Highly efficient and diastereoselective gold(I)-catalyzed synthesis of tertiary amines from secondary amines and alkynes: Substrate scope and mechanistic insights

Article abstract of DOI:10.1002/chem.201101982

An efficient method for the synthesis of tertiary amines through a gold(I)-catalyzed tandem reaction of alkynes with secondary amines has been developed. In the presence of ethyl Hantzsch ester and [{(tBu) ₂(o-biphenyl)P}AuCl]/AgBF₄ (2 mol %), a variety of secondary amines bearing electron-deficient and electron-rich substituents and a wide range of alkynes, including terminal and internal aryl alkynes, aliphatic alkynes, and electron-deficient alkynes, underwent a tandem reaction to afford the corresponding tertiary amines in up to 99 % yield. For indolines bearing a preexisting chiral center, their reactions with alkynes in the presence of ethyl Hantzsch ester catalyzed by [{(tBu)₂(o-biphenyl)P}AuCl]/AgBF ₄ (2 mol %) afforded tertiary amines in excellent yields and with good to excellent diastereoselectivity. All of these organic transformations can be conducted as a one-pot reaction from simple and readily available starting materials without the need of isolation of air/moisture-sensitive enamine intermediates, and under mild reaction conditions (mostly room temperature and mild reducing agents). Mechanistic studies by NMR spectroscopy, ESI-MS, isotope labeling studies, and DFT calculations on this gold(I)-catalyzed tandem reaction reveal that the first step involving a monomeric cationic gold(I)-alkyne intermediate is more likely than a gold(I)-amine intermediate, a three-coordinate gold(I) intermediate, or a dinuclear gold(I)-alkyne intermediate. These studies also support the proposed reaction pathway, which involves a gold(I)-coordinated enamine complex as a key intermediate for the subsequent transfer hydrogenation with a hydride source, and reveal the intrinsic stereospecific nature of these transformations observed in the experiments. Producing tertiary amines: The Au^I-catalyzed tandem reaction of alkynes with secondary amines provides simple and efficient access to highly substituted tertiary amines with excellent yields and good to excellent diastereoselectivity. Mechanistic studies confirm that a possible reaction pathway involves intermolecular hydroamination via a monomeric cationic gold(I)-alkyne intermediate and subsequent transfer hydrogenation via a gold(I)-coordinated enamine intermediate. Copyright

Full text of DOI:10.1002/chem.201101982

DOI: 10.1002/chem.201101982
Highly Efficient and Diastereoselective Gold(I)-Catalyzed Synthesis of
Tertiary Amines from Secondary Amines and Alkynes: Substrate Scope and
Mechanistic Insights
Xin-Yuan Liu, Zhen Guo, Sijia S. Dong, Xiao-Hua Li, and Chi-Ming Che*[a]
12932
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Chem. Eur. J. 2011, 17, 12932 – 12945

FULL PAPER
Abstract: An efficient method for the
synthesis of tertiary amines through a
gold(I)-catalyzed tandem reaction of
alkynes with secondary amines has
been developed. In the presence of
ethyl Hantzsch ester and [{(tBu)2(o-bi-
Hantzsch ester catalyzed by [{(tBu)2(o-
biphenyl)P}AuCl]/AgBF4 (2 mol%) af-
forded tertiary amines in excellent
yields and with good to excellent dia-
stereoselectivity. All of these organic
transformations can be conducted as a
one-pot reaction from simple and read-
ily available starting materials without
the need of isolation of air/moisture-
sensitive enamine intermediates, and
under mild reaction conditions (mostly
room temperature and mild reducing
agents). Mechanistic studies by NMR
spectroscopy, ESI-MS, isotope labeling
studies, and DFT calculations on this
gold(I)-catalyzed
tandem
reaction
reveal that the first step involving a
monomeric cationic gold(I)–alkyne in-
termediate is more likely than
a
phenyl)P}AuCl]/AgBF4 (2 mol%),
a
gold(I)–amine intermediate, a three-co-
ordinate gold(I) intermediate, or a di-
nuclear gold(I)–alkyne intermediate.
These studies also support the pro-
posed reaction pathway, which involves
a gold(I)-coordinated enamine complex
as a key intermediate for the subse-
quent transfer hydrogenation with a
hydride source, and reveal the intrinsic
stereospecific nature of these transfor-
mations observed in the experiments.
variety of secondary amines bearing
electron-deficient and electron-rich
substituents and a wide range of al-
kynes, including terminal and internal
aryl alkynes, aliphatic alkynes, and
electron-deficient alkynes, underwent a
tandem reaction to afford the corre-
sponding tertiary amines in up to 99%
yield. For indolines bearing a preexist-
ing chiral center, their reactions with
alkynes in the presence of ethyl
Keywords: alkynes · density func-
tional calculations · diastereoselec-
tivity · gold · tertiary amines
Introduction
nation and transfer hydrogenation to give tertiary amines.
Some studies, including our own work, have revealed that
cationic gold(I) complexes bearing bulky phosphine or NHC
ligands could catalyze the intermolecular hydroamination of
alkynes with secondary amines to give the corresponding en-
amines.[3b,4,5] Compared to imines or iminium ions that dis-
play high reactivity toward Hantzsch ester,[6] unfunctional-
ized enamines show diminished electrophilic character.
Their low propensity to react with hydrides under mild reac-
tion conditions is attributed to the delocalization of the
Transition-metal-catalyzed tandem carbon–carbon and
carbon–heteroatom bond-formation reactions have emerged
as powerful tools for the synthesis of valuable synthetic
building blocks starting from relatively simple and readily
available precursors.[1] Among these transition-metal cata-
lysts, the use of gold complexes as catalysts has recently
been proven to be a useful approach for the synthesis of di-
verse classes of organic compounds with complexity, selec-
tivity, and high atom economy under mild reaction condi-
tions.[2] In this area, we have developed a series of gold-cata-
lyzed tandem reactions for the construction of synthetically
useful polycyclic compounds.[3]
À
lone-pair electrons of nitrogen atom to the C C double
bond.[7,8] In the literature, gold catalysts have been found to
À
display an exceptional ability to activate C C multiple
bonds for nucleophilic attack through p-acid activation.[9]
We recently reported a gold(I)-catalyzed tandem reaction
of primary amines with alkynes to give secondary amines.
The mechanism of the reaction involves initial formation of
an imine intermediate through an intermolecular hydroami-
nation process followed by a subsequent transfer hydrogena-
tion with Hantzsch ester (HEH).[3d] Subsequently, we ex-
plored whether secondary amines could also undergo this
similar reaction through tandem intermolecular hydroami-
We envisioned that gold complex could coordinate to the
À
C C double bond of the enamine intermediate generated in
situ. The coordination would cause enamine intermediate
less electron rich and thereby increase the reactivity of the
double bond of enamine for nucleophilic attack.[9c] The
gold-stabilized enamine intermediate could then enter the
subsequent catalytic transfer hydrogenation with a hydride
source such as HEH. This new method for the synthesis of
tertiary amines from secondary amines and alkynes cata-
lyzed by gold(I) complex is reported herein (Scheme 1).
