Palladium-Catalyzed Hydrocarbonylative Cyclization Enabled by Formal Insertion of Aromatic Ca? N Bonds into Pd-Acyl Bonds

Article abstract of DOI:10.1021/acs.orglett.9b03503

An efficient new formal insertion strategy via combination of reductive elimination and oxidative addition sequence was reported, in which the transient N-acyliminium ions formed via hydrocarbonylation function as key intermediates. This strategy has enabled a novel palladium-catalyzed hydrocarbonylative cyclization of azaarene-tethered alkenes or dienes via sequential insertion of a Ca? C bond, CO, and a Ca? N bond into palladium-hydride bonds. This method provides a new and highly efficient synthetic approach to quinolizinones and its derivatives with extended ?-conjugated systems, possessing tunable emission wavelengths and good photoluminescence capabilities.

Full text of DOI:10.1021/acs.orglett.9b03503

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Hydrocarbonylative Cyclization Enabled by
Formal Insertion of Aromatic CN Bonds into Pd−Acyl Bonds
Xibing Zhou,† Anrong Chen,† Wei Du,‡ Yawen Wang,‡ Yu Peng,‡ and Hanmin Huang*,†,‡
†Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, Center for Excellence in
Molecular Synthesis, University of Science and Technology of China, Chinese Academy of Sciences, Hefei, 230026, People’s
Republic of China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, People’s Republic of China
S
* Supporting Information
ABSTRACT: An efficient new formal insertion strategy via combination of
reductive elimination and oxidative addition sequence was reported, in
which the transient N-acyliminium ions formed via hydrocarbonylation
function as key intermediates. This strategy has enabled a novel palladium-
catalyzed hydrocarbonylative cyclization of azaarene-tethered alkenes or
dienes via sequential insertion of a CC bond, CO, and a CN bond into
palladium−hydride bonds. This method provides a new and highly efficient synthetic approach to quinolizinones and its
derivatives with extended π-conjugated systems, possessing tunable emission wavelengths and good photoluminescence
capabilities.
Scheme 1. Hydrocarbonylative Cyclization via Sequential
CC, CO, and CN Bond Insertion
ransition-metal-catalyzed carbonylation reactions are
Twidely utilized, not only for the industrial production of
fine and bulk chemicals, but also for the preparation of natural
products and bioactive compounds.1 Among them, the
palladium-catalyzed hydrocarbonylation of alkenes or alkynes
constitutes one of the most atom-economical and efficient
processes, considering the easy availability of alkenes and
alkynes, as well as the synthetic versatility of carbonyl-
containing products.2 The synthetic significance of this
transformation is further enhanced when it is applicable to
the construction of N-heterocycles, which are important and
privileged structures in bioactive compounds.3 Mechanistically,
acylpalladium complexes are recognized as key intermediates
in these reactions. Therefore, understanding the reactivity of
acylpalladium complexes and development of new strategies
for intercepting them are crucial for new reaction discovery.4
One of the general strategies to intercept the acylpalladium
species is by using nucleophiles, whereby the corresponding
carboxylic acids and their derivatives can be produced (Scheme
1A-1).1,2 As an alternative strategy, the insertion of unsaturated
2π-units into the Pd-acyl bond has also long been pursued and
strenuously developed.5 However, the scope of the unsaturated
2π-units that can undergo such a insertion sequence have been
primarily restricted to nonpolar carbon−carbon multiple
bonds (Scheme 1A-2). There are very few examples of those
that bring about the insertion of carbon−nitrogen double
bonds (CN) into the M−acyl bond, although it would be
potentially utilized for construction of amide bonds (Scheme
1A-3).6 Moreover, to the best of our knowledge, catalytic
hydrocarbonylation reactions proceeded via sequential in-
sertion of CC, CO, and aromatic CN bonds into
palladium−hydride bonds remain largely elusive.6c The
underlying reason might be attributed to the tendency for
electrophilic metals to form σ-complexes with the N atom of
CN bonds, instead of π-complexes, because of the Lewis
basicity of the nitrogen, which makes the CN insertion
unfavorable.7
Stimulated by the pharmaceutical importance of carbonyl-
containing N-heterocycles and the pivotal role of amide-bond
Received: October 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03503
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Letter
a
formation in synthetic organic chemistry, we have been
fascinated by the transition-metal-catalyzed hydrocarbonyla-
tion reaction with CN bonds of azaarenes as 2π-units to
