Palladium-Catalyzed Dearomative Cyclocarbonylation by C-N Bond Activation

Article abstract of DOI:10.1002/anie.201504805

A fundamentally novel approach to bioactive quinolizinones is based on the palladium-catalyzed intramolecular cyclocarbonylation of allylamines. [Pd(Xantphos)I₂], which features a very large bite angle, has been found to facilitate the rapid carbonylation of azaarene-substituted allylamines into bioactive quinolizinones in good to excellent yields. This transformation represents the first dearomative carbonylation and is proposed to proceed by palladium-catalyzed C-N bond activation, dearomatization, CO insertion, and a Heck reaction.

Full text of DOI:10.1002/anie.201504805

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Angewandte
Communications
International Edition: DOI: 10.1002/anie.201504805
Synthetic Methods
German Edition:
DOI: 10.1002/ange.201504805
À
Palladium-Catalyzed Dearomative Cyclocarbonylation by C N Bond
Activation
Hui Yu, Guoying Zhang, and Hanmin Huang*
Abstract: A fundamentally novel approach to bioactive
quinolizinones is based on the palladium-catalyzed intramo-
lecular cyclocarbonylation of allylamines. [Pd(Xantphos)I2],
which features a very large bite angle, has been found to
facilitate the rapid carbonylation of azaarene-substituted allyl-
amines into bioactive quinolizinones in good to excellent
yields. This transformation represents the first dearomative
carbonylation and is proposed to proceed by palladium-
a great opportunity to accelerate biological and biosynthetic
studies of these valuable compounds.[3]
Transition-metal-catalyzed aminocarbonylation is a versa-
tile process that has been strenuously developed and emerged
as a convenient method for the synthesis of amides.[4] Among
À
many efficient methods, the carbonylation of C N bonds,
À
a strategy that involves transition-metal-catalyzed C N bond
activation followed by insertion of CO to furnish the amide
group, has proven to be one of the most direct and promising
ways to access a range of valuable amides.[5] Allylamines are
suitable substrates for such catalytic processes, as they can
smoothly undergo oxidative addition with Pd0 to cleave the
À
catalyzed C N bond activation, dearomatization, CO inser-
tion, and a Heck reaction.
Q
uinolizinones and related molecules that contain an
À
amide group and a nitrogen atom at the ring junction are
a unique class of heterocycles with valuable physicochemical
properties and are emerging as key pharmacophores for the
treatment of Alzheimerꢀs disease, Type 2 diabetes, HIV, and
spinal muscular atrophy (Figure 1).[1] In spite of the long-
C N bond for the generation of a p-allylpalladium species I
and have thus been successfully applied in Pd-catalyzed
aminocarbonylation reactions in the presence of CO (Sche-
me 1a).[6] However, once an azaarene such as pyridine or
À
Scheme 1. Dearomative cyclocarbonylation by C N bond activation.
Figure 1. Examples of quinolizinone-containing bioactive molecules.
standing biological and synthetic interest in these valuable
compounds, it is surprising that a general method for the
construction of such bicyclic ring systems has not been
reported thus far.[2] Existing methods commonly rely on
multistep syntheses, but their widespread use has been
precluded by a restricted substrate scope, inconvenient
reaction procedures, and lengthy syntheses of the reagents.
A general catalytic method to various quinolizinones is
therefore in high demand and would also serve to provide
quinoline is introduced into the allylamine system, the
À
p-allylpalladium species I generated by C N bond activation
might be transformed into the dearomatized palladium amide
species II, with the shift of the double bond incurred by
dearomatization of the heterocycle.[7] We reasoned that the
dearomatization process could be further enhanced in the
presence of CO, owing to the lower electron density at
Pd(CO).[8] Moreover, CO would prefer to insert into the less
À
À
hindered planar pyridyl N Pd bond, and the R2N moiety
contained in metal complex II could then act as an intra-
molecular base to promote the subsequent Heck reaction. It
should thus be possible to realize a catalytic tandem reaction
[*] H. Yu,[+] G. Zhang,[+] Prof. Dr. H. Huang
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences
Lanzhou, 730000 (China)
E-mail: hmhuang@licp.cas.cn
[+] These authors contributed equally to this work.