[a] Dr. X.-Y. Liu,+ Dr. Z. Guo,+ S. S. Dong,+ Dr. X.-H. Li,
Prof. Dr. C.-M. Che
Department of Chemistry
State Key Laboratory of 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)2857-1587
E-mail: cmche@hku.hk
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101982.
Scheme 1. The highly selective formation of tertiary amines from the
gold(I)-catalyzed tandem reaction.
Chem. Eur. J. 2011, 17, 12932 – 12945
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12933

C.-M. Che et al.
Tertiary amines constitute a valuable class of chemical
compounds that have potential for pharmaceutical, agro-
chemical, and industrial applications.[10] For this reason,
there has been continued interest in the development of ef-
ficient methods for the synthesis of tertiary amines bearing
multiple and diverse substituent pattern. The reduction of
unfunctionalized tertiary enamines employing nucleophilic
hydride donors is a useful transformation for the synthesis
of tertiary amines;[11] however, there are a number of signifi-
cant challenges impeding such developments. These include
the use of enamine substrates that are not always easy to be
prepared due to stability issue.[7] On the other hand, these
reduction methods normally require the use of highly reac-
tive reagents, such as aluminum hydride and boron hydride
as the hydride sources,[5b,11] thus rendering the synthetic util-
ity of such hydride reagents limited to the harsh reaction
conditions, low functional-group tolerance and tedious pu-
rification procedures.
Over the past decades, air- and moisture-stable Hantzsch
ester has been introduced as a convenient reagent for a
number of transfer hydrogenation reactions of unsaturated
organic compounds.[6,12] However, only a few examples on
the reduction of unfunctionalized tertiary enamines by using
HEH as the reducing agent have been reported, and all of
these reduction reactions require the use of stoichiometric
or excess amounts of strong Brønsted acids to facilitate the
formation of iminium ion intermediate.[13] Therefore, the de-
velopment of an efficient catalyst to stabilize unfunctional-
ized tertiary enamines for subsequent reduction by mild re-
ducing agent would be highly desirable. The method report-
ed herein (Scheme 1) is useful for the construction of ter-
Hantzsch ester (3) catalyzed by
a
combination of
[(Ph3P)AuCl] (5 mol%) and AgBF4. We found that
[(Ph3P)AuCl]/AgBF4 could catalyze this reaction in CH3NO2
at 608C to form the desired product 4Aa in 42% yield
(Table 1, entry 1). Further investigation showed that the sol-
Table 1. Optimization of reaction conditions for the synthesis of tertiary
amine.[a]
Catalyst
Solvent
T
t
Yield
[oC] [h] [%][b]
1
2
3
4
5
N
CH3NO2 60
16 42
16 20
16 26
16 24
16 52
21 21
21 11
CH3CN
EtOH
toluene
THF
60
60
60
60
60
60
6
AuCl
THF
7
8
KAuCl4
A
THF
THF
(NHC)AuCl[c]/AgBF4
RT 21 78
RT 98
9
A
8
10[d]
11[e]
12[f]
13
N
RT 10 96
RT 18 63
RT 18 34
THF
60
21
6
[a] Reaction
conditions:
indoline
(0.5 mmol),
phenylacetylene
(0.6 mmol), ethyl Hantzsch ester (3) (0.75 mmol), and catalyst (5 mol%).
[b] Yield was determined by 1H NMR spectroscopy. [c] NHC=N,N’-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene. [d] Catalyst loading was
2 mol%. [e] Catalyst loading was 1 mol%. [f] Catalyst loading was
0.5 mol%.
ACHTUNGTRENNUNGtiary amines bearing multiple substituents using a mild re-
ducing agent, such as HEH, and without the need of
workup and isolation of air/moisture-sensitive tertiary enam-
ine intermediate(s). Also, this process proceeds under mild
conditions and leads to tertiary amines, with a very broad
substrate scope, in up to 99% yields. When secondary
amines bearing a preexisting chiral center were employed,
excellent diastereoselectivity (up to >20:1) was achieved.
Also reported here are our mechanistic studies of the
gold(I)-catalyzed tandem reaction of alkynes with secondary
amines employing a combination of experimental and com-
putational techniques.
vent had no significant effect on the conversion of this
tandem reaction (Table 1, entries 1–5). We then turned our
attention to examine the activity of other gold catalysts on
this reaction. Simple gold salts, such as AuCl or KAuCl4, all
failed to give the desired product in good yield (Table 1, en-
tries 6 and 7). While using a combination of (NHC)AuCl/
AgBF4 (5 mol%; NHC=N,N’-bis(2,6-diisopropylphenyl)-
imidazol-2-ylidene) as the catalyst, which was previously re-
ported by Nolan and co-workers to have useful applications
in gold catalysis,[14] the desired product was formed in 78%
yield in THF at room temperature (Table 1, entry 8). The
use of [{(tBu)2(o-biphenyl)P}AuCl]/AgBF4, a catalyst previ-
ously reported by Echavarren and co-workers,[15] afforded
4Aa in 98% yield for only 8 h at room temperature
(Table 1, entry 9). We next studied this reaction at room
temperature in the presence of [{(tBu)2(o-biphenyl)P}AuCl]/
AgBF4 with different loadings. It should be noted that the
catalyst loading could be reduced from 5 to 2 mol% without
affecting the yield of 4Aa (Table 1, entry 10). Notably, a
control experiment revealed that AgBF4 as the catalyst gave
4Aa in only 6% NMR yield (Table 1, entry 13). The optimal
reaction conditions were found to be of [{(tBu)2(o-biphe-
nyl)P}AuCl]/AgBF4 (2 mol%) with THF as the solvent at
Results and Discussion
Gold(I)-catalyzed tandem synthesis of tertiary amines: Our
prior observation that gold(I) complexes can efficiently cata-
lyze the synthesis of secondary amines from primary amines
and alkynes in the presence of HEH,[3d] and the possibility
that this catalyst could lead to the synthesis of tertiary
amine when secondary amine is used as a substrate, led us
to further explore the substrate scope and mechanism of
this reaction. To do so, we initiated these investigations by
examining the reaction of indoline (1A) with phenylacety-
lene (2a) in the presence of commercially available
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Chem. Eur. J. 2011, 17, 12932 – 12945

Gold Catalysis
FULL PAPER
room temperature for 10 h, and gave the product 4Aa in
96% yield (Table 1, entry 10).
used as the substrates in the presence of gold catalyst to
afford the corresponding tertiary amines 4Ah and 4Ai in
excellent yields (Table 2, entries 8 and 9). Interestingly, a
good yield (79%) of 4Aj was achieved when 4,4’-diethynyl-
biphenyl (2j) bearing two terminal alkyne groups was treat-
ed with 1A (2.5 equiv) under similar reaction conditions
(Table 2, entry 10). We then turned our attention to the re-
action with internal alkynes. For example, the catalytic reac-
tion of 1,2-biphenylethyne (2k) with 1A in the presence of
[{(tBu)2(o-biphenyl)P}AuCl]/AgBF4 at 408C led to the cor-
responding product 4Ak, albeit with decreased product
yield (44%; Table 2, entry 11). It is also worth noting that
the reaction with electron-deficient alkynes such as methyl
propiolate (2l) proceeded smoothly, but only a moderate
yield (54%) was achieved under the same conditions
(Table 2, entry 12). These results indicate that a variety of
alkynes, from electron-rich ones including terminal and in-
ternal aryl alkynes, aliphatic alkynes, to electron-deficient
alkyne, can be used as substrates for this gold(I)-catalyzed
tandem reaction.
