Divergent Syntheses of Pyridoacridine Alkaloids via Palladium-Catalyzed Reductive Cyclization with Nitro-Biarenes

Article abstract of DOI:10.1002/cjoc.202100094

A divergent and novel protocol for the preparation of both pyrido[2,3,4-kl]acridine and pyrido[4,3,2-kl]acridine alkaloids was developed. This method featured the remote palladium-catalyzed reductive cyclization with Mo(CO)₆ as reductant. A wide range of substrates including three types of nitro arenes were tolerated and afforded corresponding products in good to excellent yields. This method has been successfully applied to the total synthesis of norsegoline, styelsamine C and the skeleton of necatorone.

Full text of DOI:10.1002/cjoc.202100094

Chinese Journal
of Chemistry
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中 国 化 学 - An International Journal
Accepted Article
Title: Divergent Syntheses of Pyridoacridine Alkaloids via Palladium-Catalyzed
Reductive Cyclization with Nitro-Biarenes
Authors: Bo Liu, Shuping Wang, Changhao Bian, Hongze Liao* and Hou-Wen Lin*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2021, 39, 10.1002/cjoc.202100094.
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published online in Early View: http://dx.doi.org/10.1002/cjoc.202100094.
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Liao Hongze (Orcid ID: 0000-0003-1340-6811)
Cite this paper: Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
Divergent Syntheses of Pyridoacridine Alkaloids via Palladium-
Catalyzed Reductive Cyclization with Nitro-Biarenes
Bo Liu,# Shuping Wang,# Changhao Bian, Hongze Liao* and Hou-Wen Lin*
Research Center for Marine Drugs, State Key Laboratory of Oncogene and Related Genes, Department of Pharmacy, Ren Ji Hospital, School
of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Keywords
Polycyclic Heteroaromatics | Palladium-Catalyzed Reductive Cyclization | Marine Nature Alkaloids | Divergent Syntheses | Pyridoacri-
dine
Main observation and conclusion
A divergent and novel protocol for the preparation of both pyrido[2,3,4-kl]acridine and pyrido[4,3,2-kl]acridine alkaloids was devel-
oped. This method featured the remote palladium-catalyzed reductive cyclization with Mo(CO)6 as reductant. A wide range including
three types of nitro arenes were tolerated and afforded corresponding products in good to excellent yields. This method has been
successfully applied to the total synthesis of norsegoline, styelsamine C and the skeleton of necatorone.
Comprehensive Graphic Content
X
N
R1
R1
R1
Y
Palladium-Catalyzed
Reductive
N
Cyclization
or
HN
NO2
N
O2
R2
R2
R2
=
=
=
examples
examples
kl
X
X
Y
N,
CH,
13
CH,
Pyrido[2,3,4- ]acridine:
=
kl
Y
N, 21
Pyrido[4,3,2- ]acridine:
# The authors contributed equally to this work.
*E-mail: lhzseed@live.com (ORCID:0000-0003-1340-6811),
franklin67@126.com (ORCID: 0000-0002-7097-0876).
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Supporting Information
Chin. J. Chem. 2021, 39, XXX－XXX©
2021
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CAS,
Shanghai,
&
WILEY-VCH
GmbH
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/cjoc.202100094
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First author et al.
Report
Background and Originality Content
Previous Work:
reaction
Cadogan
(a)
Pyridoacridine alkaloids are a series of structurally fascinating
tetracyclic aromatic compounds sharing the pyridine ring fused ac-
ridine framework. There are total 15 isomers according to the dif-
ferent ring systems distributed in a broad range of functional prod-
ucts, but only two isomers sharing two common bonds are well-
known owing to their existence in natural alkaloids (Figure. 1).1 Pyr-
ido[2,3,4-kl]acridine is a large family and more than 100 of these
polycyclic heteroaromatics have been isolated from sessile marine
invertebrates.2 Correspondingly, pyrido[4,3,2-kl]acridine is a quite
small family and only discovered in nature as the necatorone and
its dimer from fungi Lactarius necator.3
O
O
N
N
O
O
180 °C
P,
(EtO)3
NO2
HN
O
O
77%
kl
skeleton
pyrido[2,3,4- ]-acridine
and
Reduction
intramolecular amination
(b)
HN
N
N
O2
10% Pd/C
EtOH, 60 °C
36%
N
O
OMe
N
Ph
Ph
N
N
S
N
N
kl
skeletion
pyrido[4,3,2- ]-acridine
This Work:
Palladium-Catalyzed Reductive
SMe
MeO2C
O
HN
N
HN
N
(c)
Cyclization
phen,
NH
X
Y
N
O
R1
R1
7H
kl
R1
-pyrido[2,3,4- ]-
acridine
N
kuanoniamine A
norsegoline
isodiplamine
[Pd],
Mo(CO)6
or
DCE, 120 °C
HN
NO2
N
O2
O
N
OH HO
O
R1 R2
OH OH
58%-93%
R2
HO
O
R2
R2
N
N
N
=
=
=
CH,
X
X
Y
kl
kl
N,
CH,
pyrido[2,3,4- ]acridine
pyrido[4,3,2- ]acridine
OH
H
H
HN
=
N
Y
N,
OH
N
N
R1
R2
OH
7H
kl
-pyrido[4,3,2- ]-
acridine
Scheme 1 Reported and current work on construction of pyridoacri-
dine from nitro-biarenes.