À
that consists of C N bond activation, dearomatization, CO
insertion, and a Heck reaction for the synthesis of quinolizi-
nones under palladium catalysis. Herein, we report the
development of the first palladium-catalyzed dearomative
cyclocarbonylation of azaarene-substituted allylamines,
which provides biologically active quinolizinones (Sche-
me 1b). Notably, this transformation is mechanistically
unique in comparison with traditional base-promoted pyri-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504805.
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À
dine dearomatization processes that involve C N bond
which features a larger bite angle, was used as part of the
activation.[7]
catalyst system, product 2a was obtained in 59% yield.
Moreover, further increasing the steric bulk and bite angle of
the phosphine ligand by using Xantphos led to a substantial
increase in catalytic activity, and the desired carbonylation
product 2a was isolated in 81% yield (entry 12). When
NiXantphos, with a very similar bite angle, was used, the
desired product was formed in an almost identical yield. The
exceptionally high reactivity of the Xantphos-containing
catalyst might be due to the unique structure of the ligand,
which is capable of forming both cis and trans Pd complexes,
thus facilitating the catalytic process. The huge bite angle of
154.788 can be clearly seen in the X-ray structure of
[Pd(Xantphos)I2].[10] Screening some representative solvents
revealed that the reaction was most efficient in toluene, in
which the desired product 2a was obtained in good yield
(entry 12). The reaction reached completion in one hour to
yield the corresponding product in 87% yield (entry 20).
With optimized reaction conditions in hand, substrates
with various leaving groups were subjected to the standard
conditions. As summarized in Table 2, substrates containing
Our investigations began with the direct cyclocarbonyla-
tion of N,N-diisopropyl-3-(pyridin-2-yl)prop-2-en-1-amine
(1a) in toluene by palladium catalysis under CO atmosphere
at 1208C (Table 1). After an extensive screening of catalysts,
Table 1: Optimization of the reaction conditions.[a]
Entry
[Pd]
Ligand
Solvent
Yield[b] [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20[c]
21
PdCl2
PdBr2
PdI2
[Pd(cod)I2]
[Pd(CH3CN)2Cl2]
[{Pd(allyl)Cl}2]
PdI2
PdI2
PdI2
PdI2
PdI2
PdI2
PdI2
PdI2
PdI2
PdI2
PdI2
–
–
–
–
–
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
<5
14
67
63
<5
<5
<5
<5
59
<5
<5
84 (81)
83
DPPE
DPPP
DPPB
DPPF
BINAP
Xantphos
NiXantphos
DPEphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
–
Table 2: Influence of the leaving group.[a]
42
83
82
84
80
70
91 (87)
0
mesitylene
benzene
PhCF3
NMP
toluene
toluene
Entry
Substrate
X
Yield[b] [%]
1 h
91
80
81
<5
<5
<5
<5
<5
24 h
PdI2
PdI2
PdI2
–
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
N(iPr)2
NEt2
N(Cy)2
NPh2
NBn2
OH
–
–
–
16
55
15
73
13
[a] Reaction conditions: 1a (0.5 mmol), [Pd] (0.025 mmol), ligand
(0.03 mmol), solvent (2 mL), CO (10 atm), 1208C, 24 h. [b] Yields were
determined by GC analysis using n-hexadecane as an internal standard;
yields of isolated products are given in parentheses. [c] One hour.
