Expeditious synthesis of phenanthridines through a Pd/MnO2-mediated C-H arylation/oxidative annulation cascade from aldehydes, aryl iodides and amino acids

Article abstract of DOI:10.1039/d0cc00300j

The expeditious construction of phenanthridine scaffolds via a Pd/MnO₂-mediated C-H arylation/oxidative annulation cascade involving aldehydes, aryl iodides and amino acids is disclosed. This reaction proceeds smoothly involving the formation of multiple chemical bonds with the tolerance of a wide range of functional groups. The control experiments suggest a radical mechanism for C-N bond formation via MnO₂-promoted oxidative annulation of imine compounds. The synthetic utility of this transformation has been demonstrated via the straightforward access to bioactive natural alkaloid trisphaeridine and its analogue.

Full text of DOI:10.1039/d0cc00300j

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DOI: 10.1039/D0CC00300J
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Expeditious Synthesis of Phenanthridines through Pd/MnO2-
Mediated C-H Arylation/Oxidative Annulation Cascade from
Aldehydes, Aryl Iodides and Amino Acid
Received 00th January 20xx,
Accepted 00th January 20xx
Jian Fan, Li Li, Jitan Zhang* and Meihua Xie*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The expeditious construction of phenanthridine scaffold via the
Pd/MnO2-mediated C-H arylation/oxidative annulation cascade
involving aldehydes, aryl iodides and amino acid is disclosed. This
reaction proceeds smoothly involving multiple chemical bonds
formation with the tolerance of a wide range of functional groups.
The control experiments suggest a radical mechanism for the C-N
bond formation via MnO2-promoted oxidative annulation of
imine compounds. The synthetic utility of this transformation has
been demonstrated via the straightforward access to bioactive
natural alkaloid trisphaeridine and its analogue.
N
Me
N
N
Me
O
N
OMe
OMe
O
O
O
OMe
O
O
O
O
OMe
Trispheridine
Bicolorine
Chelerythrine
Norchelerythrine
Fig. 1 Biologically active phenanthridine derivatives.
a) Previous approaches for the construction of phenanthridine core:
N
N
Model I
N
Model II
Phenanthridines, representing a kind of highly privileged
structural motif, are ubiquitous in natural products and
biologically relevant compounds which exhibit potent
antitumor, antimicrobial, and antiviral agents (Figure 1).1
Therefore, the development of efficient methodologies for the
preparation of these valuable compounds has become a
subject of great interest in organic chemistry.2 In general, the
documented methods to construct phenanthridine core are
always accomplished through the following models (Figure 2):
1) Caryl-Nimine formation via intramolecular cyclization of ortho-
aryl imines, benzylamines, or benzonitriles;3 2) Cimine-Caryl
formation via intramolecular cyclization of ortho-aryl anilines
or arylisonitriles;4 3) Caryl-Caryl formation via intramolecular
cyclization of functional imines or anilines;5 4) Cimine-Caryl and
Caryl-Caryl formation via intermolecular cyclization of ortho-
halogen imines and ArX (X = I, OTf).6 However, the
prefunctionalization of the coupling partners, such as
halogenation, preparation of biaryls or imines, is necessary for
these protocols, which limited their synthetic application
dramatically. In this regard, efforts towards the expeditious
synthesis of phenanthridines and their functional derivatives
from simple and commercially building blocks would be always
in high demand.
Model IV
Model V
Model III
b) Pd/MnO2-mediated C-H arylation/oxidative annulation cascade from
aldehydes, aryl iodides and amino acid (this work):
H
H
N
Pd
O
H
+
+
"N"
I
Ar
Ar
Ar
Mn
Ar
three components cascade
amino acid serves as DG and N source
multiple chemical bonds formation
wide range of functional groups
Fig. 2 Strategies for the construction of phenanthridine core.
Very recently, the transient auxiliary enabled direct C-H
functionalization of naturally abundant aldehydes involving an
imine intermediate has emerged as a powerful and promising
strategy for the synthesis of diverse structurally complicated
molecules with atom and step economy.7 Since the
breakthrough achieved by Yu and co-workers,8 in which the
commercially available amino acids were employed as the
transient directing groups, this catalytic logic has been
explored frequently, and a series of elegant transformations
have been developed.9 Inspired by the aforementioned
seminal reports and our endeavors on the development of
practical methodologies for highly efficient construction of
heterocyclic compounds,9a,10 we, herein, report a practical and
Key Laboratory of Functional Molecular Solids (Ministry of Education), Anhui Key
Laboratory of Molecular Based Materials, College of Chemistry and Materials
Science, Anhui Normal University, Wuhu 241002, China.