necatorone
binecatorone
Figure. 1 Selective natural products containing pyrido[2,3,4-kl]acri-
dine or pyrido[4,3,2-kl]acridine skeleton.
Results and Discussion
Both two types of pyridoacridine alkaloids have received enor-
mous attentions due to the unique biological properties and many
efforts have been devoted to construct these pyridoacridine frame-
works, involving condensation of amino-ketone substrates,4 cycliza-
tion of anionic nucleophilic addition,5 electrocyclic ring closure,6 Ca-
dogan reaction7 and biomimetic cascade reaction.8 However, these
methods suffered from the drawbacks such as use of harsh condi-
tions, prolonged reaction times and especially the narrow substrate
scopes and could not be applied in different ring systems. Accord-
ingly, for further screening biological evaluation, the development
of a divergent and efficient access for both pyrido[2,3,4-kl]acridine
and pyrido[4,3,2-kl]acridine analogues is still of great interest.
In past decades, the use of nitroarenes or nitroalkenes to syn-
thesize N-heterocycles via transition-metal catalyzed reductive cy-
clization have progressed rapidly, which lead to directly generate
the final products and save several synthetic steps.9 Carbon monox-
ide is the most frequently employed reductant due to the good se-
lectivity and atomic economy.10 Recently, CO-surrogates were de-
veloped to overcome the limitation of hazardous pressurized gas
manipulation,11 but most cases focus on the construction of 5-
membered ring containing heterocycles. As part of our efforts to
develop N-heterocycles synthesis, we have demonstrated that pal-
ladium-catalyzed reductive cyclization with Mo(CO)6 can success-
fully applied in nitroalkene system to afford indole alkaloids.11a In-
spired by the pioneered reports and our previous work, we pro-
posed that the tetracyclic pyridoacridine skeleton could be
achieved by reductive cyclization of nitro biarenes. To the best of
our knowledge, a relative remote reductive cyclization of nitro
biarenes to construct new pyridine ring of polycyclic heteroaro-
matic has never been developed. Furthermore, this method pro-
vides a useful synthetic tool to access diverse types of pyridoacri-
dines (Scheme. 1).
Table 1 Optimization of palladium-catalyzed reductive cyclization of
1a.a
Me
Me
N
N
Pd cat,
ligand
NO2
reductant, solvent
HN
1a
2a
Entry Reductant
Catalyst/Ligand
Pd(OAc)2/phen
Pd(OAc)2/phen
Pd(OAc)2/phen
Pd(OAc)2/phen
Pd(CH3CN)2Cl2/phen
Solvent Yield[d]
%
1
HCOOPh
Cr(CO)6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
38
36
42
56
70
62
63
68
62
72
65
54
2
3
W(CO)6
4
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
5
6
[Pd(Phen)2][BF4]2/ phen CH3CN
7
Pd(dppf)Cl2/phen
Pd(CH3CN)2Cl2/tmphen
Pd(CH3CN)2Cl2/phen
Pd(CH3CN)2Cl2/ phen
Pd(CH3CN)2Cl2/ phen
Pd(CH3CN)2Cl2/ phen
CH3CN
CH3CN
DMF
DCE
8
9
10
11[b]
12[c]
DCE
DCE
[a] Reaction conditions: 1a (0.1 mmol), Reductant (0.1 mmol), Pd catalyst
(10 mol %), Ligand (20 mol %), solvent (2 mL), 120 oC, 3h; [b] The reaction
was carried out at 140 oC; [c] 5 mol % Pd(CH3CN)2Cl2, 10 mol % phen used;
[d] isolated yield. phen = 1,10-phenanthroline, tmphen = 3,4,7,8-tetrame-
thyl-1,10-phenanthroline, DCE = 1,2-dichloroethane, DMF = dimethyforma-
mide.
