Achieving Aliphatic Amine Addition to Arylalkynes via the Lewis Acid Assisted Triazole-Gold (TA-Au) Catalyst System

Article abstract of DOI:10.1021/acs.orglett.1c02098

Transition metal catalyzed intermolecular hydroamination of the arylalkynes with aliphatic amine is generally problematic due to the good coordination between amine and metal cation. With the combination of 1,2,3-triazole coordinated gold(I) catalyst (TA-Au) and Zn(OTf)2 cocatalyst, this challenging transformation was achieved with good to excellent yields and regioselectivity. Compared to previously reported methods, this approach offered an alternative catalyst system to achieve this fundamental chemical transformation with high efficiency and practical conditions.

Full text of DOI:10.1021/acs.orglett.1c02098

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Letter
Achieving Aliphatic Amine Addition to Arylalkynes via the Lewis
Acid Assisted Triazole-Gold (TA-Au) Catalyst System
Teng Jia, Shengyu Fan, Fengmian Li, Xiaohan Ye, Wenke Zhang, Zhiguang Song,* and Xiaodong Shi*
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ABSTRACT: Transition metal catalyzed intermolecular hydro-
amination of the arylalkynes with aliphatic amine is generally
problematic due to the good coordination between amine and
metal cation. With the combination of 1,2,3-triazole coordinated
gold(I) catalyst (TA-Au) and Zn(OTf)2 cocatalyst, this challenging
transformation was achieved with good to excellent yields and
regioselectivity. Compared to previously reported methods, this
approach offered an alternative catalyst system to achieve this
fundamental chemical transformation with high efficiency and
practical conditions.
Scheme 1. TA-Au Catalyzed Hydroamination of Alkynes
ydroamination of alkene and alkyne is one of the critical
transformations in chemical synthesis since it offers the
H
atom economic approach through direct C−N bond con-
struction.1 Compared with the alkene, alkyne activation is more
challenging due to the high reaction kinetic barrier, especially for
nonactivated (by EWG or EDG) internal alkynes.2 With the
combined efforts from researchers worldwide, various catalytic
systems have been developed to achieve effective alkyne
activation under mild conditions.3 The choice of amine is also
one important concern, which has been often overlooked.
Compared to commonly used stabilized amine (such as aniline
and amide), aliphatic amines are more basic with a better
coordination ability toward metal cations. Therefore, aliphatic
amines are usually problematic substrates in hydroamination
reactions as the N-metal coordination significantly reduces both
amine nucleophilicity and metal catalyst π-activation capability.4
As a result, alkyne hydroamination with aliphatic amine is one
extremely challenging task, and new methods to achieve this
transformation under mild conditions are highly desirable.
Over the past two decades, homogeneous gold catalysis has
been considered one of the most effective strategies for alkyne
activation due to its superior π-acid reactivity.5 Both Au(I) and
Au(III) catalytic systems have been applied for alkyne
hydroamination.6 However, while reactions with stabilized
amine work well, most reported systems gave a poor
performance with the aliphatic amine. This is mainly due to
the amine coordination, which quenched gold catalyst reactivity
(Scheme 1A). A high reaction temperature is generally
demanded, facilitating the needed alkyne activation by releasing
gold cation from dynamic Au−N binding. However, gold cation
decomposition at an elevated temperature significantly reduced
the overall efficiency of the transformation with a low gold
catalyst turnover number (TON). To overcome the stability and
reactivity dilemma, some special ligands have been developed
and applied in this challenging aliphatic amine addition to the
alkyne. Two representative recent examples are the cyclic-
(alkyl)(amino)carbene (CAAC) ligand7 and P,N-ligand Mor-
DalPhos ligand.8 In both cases, a special bulky counterion such
−
as B(C6F5)4 was required to achieve satisfying results by
minimizing potential base-mediated elimination. The require-
Received: June 22, 2021
Published: July 19, 2021
https://doi.org/10.1021/acs.orglett.1c02098
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6019−6023
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ment of special primary ligand and counteranion not only
reduced the practicality of these gold catalytic systems but also
highlighted the challenges associated with this transformation.
To overcome gold cation stability issue, our group developed
the 1,2,3-triazole gold complexes (TA-Au) as effective catalyst
with enhanced stability, especially at elevated temperatures.9
The general idea of TA-Au catalysis was to have 1,2,3-triazole
serving as the dynamic L-ligand (DLL), forming stable [L-Au-
(DLL)]+ precatalyst as the off-cycle resting state. Our initial
assumption was that triazole could dissociate from [L-Au-
(DLL)]+, giving the active [L-Au]+ catalysts to react with alkyne
substrates. On the basis of this assumption, several new
transformations with the TA-Au system have been discovered.