Under the optimized reaction conditions, we examined
the substrate scope of the gold(I)-catalyzed tandem reac-
tion. A variety of aromatic alkynes were similarly treated
with indoline (1A) in the presence of of [{(tBu)2(o-biphe-
nyl)P}AuCl]/AgBF4 (2 mol%). As depicted in Table 2,
Table 2.
ACHTUNGTRENNUNG[{(tBu)2(o-biphenyl)P}AuCl]/AgBF4-catalyzed synthesis of terti-
ary amines with various alkynes.[a]
Alkyne
Product
t
Yield
[%][b]
[h]
The gold(I)-catalyzed tandem reaction of various secon-
dary amines with phenylacetylene (2a) was performed
under the optimized conditions as depicted in Table 3. The
reaction of 2a with 5-bromoindoline (1B) in the presence of
[{(tBu)2(o-biphenyl)P}AuCl]/AgBF4 (2 mol%) at room tem-
perature gave the corresponding product 4Ba in 99% yield
(Table 3, entry 1). Furthermore, 1,2,3,4-tetrahydroquinolines
were also applicable, and the reaction afforded tertiary
1
2
3
4
5
6
7
R=H (2a)
4Aa
4Ab
4Ac
4Ad
4Ae
4Af
4Ag
10
10
8
8
8
96
94
98
92
95
97
91
R=4-Me (2b)
R=4-OMe (2c)
R=3-OMe (d)
R=2-OMe (2e)
R=4-F (2 f)
16
24
R=4-CN (2g)
8
9
R=nBu (2h)
R=n-hexyl (2i)
4Ah
4Ai
17
16
92
90
Table 3.
ACHTUNGRTEN[NUNG {(tBu)2(o-biphenyl)P}AuCl]/AgBF4-catalyzed synthesis of terti-
ary amines with various secondary amines.[a]
10[c]
24
79
11[d]
24
24
44
54
Amine
Product
t
Yield
[%][b]
[h]
12
1
12
99
[a] Reaction conditions: indoline (0.5 mmol), alkyne (0.6 mmol), ethyl
Hantzsch ester (3) (0.75 mmol), [{(tBu)2(o-biphenyl)P}AuCl]/AgBF4
(2 mol%), THF (2 mL) at room temperature. [b] Isolated yield based on
indoline. [c] Alkyne:indoline=1:2.5; isolated yield based on alkyne.
[d] Reaction temperature was 40oC.
2[c]
3[c]
R=H (1C)
R=OMe (1D)
4Ca
4Da
21
26
85
94
under the optimized conditions, the functional groups,
methyl, methoxy, fluoro, and CN groups at the para-position
of the benzene ring were well-tolerated, giving the corre-
sponding products in excellent yields (Table 2, entries 2, 3, 6,
and 7). Notably, the introduction of a methoxy group at the
para-, meta-, or ortho-position in the phenyl group of aro-
matic alkynes did not affect the product yield either
(Table 2, entries 3–5). Aliphatic alkynes were also efficiently
4[c]
5[c]
R=H (1E)
R=OMe (1F)
4Ea
4Fa
26
26
86
98
[a] Reaction conditions: secondary amine (0.5 mmol), phenylacetylene
(0.6 mmol), ethyl Hantzsch ester (3) (0.75 mmol), [{(tBu)2(o-biphenyl)-
P}AuCl]/AgBF4 (2 mol%), THF (2 mL) at room temperature. [b] Isolated
yield based on amine. [c] Reaction temperature was 60oC.
Chem. Eur. J. 2011, 17, 12932 – 12945
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12935

C.-M. Che et al.
amines 4Ca and 4Da in 85 and 94% yields, respectively
yields, but similar diastereoselectivity was achieved in all
cases (Table 4, entries 3–5). Further screening of solvents re-
vealed that benzene gave the best result for the formation
of the desired product with improved diastereoselectivity
(15:1) (Table 4, entry 8), while the polar solvents THF and
acetonitrile both gave lower levels of diastereoselectivity
(Table 4, entries 1 and 6). Another hydride source, tert-butyl
Hantzsch ester, was also tested under the same reaction con-
ditions; however, lower yield and diastereoselectivity were
found comparing with ethyl Hantszch ester (Table 4,
entry 9).
As highly diastereoselective formation of tertiary amine
catalyzed by [{(tBu)2(o-biphenyl)P}AuCl]/AgBF4 (2 mol%)
with benzene as solvent had been achieved for the model
substrate, the scope of this tandem reaction with regard to
alkynes and indolines bearing a preexisting chiral center was
next examined. The results are summarized in Table 5. The
generality of the protocol is proven by the reactions of a
series of alkynes with amines, giving the desired products in
excellent yields with good levels of diastereoselectivity. Aryl
alkynes with an electron-donating para-substituent on the
phenyl ring could be successfully employed to afford tertiary
amines in 90–99% yields with good diastereoselectivity (up
to 15:1; Table 5, entries 1, 2, and 5). Notably, for meta- and
ortho-substituted aryl alkynes bearing electron-donating
group, such as o-, m-methoxy- and o-methyl aryl alkynes,
the corresponding products 4Gd, 4Ge, and 4Gm were ob-
tained with improved diastereoselectivity (up to 19:1) in 83–
97% yields (Table 5, entries 3, 4, and 6). The electron-defi-
cient aryl alkyne 2n gave the product 4Gn as a 12:1 mixture
of diastereomers in excellent yield (93%), although an in-
creased catalyst loading, a higher reaction temperature
(408C) and a longer reaction time in the presence of activat-
ed, powdered molecular sieves (MS, 5 ꢁ) were required for
complete substrate conversion (Table 5, entry 7).
Next, we turned our attention to this tandem reaction of
1-ethynyl-3-methoxybenzene (2d) with other indolines that
have an a-substituent under the same reaction conditions.
With 2-phenethylindoline (1H) as the secondary amine
component, 4Hd was obtained in 92% yield with a diaster-
eometric ratio of 14:1 (Table 5, entry 8). The introduction of
a phenyl group possessing either electron-donating or elec-
tron-withdrawing substituent at the a-position in indolines
greatly increased the diastereoselectivity of the amine prod-
ucts, and the corresponding products 4Id–4Kd were ob-
tained with excellent levels of diastereoselectivity (up to
>20:1) in 94–98% yields (Table 5, entries 9–11). The rela-
tive configuration of 4Gm was determined by X-ray crystal-
lographic analysis (Figure 1).[18] The relative configuration of
all other products was determined with reference to 4Gm.
