Palladium-catalyzed ring-closing reaction via C-N bond metathesis for rapid construction of saturated N-heterocycles

Article abstract of DOI:10.1021/jacs.0c10615

The ring-closing reactions based on chemical bond metathesis enable the efficient construction of a wide variety of cyclic systems which receive broad interest from medicinal and organic communities. However, the analogous reaction with C-N bond metathesis as a strategic fundamental step remains an unanswered challenge. Herein, we report the design of a new fundamental metallic C-N bond metathesis reaction that enables the palladium-catalyzed ring-closing reaction of aminodienes with aminals. The reactions proceed efficiently under mild conditions and exhibit broad substrate generality and functional group compatibility, leading to a wide variety of 5- to 16-membered N-heterocycles bearing diverse frameworks and functional groups.

Full text of DOI:10.1021/jacs.0c10615

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Palladium-Catalyzed Ring-Closing Reaction via C−N Bond
Metathesis for Rapid Construction of Saturated N‑Heterocycles
Bangkui Yu, Suchen Zou, Hongchi Liu, and Hanmin Huang*
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ABSTRACT: The ring-closing reactions based on chemical bond metathesis enable the efficient construction of a wide variety of
cyclic systems which receive broad interest from medicinal and organic communities. However, the analogous reaction with C−N
bond metathesis as a strategic fundamental step remains an unanswered challenge. Herein, we report the design of a new
fundamental metallic C−N bond metathesis reaction that enables the palladium-catalyzed ring-closing reaction of aminodienes with
aminals. The reactions proceed efficiently under mild conditions and exhibit broad substrate generality and functional group
compatibility, leading to a wide variety of 5- to 16-membered N-heterocycles bearing diverse frameworks and functional groups.
he discovery of novel metal complexes and their new
transformations plays a crucial role in the development of
the seminal work on the Pd-catalyzed amine exchange
reaction20 and the transition-metal-catalyzed σ-bond meta-
thesis21 prompted us to propose that the aminomethyl metal
complex might be utilized to realize the desired metallic C−N
bond metathesis with a secondary amine via reversible
reductive elimination, 1,3-hydrogen transfer, and oxidative
addition sequence (Scheme 1a). Given these considerations,
we speculated that the palladium-catalyzed C−N bond
T
transition-metal-catalyzed new reactions. In this context, the
discovery of metal-carbene and involving fundamental [2 + 2]
cycloaddition as well as [2 + 2] cycloreversion reaction has
established an alkene metathesis reaction, which has
revolutionized the CC bond formation paradigm and
proved remarkably powerful for constructing previously
inaccessible complex molecules for both industrial and
academic settings.1−3 Intramolecular application of alkene
metathesis, i.e. the ring-closing alkene metathesis (RCM)
reaction, has been widely employed for the construction of
various cyclic molecular architectures.4 Inspired by the power
of RCM, the ring-closing reactions via the metathesis of other
chemical bonds have also been developed and shown to be
promising in the preparation of complex molecules.5−8
Scheme 1. Catalytic Ring-Closing Reaction via C−N Bond
Metathesis
The recent clinical success achieved by increasing the
proportion of sp3 carbon atoms of potential drug candidates
has inspired considerable interest in the development of new
synthetic approaches to saturated N-heterocycles.9−14 To date,
modular and predictable synthetic methods for the preparation
of these compounds, especially medium-sized and large-sized
rings, are limited, and these in turn limit medicinal chemists’
ability to explore potentially fertile regions of chemical
space.15,16 We envisioned that a methodology leveraging C−
N bond metathesis for forming saturated N-heterocycles had a
broadly beneficial impact on the molecular sciences and drug
development. To our chagrin, catalytic reactions for the
synthesis of N-heterocycles with C−N bond metathesis as a
strategic fundamental reaction step remain largely elusive,
while CN bond metathesis17,18 and amidic C−N bond
metathesis19 have been reported for a long time.
Received: October 6, 2020
Carbon−nitrogen bond metathesis swaps the respective
nitrogen moiety in a manner analogous to alkene metathesis.