In initial studies, the reductive cyclization of nitro phene-quin-
oline biarene 1a was carried out in the presence of a catalytic
amount of Pd(OAc)2 and phenanthroline with phenyl formate as re-
ductant in acetonitrile at 120oC for 3h. To our delight, the desired
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Running title
Chin. J. Chem.
pyrido[2,3,4-kl]acridine 2a was furnished in 38% yield (Table 1, en-
try 1). To improve the yields, different reductants, palladium cata-
lysts and ligands were tested as summarized in Table 1. It was found
that Mo(CO)6 was most suitable for this reaction and other CO-sur-
rogates gave lower yields (Table 1, entries 2-4). All the commer-
cially available palladium catalysts were active for this reaction and
Pd(CH3CN)2Cl2 afforded the best result (Table 1, entries 5-7). The
ligand with bulky substituent was less detrimental than phenan-
throline (Table 1, entry 8). Solvent screening was also conducted
and DCE was optimal to other solvents. (Table 1, entries 9, 10). In-
Moreover, it should be noted that the carbon-halogen bonds were
tolerated under the optimal condition, which assures further func-
tionalization through transition-metal catalyzed cross-coupling re-
actions.
Table 3 Substrate scope of reductive cyclization with phene-isoquino-
line N-biarene 3 a, b
.
R1
mol%) R1
Pd(OAc)2 (10
mol%)
N
N
phen (20
N
O2
HN
Mo(CO)6 (1 equiv.)
DCE, 120 °C
o
creasing the reaction temperature to 140 C or reducing the cata-
R2
R2
lysts loading (5% mol palladium, 10% mol ligand) were proved to be
negative for the conversion (Table 1, entries 11, 12).
3
4
O
O
O
O
O
O
This result motivated us to further investigate the substrate
scope of this transformation. Gratifyingly, the desired pyrido[2,3,4-
kl]acridine 2 were obtained in medium to good yields and the re-
sults are summarized in Table 2. A comparison of the substituents
on phenyl ring showed that those substrates with electron donating
substituents produced higher yields than electron withdrawing
substituents, which could be ascribed to that electron deficient
substrates were disfavored for this electrophilic reductive cycliza-
tion. To demonstrate the utility of this method, reactions of 1a and
1b on gram scale (4 mmol) were carried out and the products were
afforded in reliable yield (Table 2, 2a and 2b).
N
N
N
N
O
O
HN
HN
HN
HN
O
O
4b
4a
71%
4c
75%
,
72%
,
4d
,
70%
,
O
O
O
O
O
O
N
N
N
N
HN
HN
HN
4g
HN
Cl
CF3
66%
F
4h
4f
58%
,
4e
, 61%
Table 2 Substrate scope of reductive cyclization with phene-quinoline
N-biarene 1a, b
,
, 63%
[a] Reaction conditions: 3 (0.1 mmol), Mo(CO)6 (0.1 mmol), Pd(OAc)2 (10
N
N
mol %), Phen (20 mol %), DCE (2 mL), 120 oC, 3h; [b] isolated yield.
R1
CN)2Cl
Pd(CH3
mol%) R1
mol%)
2 (10
phen (20
NO2
equiv.)
Table 4 Substrate scope of reductive cyclization with phene-dihydroi-
Mo(CO) (1
6
HN
DCE, 120 °C
soquinoline N-biarene 5 a, b
.
R2
R2
N
1
2
Me
Me
R1
R1
mol%)
Pd(OAc)2 (10
mol%)
Me
Me
N
N
N
phen (20
N
N
N
O2
HN
N
Mo(CO)6 (1 equiv.)
DCE, 120 °C
R2
R2
HN
HN
HN
HN
Me
5
6
O
O
O
O
O
O
O
O
Me
93%
N
c
c
N
O
2a
2b
2d
93%
,
72%
91%
,
,
2c
,
N
(70%)
(87%)
HN
HN
Me
HN
O
Me
HN
O
N
N
N
N
O
O
O
O
HN
c
c
HN
6a
6b 91%
,
6c
,
6d
93%
,
87%
90%
,
HN
F
(84%)
(88%)
HN
O
O
O
O
O
O
O
Cl
83%
Me
81%
N
N
N
N
2e
,
2f
81%
,
O
2g 77%
,
2h
,
HN
HN
O
HN
HN
6h
O
O
O
N
N
N
N
F
Cl
80%
F
80%
,
6e
88%
6f
,
6g
85%
,
HN
,
HN
HN
F
HN
O
O
O
O
O
O
N
O
84%
N
N
F
N
2j
88%
2i
,
2k
,
2l
75%
71%
,
,
HN
HN
F
HN
HN
[a] Reaction conditions:
Pd(CH3CN)2Cl2, (10 mol %), Phen (20 mol %), DCE (2 mL), 120 C, 3h.