(Table 3, entries 2 and 3).[16] Simple acyclic amines were also
effective substrates. The reactions of 4-meth
ACHTUNGTRENoNUNG xy-N-methyl-
ACHTUNGTRENNUNGaniline (1E) or N-methylaniline (1F) with 2a in the pres-
ence of [{(tBu)2(o-biphenyl)P}AuCl]/AgBF4 (2 mol%) at
608C led to the corresponding amines 4Ea or 4Fa in 86 and
98% yields, respectively (Table 3, entries 4 and 5).
Gold(I)-catalyzed, diastereoselective synthesis of tertiary
amines: An objective of developing a new metal-catalyzed
reaction stems from the expectation that this new reaction
would occur, not only with a high catalytic activity, but also
with a high degree of selectivity.[17] In this work, we investi-
gated the gold(I)-catalyzed reaction of alkynes with secon-
dary amines containing a preexisting chiral center. It was an-
ticipated that this preexisting chiral center in secondary
amine would induce a high degree of stereospecificity in the
formation of tertiary amines having two stereocenters.
To ascertain the feasibility of this hypothesis, we carried
out a catalytic diastereoselective tandem reaction of 2-meth-
ylindoline (1G) with phenylacetylene (2a) in the presence
of ethyl Hantzsch ester (3) and [{(tBu)2(o-biphenyl)P}AuCl]/
AgBF4 (2 mol%). To our delight, the desired product 4Ga
was obtained with a diastereomeric ratio of 10:1 in 92%
yield (Table 4, entry 1). To improve the diastereoselectivity,
a panel of gold(I) complexes with different ancillary ligands
were screened for the activity and diastereo-induction in the
tandem reaction. No reaction was observed when
[(Ph3P)AuCl]/AgBF4 was used as the catalyst (Table 4,
entry 2). Use of gold complexes bearing different auxiliary
ligands including NHC, (Cy)2(2’,4’,6’-triisopropyl-o-biphe-
nyl)P and (tBu)2(2’,4’,6’-triisopropyl-o-biphenyl)P also re-
sulted in the formation of product 4Ga in moderate to good
Table 4. Optimization of reaction conditions for the diastereoselective
synthesis of tertiary amines.[a]
Catalyst
Solvent
t
Yield d.r.[c]
[h] [%][b]
1
2
3
4
5
6
7
N
17
47
47
47
47
92
–
10:1
–
9:1
9:1
8:1
[d]
[d]
89
61
58
69
90
95
86
6:1
14:1
15:1
8:1
8
9[h]
[a] Reaction conditions: 2-methylindoline (0.5 mmol), phenylacetylene
(0.6 mmol), ethyl Hantzsch ester (3) (0.75 mmol), catalyst (2 mol%), sol-
vent (2 mL) at room temperature. [b] Isolated yield based on amine.
[c] Diastereomeric ratio determined by 1H NMR spectroscopy; major
isomer shown. [d] Product was not detected. [e] NHC=N,N’-bis(2,6-di-
Mechanistic studies: In recent years, there has been a surge
of interest to study the mechanism of gold-catalyzed reac-
tions by DFT calculations.[19] In this work, several mechanis-
tic scenarios were considered for the gold(I)-catalyzed syn-
thesis of tertiary amines from secondary amines and alkynes.
Generally, two mechanisms are used to describe hydroami-
ACHTUNGTRENNUNG
isopropylphenyl)-imidazol-2-ylidene. [f] L1 ={(Cy)2(2’,4’,6’-triisopropyl-o-
biphenyl)P}. [g] L2 ={(tBu)2(2’,4’,6’-triisopropyl-o-biphenyl)P}. [h] tert-
butyl Hantzsch ester was used as the hydride source.
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Chem. Eur. J. 2011, 17, 12932 – 12945

Gold Catalysis
FULL PAPER
Table 5. Gold(I)-catalyzed diastereoselective synthesis of tertiary amines with various aryl alkynes and indoli-
nes.[a]
been supported by experimen-
tal and/or computational stud-
ies, as reported by Ujaque[21a,b]
and Toste.[21c,22] While a mech-
anism of complexation of both
the amine functionality and
À
the unsaturated C C bond
Indoline
Alkyne
Product
t
Yield
[%][b]
d.r.[c]
with the gold catalyst through
a three-coordinate gold inter-
mediate II has been proposed
for intermolecular hydroami-
nation involving the more
basic simple amines (reaction 2
in Scheme 2),[5b,23] recent inves-
tigations by Bertrand and co-
workers indicated that gold-
catalyzed intramolecular hy-
droamination of alkynes with
simple secondary amines could
proceed by means of an alter-
native reaction pathway in-
volving alkyne activation/nu-
cleophilic attack through an
alkyne-coordinated gold inter-
[h]
1
2
3
4
R1 =Me (1G)
R1 =Me (1G)
R1 =Me (1G)
R1 =Me (1G)
R1 =Me (1G)
R1 =Me (1G)
R1 =Me (1G)
R2 =Ph (2a)
4Ga
4Gc
4Gd
4Ge
4Gb
4Gm
4Gn
17
9
24
9
22
22
48
95
99
97
93
90
83
93
15:1
R2 =4-MeOPh (2c)
R2 =3-MeOPh (2d)
R2 =2-MeOPh (2e)
R2 =4-MePh (2b)
R2 =2-MePh (2m)
R2 =4-CF3Ph (2n)
13:1
19:1
19:1
13:1
15:1
12:1
5
6
7[d]
mediate
I
(reaction 1 in
8
9
10
11
R1 =Ph
ACHTUNGTRENNUNG(CH2)2 (1H)
R2 =3-MeOPh (2d)
R2 =3-MeOPh (2d)
R2 =3-MeOPh (2d)
R2 =3-MeOPh (2d)
4Hd
4Id
4Jd
4Kd
20
22
20
18
92
98
95
94
14:1
>20:1
>20:1
>20:1
R1 =Ph (1I)
Scheme 2).[24] On the other
hand, although a monomeric
cationic gold(I) complex[25] has
been proposed to be the cata-
lytically relevant species for
nucleophilic addition of amine
to terminal alkyne catalyzed
by gold(I) complex, on the
basis of conventional reaction
R1 =4-MePh (1J)
R1 =4-ClPh (1K)
[a] Reaction conditions: indoline derivatives (0.5 mmol), alkyne (0.6 mmol), ethyl Hantzsch ester (3)
(0.75 mmol), [{(tBu)2(o-biphenyl)P}AuCl]/AgBF4 (2 mol%), benzene (2 mL) at room temperature. [b] Isolated
yield based on amine. [c] Diastereomeric ratio determined by 1H NMR spectroscopy; major isomer shown.
