Palladium-Catalyzed Ring-Forming Aminoalkenylation of Alkenes with Aldehydes Initiated by Intramolecular Aminopalladation

Article abstract of DOI:10.1002/anie.201611853

A palladium-catalyzed aminopalladation reaction followed by nucleophilic addition with aldehydes and dehydration is described. This direct and operationally simple procedure provides a rapid and reliable approach to a wide range of functionalized tetrahydroisoquinolines with high selectivity. Mechanistic studies disclosed that the nucleophilic addition, performed via a highly ordered transition-state, is the turnover-limiting step in which the inherent β-hydride elimination of the key Csp³?Pd species was controlled by the confined conformation and the nucleophilicity of the Csp³?Pd bond was enhanced by the strong electron-donating effect of the nitrogen atom.

Full text of DOI:10.1002/anie.201611853

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611853
German Edition: DOI: 10.1002/ange.201611853
Cyclization Reactions
Palladium-Catalyzed Ring-Forming Aminoalkenylation of Alkenes
with Aldehydes Initiated by Intramolecular Aminopalladation
Yue Hu, Yinjun Xie, Zhiqiang Shen, and Hanmin Huang*
Abstract: A palladium-catalyzed aminopalladation reaction
followed by nucleophilic addition with aldehydes and dehy-
dration is described. This direct and operationally simple
procedure provides a rapid and reliable approach to a wide
range of functionalized tetrahydroisoquinolines with high
selectivity. Mechanistic studies disclosed that the nucleophilic
addition, performed via a highly ordered transition-state, is the
turnover-limiting step in which the inherent b-hydride elimi-
3
À
nation of the key Csp Pd species was controlled by the
3
À
confined conformation and the nucleophilicity of the Csp Pd
bond was enhanced by the strong electron-donating effect of
the nitrogen atom.
T
ransition-metal-catalyzed nucleophilic addition of organo-
metallics to carbon–heteroatom multiple bonds is widely used
in synthetic organic chemistry.[1] Crucial to the scenario was
the formation of active transition-metal–carbon species
through transmetalation with stoichiometric amounts of
organometallics, which often produced a large amount of
wasteful byproducts. To avoid the use of stoichiometric
Scheme 1. Palladium-catalyzed nucleophilic addition initiated by ami-
nopalladation.
hydride elimination of the resulting alkylpalladium species,
and tuning the electronic nature of the amine moiety. Such
a reaction would be particularly valuable for the synthesis of
tetrahydroisoquinolines, which represent a ubiquitous motif
widely found in many natural alkaloids and biologically active
compounds.[4]
amounts of organometallics, Lu and co-workers developed
an elegant strategy for the generation of active Csp Pd
2
À
species through acetoxypalladation, aminopalladation, or
hydropalladation of alkynes, which established a series of
Pd-catalyzed tandem reactions without wasteful byproducts
generation.[2] Despite tremendous efforts over the last decade,
such reactions only can be performed with alkynes as coupling
partners (Scheme 1). The same type of tandem reactions
using alkenes as coupling partners has remained largely
unexplored, and the underlying reason for this deficiency may
stem from the rapidly occurring b-hydride elimination of the
alkylpalladium species resulting from the corresponding
nucleopalladation of alkenes.[3] Herein, we report a unified
approach for realizing this kind of tandem reaction with an
alkene as the coupling partner by controlling the inherent b-
Aminopalladation of alkenes is a fundamental process for
generation of alkylpalladium intermediates, which commonly
undergo b-hydride elimination to produce oxidative amina-
tion products.[5] On the other hand, such intermediates could
be further converted into valuable functionalized products by
controlling the inherent b-hydride elimination. Previous work
pioneered by Sanford and co-workers has demonstrated that
oxidizing the alkylpalladium(II) species to a high-valent
alkyl-PdIV complex is an efficient strategy for direct con-
3
À
À
version of the Csp Pd bond into diverse C X bonds by
suppressing the b-hydride elimination.[6,7] However, such
interception is not compatible with non-redox addition
reactions, and stoichiometric amounts of strong oxidants
were also needed, leading to the generation of wasteful
byproducts. In principle, b-hydride elimination occurs most
readily from metal–alkyl complexes that can adopt a syn-
coplanar arrangement of the metal and the hydride groups.[8]
On the basis of this concept, we reasoned that the inter-
mediate A, accessed from the reversible intramolecular
aminopalladation of 2-vinylbenzylamine 1, could slow the b-
[*] Y. Hu, Dr. Y. Xie, Z. Shen, Prof. Dr. H. Huang
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences
Lanzhou 730000 (P. R. China)
E-mail: hanmin@ustc.edu.cn
Prof. Dr. H. Huang
Department of Chemistry
University of Science and Technology of China
Hefei, 230026 (P. R. China)
hydride elimination due to the unfavorable conformation.