intercept the active acylpalladium species. However, since the
aromatic CN bonds were confined in the azaarene rings, the
insertion of the CN bond into the M−acyl bond is more
challenging, exacerbated by the inherent aromaticity. Previous
work in this area has recourse to the developing efficient
strategies for dearomatization of azaarenes to convert the
dative M−N bonds into the corresponding covalent M−N
bonds prior to the reductive elimination step. However, these
systems suffer from the significant disadvantage that they
require special substrates that could undergo proton shift for
dearomatization,8 which limits the substrate scope and could
not be applied in the hydrocarbonylative reactions. To address
these challenges, the identification of an efficient strategy for
insertion or formal insertion of the aromatic CN bond into
the M−acyl bond is in high demand. Being aware that
pyridine-derived N-acyliminium ions could be facilely formed
through the reductive elimination of CN bond-coordinated
σ-complexes and are capable of undergoing oxidative addition
with low-valent metal to form the corresponding metal−
carbon complexes,9 we reasoned that the formal insertion of
the CN bond into the M−acyl bonds could be furnished via
the sequential reductive elimination and oxidative addition of
the CN bond-coordinated σ-complexes. Herein, we report
that a highly efficient palladium-catalyzed hydrocarbonylative
cyclization of azaarene-tethered alkenes or dienes through
sequential insertion of CC, CO, and aromatic CN bond
into the palladium−hydride bond, which leads to the
development of a new and efficient reaction for construction
of quinolizinones that comprise the core of numerous bioactive
agents and fluorophores (Scheme 1B).10 Kinetic isotope effect
experiments and control experiments suggested that the
palladium-complex C is indeed involved in the present
reaction, which underwent a unique long-distance reductive
elimination to recycle the catalyst and deliver the desired
products. To the best of our knowledge, this is the first direct
observation of the formal insertion of aromatic CN bonds
into palladium−acyl bonds. The interest in this chemistry lies
in not only the establishing new carbonylative cyclization
reactions, but also the potentially new route to C−N bond
formation.
To test this hypothesis, initial studies were focused on the
reaction of 2-(2-vinylphenyl)pyridine 1a with CO in the
presence of Pd catalyst (see Table 1). After extensive
examination of different reaction parameters, the mixture
containing Pd(t-Bu3P)2 (1 mol %) as the catalyst and
MeONH2·HCl (1 mol %) as an additive in toluene at 120
°C under 30 atm of CO facilitated the desired reaction, and the
product 2a was obtained in 97% isolated yield (Table 1, entry
1). As expected, controlling experiments clearly demonstrated
the crucial roles of the catalyst and acid for maintaining the
reaction efficiency (Table 1, entries 2 and 3). Various
palladium catalyst systems that consisted of different
phosphine ligands employing PdBr2(cod) as a palladium
precursor were screened, but all resulted in lower efficiency
except t-Bu3P (Table 1, entries 4−7). We also attempted to
investigate the impact of acid on the reactivity of the process,
while no satisfactory result was obtained by using other
Brønsted acids (Table 1, entries 8−10). Regarding the solvent
effect, toluene was the most effective for this transformation
(Table 1, entries 11−13). The efficiency of the reaction
Table 1. Optimization of Reaction Conditions
b
entry
variations from “standard conditions”
none
without MeONH2·HCl
yield (%)
1
2
97
0
0
61
25
83
33
trace
85
trace
76
83
91
65
92
3
without Pd(t-Bu3P)2
4
5
6
7
8
9
PdBr2(cod) (5 mol %)/Davephos (11 mol %)
PdBr2(cod) (5 mol %)/PCy3 (11 mol %)
PdBr2(cod) (5 mol %)/t-Bu3P (11 mol %)
PdBr2(cod) (5 mol %)/Xantphos (6 mol %)
replace MeONH2·HCl with NH4Cl
replace MeONH2·HCl with NMP·HCl
replace MeONH2·HCl with PhSO3H
replace toluene with MeCN
replace toluene with DMSO
replace toluene with DME
CO (20 atm)
PdClH(t-Bu3P)2, without MeONH2·HCl
Pd(t-Bu3P)2 (0.1 mol %)
10
11
12
13
14
15
c
16
77 (1.61 g)
a
Standard conditions: 1a (0.3 mmol), CO (30 atm), Pd(t-Bu3P)2 (1
mol %), MeONH2·HCl (1 mol %), toluene (2.0 mL), 120 °C, 12 h.
b
c
Isolated yield. 24 h.
decreased under 20 atm of CO atmosphere (Table 1, entry
14). Almost the same efficiency was observed when PdClH(t-
Bu3P)2 was utilized as a catalyst in the absence of acid, which
confirmed that the reaction was initiated by the Pd−H species
(Table 1, entry 15). In addition, the method is synthetically
useful, with a good efficiency maintained when running the
reaction on a large scale in the presence of 0.1 mol % of Pd(t-
Bu3P)2 (Table 1, entry 16).