E-mail: zhangjt@ahnu.edu.cn; xiemh@mail.ahnu.edu.cn
Electronic Supplementary Information (ESI) available. Experimental procedures straightforward
procedure
for
the
assembly
of
and characterization data for new compounds. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2019, 00, 1-5 | 1
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phenanthridines
via
the
Pd/MnO2-promoted
C−H while TFA and TsOH·H2O were ineffective for this reaction
View Article Online
DOI: 10.1039/D0CC00300J
arylation/oxidative annulation cascade involving aromatic (Table S1, entries 18-21).
aldehydes and aryl iodides using amino acids as the in-situ
With the optimized conditions in hand, the scope of the
auxiliary, as well as the N source. Despite the propensity of benzaldehydes was investigated to examine the generality of
aryl aldehydes toward the formation of biaryl aldehydes11 and this method. As shown in Scheme 1, various ortho and meta
the sequential intramolecular dehydrogenative cyclization substituted aldehydes were well tolerated in the reaction to
under oxidative conditions,12 our reaction proceeds afford the desired products in moderate to good yields (3ba-
chemoselectively to produce the desired heterocycles, by 3ia). When benzaldehyde and para substituted aldehydes
featuring double C-H bonds cleavage and multiple chemical were employed, the diarylation results were inevitably
bonds (C-C, C=N and C-N) formation with the tolerance of a obtained along with the mono-type products (3ja-3la, 3jaa-
wide range of readily available starting materials.
3laa). Gratifyingly, a number of disubstituted phenanthridines
(3ma-3qa) could be obtained in moderate yields, albeit low
efficiency was obtained for the substrate bearing methoxyl
group (3ra). Notably, the access to bioactive natural alkaloid
trisphaeridine and its analogue (3sa-3ta) were also achieved
successfully in this transformation. Besides, by use of 2-
I
Pd(OAc)2 (10 mol%)
N
L-tert-leucine (1 eq)
+
CHO
Ar
Ar
MnO2 (2 eq), AgTFA (2 eq)
AcOH (4 eq), HFIP (0.2 M)
110 oC, 24 h
1
2a
3
3ea
3fa
3ga
3ha
3ia
, R = Cl, 57%
3ba
, R = F, 66%
, R = Cl, 66%
, R = Br, 55%
, R = Me, 31%
R
N
N
naphthaldehyde,
a
π-extended
scaffold
, R = Br, 53%
3aa
3ca
3da
, R = CF3, 41%
, R = Me, 57%
, R = OMe, 46%
benzo[k]phenanthridine (3ua) was furnished in 25% yield.
Unfortunately, the ketone compound (1v) could not be
tolerated in this catalytic system.
R
N
mono: 3ja, R = H, 36%c
N
di: 3jaa, R = H, 43%c
3kaa
, R = Cl, 31%
I
Pd(OAc)2 (10 mol%)
L-tert-leucine (1 eq)
c
c
3ka
, R = Cl, 30%
N
c
c
3la
3laa
, R = Me, 36%
, R = Me, 30%
Ar
+
CHO
Ar
MnO2 (2 eq), AgTFA (2 eq)
AcOH (4 eq), HFIP (0.2 M)
110 oC, 24 h
Ar
Ar
R
R
1
2
3
Br
N
Br
N
Cl
N
Cl
N
3ad
3ae
, R = Me, 65%
, R = OMe, 53%
Cl
N
Cl
N
3ab
, R = F, 45%
3ac
, R = Cl, 41%
Me
F
Cl
Cl
3af, R = F, 65%
R
3ag
, R = CF3, 64%
3ma
3na
, 43%
3oa
, 30%
3pa
, 57%
, 42%
3ah
R
, R = CO2Me, 57%
Br
N
N
N
Cl
N
Cl
N
o
Cl
Cl
N
R
o'
3ai
3aj
3ai'
, R = F, 37%
3aj', R = Cl, 31%
, R = F, 36%
, R = Cl, 47%
MeO
O
Cl
o'
O
O
MeO
O
R
o
d
e
d
e
d
3qa
, 60%
3ra
1r
3sa
1s
3ta
, 40%
Cl
N
Cl
N
Cl
N
Me
Me
, 18% ; , 60%
, 22% ; , 58%
N
Cl
N
Me
N
Cl
Cl
CF3
Me
3ak
,
3al
,
3am
3an
, 46%
63%
58%
, 76%
Cl
N
Cl
N
H3C
N
Cl Cl
N
e
d
e
3va
1v
3ua
1u
, 0%; , 98%
, 25% ; , 57%
Me
Cl
CO2Me
aReaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), L-tert-leucine (0.2 mmol),
Pd(OAc)2 (0.02 mmol), AgTFA (0.4 mmol), MnO2 (0.4 mmol), AcOH (0.8 mmol),
HFIP (1 mL), 110 oC, 24 h. b Isolated yield by flash column chromatography. c3
equiv of 2 was used. dThe reaction run for 48 h. e Recovery of aldehyde.
