Palladium-catalyzed dearomative cyclocarbonylation of allyl alcohol for the synthesis of quinolizinones

Article abstract of DOI:10.1039/d0ob02529a

An approach for the synthesis of quinolizinone with potential bioactivity has been developedviapalladium-catalytic dearomative cyclocarbonylation of allyl alcohol. Diverse quinolizinone compounds could be attained with good efficiencies. A feasible reaction pathway could be a successive procedure of allylation, dearomatization, CO insertion and the Heck reaction.

Full text of DOI:10.1039/d0ob02529a

Organic &
Biomolecular Chemistry
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Palladium-catalyzed dearomative
cyclocarbonylation of allyl alcohol for the
synthesis of quinolizinones†
Cite this: Org. Biomol. Chem., 2021,
19, 1274
Received 18th December 2020,
Accepted 10th January 2021
Pengcheng Xu,a,b Bo Qian, *a Zaojuan Qi,a Bao Gao,c Bin Hu *a and
a,c
DOI: 10.1039/d0ob02529a
Hanmin Huang
*
rsc.li/obc
An approach for the synthesis of quinolizinone with potential environmentally benign route for quinolizinone formation are
bioactivity has been developed via palladium-catalytic dearomative highly desired. With this point of view, we sought to employ
cyclocarbonylation of allyl alcohol. Diverse quinolizinone com- allyl alcohol in place of allyl amine to provide quinolizinone
pounds could be attained with good efficiencies. A feasible reac- compounds through palladium-catalyzed dearomative cyclo-
tion pathway could be a successive procedure of allylation, dearo- carbonylation. Although the mechanism of this transformation
matization, CO insertion and the Heck reaction.
is similar to that of the palladium-catalyzed dearomative cyclo-
carbonylation of allyl amine, the advantages of having water as
a cleaner by-product, atom efficiency, and easily obtainable
allyl alcohol are well presented in this protocol (Scheme 1c).
Palladium-catalyzed carbonylation reactions of allyl alcohol
as a classic methodology have been applied in the formation
Introduction
Quinolizinones are significant nitrogen-containing hetero-
cyclic derivatives with curative activity for various diseases,
such as cancer, HIV, Alzheimer’s, spinal muscular atrophy, etc.
(Scheme 1a).1 Traditional preparation methods of quinolizi-
nones usually require multi-step procedures, restraining their
widespread application.2 Recently, palladium-catalyzed
carbonylation reactions have largely improved the situation for
the synthesis of quinolizinones, particularly by using carbon
monoxide as a carbonyl source through a one-step reaction.3,4
Among these achievements, our group first established the
dearomative cyclocarbonylation of allyl amines through palla-
dium-catalyzed C–N bond activation, in which we described a
catalytic mechanism involving sequential allyl palladium for-
mation, dearomatization, CO insertion and the Heck reaction
(Scheme 1b).3b Nevertheless, working with allyl amine is
special, leading to increases in synthetic difficulty.
Additionally, stoichiometric amounts of the secondary amine
by-product as pollution were generated along with the C–N
bond cleavage. Therefore, both an accessible substrate and an
aState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, P. R. China.
E-mail: boqian@licp.cas.cn, hcom@licp.cas.cn, hanmin@ustc.edu.cn
bUniversity of Chinese Academy of Sciences, Beijing 100049, P. R. China
cHefei 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, P. R. China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0ob02529a
Scheme 1 Pd-Catalyzed dearomative cyclocarbonylation.
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of unsaturated/saturated acids, unsaturated esters, cyclized lac- 120 °C for 12 hours in toluene, giving quinolizinone 2a in only
tones and linear amides.5 Despite having such improvements, a 20% yield (entry 1). Other palladium-catalysts such as PdBr2,
the carbonylation of allyl alcohol is still challenging mainly PdCl2, [Pd(allyl)Cl]2, Pd(OAc)2 and Pd(TFA)2 with Xantphos
owing to the poor leaving capability of the hydroxyl group.6,7 obviously improved the efficiencies of transformation (entries
In order to address this challenge, acid or water was used to 2–6). Gratifyingly, PdCl2 in particular possessed the highest
accelerate the leaving rate of the hydroxyl group.5k,o,7 activity to provide 88% of product 2a (entry 3). Thus, different
Alternatively, inspired by our reported works with respect to phosphine ligands were screened when using PdCl2 as the
palladium-catalyzed carbonylation and allyl alcohol conversion catalyst for the further optimization. Monodentate ligands
reactions,8 a solution with additive-free conditions was demon- (PPh3, PCy3, and P(C6F5)3) presented poor results, affording
strated in this research. We utilized a catalytic amount of the desired product in 16–25% yields (entries 7–9).
hydrogen chloride in situ derived from the reduction of palla- Additionally, bidentate ligands such as DPPE (1,2-bis(diphenyl-
dium(II) to palladium(0), efficiently enhancing the leaving phosphino)ethane),
DPPB
(1,4-bis(diphenylphosphino)
ability of the hydroxyl group. To the best of our knowledge, butane), DPPF (1,1′-bis(diphenylphosphino)ferrocene), and
this is an unprecedented example of the palladium-catalyzed DPEPhos (bis(2-diphenylphosphinophenl)ether) were not ben-
dearomative cyclocarbonylation reaction of allyl alcohol to eficial for the dearomative cyclocarbonylation of allyl alcohol
afford the cyclic amide compound quinolizinone without any (entries 10–13, 16–41% yields). Therefore, the larger bite angle
external additives.
ligand Xantphos is indeed capable of increasing the reactivity
of this carbonylation process. After determining the catalyst
system of palladium with ligand, other solvents (i-PrOH, THF