With the optimal reaction conditions identified, the
investigation into the substrate scope for the present
carbonylative cyclization reaction was pursued. As shown in
Table 2, for 2-(2-vinylphenyl)pyridines, a series of functional
groups contained in the pyridine core were compatible with
the present catalytic system, and the desired products were
isolated in good to excellent yields (73%−97% yields, 2a−2l).
The reaction seems to be less efficient for the substrates
bearing electron-withdrawing groups on the pyridine ring,
which might be due to the decreased nucleophilicity incurred
by the electron-withdrawing substituents. On the other hand,
the electron-donating and electron-withdrawing groups con-
tained in the phenyl ring were tolerated well (2m−2p).
Notably, product 2m with an intact alkene on the phenyl-ring
indicated the good tolerance of these reaction conditions and
provided the opportunity for further elaborations. Interest-
ingly, nonterminal alkenes with pendent functional groups,
such as nitrile, were also feasible substrates, affording the
desired products 2q and 2r in good yields. When pyridine core
was replaced with pyrimidine (1s), pyrazine (1t), quinoline
(1u), isoquinoline (1v), and 7,8-benzoquinoline (1w), the
carbonylation reaction still proceeded well to give the
corresponding products 2s−2w in moderate to excellent yields
(52%−98% yields). To our delight, benzoxazole (1x) and
benzothiazole (1y) tethered alkenes were also found to be
suitable for the present reaction to give the (2x and 2y) in
good to excellent yields. The structure of 2c and 2f were
confirmed by X-ray diffraction (XRD) analysis.
B
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a
a
Table 2. Substrate Scope of Azaarene-Tethered Alkene
Table 3. Substrate Scope of Azaarene-Diene
a
Reaction conditions: 3 (0.3 mmol), CO (20 atm), PdBr2(cod) (5
mol %), t-Bu3P (11 mol %), MeONH2·HCl (5 mol %), toluene (2
b
mL), 120 °C, 12 h, isolated yield. MeONH2·HCl (0.03 mmol), CO
(40 atm), 120 °C, 24 h.
fluorophores have good photoluminescence capabilities with
ΦF values ranging from 0.002 to 0.79. The relatively large
Stokes shifts were also obtained (see the Supporting
Information). This salient feature of these compounds
indicated that they should find broad applications in material
chemistry.11
This transformation is amenable to late-stage carbonylative
functionalization of intermediates in the synthesis of complex
molecules for biological evaluation. One example is Fenofi-
brate, which is a drug for lipid-lowering therapy.12 Introducing
a pyridine and alkene moieties into the backbone of
Fenofibrate delivers 1z. Treatment of 1z with CO under the
standard reaction conditions gives the product 2y in 74%
isolated yield. Moreover, the obtained cycloadducts are useful
synthetic intermediates. For example, the Pd/C-catalyzed
reduction of 2a with H2 in EtOH formed piperidine 5a in
92% yield as a 20:1 mixture of trans and cis isomers. In
addition, compound 6a was obtained in 81% yield at 120 °C in
MeOH, under otherwise identical conditions (see Scheme 2).
To gain insight into the mechanism, we conducted
competition experiments between 2-(2-vinylphenyl)pyridine
and deuterated analogue 2-(2-vinylphenyl)pyridine (see
Scheme 3) with various substrates containing substituents in
a
Reaction conditions: 1 (0.3 mmol), Pd(t-Bu3P)2(1 mol %),
MeONH2·HCl (1 mol %), CO (30 atm), toluene (2 mL), 120 °C,
12 h, isolated yield. bPd(t-Bu3P)2 (2 mol %), MeONH2·HCl (2
mol %).