However, the different reactivity of TA-Au catalyst (even with
the same primary ligand) raised our concern on whether this
simple TA-releasing hypothesis was accurate as different
reactivity was observed between TA-Au and [L-Au]+.10 Through
detailed mechanistic investigation using react IR and in-suit
NMR, we successfully confirmed the dissociation mechanism
with alkyne direct addition to TA-Au, forming alkyne-TA-Au π-
complex without going through the formation of [L-Au]+.11 This
study not only explains the significantly improved gold catalyst
stability observed with TA-Au but also offers new mechanistic
insight into achieve new reactivity with TA-Au over the [L-Au]+
even bearing same primary ligand. Taking advantage of TA-Au
catalytic system, we reported the alkyne hydroamination with
stabilized amine (aniline) at a high temperature. However, the
reaction did work well with aliphatic amines using only TA-Au,
giving poor yields (<20%).9 Herein, we report a combination of
TA-Au and Zn(OTf)2 as a practical system for aliphatic amine
addition to both internal and terminal alkynes, giving
corresponding hydroamination products in good to excellent
yields (up to 95%) with a large scope of amine choices (>50
examples).
Our interest in tackling this challenging problem was initiated
by the counteranion effect associated with [(CAAC)-Au]+
system for the aliphatic amine addition to the alkyne, where
B(C6F5)4− produced the optimal result while other anions gave
significantly worse results. Although it makes sense that the
electron-rich CAAC ligand helps keep [L-Au]+ stable from
decomposition, it is not apparent that why noncoordinated
anion B(C6F5)4− is also critical for improved performance. After
carefully considering the plausible reaction pathway, we
postulated that Lewis base-assisted gold reduction might cause
trouble in gold catalyzed reaction involving aliphatic amines. As
shown in Scheme 1A, aliphatic amine could easily coordinate
with [L-Au]+, forming [L-Au-NHR2]+ as the dominated gold
species in the reaction mixture. Therefore, a high temperature is
required to break this coordination (releasing [L-Au]+ catalyst).
Aliphatic amine usually contains α-proton, which might cause
gold reduction (decomposition) through a potential elimination
pathway, especially in the presence of coordination anions as
base at a high temperature. Therefore, the key to facilitating
effective aliphatic amine hydroamination is to avoid the
formation of this gold-amine complexes.
Figure 1. Prevent gold decomposition with TA-Au.
even at room temperature, suggesting the good binding ability of
aliphatic amine toward gold cations even over 1,2,3-triazole.
After screening various amine-scavengers,12 Zn(OTf)2 was
identified as the optimal choice, recovering the formation of TA-
Au in almost 80% with the addition of 1eq of Zn2+ salt. This
result suggested that the addition of Zn(OTf)2 will help to break
the equilibrium between TA-Au and [L-Au-amine]+, avoiding
the formation of the undesired [L-Au-amine]+ intermediates. As
the result, the combination of TA-Au and Zn(OTf)2 could be
the potential solution for the challenging alkyne hydroamination
with the aliphatic amine (see SI for details). To testify to this
hypothesis, reactions between internal alkyne 1a and amine 2a
were performed under various gold-catalyzed conditions. The
results are summarized in Figure 1B. First, simple [L-Au]+ gave
almost no conversion due to a rapid gold decomposition at high
temperatures. In addition, only a trace amount of hydro-
amination product 3a was observed while using TA-Au alone,
indicating the stabilization effect of triazole at a high
temperature. Notably, the low yield with TA-Au suggested
that [L-Au-amine]+ is the dominant gold-complexes in the
catalytic cycle, which is subjected to decomposition. Finally, the
combination of TA-Au (5 mol %) and Zn(OTf)2 (10 mol %)
gave the desired product 3 in 20% yield. This result was
promising and proved the feasibility of Lewis Acid as an amine-
scavenger to promote the TA-Au alkyne activation. Further
condition optimization was performed. Therefore, 5 mol %
JohnsPhosAu(TA-Me)OTf, 10 mol % Zn(OTf)2 in toluene (1
M) at 110 °C was identified as the optimal conditions, giving 3a
in 95% yield. Reaction results with some representative
alternative conditions are summarized in Table 1.