3
À
Because the nucleophilicity of the Csp Pd species is stronger
Y. Hu
2
3
À
À
than that of Csp Pd species and the polarity of the Csp Pd
bond in intermediate A would be increased by the electron-
donating effect of the nitrogen atom located at the b-
position,[2] it would be expected that the intermediate A
University of Chinese Academy of Sciences
Beijing 100049 (P. R. China)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201611853.
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might be intercepted by a electrophile through irreversible
nucleophilic addition to drive the equilibrium toward the
product. One potential problem facing the development of
this tandem reaction is the competition between b-nitrogen
elimination and the proposed nucleophilic addition with
aldehydes. We believed that these rates could be controlled by
tuning the electronic nature of the nitrogen and the ligand
environment in the palladium complex. Given the formidable
challenge of controlling the b-hydride elimination of alkyl-
palladium species, this investigation should be of great
interest for the development of palladium-catalyzed alkene
difunctionalization reactions.
To test the viability of the envisioned strategy, we started
the investigation by exploring the reaction of N-benzyl-1-(2-
vinylphenyl)methanamine (1a) with benzaldehyde (2a) in the
presence of palladium catalyst. To our delight, the trisubsti-
tuted alkene 3aa with a tetrahydroisoquinoline skeleton was
obtained in 47% yield when the reaction was conducted at
1108C in 2-PrOH with PdCl2/Xantphos as catalyst. The solid
structure of 3aa was unambiguously determined by single-
crystal X-ray diffraction analysis.[9] The product of 3aa could
be viewed as the dehydration product of the corresponding
alcohol derived from nucleophilic addition, which indicated
that the tandem aminopalladation and nucleophilic addition
indeed took place. Inspired by this result, we started to
optimize the reaction condition by screening the catalyst
system (Supporting Information) and observed that [Pd-
(allyl)Cl]2/Xantphos turned out to be far superior, providing
3aa in 72% yield (Table 1, entries 4). In contrast, no reaction
occurred when Pd2(dba)3/Xantphos was utilized as catalyst,
which indicated that this reaction was most likely initiated
with PdII. Moreover, other typical Lewis acids, such as
Zn(OTf)2, AlCl3, and Fe(OTs)3, were ineffective for promot-
ing this reaction (Supporting Information), suggesting that
the reaction is most likely not Lewis-acid-catalyzed. Apart
from 2-PrOH, the reaction could also be conducted in other
protic solvents such as CH3OH, C2H5OH, and n-PrOH
(Table 1, entries 7–9). Other non-protic solvents like
CH3CN were also suitable for this reaction, but only moderate
yields were obtained (Table 1, entry 10). Among the solvents
tested, C2H5OH was found to be the most effective. Further
examination showed that when the ratio of 1a:2a was
changed from 1:1 to 1:1.5, the yield of 3aa was raised to
86% (Table 1, entry 8 and entries 11–12). Subsequently, the
effect of temperature was also investigated. When the
temperature raised to 1208C, the yield of 3aa was increased
to 86% while the ratio of 1a:2a was kept in 1:1.2 (Table 1,
entry 13). However, when the temperature decreased to
1008C, the yield of 3aa sharply dropped to 56% (Table 1,
entry 14). Finally, control experiments showed that the
desired product 3aa was not formed in the absence of
palladium catalyst (Supporting Information). It is worth
mentioning that the reaction is highly selective to give the
Z-isomer as the only product and no b-hydride elimination
product was observed.
With the optimized conditions in hand, we next examined
the scope of aldehydes for this reaction. A series of aromatic
aldehydes with electron-donating or -withdrawing groups
gave the desired products 3aa–3ai in good yields (Table 2).
The steric hindrance of the substituents on the aryl ring of the
aldehydes exerted a strong influence on the reactivity (3aa vs.