Inspired by the above results, we extended the present
reaction to azaarene-tethered dienes. With PdBr2(cod)/t-Bu3P
as a catalyst precursor, a series of pyridine dienes bearing
electron-withdrawing or electron-donating substituents on the
pyridine ring were compatible, giving the expected products
4a−4i in good to excellent yields (see Table 3). Furthermore,
the presence of an alkyl group on the double bond of the diene
provides the corresponding adducts in 53%−94% yields (4j−
4m), while 2-(3-methylbuta-1,3-dien-1-yl)pyridine could not
be converted to the desired product. Under the slightly
modified reaction conditions, 2-(buta-1,3-dien-1-yl)pyrazine
3n and 1-(buta-1,3-dien-1-yl)isoquinoline 3o could also be
converted to the corresponding adducts in moderate yields. It
is noteworthy both the E-isomer and the Z-isomer could be
efficiently converted to the desired cycloadducts.
Scheme 2. Synthetic Applications
Compounds listed in Tables 2 and 3 exhibit interesting
photophysical properties. The different emission bands from
480 nm to 624 nm were observed by tuning the substituent
group and extension of the π-conjugated systems. (See the
Supporting Information.) Accordingly, the fluorescence colors
including blue, green, yellow, orange, and red covers almost the
full color wavelengths of the visible spectrum. These
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Scheme 3. Kinetic Isotope Effect Experiments
Scheme 4. Proposed Catalytic Cycle
the para-position of pyridine. On the insertion of pyridyl C
N bond into the Pd-acyl bond, the α-carbon adjacent to N
atom undergoes a formal rehybridization from sp2 to sp3,
which, in principle, should lead to the observation of an inverse
secondary isotope effect (kH/kD < 1) if this formal insertion is
turnover-limiting.13 Furthermore, the magnitude of kH/kD
should vary in concert with the position of the transition
state: later transition states, in which α-carbon adjacent to N
atom has more sp3 character, should exhibit smaller values of
kH/kD. In this context, the substrates with electron-donating
substituents on the pyridine ring possessing lower oxidation
ability should hold later transition states, since the correspond-
ing oxidative addition of N-acyliminium ions B to Pd(0) is
more difficult.14 The observed secondary isotope effects (kH/
kD < 1) are indicative of significant Csp2 to Csp3
rehybridization in the transition state for the cyclization
process. These results also support in a compelling and
quantitative manner that the palladium-complex C is most
likely formed in the catalytic system. Furthermore, the
experimental data reveal a direct correlation between kH/kD
and σp (see Figure 1), indicating that the electronic character
bond insertion to give the key intermediate C, which
underwent long-distance reductive elimination promoted by
the base to give the desired product and Pd(0). The Pd(0)
reacted with MeONH2·HCl to form the active Pd−H species
for the next catalytic cycle.
In conclusion, we have developed a first catalytic protocol
for formal insertion of aromatic CN bonds into Pd-acyl
bonds, which enabled an highly efficient palladium-catalyzed
hydrocarbonylative cyclization of azaarene-tethered alkenes or
dienes. The reaction is compatible with a diverse range of
alkenes and azaarenes and allows the efficient synthesis of
quinolizinone and its derivatives with lower catalyst loading.
Preliminary mechanistic studies suggested that the catalytic
reaction proceeds via sequential insertion of the CC bond,
CO, and the CN bond into the palladium−hydride bond.
Furthermore, this transformation leads to the formation of a
family of fluorophores. More mechanistic investigation and
further applications of this chemistry are underway.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03503.
Experimental details and full spectroscopic data for all
new compounds (PDF)
Accession Codes
CCDC 1905727 and 1905732 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Figure 1. Correlation of the kinetic isotope effect in the hydro-
carbonylative cyclization of 2-(2-vinylphenyl)pyridine versus 2-(2-
vinylphenyl)pyridine-6-d, as a function of the σp values of substituent
X in substrates.
of the pyridine moiety does indeed alter the rate of oxidative
addition of N-acyliminium ions to Pd(0). On the other hand,
the independent measurement of the reaction rate of 2a and
deuterated analogue 8 (reaction rate was estimated by
determining the reaction yields over time via 1H NMR)
revealed only a small difference in rate (kH/kD = 1.17). This
value suggests that C−H cleavage is not turnover-limiting.
On the basis of the above experimental data, a plausible
reaction mechanism was proposed (see Scheme 4). The
reaction was initiated by the formation of the Pd−H species
and followed by sequential CC bond, CO, and formal CN
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hanmin@ustc.edu.cn.
ORCID
Yu Peng: 0000-0002-3862-632X
Hanmin Huang: 0000-0002-0108-6542
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research was supported by the National Natural Science
Foundation of China (Nos. 21790333, 21702197, and
21672199).
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