We envisaged that once the C−N bond metathesis occurred in
a C−N bond-containing metal-complex, such a process could
be viewed as an alternative elementary reaction to incorporate
a nitrogen nucleophile into the metal center. In this context,
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activation of aminals recently reported by our laboratory might
be an ideal platform for the development of such a C−N bond
metathesis reaction.22−26 The unique palladacycle-complex A
could be generated readily by the oxidative addition of aminal
to Pd(0). The X-ray diffraction analysis22 and DFT
calculations27 suggested that the Pd(0)-iminium cation
complex was one limiting resonance form of the pallada-
cycle-complex A. It indicates that the methylene of A is
electrophilic and prone to be attacked by a secondary amine to
furnish the desired C−N bond metathesis. Once an amino-
diene was utilized as the secondary amine, the diene-tethered
palladium-complex B would form via the C−N bond
metathesis, which could undergo further transformations to
afford functionalized N-heterocycles (Scheme 1b). Herein, we
disclose an applicable and highly efficient C−N bond
metathesis strategy, which enables a palladium-catalyzed ring-
closing reaction between aminodienes and aminals. The
reaction proceeds efficiently under mild conditions and
exhibits broad substrate generality and functional group
compatibility, leading to a wide variety of 5- to 16-membered
N-heterocycles bearing diverse frameworks and functional
groups.
Table 1. Substrate Scope for Six-Membered N-
Heterocycles
a
For a proof-of-concept for the proposed ring-closing C−N
bond metathesis reaction, we treated diene-tethered amine S1
(N-benzylhepta-4,6-dien-1-amine) with a stoichiometric
amount of Xantphos-ligated cyclopalladated complex A at 30
°C. To our delight, the reaction indeed took place and the
desired piperidine 3 was isolated in 44% yield. The C−N bond
of the aminomethyl group (−CH2NR2) contained in the
cyclopalladated complex A was cleaved, and the methylene was
incorporated into the backbone of the piperidine ring, implying
the involvement of C−N bond metathesis in the reaction.
a
Reaction conditions: S (0.36 mmol), 2 (0.30 mmol), [Pd(allyl)Cl]2
(2.5 mol %), Xantphos (6 mol %), AgOTf (5 mol %), CH2Cl2 (1.0
mL), 30 °C, 12 h. Isolated yield. 80 °C. 100 °C.
b
c
was less efficient for substrates bearing gem-disubstituents at
the tether backbones (28−31) due to the Thorpe−Ingold
effect. In contrast, the efficiency was improved when only one
substituent was present at the C2 position (32). The benzyl-
tethered aminodiene also underwent the desired cyclization to
afford the tetrahydroisoquinoline (33) with exocyclic allyl-
amine at the C4-position in 80% yield.
Motivated by the successful construction of the piperidine
products, we sought to extend the C−N bond metathesis
reaction to more synthetically challenging saturated N-
heterocycles with smaller or larger ring sizes (Table 2) by
changing the tether length. As expected, with a two-methylene
tether, the allylamine-containing pyrrolidine (34) was obtained
in 79% yield. Besides, a series of allylamine-containing
azepanes, oxazepanes, diazepanes, and their derivatives with
seven-membered rings (35−50) were obtained in 50−89%
yields by further prolonging the tether length of the
aminodienes. The substituent on the diene moiety could be
tolerated to give the corresponding product 45 with a
quaternary carbon chiral center. The electron-withdrawing
substituents, such as ester, nitrile, and hydroxyl, could be
attached in the amine-protection groups (42−44), and the
amide functionality (47) could be tolerated in the ring system
as well. Moreover, the pharmaceutically relevant heterocycles,
such as pyrrole, benzimidazole, and indole, could be
introduced into the tether backbone to afford the correspond-
ing products (48−50) in 60−86% yields. When a chiral tether
was employed, the corresponding saturated azepanes were
obtained with lower diastereoselectivities (39−40 and 46).