[d] 5 mol% of [{(tBu)2(o-biphenyl)P}AuCl]/AgOTf was used in the presence of activated, powdered molecular
sieves (5 ꢁMS) at 408C.
mechanism widely proposed for palladium[26] and platinum
complexes,[27] several vinyl–gold dimer intermediates III (re-
action 3 in Scheme 2) derived from gold-mediated addition
of nucleophiles to terminal alkynes have been isolated and
characterized.[28] Furthermore, Toste and co-workers recent-
ly reported experimental and computational evidences for
dinuclear gold(I) complexes as key intermediates in gold(I)-
catalyzed allenyne cyclization.[29]
According to these recent experimental and computation-
al studies, three possible pathways for the gold(I)-catalyzed
tandem reaction of alkynes with basic secondary amines de-
scribed in this work are depicted in Scheme 2, one of which
features activation of the alkyne linkage, whereas the others
involve either activation of the amine functionality followed
by the coordination of alkyne to form a three-coordinate
gold intermediate II, or dinuclear gold(I) species III as a
possible intermediate. In an effort to understand the mecha-
nism of this tandem reaction and to account for the good
diastereoselectivity, we have made attempts to detect the re-
action intermediate(s) by NMR spectroscopy and ESI-MS;
we have also performed isotope-labeling studies and DFT
calculations.
Figure 1. Molecular structure of compound 4Gm.
À
nation of unsaturated C C bonds catalyzed by transition-
metal complexes. One is based on nucleophilic addition of
À
amine to a coordinated unsaturated C C bond (reaction 1
in Scheme 2), the other involves complexation of both
À
amine functionality and the unsaturated C C bond with the
À
metal catalyst followed by insertion of the unsaturated C C
bond into the metal–amine bond (reaction 2 in Scheme 2).[20]
In the cases of gold(I)-catalyzed hydroamination of alkenes
and allenes with less basic amides or carbazates, nucleophilic
À
attack of an amide on a gold(I)-coordinated C C multiple
bond has been proposed (reaction 1 in Scheme 2), which has
Chem. Eur. J. 2011, 17, 12932 – 12945
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12937

C.-M. Che et al.
Scheme 2. Possible pathways of gold(I)-catalyzed tandem reaction of alkynes with secondary amines.
Identification of reaction intermediate(s) by NMR spectros-
copy and ESI-MS: The interaction between the gold(I) cata-
lyst and substrate/product was studied by 31P NMR spectros-
copy, because the 31P signal of the phosphine ligand is sensi-
tive to the electronic environment around the gold
center.[22,30] Model gold(I) complexes containing alkyne, sec-
ondary amine, or tertiary amine moieties were prepared
biphenyl)PAu
ACHTUNGTERNNUG(CH3CN)]ACHTUNGTERN[NUGN SbF6] and indoline (1A) in a 1:1
ratio showed a 31P NMR signal at d=58.2 ppm, and another
sample containing [(tBu)2(o-biphenyl)PAuACTHNUTRGENNUG(CH3CN)]ACHTUNGTRENNUNG[SbF6]
and product 4Aa in a 1:1 ratio showed a similar 31P NMR
signal at d=57.6 ppm. However, the 31P NMR signal of
[(tBu)2(o-biphenyl)PAuACHTUNTRGENNUG(CH3CN)]ACHUTNGTREN[NNGU SbF6] alone was observed
at d=60.1 ppm. Next, the reaction of 1 A with 2a in the
presence of Hantzsch ester (3) catalyzed by [(tBu)2(o-
[SbF6][31] in CDCl3 at
from [(tBu)2(o-biphenyl)PAuACHTUNGTRNENUG(CH3CN)]CAHTUNGTRENNUGN
room temperature (Scheme 3). We found that the 31P signals
of the gold(I) complexes containing alkyne, secondary
amine, or tertiary amine moieties are significantly different
from each other, thus enabling identification of reaction in-
termediate(s) by 31P NMR spectroscopy. The sample con-
biphenyl)PAuACTHNGUTREN(NUG CH3CN)]ACHTUNGRTEN[NUGN SbF6] (10 mol%) in CDCl3 at room
temperature was monitored by 31P NMR spectroscopy
(Figure 2). In this experiment, we found that the signal cor-
responding to [(tBu)2(o-biphenyl)PAu
60.1 ppm) vanished and a new peak at d=62.9 ppm was ob-
served when [(tBu)2(o-biphenyl)PAu(CH3CN)][SbF6] was
ACHTUGTNRNENUG(CH3CN)]ACHTUNGTNER[NUGN SbF6] (d=
taining [(tBu)2(o-biphenyl)PAu
(CH3CN)]
C
A
ACHTUNGTRENNUNG
acetylene (2a) in a 1:2 ratio showed a 31P NMR signal at d=
62.9 ppm. By comparison, the sample containing [(tBu)2(o-
added to a reaction mixture of 1A, 2a, and 3. As the reac-
tion progressed to higher conversion (up to 86%), a second
peak at d=57.9 ppm developed, and this peak is attributed
to [(tBu)2(o-biphenyl)PAu
signal was observed if mixing just 4Aa with [(tBu)2(o-
biphenyl)PAu(CH3CN)]SbF6 in CDCl3 (Scheme 3). The
(4Aa)]SbF6, because the same 31P
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
signal at d=62.9 ppm observed in the catalytic reaction is
consistent with the 31P NMR signal of [(tBu)2(o-
biphenyl)PAuACTHUNRGTNEUNG(2a)]SbF6, suggesting the possibility of coordi-
nation of the alkyne to cationic AuI. The presence of coordi-
nated alkyne intermediate and the absence of gold–amine
species in the reaction of 1A with 2a in the presence of 3
catalyzed by [(tBu)2(o-biphenyl)PAuACTHNUGRTENN(UG CH3CN)]CAHTUNGTREN[NGUN SbF6] might
be consistent with a mechanism involving nucleophilic
attack of secondary amine to a gold(I)-coordinated alkyne.
A similar reaction mechanism of hydroamination involving
less basic nitrogen nucleophiles had previously been report-
ed by both Toste and Ujaque.[21,22]
We hypothesized that gold(I)-coordinated enamine may
be a key intermediate in this gold(I)-catalyzed tandem reac-
tion of alkynes with amines. To detect the gold(I)-coordinat-
ed enamine intermediate, we examined the reaction mixture
by electrospray ionization mass spectrometry (ESI-MS).
ESI-MS analysis of a solution mixture containing 1A, 2a
and [(tBu)2(o-biphenyl)PAuACHTNUTRGENN(UG CH3CN)]ACHTUTGNREN[NUGN SbF6] (20 mol%) in
CH2Cl2 after stirring for 15 min at room temperature
showed a cluster peak at m/z 716.1, attributed to the com-
plex formed between [(tBu)2(o-biphenyl)PAu]+ and the en-
Scheme 3. Reactions of phenylacetylene (2a), indoline (1A) and product
4Aa with a stoichiometric amount of [(tBu)2(o-biphenyl)PAu
[SbF6].
ACHTUNGTERN(NUNG CH3CN)]-
ACHTUNGTRENNUNG
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Gold Catalysis
FULL PAPER
formation of
a new ion at
m/z 494.7, which could be
attributed to fragmentation
of
[(tBu)2(o-biphenyl)PAu-
AHCTUNGTRENNUNG
(C16H15N)]+ into [(tBu)2(o-bi-
phenyl)PAu]+ apparently by
loss of enamine (see the Sup-
porting
Information,
Fig-
ure S6). These data reveal that
in the course of this reaction,
transfer hydrogenation might
proceed via a gold(I)-coordi-
nated enamine intermediate.