Similar to other literature reported hydroamination of internal
alkynes, cis-addition was observed as the only product due to the
enamine equilibrium to the formation of more stable isomers
under this condition.7,8 The primary ligands were crucial for
good reaction performance. In general, electron-deficient
phosphine ligands, such as PPh3 and (ArO)3P, gave poor results
due to the quick catalyst decomposition, even with triazole as a
stabilization factor (entries 2 and 3). Electron-rich phosphine
ligands, such as XPhos, can promote this reaction due to a more
stabilized gold cation (entry 4). JohnsPhosAuNTf2 was tested as
an alternative silver-free catalyst. As expected, a lower yield was
observed (30%, entry 5). Screening of Lewis acids (Ga2+, Yb3+,
In3+, Cu2+ etc.) revealed Zn(OTf)2 as the optimal choice. A
On the basis of this analysis and previously reported TA-Au
catalytic reaction mechanism, one solution to prevent the
intrinsic aliphatic amine reduction pathway is to develop a
practical system adopting TA-Au as the resting state instead of
the [L-Au-amine]+. With this proposed solution in mind, we first
monitored the DLL ligand exchange between TA-Au and
morpholine 2a using 31P NMR. As shown in Figure 1A, mixing
2a with TA-Au Cat-1 gives the formation of [L-Au-2a]+ instantly
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a b
,
a b
,
Table 1. Reaction Conditions Screening
Scheme 2. Reaction Scope for Alkyne and Aliphatic Amine
entry
reaction conditions vary from standard
none
yield of 3
1
2
3
4
5
6
7
8
95%
6%
n.r.
PPh3Au(TA-Me)OTf
(ArO)3PAu(TA-Me)OTf
XPhosAu(TA-Me)OTf
JohnPhosAuNTf2, no Zn(OTf)2
JohnPhosAuNTf2 instead
JohnPhosAuCl instead
no Zn(OTf)2
Cu(OTf)2 as Lewis acid
Ga(OTf)3, Yb(OTf)3, or In(OTf)3 as Lewis acid
Zn(NTf2)2 instead of Zn(OTf)2
Zn(OAc)2 instead of Zn(OTf)2
dioxane as solvent
85%
30%
60%
40%
39%
60%
40−42%
70%
45%
85%
85%
87%
n.r
9
10
11
12
13
14
15
16
0.5 M
at 100 °C
no gold
a
General reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2 (0.4 mmol,
2.0 equiv), [Au] catal. (0.01 mmol, 5 mol %), Lewis acid (0.02 mmol,
b
10 mol %) in dry solvent (0.2 mL) under Ar at 110 °C. Yield was
determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal
standard.
similar LA-assisted effect was also observed with Cu(OTf)2 as
cocatalyst, though less effective than Zn(OTf)2 (entry 9). Other
commonly used Lewis acids, such as Ga2+, Yb3+, and In3+, could
not increase the yield of desired hydroamination product 3a
(entry 10) compared to the reaction without Lewis acid (entry
8). This result suggested that these Lewis acids were not valid
amine-scavengers. With JohnPhosAuNTf2 in the presence of
Zn(OTf)2, the desired product was obtained in 60% yield (entry
6). The yield was increased compared to the one without
Zn(OTf)2 (entry 5). Although significant gold decomposition
was observed (by formation of gold mirror), this experiment
offered an additional evidence for our hypothesis on the role of
Zn(OTf)2 to assist morpholine releasing as the key influence.
The coordination counterions, NTf2 and OAc, led to decreased
yields (entries 11 and 12), which further supported our
hypothesis on the Lewis base induced gold decomposition
pathway. Dioxane was also suitable solvent with a slightly
decreased yield (entry 13). This reaction required a relatively
harsh condition (high temperature at 110 °C and concentration
1 M) to reach the complete conversion, in which the most gold
catalyst suffered from decomposition. No gold decomposition
(by forming the gold mirror) was observed using our TAAu/LA
system, highlighting the advantage of enhancing thermal
stability while remaining high catalyst efficiency (entries 14
and 15). A control experiment showed that early transition metal
Zn(OTf)2 alone could not catalyze the reaction, ruling out the
possible Zn catalyzed alkyne activation pathway13 (entry 16).
With the optimal condition in hand, the reaction scope was
explored.14 The results are summarized in Scheme 2. We first
evaluated the scope of alkynes. For diaryl alkyne (4a−4c), the
reaction works well for both electro-deficient and electron-rich
aromatic rings. Alkynes with electron-rich aromatic ring afforded
desired hydroamination product with good to excellent yields.
In comparison, electron-deficient aromatic alkynes gave
a
Conditions: For internal alkyne: 1 (0.2 mmol, 1.0 equiv), [Au] cat.
(5.0 mol %), Zn(OTf)2 (10.0 mol %), and 2 (0.4 mmol, 2.0 eq) were
added into dry toluene (1 M) under Ar. The reaction mixture was
stirred at 110 °C for 12 h. For terminal alkyne: 1 (0.2 mmol, 1.0
equiv), [Au] cat. (5.0 mol %), Zn(OTf)2 (10.0 mol %), and 2 (0.3
mmol, 1.5 equiv) were added into dry toluene (0.05 M) under Ar.
b
The reaction mixture was stirred at 110 °C for 6 h. Isolated yield.
c
Ratio of 4 and 5 was determined by crude 1H NMR spectra of
d
reaction mixture. 80 °C.
moderate yields (i.e., 6k). Unsymmetric alkynes (4e−4g)
were also evaluated, affording good to excellent regioselectivity.