Further prolonging the tether length, a series of eight-
membered ring products (51−55) were produced in moderate
to good yields (55−86%). Similar to the formation of seven-
membered ring products, the incorporation of nitrogen or
oxygen into the backbone of the azocanes was possible, and the
unique spirocyclic azocanes (52) were also obtained in 58%
Based on the stoichiometric reaction described above,
optimization of the reaction conditions (see Supporting
Information (SI), Table S1) was achieved by conducting the
reaction at 30 °C in CH2Cl2 with [Pd(allyl)Cl]2/Xantphos/
AgOTf combination as the catalyst system. Furthermore,
typical Lewis acids and Brønsted acids were ineffective for this
reaction (see SI), which indicated that the aza-Prins reaction is
most likely not involved in the present protocol.28,29 With the
optimized reaction conditions in hand, we first targeted the
synthesis of the piperidine-containing allylamines, a class of
compounds bearing scaffolds of pharmaceutical interest.30
A
variety of hepta-4,6-dien-1-amines with several different large
substituents on the nitrogen atom reacted with aminal 2a
smoothly, leading to the corresponding products in 51−89%
yields (Table 1, 3−13). In addition, a series of aminals derived
from benzylamines were examined and the ring-closing
products were obtained in good yields (Table 1, 4 and 14−
22). Fluorine, chlorine, and bromine were all tolerated under
the reaction conditions. Besides, aminals prepared from the
simple aliphatic amines were also applicable in this reaction
system to give the corresponding products (23−27) in 32−
76% yields. We further explored the generality of the present
method by varying the substituents on the backbone of the
diene-tethered amines. It was found that the transformation
B
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a
a
Table 2. Substrate Scope of Linear Aminodienes
Table 3. Substrate Scope of Branched Aminodienes
a
Reaction conditions: S (0.36 mmol), 2 (0.30 mmol), [Pd(allyl)Cl]2
(2.5 mol %), Xantphos (6 mol %), AgOTf (5 mol %), CH2Cl2 (1.0
b
mL), 30 °C, 12 h. Isolated yield. 80 °C.
most reliable methods to date for the preparation of a wide
range of saturated N-heterocycles with allylic amine sub-
stitutions, which are attractive scaffolds for medicinal chemistry
and difficult to prepare by traditional synthetic methods.30−32
It is also worth pointing out that the deuterium-labeled
products (34D, 38D, and 54D), which are potentially valuable
for drug design,33 could be facilely obtained in good yields by
using D-labeled aminal 2a-d2 as the reactant.
The synthetic potential of this method can be demonstrated
in the synthesis of natural products (Scheme 2). With pyridine-
Scheme 2. Synthetic Applications
a
Reaction conditions: S (0.36 mmol), 2a (0.30 mmol), [Pd(allyl)Cl]2
(2.5 mol %), Xantphos (6 mol %), AgOTf (5 mol %), CH2Cl2 (1.0
b
c
d
mL), 30 °C, 12 h. Isolated yield. 80 °C. 100 °C. [Pd(allyl)Cl]2 (5
mol %), Xantphos (12 mol %), AgOTf (10 mol %), CH2Cl2 (20 mL),
100 °C, 36 h.
yields. To our delight, the challenging 9-, 12-, 14-, and even 16-
membered ring products (56−59) with multiple N-atoms were
also successfully produced in low-to-moderate yields. The
cyclization of estrone derived aminodiene bearing a steroid
scaffold led to two separable diastereoisomers (60) in good
yields.31 In addition, several substrates were demonstrated on a
1−10 g scale with lower catalyst loading to demonstrate the
practical laboratory-scale utility (41, 47, and 50).
Except for the linear aminodienes, the branched counter-
parts could also be smoothly converted to the desired products
(61−63) in good yields under standard conditions (Table 3).
The amine-tethered cyclohexa-1,3-dienes could also be
employed in the present protocol to afford a series of
spirocyclic N-heterocycles (64−69) in good yields at 80 °C
(Table 3). The results demonstrated here represent one of the
containing aminodiene as starting material, the separable syn-
70 and anti-70 were obtained on a gram scale (5.39 g) with
good yields under standard reaction conditions. From syn-70,
the alkaloids jussiaeiine A, kuraramine, and cytisine34 could be
synthesized by using conventional protocols. Moreover, the
isokuraramine could also be obtained by using anti-70 as a key
starting material through similar methods (see SI).
