is highly efficient, providing
propargyl ether in good yields.19 The reaction may involve gold
alkynilide intermediates, which add to the activated C@O bond.
The catalytic processes are carried out under mild conditions to
provide propargyl ethers in good yields.
The scope of the three-component reaction17
5 mol% AgOTf
OEt
O
5 mol% AuPPh3Cl
R2
2a~f
R1
+
+ HC(OEt)3
R1
H
DCE, reflux
R2
4a~f
3a~r
Entry
4, R1
2, R2
t (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
a, C6H5
a, C6H5
1
2
2
4
3
6
2
2
15
3
15
2
2
4
1
12
4
2
3a, 87
3b, 82
3c, 55
3d, 80
3e, 81
3f, 76
3g, 87
3h, 82
3i, 87
3j, 88
3k, 80
3l, 66
3m, 71
3n, 38
3o, 76
3p, 51
3q, 30b
3r, 32c
b, o-CH3C6H4
a, C6H5
c, o-AllylOC6H4
d, m-BrC6H4
e, m-CH3OC6H4
f, m-CF3C6H4
g, p-BrC6H4
h, p-ClC6H4
i, p-C6H5C6H4
j, 1-Naphthyl
k, 2-Naphthyl
a, C6H5
a, C6H5
a, C6H5
a, C6H5
a, C6H5
a, C6H5
a, C6H5
a, C6H5
a, C6H5
a, C6H5
b, p-BrC6H4
c, p-PhC6H4
e, p-NO2C6H4
f, 2-Naphthyl
b, p-BrC6H4
a, C6H5
Acknowledgments
a, C6H5
a, C6H5
a, C6H5
l, C6H11
The project is generously supported by Natural Science Founda-
tion of China (Grant No. 20832002, 20772003, 20821062), the Min-
istry of Education of China, and National Basic Research Program of
China (973 Program, No. 2009CB825300).
m, p-CH3OC6H4
n, trans-C6H5CH@CHC6H4
a, C6H5
a
b
c
Isolated yield.
1,5-Diphenyl-3-(p-methoxyphenyl) pent-1,4-diyne was isolated in 52%.
The product was 1:1 mixture of 3r and trans-1-Methoxy-3,5-diphenyl-1- pen-
Supplementary data
ten-4-yne.
Supplementary data (characterization data, 1H and 13C NMR
spectra for all new compounds, these materials are available free
of charge via the Internet) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2009.08.049.
AuL
Ph
H
References and notes
2a
A
OEt
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6056
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