[b] isolated yield. [c] Reaction was carried out on scale of 4 M.
1 (0.1 mmol), Mo(CO)6 (0.1 mmol),
o
CF3
82%
6i 77%
,
6l
90%
6k
,
,
6j
76%
,
Next, the transformation from isoquinoline-derived N-biarene
3 to pyrido[4,3,2-kl]acridine 4 was further investigated. Different
palladium sources, ligands and solvents were also screened and the
combination of Pd(OAc)2 and phenanthroline in DCE was proved to
the optimal for this substrate (see Supporting information). The
substrate scope investigation was also conducted and the results
suggest that the substituents on phenyl ring has similar impact on
the reaction efficiency as quinoline-derived substrates (Table 3).
[a] Reaction conditions: 3 (0.1 mmol), Mo(CO)6 (0.1 mmol), Pd(OAc)2 (10
mol %), Phen (20 mol %), DCE (2 mL), 120 oC, 3h; [b] isolated yield. [c] Re-
action was carried out on scale of 4 M.
To our surprise, when the nitro phene-dihydroisoquinoline N-
biarene 5 was tested for this reaction, the desired tetracyclic aro-
Chin. J. Chem. 2021, 39, XXX－XXX
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First author et al.
Report
matic product 6 was obtained (Table 4), and the yields were signif-
icantly higher than the products from isoquinoline derived N-
biarene 3. Reactions of 5a and 5b on large scale were also tested
and the corresponding products were obtained in excellent yields.
The different reactive activity for the two substrates was rational-
ized by density functional theory (DFT) calculations12, and the dis-
tribution of Mulliken atomic charge13 on carbon 8 of 5l (-0.657)
showed higher electronic density than on the corresponding car-
bon of 3h (-0.488) (Figure. 2), which is favored for electrophilic cy-
clization process to form hydroxyl intermediate (D in Scheme 2). By
analogy with the previously reported mechanism10b, 11a and our
expermental observation, a tentative mechanism was proposed
with compound 5l: First, in the presenc of Mo(CO)6 and
phenanthroline, Pd(OAc)2 converts to palladium CO complex A.
Afterward, complex A reacts with the nitro-biarene 5l through
single-electron transfer and afforded radical anion B. Third,
reduction of B provides the nitroso intermediate C, which plays the
role of aminating species and affords the N-hydroxy tetracyclic
heterocycle D. Finally, intermediate D was transformed into desired
product 6l in this reductive system (Scheme 2). To confirm this
mechanism, nitroso N-biarene 5l’ was synthesized and subjected to
the optimized conditions, and the expected product 6a was
obtained in 91 % yield (Scheme 3).
To further demonstrate the synthetic utility of this transfor-
mation, total synthesis of three natural products containing the two
types of skeleton were investigated. Synthesis of natural alkaloid
with pyrido[2,3,4-kl]acridine starting from nitrobenzoate 7. The
chloroquinoline 9 was prepared in a three-step procedure via Mel-
drum derivative and quinolinone 8 in 65% overall yield according to
the literature.14 Next, the cross-coupling reaction of 9 with phenyl-
boronic acid gave the targeted phene-quinoline N-biarene 10 in 85%
yield. Fortunately, the carboxyl group kept intact when 10 was sub-
jected to the optimal condition and norsegoline 11 was successfully
afforded in 79% yield. Moreover, after reduction of the ester group
and the following oxidation, the known compound 127b was pro-
duced (Scheme 4). Thus, starting from commercially available nitro-
benzoate 7, we accomplished the total synthesis of norsegoline and
formal synthesis of styelsamine C in five steps and seven steps, the
overall yields were 44% and 29% respectively. Following the litera-
ture procedures, aldehyde 12 could be demethylated to give the
styelsamine C in one step.7b
O
O
O
H
N
PCl5
POCl3
acid
90°C
1. Meldrum's
NH2
N
,
HC(OEt)3
O
2. microwave
O
O
90°C, 79%
Ph2O
NO2
O
two steps
83%,
NO2
9
NO2
8
O
Cl
O
O
7
O
O
B(OH)2
N
N
CN)2Cl2
Pd(CH3
O
O
Ph
K CO
,
(PPh3)4
2
3
phen, Mo(CO)6
DCE, 120°C
79%
HN
EtOH, toluene
reflux, 85%
O
NO2
10
O
11
norsegoline
O
OH
N
N
1. DIBAL-H,
DCM, 0°C
H
H
Ref.