3ab). Several valuable functional groups, such as methyl (3ab
and 3ac), fluoro (3ad and 3ag), chloro (3ae and 3ah), and
trifluoromethyl (3ai) groups, were tolerated at different
positions of product 3, providing ample opportunity for
Table 2: Substrate scope of aldehydes.[a]
Table 1: Screening of reaction conditions.[a]
Entry
[Pd]
Ligand
Solvent
T [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
PdCl2
Pd(OAc)2
Pd2dba3
Xantphos
Xantphos
Xantphos
Xantphos
DPEphos
BINAP
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
CH3OH
C2H5OH
n-PrOH
CH3CN
C2H5OH
C2H5OH
C2H5OH
C2H5OH
110
110
110
110
110
110
110
110
110
110
110
110
120
100
47
trace
NR
72
41
29
79
81
80
48
82
86
86
56
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
9
10
11[c]
12[d]
13[c]
14[c]
[a] Reaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), [Pd(allyl)Cl]2
(0.0125 mmol), Xantphos (0.0275 mmol), C2H5OH (2 mL), 1208C for
12 h, unless otherwise noted, isolated yields are shown. Bn=benzyl.
[b] 15 h.
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), [Pd] (5 mol%),
ligand (5.5 mol%), solvent (2 mL), 12 h, unless otherwise noted.
[b] Isolated yield. Bn=benzyl. [c] 2a (0.6 mmol). [d] 2a (0.75 mmol).
2
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further elaboration of the products. Aside from the benzal-
standard conditions, affording 3ka in 86% yield (Table 3,
dehydes, naphthyl-derived aldehyde 2l was also compatible
with this process to afford the desired product 3al in 61%
yield. Furthermore, heterocyclic aldehydes such as isonicoti-
naldehyde and nicotinaldehyde were also suitable for this
reaction to provide the desired products 3aj and 3ak in 64%
and 63% yields, respectively. In addition, aliphatic aldehydes
were also applicable, but showed much lower reactivities, only
moderate yields were obtained (3am and 3an), which may
arise from their inherently lower electrophilicity.
Next, the scope and generality of substituted 2-vinyl-
benzylamines were also explored under the optimized
reaction conditions. First, as expected, the substituent on
the nitrogen atom of 1a significantly impacted the reactivity.
It was found that the electron-donating alkyl groups could
promote the reaction (Table 3, entries 1–3). In contrast, no
entry 11). In addition, a substrate with a methyl group at the
a-position of the amine could be easily converted into the
desired product 3la in 70% yield (Table 3, entry 12). The
structure of products 3ka and 3la were confirmed by X-ray
single-crystal diffraction analysis.[9]
To illustrate the mechanism of the present palladium-
catalyzed tandem reaction, d2-1a was first synthesized and
subjected to the standard reaction conditions to evaluate
whether or not the b-hydride elimination occurred in the
present reaction. The result demonstrated that the content of
deuterium in the desired product d2-3aa was almost the same
as that in substrate d2-1a [Scheme 2, Eq. (1)]. Furthermore,
Table 3: Substrate scope of 2-vinylbenzylamines.[a]
Scheme 2. Preliminary mechanistic studies.
Entry
R1
R2
R3
R4
Yield [%][b]
1
H
H
H
H
H
H
5-Me
4-Me
5-F
5-Cl
H
Bn
n-Pr
c-C6H11
H
Ac
Ts
Bn
Bn
Bn
Bn
H
H
H
H
H
H
H
H
H
H
Ph
H
H
H
H
H
H
H
H
H
H
H
H
CH3
3aa, 86
3ba, 81
3ca, 69
3da, NR
3ea, NR
3 fa, NR
3ga, 70
3ha, 78
3ia, 73
3ja, 75
3ka, 86
3la, 70
2[c]
3[d]
4
treatment of 1a with stoichiometric amounts of palladium
complex under the standard reaction conditions, resulted in
complete recovery of 1a, and no oxidative amination
products derived from b-hydride elimination were observed
[Scheme 2, Eq. (2)]. The above results support the supposi-
tion that b-hydride elimination indeed did not take place in
the present reaction system, and suggest that the amino-
palladation is reversible. To gain further mechanistic insights,
we examined the kinetics for the reactions of 1a and 2a.
Initial rates for the reactions were then measured by varying
the concentrations of 1a and 2a as well as the palladium
catalyst. These experiments revealed a first-order depend-
ence of the rate on the concentrations of both 2-vinylbenzyl-
amine 1a and aldehyde 2a. Moreover, a first-order depend-
ence of the rate on catalyst concentration was also observed
(Supporting Information). These results indicated that the
two substrates, 1a and 2a, and the catalyst were involved in
the turnover-limiting step. Because the aminopalladation is
reversible, we believe that the nucleophilic addition is most
likely to be a turnover-limiting step.[10]
5
6
7
8
9
10[e]
11[f]
12[c]
Bn
Bn
H
[a] Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), [Pd(allyl)Cl]2
(0.0125 mmol), Xantphos (0.0275 mmol), C2H5OH (2 mL), 1208C for
12 h, unless otherwise noted. [b] Isolated yields. Bn=benzyl. [c] 24 h.