Isotope-labeling studies:
A
series of control experiments
were conducted to gain insight
into the role of gold catalyst in
the hydride reduction step.
Since we were not able to iso-
late the enamine intermediate
from the reaction of indoline
(1A) with phenylacetylene
(2a), the relatively stable en-
amine 5 was prepared in order
to see whether gold catalyst
was crucial for the subsequent
transfer hydrogenation reac-
tion [Eqs. (1) and (2)]. For ex-
ample, in the absence of gold
catalyst, product 4Ea was not
obtained for the reaction of
enamine 5 in the presence of 3
Figure 2. Stacked plots of 31P NMR spectra obtained at various conversions of indoline (1A) catalyzed by
10 mol% of [(tBu)2(o-biphenyl)PAuACTHNUTRGENNG(U CH3CN)]AHCTUNGTREN[NGUN SbF6] in CDCl3 at room temperature.
(1.5 equiv) conducted at 658C
amine intermediate generated in situ (Figure 3). The ob-
seved isotopic pattern depicted in Figure 3 matches the cal-
culated pattern well (see the Supporting Information, Fig-
ure S5). Collision-induced dissociation of the [(tBu)2(o-
for 48 h [Eq. (1)]. In contrast, we observed that in the pres-
ence of [{(tBu)2(o-biphenyl)P}AuCl]/AgBF4 (5 mol%), the
reaction gave the desired product 4Ea in 84% yield after
24 h at 408C [Eq. (2)]. We also examined a reaction of 1A
with 2a in the presence of deuterated Hantzsch ester 6 cata-
lyzed by [{(tBu)2(o-biphenyl)P}AuCl]/AgBF4 (2 mol%) in
benzene at 408C for 24 h, which gave product 7 in 85%
yield with 100% deuterium incorporation at the C-1 posi-
tion [Eq. (3)]. This implies that one of the hydrides on the
carbon atom of Hantzsch ester was completely transferred
to the C-1 atom of the enamine intermediate generated in
situ from the reaction of alkyne with secondary amine cata-
lyzed by the gold complex.
biphenyl)PAuACHTUNGTRENNUNG
(C16H15N)]+ ion at m/z 716.1 resulted in the
DFT calculations: To gain a better insight into the reaction
intermediate(s) and transition state(s) involved in this
Figure 3. ESI-MS spectrum of
[(tBu)2(o-biphenyl)PAu(CH3CN)]
cluster peak at m/z 716.
a
solution containing 1 A, 2a, and
N
ACHTUGNTREN[NUNG SbF6] (20 mol%) in CH2Cl2 showing a
Chem. Eur. J. 2011, 17, 12932 – 12945
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12939

C.-M. Che et al.
deprotonation of gold(I)–amine complex A for the forma-
tion of [(H3P)AuACTHNUGTRNE(NUG NR2)] and HBF4 is unlikely.
As mentioned previously, the alkyne-coordinated gold in-
termediate I and the three-coordinate gold intermediate II
for the gold(I)-catalyzed hydroamination of alkynes with
basic amines have been proposed (Scheme 2).[5b,23] Thus, in
this work, two different reaction pathways involving either a
monomeric cationic gold(I)–alkyne complex CA or a three-
coordinate gold(I) complex B by complexation of alkyne
and secondary amine to gold(I) were investigated. As de-
picted in Figure 4, the first reaction pathway starts with in-
termediate B’ or B, in which the Au···N or Au···C bonds for
complex B or B’ are weak, as revealed by their long bond
lengths of 3.29 and 3.53 ꢁ for B and B’, respectively (see
the Supporting Information, Figure S7). This result does not
lend support to a three-coordinate gold(I) intermediate.
However, a transition state B-TS-1 with a free energy of
5.4 kcalmolÀ1 from complex B or B’ was located, which
leads to the gold(I)-coordinated enamine B-1. Next, the
second reaction pathway involving a monomeric cationic
gold(I)–alkyne complex CA was considered (Figure 4 and
Figure S8 in the Supporting Information). The calculation
showed that the nucleophilic addition of indoline to gold(I)–
activated alkyne CA is relatively facile, only requiring an ac-
tivation free energy of 2.7 kcalmolÀ1 via transition state CA-
TS-1 to afford the coordinated product CA-1. According to
our calculation, transition state CA-TS-1 is lower in energy
than B-TS-1 by 2.7 kcalmolÀ1, suggesting that the hydroami-
nation reaction via the three-coordinate gold(I) intermedi-
ate B or B’ is not energetically favored over that via the
gold(I)–alkyne intermediate CA. Also, no spectroscopically
detectable interaction between the gold center and secon-
dary amine in the reaction system was revealed by 31P NMR
measurements, thereby disfavoring the coordination of
amine to the gold catalyst followed by the formation of
gold(I)–amine complex A-1 or three-coordinate gold(I)
complex B or B’. Therefore, in the following reaction path-
ways, only the pathway(s) of the catalytic tandem reactions
starting from gold(I)–alkyne intermediate CA was consid-
ered.
tandem process (Scheme 2), we investigated the reaction
mechanism by performing hybrid density functional theory
calculations at the B3LYP/6-31G(d) (LANL2DZ for Au)
level. In all of the calculations, (S)-2-methylindoline and 2-
methylphenylacetylene were selected as the substrates to ex-
amine the origin of diastereoselectivity. The phosphine
ligand PH3, which had been used as a model of phosphine li-
gands in a number of computational studies of gold(I)-cata-
lyzed reactions,[19e,21,29] was used instead of (2-biphenyl)di-
tert-butylphosphine used in our experimental study. The first
step of this catalytic tandem process is the coordination of
cationic gold catalyst to the reactive functional group of the
substrates. In principle, [AuACHTUNGTRNEUNG
(PH3)]+ could coordinate to
either the nitrogen atom of a more basic secondary amine
[21–25]
À
or C C triple bond of alkyne.
Therefore, both gold(I)–
amine and gold(I)–alkyne complexes should be considered
as the potential catalytic species for gold(I)-catalyzed
tandem reactions of alkynes with more basic secondary
amines.
Since the metal complex could serve as precatalyst for the
formation of a protic acid to subsequently catalyze the addi-
tion of secondary amines to alkynes,[21a,32] the deprotonation
of gold(I)–amine complex A with assistance of counterion
À
BF4 for the formation of [(H3P)Au
N
The subsequent step is a [1,3]-proton-transfer process
from a nitrogen atom to a carbon atom to furnish the
gold(I)-enamine complex CA-2 (Figure 4 and Figure S8 in
the Supporting Information). The calculation shows that the
first considered. All attempts to locate the transition state
for the formation of complex A-1 were unsuccessful, thus
prohibiting the evaluation of the real reaction barrier for
À
the formation of [(H3P)Au
N
pathway of [1,3]-proton transfer, assisted by BF4 , is much
transformation of A-1 from A is significantly endothermic
by 44.8 kcalmolÀ1 (Scheme 4 and Figure S7, in the Support-
ing Information), revealing that the mechanism through the
lower in energy than that of the direct [1,3]-proton transfer
from the nitrogen atom to the carbon atom by 28.9 kcal
À
molÀ1. This might be attributed to BF4 ion acting as a
proton shuttle to lower the reaction barrier. This result
À
shows that BF4 ion plays a critical role in the [1,3]-proton-
transfer step, rendering the gold(I)-catalyzed hydroamina-
À
tion reaction more favorable. The Au C distance of 2.13 ꢁ
in complex CA-2 reveals that the phosphinegold(I) moiety
still coordinates to the C=C double bond of enamine inter-
mediate generated in situ (Figure S8 in the Supporting Infor-
mation). Electrospray ionization mass spectrometry analysis
of the reaction mixture also lends support to the formation
Scheme 4. Deprotonation process of gold(I)–amine complex A.