BINAP=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl, DPEphos=bis[2-
(diphenylphosphino)phenyl] ether, DPPB=1,4-bis(diphenylphosphino)-
butane, DPPE=1,2-bis(diphenylphosphino)ethane, DPPF=1,1’-bis(di-
phenylphosphino)ferrocene, DPPP=1,3-bis(diphenylphosphino)pro-
pane, NiXantphos=4,6-bis(diphenylphosphino)phenoxazine, Xant-
phos=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
1g
1h
OAc
Cl
[a] Reaction conditions: 1 (0.5 mmol), PdI2 (0.025 mmol), Xantphos
(0.03 mmol), solvent (2 mL), CO (10 atm), 1208C. [b] Yields were
determined by GC analysis using n-hexadecane as an internal standard.
Bn=benzyl, Cy =cyclohexyl.
to our great delight, the desired product 2a was obtained in
67% yield in the presence of a catalytic amount of PdI2
(5 mol%) and CO (10 atm). [Pd(cod)I2] was also an effective
catalyst of this reaction, giving the carbonylation product in
63% yield. As expected, no carbonylation took place without
a catalyst (entry 21), and representative palladium catalysts,
such as PdCl2, PdBr2, [Pd(CH3CN)2Cl2], and [{Pd(allyl)Cl}2],
were not effective (entries 1, 2, 5, and 6). Inspired by this
promising lead, we next sought to improve the efficiency of
the reaction. Various phosphine ligands were then screened in
combination with PdI2 as the catalyst precursor, and the
transformation was found to be sensitive to the bite angle of
the bis(phosphine) ligand (entries 7–14).[9] Catalysts derived
from bis(diphenylphosphino)-type ligands, such as DPPE,
DPPP, DPPF, or BINAP, resulted in low conversion into the
desired product based on GC analysis. However, when DPPB,
different leaving groups (1a–1h) gave the desired product in
distinctly different yields. For allylamines with N(iPr)2, NEt2,
or N(Cy)2 as the leaving group, the cycloadduct 2a could be
obtained in high yields even in one hour (entries 1–3).
However, when other leaving groups, such as NPh2, NBn2,
OH, OAc, or Cl, were installed in the allylic skeleton, the
conversion was dramatically lower under identical reaction
conditions (entries 4–8). The lower activity of these substrates
might be attributed to either the difficult cleavage of the
À
corresponding C X bonds or their reluctance to undergo
a late-stage Heck reaction.[11]
On the basis of the results described above, a variety of
azaarene-substituted allylamines with N(iPr)2 as the leaving
group were submitted to the Pd-catalyzed dearomative
cyclocarbonylation reaction to investigate its substrate scope
and generality (Table 3). A series of substituents on the
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Table 3: Alkene substrate scope.[a]
pyridyl ring of the allylamine were well tolerated regardless of
whether they were electron-donating or -withdrawing, pro-
viding the desired quinolizinones in good to excellent yields
(53–93%). The reactivity was not affected by the E/Z ratio of
the allylamines, and both the E and Z isomers could be
efficiently converted into the desired cycloadducts. The
position of the substituent on the pyridyl ring of the allyl-
amine appeared to influence the reactivity. For example,
substrate 1i, with a methyl group in the ortho position of the
pyridyl ring, gave the corresponding product in a rather low
yield (2i). Typical functional groups, such as fluorine and
chlorine substituents, were also tolerated under the reaction
conditions (Table 3, entries 6–9), giving ample opportunities
for further elaboration by transition-metal-catalyzed cou-
plings or other transformations. To our delight, substrate 1q,
which contains a hydroxymethyl group, also underwent this
cyclocarbonylation, giving the desired product 2q in 73%
yield. The free hydroxymethyl group contained in the product
is amenable to further elaboration by cross-coupling reac-
tions. Furthermore, allylamines bearing an alkyl group on the
double bond were also feasible substrates, affording the
cyclocarbonylation products 2s, 2t, and 2u in excellent yields
(entries 12–14). However, azaarene-substituted allylamines
with a substituent in the a-position of the amine, such as N,N-
diethyl-1-phenyl-3-(pyridin-2-yl)prop-2-en-1-amine and N,N-
diisopropyl-4-(pyridin-2-yl)but-3-en-2-amine, could not be
converted into the desired products (see the Supporting
Information). When the pyridine core was replaced with
a pyrazine or quinoline, the cyclocarbonylation reaction still
took place to give the corresponding carbonylation products
2v and 2w in 44% and 52% yield when the reaction time was
increased (entries 15 and 16). The structures of 2o, 2q, and
2w were confirmed by single-crystal X-ray diffraction.[10]
The synthetic versatility of the present catalytic system
was next demonstrated through a large-scale reaction and
product derivatizations (Scheme 2). The dearomative cyclo-
carbonylation on a 10 mmol scale was found to be completed
in twelve hours, even with a reduced amount of catalyst
(1.0 mol%), yielding 1.24 g of cycloadduct 2a (86% yield).