and CH3CN) were investigated. However, lower conversions
were attained in these solvents as compared with toluene
(entries 14–16). Next, the decrease of reaction temperature
indicated that 80 °C could also give a comparative reactivity
(entries 17–19). With the optimal temperature, we attempted
to reduce the CO pressure, surprisingly delivering 85% yield of
quinolizinone 2a under 1 atm of CO as well as 10 atm of CO
(entries 20 & 21).
Results and discussion
Our research started with the carbonylation of allyl alcohol 1a
as the model reaction (Table 1). Initially, PdI2 as the catalyst
precursor and Xantphos with a large bite angle as the ligand
were applied in the treatment of 1a with 20 atm of CO at
Table 1 Optimization of the reaction conditionsa
Finally, a control experiment was carried out at 80 °C with 1
atm of CO, suggesting that the palladium-catalyst system is
vital for the transformation (entry 22).
Furthermore, the substrate scope of allyl alcohol derivatives
was surveyed under the optimal reaction conditions as dis-
played in Table 2. The carbonylation product 2a was readily
isolated in 86% yield under the standard reaction conditions.
Electron-donating groups on the pyridine-ring at the meta- or
para-position could be compatible with the carbonylation reac-
tion, smoothly affording 2b–2e in good to excellent yields.
When methyl and hydroxymethyl substituents were at the
ortho-position of the pyridyl group, disappointing efficiencies
of the desired products 2f and 2g were observed due to the
steric hindrance effect albeit under higher CO pressure and
temperature. Except for the electron-donating substituents,
electron-withdrawing groups in pyridine were also tolerated in
this reaction. Allyl alcohols bearing fluoro-, chloro-, and tri-
fluoromethyl groups in the pyridine-ring were smoothly trans-
formed to the corresponding products 2h–2l in 63–85% yields.
By elevating the pressure and temperature, pyrazinyl substi-
tuted allyl alcohol successfully gave quinolizinone 2m. In
addition, the dearomative cyclocarbonylation was easily con-
ducted with the functional groups on the chain of the allyl
alcohol rather than the pyridyl group. When alkyl and phenyl
substituents were fixed on the unsaturated bond, 66–90%
yields of the target products (2n–2o) were obtained. Although
we tried to modify the reaction conditions, poor conversion of
product 2r was attained because of the generation of 3-methyl-
indolizine and a mixture. Remarkably, the gram-scale reaction
Entry
Catalyst
Ligand
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
Pdl2
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
PPh3
PCy3
P(C6F5)3
DPPE
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
i-PrOH
20
70
88
75
PdBr2
PdCl2
[Pd(allyl)Cl]2
Pd(OAc)2
Pd(TFA)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
/
54
51
25c
16c
23c
33
9
10
11
12
13
14
15
16
17
18
19
20
21
22
DPPB
DPPF
16
20
41
58
62
55
DPEPhos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
/
THF
CH3CN
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
87d
86e
62f
85e,g
85e,h
0
a Reaction conditions: 1a (0.5 mmol), catalyst (5 mol%), ligand
(6 mol%), solvent (2 mL), CO (20 atm), 120 °C, 12 h. b Yields were
determined by GC analysis using n-hexadecane as an internal stan-
dard. c Ligand (12 mol%). d 100 °C. e 80 °C. f 60 °C. g CO (10 atm). h CO
(1 atm).
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Table 2 Substrate scope of allyl alcohola
Scheme 3 A proposed reaction pathway.
dium(II) under the conditions of CO atmosphere with trace
amounts of water, simultaneously releasing HCl to activate the
hydroxyl group.8,9 The activated allyl alcohol conveniently
reacts with palladium(0), delivering allyl palladium(II) species I
and water. A proton shift procedure accompanies the for-
mation of the N–Pd bond, providing intermediate II. Next, CO
coordinates with palladium and inserts into the N–Pd bond
due to the less sterically hindered planar structure of the
pyridyl N–Pd bond, producing the acyl palladium-complex III
which then transforms to species IV via a CvC bond insertion
into the CO–Pd bond. Finally, β-elimination of the intermedi-
ate IV leads to the generation of the quinolizinone 2a and the
palladium-hydride species V. Finally, the regeneration of palla-
dium(0) which stems from palladium(II) reduction completes
the catalytic cycle.
a Reaction conditions: 1 (0.5 mmol), CO (1 atm), PdCl2 (5 mol%),
Xantphos (6 mol%), toluene (2 mL), 80 °C, 12 h, isolated yields. b CO
(20 atm), 120 °C. c Pd(Xantphos)(CH3CN)2OTf2 (5 mol%), CO (20 atm),
120 °C.
Conclusions
successfully worked under only 0.1 mol% of palladium-cataly-
sis, affording quinolizinone 2a in 59% yield after 60 hours
(Scheme 2).
Based on the carbonylation of allyl alcohol studies and our
previous works,3–9 a possible reaction pathway of this approach
is proposed (Scheme 3). The catalytic cycle began with palla-
dium(0) which is generated in situ by the reduction of palla-
In conclusion, dearomative cyclocarbonylation of allyl alcohol
with palladium-catalysis in the absence of an external additive
has been realized for the first time. A sequence of quinolizi-
none compounds could be attained with up to 91% yield
through using this method. Besides, a plausible mechanism
in this research has been proposed, involving a successive
transformation that is allylation, dearomatization, CO inser-
tion and the Heck reaction. This protocol might further enrich
the diversity of the allyl alcohol carbonylation reaction.
Conflicts of interest
Scheme 2 The gram-scale reaction.
There are no conflicts to declare.
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Acknowledgements
This research was supported by the National Natural Science
Foundation of China (21790333, 21925111, 21672199 and
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