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Gold Catalysis
FULL PAPER
and computational findings in-
dicate that a reaction mecha-
nism via a dinuclear gold(I) in-
termediate is unlikely.
Next, we turned our atten-
tion to investigate the subse-
quent hydrogen-transfer pro-
cess using HEH as a reducing
agent. As stated in previous
section, no reaction between
enamine 5 and HEH (3) was
observed in the absence of
gold catalyst [Eq. (1)], reveal-
ing that the latter plays an im-
portant role in the hydride re-
duction step. Furthermore,
there are experimental and
computational evidences re-
vealing that the phosphine-
AHCTUNGTERGgNNUN old(I) moiety coordinates to
À
the C C double bond of an
enamine intermediate generat-
ed in situ after the intermolec-
ular hydroamination. This
leads to increase of electro-
philic character of enamines
and facilitates the subsequent
attack by hydride. Therefore,
calculations starting from in-
termediate G for the hydro-
gen-transfer process were per-
formed; the computed energy
profiles and optimized key
structures are depicted in
Figure 5 and Figure S11 of the
Supporting Information. The
transition state of G-TS-1 is
Figure 4. Calculated free energies for intermolecular hydroamination reaction of alkyne with secondary amine
by two different reaction pathways using DFT approach at the B3LYP/6-31G(d) (LANL2DZ for Au) level of
theory.
stabilized by
(HEH) bonding interaction
(in which the distances of C1···Ha and Ha···C(HEH) bonds
a
C1···Ha···
CACHTUNGTRENNUNG
of gold(I)-coordinated enamine intermediate (Figure 3),
which reacts with a hydride donor to generate tertiary
amines.
ACHTUNGTRENNUNG
are 1.38 and 1.42 ꢁ, respectively), and by a F···Hb bond
through BF4 and Hb (on the nitrogen atom of HEH; see
À
Since dinuclear gold(I) complex III can also act as a key
intermediate for gold(I)-catalyzed addition of a nucleophile
to a terminal alkyne (Scheme 2),[28,29] this complex should
also be considered as a potential intermediate in our catalyt-
ic reaction. However, the calculated energy profiles show
that the reaction mechanism involving dinuclear gold(I) in-
termediate is characterized by a high barrier (by 44.8 kcal
molÀ1, see the Supporting Information, Figure S9 and S10),
which is not consistent with the mild reaction conditions.
Additionally, internal aryl alkyne 2k was a suitable substrate
for this catalytic tandem reaction under the same reaction
conditions (Table 2, entry 11). Furthermore, the hydroami-
nation of internal aryl alkynes with dialkylamine in the pres-
ence of a gold(I) complex, recently reported by Stradiotto
and co-workers,[5b] also worked well. These experimental
the Supporting Information, Figure S11). This is in concord-
ance with the finding from the deuterium incorporation ex-
periment in that the hydride on the carbon atom of HEH is
completely transferred to C-1 atom of intermediate G-1
[Eq. (3)]. The calculated result shows that the hydrogen-
transfer process requires an activation energy of 27.1 kcal
molÀ1 and is slightly exergonic by 1.3 kcalmolÀ1. Finally, the
protodemetallation through proton transfer from HEH to
complex G-1 followed by transfer of gold(I) catalyst to an-
other alkyne completes this catalytic tandem cycle.
Based on the experimental findings, we found that the an-
cillary ligand on gold(I) has little effect on the diastereose-
lectivity of the corresponding product (Table 4). In contrast,
the a-substituent group of indolines plays a key role on the
diastereoselectivity (Table 5). To explain the origin of the
Chem. Eur. J. 2011, 17, 12932 – 12945
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12941

C.-M. Che et al.
bond of enamine intermediates
(Si face for CA-2 to give (S,S)-
product and Re face for CB-2
to give (S,R)-product, respec-
tively), avoiding steric interac-
tions. For path A, the calcula-
À
tions indicate that the C N
bond formation and BF4 -as-
À
sisted [1,3]-proton transfer re-
quire free activation energies
of 2.9 and 12.6 kcalmolÀ1, re-
spectively, in the gas phase. In
sharp contrast, for path B, all
efforts to locate the transition
state for the transformation of
CB to CB-1 were unsuccessful,
Figure 5. The calculated potential energy surface for transfer hydrogenation of enamine using Hantzsch ester
as hydride source via a monomeric, cationic phosphinegold(I) intermediate.
À
indicating that the C N bond
formation might be barrierless (route in black). Subsequent
diastereoselectivity of the reaction, two pathways were ex-
amined for this tandem reaction of 2-methylphenylacetylene
with (S)-2-methylindoline through monomeric cationic phos-
phinegold(I)–alkyne intermediate: path A (route in purple)
and path B (route in black) as shown in Scheme 5. In both
À
stereospecific BF4 -assisted [1,3]-proton transfer has a free
energy barrier of 13.4 kcalmolÀ1 in the gas phase. On the
other hand, the solvent effect on the reaction energetics for
the present two pathways was calculated by CPCMACHTUNGTRENNUNG(UAHF)
pathways, the gold(I) complex first catalyzes intermolecular
model using the gas-phase geometry obtained from the
B3LYP/6-31G(d) (LANL2DZ for Au atom) level with ben-
zene as the solvent. The calculation showed that the poten-
tial-energy surface in benzene is similar to that obtained in
the gas phase (see DG values in Scheme 5). As depicted in
Scheme 5, comparison of the potential-energy surfaces re-
veals that: 1) intermediate CB-1 is lower in energy than CA-1
(by 4.5 and 3.3 kcalmolÀ1 in the gas phase and benzene, re-
spectively); and the process is potentially barrierless for
À
À
C N bond formation followed by a stereospecific BF4 -as-
sisted [1,3]-proton transfer to give gold(I)-coordinated en-
amine intermediates CA-2 and CB-2 (Scheme 5 and Figure S8
in the Supporting Information). In these intermediates, the
Au complex coordinates to either the Re face (for CA-2,
route in purple) or the Si face (for CB-2, route in black) of
À
C C double bond of resultant enamine. Hydride transfer of
À
HEH only takes place from the other face of C C double
Scheme 5. The calculated two reaction paths (path A in purple and path B in black) for hydroamination reaction of 2-methylphenylacetylene with (S)-2-
methylindoline through a monomeric, cationic phosphinegold(I) catalyst. The free energies of activation (DGsolv in kcalmolÀ1) in benzene at the CPCM
(UAHF)-B3LYP/6-31G(d) (LANL2DZ for Au) level of theory are in the parentheses.