[7b]
rt
2. MnO2
67%,
,
HN
12
O
HN
O
two steps
13
C
styelsamine
Figure. 2 Mulliken atomic charge distribution for 3h and 5l.
Scheme 4 Total synthesis of norsegoline and formal synthesis of styelsamine
C
Pd(OAc)2
N
NH2
NO2
N
Phen
HN
Mo(CO)6
N
O2
COOH
6l
POCl3
2,4,6-collidine
50°C, DCM, 79%
N
HN
O
n
O
Pd(phen)(CO)
O
15
5l
N
O2
A
N
O2
HBTU,Et3N
/CO
Mo(CO)6
DMF, rt, 85%
O
17
14
16
1. Pd/C
,
xylene
N
N
n
Pd(phen)(CO)
N
N
O
,
reflux, 83%
Pd(OAc)2 phen
DCE
O
N
O
N
,
N
Mo(CO)6
120°C, 83%
O2
B
O
HN
Cl
CH3
CH3
N
2.
H/[Pd/Mo]
N
Cl
O
rt
,
Cl
19
skeleton necatorone
D
18
CH3CN/H
81%
2O,
of
N
/CO
Mo(CO)6
[Pd/Mo]
N
Scheme 5. Synthesis of necatorone skeleton.
O
CO2
C
The synthesis of natural product with pyrido[4,3,2-kl]acridine
skeleton was also investigated. The amide 16 was first obtained
from commercially available phenylethylamine derivative 14 and 2-
nitrobenzoic acid 15 in 85% yield. Subsequent Bischler- Napieralski
reaction afforded the dihydroisoquinoline N-biarene 17 in 79%
yield. Next, the catalytic reductive cyclization of 17 successfully
formed the new pyridine ring and the pyrido[4,3,2-kl]acridine prod-
uct 18 was obtained in 83% yield. Finally, after aromatization and
oxidation, the skeleton of necatorone15 was acquired in five steps
and 15% overall yield (Scheme 5).
Scheme 2 Proposed reaction mechanism.
N
N
,
Pd(OAc)2 phen
DCE
,
ON
Mo(CO)6
120 °C, 91%
HN
6l
5l'
Scheme 3 Reductive cyclization of nitroso N-biarene 5l’.
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Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
Lett. 1984, 25, 3575-3578.
Conclusions
(a) Borah, A.; Sharma, A.; Hazarika, H.; Sharma, K.; Gogoi, P. Synthesis
of 1‑Azaanthraquinone: Sequential C−N Bond Formation/Lewis Acid
Catalyzed Intramolecular Cyclization Strategy, J. Org. Chem. 2017, 82,
8309-8316; (b) Yin, H.; Shan, N.; Wang, S.; Yao, Z. J. Total Synthesis of
Ascididemin-Type Alkaloids Using Alkyne Building Blocks, J. Org. Chem.
2014, 79, 9748-53; (c) Yin, H.; Kong, F.; Wang, S.; Yao, Z.-J. Assembly of
pentacyclic pyrido[4,3,2-mn]acridin-8-ones via a domino reaction ini-
tiated by Au(I)-catalyzed 6-endo-dig cycloisomerization of N-propar-
gylaminoquinones, Tetrahedron Lett. 2012, 53, 7078-7082; (d) Fei, N.;
Yin, H.; Wang, S.; Wang, H.; Yao, Z. J. CuCl2-Promoted 6-endo-dig Chlo-
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tion of 1-Azaanthraquinones from N-Propargylaminoquinones, Org.
Lett. 2011, 13, 4208-4211.
In summary, we have developed a divergent and novel method
to synthesize two types of pyridoacridine alkaloids through palla-
dium-catalyzed reductive cyclization with Mo(CO)6 as reductant.