[d] 1408C for 48 h. [e] 18 h. [f] 1408C for 24 h.
reaction occurred when an electron-withdrawing group such
as tosyl and acetyl was installed onto the nitrogen atom
(Table 3, entries 5–6). This is in sharp contrast with the many
reported aminopalladation reactions in which substrates with
electron-withdrawing groups on the nitrogen atom showed
higher reactivity.[5–7] We attribute this difference in reactivity
to the electron-donating group at the nitrogen atom, which
could increase the electron-donating effect of the nitrogen to
enhance the nucleophilicity of the resulting alkylpalladium
species. Substrates without substituent on the nitrogen atom
were also tried, and the corresponding imine resulting from
the aldehyde was obtained and no desired product was
detected (Table 3, entry 4). Next, the substituents on the
benzene ring were investigated and found that substrates with
electron-donating or electron-withdrawing groups gave the
corresponding adducts in good yields (Table 3, entries 7–10).
Interestingly, the internal alkene 1k proved amenable to the
On the basis of the kinetic analysis and control experi-
ments, a plausible reaction mechanism for this process is
proposed (Figure 1).
À
Initially, the coordination of the C C double bond to the
PdII center followed by aminopalladation produces the
alkylpalladium species I, which is reversible, to convert into
the reactant 1 via b-nitrogen elimination. The strong electron-
donating effect of the nitrogen atom makes the transient
alkylpalladium species nucleophilic enough to be trapped by
an aldehyde through the highly ordered transition state II,
leading to the intermediate III to drive the equilibrium
toward the product. Protonolysis of intermediate III gives rise
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Figure 1. Plausible reaction mechanism.
to intermediate IV with regeneration of the palladium
catalyst. Dehydration of intermediate IV takes place at high
temperature to release the final product 3 together with one
equivalent of H2O as the sole byproduct.
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hydride elimination and enhancing the nucleophilicity of
3
À
alkylpalladium (Csp Pd) species generated in the amino-
palladation of alkenes was established and enabled the
development of a new palladium-catalyzed tandem reaction
À
=
of aminoalkenes with aldehydes. One C N and one C C
bond are formed in this transformation, providing facile
access to a wide range of biologically active functionalized
tetrahydroisoquinolines. Mechanistic studies demonstrated
À
À
that the effective C N and C C bond formation possibly
results from the confined conformation and strong electron-
donating effect of the nitrogen atom of the alkylpalladium
species. Further detailed mechanistic studies and applications
based on this chemistry are currently in progress.
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Sanford, J. Am. Chem. Soc. 2004, 126, 9542; b) A. R. Dick, K. L.
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Acknowledgements
This research was supported by the CAS Interdisciplinary
Innovation Team, and the National Natural Science Founda-
tion of China (21672199 and 21372231).
[7] For leading reviews on Pd-catalyzed difunctionalization of
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Conflict of interest
The authors declare no conflict of interest.
Keywords: aminopalladation · b-hydride elimination ·
nucleophilic addition · palladium · tandem reactions
[1] For reviews, see: a) S. Kobayashi, H. Ishitani, Chem. Rev. 1999,
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4
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137, 2480; m) C. Chen, P. Chen, G. Liu, J. Am. Chem. Soc. 2015,
137, 15648.
[8] J. F. Hartwig, Organotransition Metal Chemistry: From Bonding
to Catalysis, University Science Books, Sausalito California,
2010, p. 398.
[10] The Eyring plot generated from these data was obtained and the
activation parameters of DH° = 47.7 kJmolÀ1 and DS° =
À99.96 JmolÀ1 KÀ1 for the present reaction were also obtained
(see the Supporting Information).
[9] CCDC 1518059 (3aa), 1518060 (3ka), and 1518918 (3la) contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
Manuscript received: December 6, 2016
Revised: December 28, 2016
Final Article published: && &&, &&&&
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Communications
Cyclization Reactions
Controlling b-hydride elimination: An
palladium-catalyzed tandem reaction of
aminoalkenes with aldehydes provides
a simple and reliable approach for the
synthesis of biologically active tetrahy-
droisoquinolines. The turnover-limiting
step is shown to be nucleophilic addition
via a highly ordered transition state.
Y. Hu, Y. Xie, Z. Shen,
H. Huang*
&&& — &&&
Palladium-Catalyzed Ring-Forming
Aminoalkenylation of Alkenes with
Aldehydes Initiated by Intramolecular
Aminopalladation
6
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