Partial hydrogenation of 2a catalyzed by Pd/C afforded 3,4-
dihydro-1H-quinolizin-6(2H)-one (3a) in 87% yield under
1 atm of H2 at room temperature. Complete hydrogenation of
2a to 3b could also be realized under 10 atm of H2 at 508C
catalyzed by Pd/C. The desired hexahydro-1H-quinolizin-
4(6H)-one was isolated in 98% yield. Such moieties are
common core structures found in numerous alkaloids and
biologically active compounds.[12] Moreover, we have also
developed an efficient formal synthesis of alkaloid 3d. As
shown in Scheme 2, full hydrogenation of 2q gave the desired
product 3c in 85% yield; further reduction of 3c according to
a previously reported procedure should then lead to 3d.[13]
Although the mechanistic details of this transformation
are not clear at this stage, on the basis of the present results
and precedent reports,[6] a plausible reaction pathway was
proposed (Figure 2). Under the reaction conditions, and in the
presence of CO, an active Pd0 species is expected to be
formed, which undergoes oxidative addition with allylamine
1a to give p-allylpalladium intermediate I by cleavage of the
Entry
1
1
t (h)
2
Yield[b] [%]
87
1
2
3
4
3
1
1
53
88
84
5
6
7
1
1
1
88
82
84
8
9
1
1
75
64
10
11
12
6
73
91
12
13
14
15
16
12
3
92
83
93
44
52
12
21
24
[a] Reaction conditions: 1 (0.5 mmol), CO (10 atm), PdI2 (0.025 mmol),
Xantphos (0.03 mmol), toluene (2 mL), 1208C. [b] Yield of isolated
product. MOM=methoxymethyl.
À
C N bond. Dearomatization of I quickly takes place under
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Acknowledgements
This research was supported by the Chinese Academy of
Sciences and the National Natural Science Foundation of
China (21222203, 21172226, and 21133011).
À
Keywords: C N activation · cyclocarbonylation ·
dearomatization · palladium · quinolizinones
How to cite: Angew. Chem. Int. Ed. 2015, 54, 10912–10916
Angew. Chem. 2015, 127, 11062–11066
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Scheme 2. Synthetic versatility of the present catalytic system. Reaction
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(10%, 7.3 mg), EtOH (1 mL), H2 (1 atm), RT, 12 h; c) 2a (1.0 mmol),
Pd/C (10%, 14.5 mg), EtOH (2 mL), H2 (10 atm), 508C, 12 h; d) 2q
(0.5 mmol), Pd(OH)2/C (25%, 22 mg), EtOH (3 mL), H2 (40 atm),
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Figure 2. Proposed reaction mechanism. The ligand was omitted for
clarity.
CO atmosphere to give rise to intermediate II. Selective
insertion of CO into the pyridyl nitrogen–palladium bond
results in the formation of intermediate III. Subsequent
double bond migratory insertion leads to intermediate IV,
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desired product 2a and reductive elimination to regenerate
the active Pd0 species to complete the catalytic cycle.[14]
In summary, we have developed an unprecedented
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allylamines with CO. This unique reaction was accomplished
À
by synergistically combining palladium-catalyzed C N bond
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compatible with this operationally simple and efficient
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Received: May 27, 2015
Revised: June 30, 2015
Published online: July 21, 2015
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