This transformation has a wide scope demonstrated by the prepa-
ration of total 34 analogues of both pyrido[2,3,4-kl]acridine and
pyrido[4,3,2-kl]acridine skeletons. The potential of employing this
method as a valuable synthetic tool to access polycyclic N-hetero-
cycles is attractive and intriguing due to the versatility of N-hetero-
cycle family in marine natural products, and we have demonstrated
it by the accomplishment of total synthesis of norsegoline, styelsa-
mine C and the necatorone skeleton.
(a) Melzer, B. C.; Plodek, A.; Bracher, F. Functionalization of 4-bromo-
benzo[c][2,7]naphthyridine via regioselective direct ring metalation. A
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Synthesis of the Azaoxoaporphine Alkaloid Sampangine and Ascidide-
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sure, Eur. J. Org. Chem. 2015, 2015, 1302-1308; (c) Melzer, B.; Plodek,
A.; Bracher, F. Total Synthesis of the Marine Pyridoacridine Alkaloid
Demethyldeoxyamphimedine, J. Org. Chem. 2014, 79, 7239-7242; (d)
Kristensen, J.; Petersen, I. Synthesis of pyridoacridines through anionic
cascade ring closure, Synthesis 2014, 46, 1469-1474; (e) Petersen, I. N.;
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cascade ring closure, Chem. Commun. 2012, 48, 9092-9094.
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Experimental
In a 10 mL Schlenk tube, N-biarene (1 mmol, 1 equiv), Pd cata-
lyst (0.1 mmol, 10 mol%), 1,10-phenanthroline (0.2 mmol, 20
mol%) and Mo(CO)6 (1 mmol, 1 equiv) was dissolved in DCE (2 ml)
under nitrogen atmosphere. The solution was allowed to be heated
at 120 °C for 3-12 hours. After complete conversion of starting ma-
terial, the solvent was removed. Purification was achieved by col-
umn chromatography on silica gel using PE/EA as the eluent to give
the corresponding pyridoacridine.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2021xxxxx.
Acknowledgement
This project is financially supported by National Key Research
and Development Program of China (No. 2018YFC0310900), Na-
tional Natural Science Foundation of China (No. 81903499,
41729002), Innovative Research Team of High-Level Local Universi-
ties in Shanghai (No. SSMU-ZLCX20180702).
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2021
Manuscript revised: XXXX, 2021
Manuscript accepted: XXXX, 2021
Accepted manuscript online: XXXX, 2021
Version of record online: XXXX, 2021
www.cjc.wiley-vch.de
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2021, 39, XXX－XXX

Entry for the Table of Contents
Divergent Syntheses of Pyridoacridine Alkaloids via Palladium-Catalyzed Reductive Cyclization with Nitro-Biarenes
Bo Liu,# Shuping Wang,# Changhao Bian, Hongze Liao* and Hou-Wen Lin*
Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
Reductive
Reductive
Cyclization
Cyclization
X
X
N
N
R
R11
R
R11
R
R11
Y
Y
N
N
[Pd], Mo(CO)
[Pd], Mo(CO)66
or
or
DCE, 120 °C
phen, DCE, 120 °C
phen,
HN
HN
NO
NO22
N
O
O22N
R
R2
R
R22
R
R22
=
=
examples
kl
13
Pyrido[2,3,4-kl]acridine: X = NN,, Y = CH, 13 examples
X
Y
CH,
Pyrido[2,3,4- ]acridine:
=
=
examples
21
Pyrido[4,3,2-kl]acridine: X = CH, Y = N,, 21 examples
kl
X
Y
CH,
Pyrido[4,3,2- ]acridine:
Synthetic
Synthetic
Application:
Application:
OH
OH
O
O
N
N
N
N
N
N
O
O
H
H
O
O
N
N
HN
HN
O
O
HN
HN
O
O
Cl
Cl
norsegoline
norsegoline
C
skeleton of
necatorone
styelsamine C
styelsamine
skeleton of necatorone
A divergent and efficient method for preparing pyrido[2,3,4-kl]acridine and pyrido[4,3,2-kl]acridine alkaloid is reported. This method featured a novel
remote palladium-catalyzed reductive cyclization with Mo(CO)6 as reductant by nitro biarenes, and a wide scope of substrates were tolerated and total
34 analogues containing the two types of polycyclic heteroaromatic skeleton were prepared. Furthermore, the potential synthetic application of this
method was demonstrated by the accomplishment of synthesis of norsegoline, styelsamine C and the necatorone skeleton.
Chin. J. Chem. 2018, template© 2018 SIOC, CAS, Shanghai,
&
WILEY-VCH Verlag GmbH
&
Co. KGaA,
Weinheim