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Gold Catalysis
FULL PAPER
path B rather than the activation barrier of 2.9 and 2.5 kcal
molÀ1 in the gas phase and in benzene for path A, respec-
tively. 2) Although the BF4 -assisted [1,3]-proton transfer is
rate-limiting for formation of the gold(I)-coordinated enam-
ine intermediates CA-2 and CB-2, the reaction barriers for
both pathways are marginally different in energy (0.8 and
0.1 kcalmolÀ1 in the gas phase and benzene, respectively).
This result indicates that the origin of diastereoselectivity is
also support the proposed reaction pathway involving the
gold(I)-coordinated enamine complex as a key intermediate
for the subsequent transfer hydrogenation with a hydride
source.
À
Conclusion
À
closely related to the process for C N bond formation.
We have developed an efficient gold(I)-catalyzed tandem
hydroamination/transfer hydrogenation of alkynes with sec-
ondary amines to furnish tertiary amines in excellent yields
and with good to excellent diastereoselectivity. All of these
organic transformations can be conducted as a one-pot reac-
tion from simple and readily available starting materials,
without the need of isolation of air/moisture-sensitive ter-
À
Therefore, the formation of C N bond in path B is probably
responsible for a preference of (S, R)-product when (S)-2-
methylindoline is used as the substrate. It can also be seen
that the diastereoselectivity of the reaction is affected by
steric interaction between the a-substituent group of indo-
line and the phenyl group of alkyne, which is also consistent
with the experimental findings that the more sterically de-
manding substrates with the a-substituent group resulted in
AHCTUNGTREGtNNUN iary enamine intermediates, and under mild reaction condi-
tions (mostly room temperature and mild reducing agents).
The procedure is easy to perform and allows for a straight-
forward, diversity-oriented, and highly diastereoselective
synthesis of tertiary amines with a broad substrate scope,
thus rendering the method a valuable complementary ap-
proach to the conventional synthesis of tertiary amines. To
gain mechanistic insight into gold(I)-catalyzed tandem reac-
tion, a comprehensive experimental and computational in-
vestigation has been conducted. These studies reveal that a
the products with higher dia
Table 5).
ACHUTNGTRENNUGsterACHTUNGTNEReNUGN oselectivity (4Id–4Kd,
On the basis of the above NMR, ESI-MS, isotope label-
ing, and computational studies, we propose a mechanism for
this gold(I)-catalyzed tandem reaction, as depicted in
Scheme 6. Coordination of an alkyne to the cationic gold(I)
À
mechanism involves: 1) C N bond formation through nucle-
ophilic attack of the amine on a monomeric cationic
À
gold(I)–alkyne intermediate; 2) the cleavage of the Au C
bond by means of BF4 -assisted proton transfer from the
À
amine unit to C=C bond, with subsequent formation of a
gold(I)-coordinated enamine intermediate; and 3) transfer
hydrogenation of this gold(I)-coordinated enamine inter-
mediate with HEH to give tertiary amine. This mechanistic
study has important implications for the understanding of
other gold(I)-catalyzed tandem reactions involving the hy-
droamination step, and future designing of new tandem re-
actions catalyzed by gold(I) complexes.
Experimental Section
Typical procedure for the gold(I)-catalyzed tandem synthesis of tertiary
amines: Amine (0.5 mmol) and alkyne (0.6 mmol), followed by the addi-
tion of ethyl Hantzsch ester (0.75 mmol), were added to a mixture of
[{(tBu)2(o-biphenyl)P}AuCl] (0.01 mmol) and AgBF4 (0.01 mmol) in dry
solvent (2.0 mL) with stirring. The reaction mixture was capped and
stirred at RT–608C and monitored by TLC. Upon completion of the re-
action, the crude product was purified by flash chromatography on silica
gel (eluent: hexane/ethyl acetate=80:1).
Scheme 6. Proposed reaction pathway.
complex gives a cationic gold(I)–alkyne intermediate. Nu-
cleophilic attack takes place followed by BF4 -assisted [1,3]-
À
proton transfer to generate gold(I)-coordinated enamine in-
Procedure for the [{(tBu)2(o-biphenyl)P}AuCl]/AgBF4-catalyzed reaction
of N-methyl-N-(1-phenylvinyl)aniline (5) with ethyl Hantzsch ester: N-
Methyl-N-(1-phenylvinyl)aniline (5) (0.2 mmol) and ethyl Hantzsch ester
À
termediate. Subsequent BF4 -assisted transfer hydrogena-
tion with HEH, followed by the protodemetallation of inter-
mediate III’, affords tertiary amines and regenerates the
gold(I) catalyst. The findings from both experimental and
computational studies suggest that the first step of this
tandem reaction involving a monomeric cationic gold(I)–
alkyne intermediate is more likely to occur than a gold(I)–
amine intermediate, a three-coordinate gold(I) intermediate,
or a dinuclear gold(I)–alkyne intermediate. These studies
(0.3 mmol) were added to
a mixture of [{(tBu)2(o-biphenyl)P}AuCl]
(5 mol%) and AgBF4 (5 mol%) in dry THF (2.0 mL) with stirring. The
reaction mixture was capped and stirred at 408C for 24 h. The crude re-
action mixture was then purified by flash chromatography on silica gel
(eluent: hexane/ethyl acetate=80:1) to afford the final product 4Ea
(84% yield) as a clear oil.
Procedure for the isotope studies: Indoline (0.2 mmol) and phenylacety-
lene (0.24 mmol), followed by deuterated ethyl Hantzsch ester (6)
Chem. Eur. J. 2011, 17, 12932 – 12945
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12943

C.-M. Che et al.
(0.3 mmol), were added to a mixture of [{(tBu)2(o-biphenyl)P}AuCl]
(2 mol%) and AgBF4 (2 mol%) in dry benzene (2.0 mL) with stirring.
The reaction mixture was capped and stirred at 408C for 24 h. The crude
reaction mixture was then purified by flash chromatography on silica gel
(eluent: hexane/ethyl acetate=80:1) to afford the product 7 (85% yield)
as a clear oil, which was analyzed using 1H NMR spectroscopy to deter-
mine the content of the deuterium incorporation. 1H NMR (CDCl3,
TMS, 300 MHz): d=7.36 (m, 5H), 7.06 (m, 2H), 6.63 (t, J=7.3 Hz, 1H),
6.39 (d, J=7.8 Hz, 1H), 3.39 (m, 2H), 2.97 (t, J=8.5 Hz, 2H), 1.56 ppm
(s, 3H).
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We are thankful for the financial support of The University of Hong
Kong (University Development Fund), the Hong Kong Research Grants
Council (HKU 700708P and HKU 700810P), the Collaborative Research
Fund HKU1/CRF/08 and the University Grants Committee of the Hong
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Received: June 27, 2011
Published online: October 20, 2011
Chem. Eur. J. 2011, 17, 12932 – 12945
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12945