Interestingly, the regioselectivity could be improved by
employing the electron-rich aromatic rings, leading to 4g as
the only product. This result is consistent with previously
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reported examples using Mor-DalPhos-Au. Besides internal
alkynes, the scope of terminal alkynes (4i−4r) was also explored.
Similarly, both electron-deficient and electron-rich aromatic
alkynes worked well, giving the desired products in good to
excellent yields. Aromatic rings with electron-donation groups
gave high yields due to the better coordination capability.
Notably, electron-rich heterocyclic thiophene alkyne (4r) was
suitable substrate for this transformation, though with modest
yields. No reaction was observed with 1-Hexyne or 3-Hexyne,
indicating a higher activation barrier for aliphatic alkynes.
Various aliphatic amines were applied to this transformation.
To our great satisfaction, many of these substrates are suitable
for this transformation. Both 1-phenylpiperazine (6a, 6f−6k)
and 1-pyridylpiperaziene (6l−6s) were applied to react with
either internal or terminal alkynes, giving the desired products in
good to excellent yields. Interestingly, the 2-pyridine group on
nitrogen (6v, 6w) was tolerated under this condition, suggesting
good coordination capability of triazole over pyridine and
highlighting the good reactivity of TA-Au. Though under strong
Lewis-acid conditions, the N-Boc carbamate (6b) was
compatible, giving the desired product in excellent yield. This
result highlighted the relative mild condition of gold catalyzed
hydroamination, allowing further N-modification through
simple Boc-deprotection and NH coupling. Both acyclic
secondary amines (6c, 6e, 6z−6ah) and benzyl amine (6d)
worked well in this transformation, giving the desired products
in good yields in general.
Xiaodong Shi − Department of Chemistry, University of South
Florida, Tampa, Florida 33620, United States; orcid.org/
0000-0002-3189-1315; Email: xmshi@usf.edu
Authors
Teng Jia − State key Laboratory of Supramolecular Structure
and Materials, College of Chemistry, Jilin University,
Changchun, Jilin 130012, China
Shengyu Fan − State key Laboratory of Supramolecular
Structure and Materials, College of Chemistry, Jilin University,
Changchun, Jilin 130012, China
Fengmian Li − State key Laboratory of Supramolecular
Structure and Materials, College of Chemistry, Jilin University,
Changchun, Jilin 130012, China
Xiaohan Ye − Department of Chemistry, University of South
Florida, Tampa, Florida 33620, United States
Wenke Zhang − State key Laboratory of Supramolecular
Structure and Materials, College of Chemistry, Jilin University,
Changchun, Jilin 130012, China; orcid.org/0000-0002-
4569-6035
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02098
Notes
The authors declare no competing financial interest.
Primary aliphatic amine, 1-butylamine, did not give any
conversion, likely due to a stronger coordination toward gold
cation. Nevertheless, this result revealed a new facile route to
achieve 2-benzyl amine derivatives with high efficiency.
ACKNOWLEDGMENTS
■
We are grateful to the NSF (CHE-1665122), the NIH
(1R01GM120240-01), and Jilin Province (20170307024YY,
20190201080JC) for financial support.
In summary, we disclosed a new protocol to achieve aliphatic
amine addition to terminal and internal arylalkynes using the
combination of TA-Au and Zn(OTf)2. The amine binding with
gold cation was the main challenge for the observed poor
performance of aliphatic amine hydroamination. The key
discovery here is the application of Zn(OTf)2 as amine-
scavengers to release TA-Au and reactivate the reaction path
for the formation of gold-alkyne π-complexes. TA was crucial to
enhance the stability of gold catalyst, especially at elevated
temperatures. The process was proved by NMR study, and
challenging aliphatic amine hydroamination was achieved with
broad substrate scope and good overall yields. This new catalytic
system not only revealed an effective and practical strategy to
construction synthetic challenge aliphatic amine derivatives but
also suggested the great advantage of triazole as dynamic-L-
Ligand in tuning metal center reactivity. The appreciation of
TA-Au and Lewis acid catalytic systems in other challenging
transformations is expected and under investigation.
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Experiment procedures, conditions optimization, charac-
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AUTHOR INFORMATION
Corresponding Authors
■
Zhiguang Song − State key Laboratory of Supramolecular
Structure and Materials, College of Chemistry, Jilin University,
Changchun, Jilin 130012, China; Email: szg@jlu.edu.cn
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separation using silica column chromatography. Therefore, the
reduction was performed.
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