We propose a tentative mechanism for the reaction, which
begins with palladacycle-complex A (Scheme 3a). First, the
C
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Pd(II)-intermediate D through β-hydride elimination and Pd−
H reinsertion (see SI). The desired cyclization adduct 33
formed in 52% yield when the reaction was performed in the
presence of Et3N. Moreover, complex A was found to be
capable of catalyzing the desired ring-closing reaction with
almost no H/D-scrambling when S16-d2 was utilized as the
starting material (Scheme 3c). These results indicate the
plausible intermediacy of complex A and D before being
intercepted by aminal in the catalytic cycle.23 Kinetic analysis
of the catalytic reaction discloses that the formation of product
3 proceeds with the first-order dependence on aminodiene S1
concentration, aminal 2a concentration, and palladium-catalyst
concentration (see SI). These results are consistent with the
formation of complex A from intermediate D as rate-
determining in catalysis. To provide a support for the rate-
limiting formation of complex A, we conducted competition
experiments between aminal 2a and deuterated 2a-d2 (Scheme
3c). Based on carbon-hybridization change from sp3 to sp2 as
expected, we observed a normal secondary isotope effect (kH/
kD) of 1.37 0.07. Moreover, an inverse secondary kH/kD =
Scheme 3. Proposed Catalytic Cycle and Mechanistic
Studies
0.86
0.02 was observed in the competition experiments
between S16 and deuterated S16-d2 (Scheme 3c), indicating a
significant Csp2 to Csp3 rehybridization in the transition state
of the C−N formation process.35 These results suggested that
the formation and consumption of the transient intermediate E
was involved in the rate-determining step. The three-
component reaction with HCHO (Scheme 3d) and the
primary enantioselective reaction established by chiral Pd/
ligand complexes (Scheme 3e) further ruled out that the aza-
Prins mechanism was involved in this reaction (see SI).28,29
In summary, we describe a novel cyclization strategy via the
C−N bond metathesis of aminodienes as well as its successful
applications to a wide variety of substrates and ring sizes. We
anticipate that the palladium-catalyzed ring-closing reactions
demonstrated herein will enhance chemists’ access to a diverse
array of saturated and functionalized N-heterocycles. From a
broader perspective, we envision that this fundamental C−N
bond metathesis strategy will not only be a versatile platform
for medicinal chemists to explore the structure−activity
relationship but also inspire more research into leveraging
C−N bond metathesis for synthetic methodology develop-
ment.
palladium-complex A is generated in situ via the reaction of
aminal 2 with [Pd(allyl)Cl]2, AgOTf, and Xantphos (see SI),
which is then converted to the active diene-tethered palladium-
complex B through the putative C−N bond metathesis via
reversible reductive elimination, 1,3-hydrogen transfer, and
oxidative addition sequence. The intermediate B then
isomerizes to C, in which the internal alkene coordinates
with the Pd(II) center. Intramolecular alkene-migratory
insertion generates the π-allylpalladium species D, which is
then intercepted by an aminal 2 to form intermediate E via
reductive elimination to forge an allylic C−N bond. Finally, the
oxidative addition of intermediate E to Pd(0) delivers the
saturated N-heterocycles together with regenerating the active
palladium-complex A to complete the catalytic cycle.
Several experiments were conducted to gain insights into the
mechanism. Treatment of the palladium-complex A with a
stoichiometric amount of aminodiene S16 at 30 °C resulted in
the near-quantitative formation of Pd(II)-complex F (Scheme
3b). The complex F was fully characterized by NMR, X-ray
diffraction analysis, HRMS, and XPS. In situ 31P NMR and
HRMS studies indicated that complex F was generated from
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c10615.
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Experimental details and full spectroscopic data for all
new compounds (PDF)
Crystallographic data for complex F (CIF)
Crystallographic data for 3 (CIF)
Crystallographic data for 60 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
Hanmin Huang − Hefei National Laboratory for Physical
Sciences at the Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei 230026,
P. R. China; Center for Excellence in Molecular Synthesis of
CAS, Hefei 230026, P. R. China; orcid.org/0000-0002-
0108-6542; Email: hanmin@ustc.edu.cn
D
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Bangkui Yu − Hefei National Laboratory for Physical Sciences at
the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei 230026, P. R. China
Suchen Zou − Hefei National Laboratory for Physical Sciences
at the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei 230026, P. R. China
Hongchi Liu − Hefei National Laboratory for Physical Sciences
at the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei 230026, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c10615
Notes
(20) Murahashi, S.-I.; Hirano, T.; Yano, T. Palladium Catalyzed
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The authors declare no competing financial interest.
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The authors are grateful for financial support by the National
Natural Science Foundation of China (21672199, 21925111,
21790333, and 21702197).
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contain the supplementary crystallographic data for this paper. This
data can be obtained free of charge from The Cambridge
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