Me
Cl
Cl
Cl
3ao
3ap
3dm
, 55%
3nh
, 57%
, 65%
, 40%
Cl
N
Scheme 1 Substrate scope of aldehydes a,b
Cl
N
S
The initial setup for this reaction started with o-
chlorobenzaldehyde (1a), iodobenzene (2a) and L-tert-leucine
in the presence of Pd(OAc)2 (10 mol%), AgOAc (2 eq), MnO2 (2
c
c
d
3aq
, 35%
3ar
1a
, 20% ; , 50%
aReaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), L-tert-leucine (0.2 mmol),
Pd(OAc)2 (0.02 mmol), AgTFA (0.4 mmol), MnO2 (0.4 mmol), AcOH (0.8 mmol),
HFIP (1 mL), 110 oC, 24 h. b Isolated yield by flash column chromatography. c The
reaction ran for 48 h. d Recovery of aldehyde.
o
eq), and AcOH (4 eq) in HFIP (1.0 mL) at 110 C under air
atmosphere for 24 h (more details, see Optimization of
Reaction Conditions and Table S1 in the Supporting
Information). To our delight, the desired product 3aa could be
obtained in 42% yield (Table S1, entry 1). Then, various silver
salts were tested and superior efficiency was obtained by the
use of AgTFA to afford 3aa in 66% yield (Table S1, entries 2-7).
Unfortunately, the reactivity could not be further improved
under argon atmosphere (Table S1, entry 8). Other Mn salts,
Scheme 2 Substrate scope of aryl iodides a,b
Next, we evaluated the reactivity of aryl iodides as
summarized in Scheme 2. The tolerance of a variety of
functional groups, such as Me, OMe, CF3, CO2Me, F, Cl,
enabled the synthesis of structurally diverse phenanthridine
products (3ab-3ah) in moderate to good yields. While
regioisomeric phenanthridines (3ai, 3aj and 3ai', 3aj') were
formed with meta-fluoro and chloro substituted aryl iodides,
meta-methyl and trifluoromethyl substrates afforded the
.
.
such as Mn(acac)2, Mn(OAc)2 4H2O, Mn(OAc)3 2H2O, as well as
different kinds of oxidants were less effective for this
transformation (Table S1, entries 9-17). Last, PivOH and
PhCO2H just furnished the desired product in depressed yields
2 | J. Name., 2019, 00, 1-5
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single regioisomeric products (3ak and 3al) due to the larger indicated that A might act as the crucial intermeVdieiawtAertifcolerOtnhlinies
steric hindrance. Additionally, several disubstituted aryl transformation and the formation of pDhOenI:a10n.t1h03ri9d/Din0eCCfr0o0m300AJ
iodides underwent this reaction smoothly to deliver the was promoted by MnO2 (Scheme 4, d and e). When the MnO2-
corresponding trisubstituted phenanthridines in up to 76% promoted annulative reaction was analyzed with a shorten
yield (3am-3ap, 3dm and 3nh). Furthermore, 1-naphthalene reaction time, imine species (C) was observed (Scheme 4, f,
iodide and 2-thiophene iodide could also participate in the and more details see in Supporting Information). Additionally,
reaction by prolonging the reaction time, although only ammonium acetate could also conduct the cyclization reaction
depressing yields were obtained. It should be pointed out that smoothly in the presence of MnO2 (Scheme 4, g and h). These
the cases with low efficiency in this catalytic system were results revealed that the imine C might be the precursor for
mainly due to the incomplete reaction.
the construction of phenanthridine. Last, the intramolecular
cyclization reaction of A with amino acid or ammonium
acetate was thoroughly prohibited by adding TEMPO or BHT
(Scheme 4, i and j), which implied the involvement of a radical
process in this reaction.
I
Pd(OAc)2 (10 mol%)
L-tert-leucine (1 eq)
Cl
N
Cl
+
AgTFA (2 eq), MnO2 (2 eq)
AcOH (4 eq), HFIP (30 mL)
110 oC, 24 h
CHO
1a
2a
, 12 mmol
3aa
, 55%, 0.94 g
, 8 mmol
Besides, deuteration experiments were also performed to
determine the kinetic isotope effects (KIEs) of this reaction. As
shown in Scheme 5, when competitive and parallel
deuteration reactions for C-H arylation were carried out, the
KIEs were found to be KH/KD = 3.7 and 4.2, respectively,
indicating that the C-H cleavage might be involved in the rate-
determining step (RDS). Furthermore, the H/D exchange
reaction provided the evidence that the C-H activation is
irreversible. In addition, a KH/KD = 1.5 was observed in the
MnO2 oxidative cyclization to exclude the involvement of C-H
cleavage in the RDS and further evidence the possible radical
way.
Scheme 3 Gram-scale synthesis of 3aa
To verify the synthetic utility of this transformation, the
scalable synthesis of 3aa was carried out. As shown in Scheme
3, the corresponding product could be obtained in 55% yield
(0.94 g) under the standard reaction conditions.
O
I
Cl
CHO
Cl
N
Cl
Cl
standard conditions
without MnO2
+
+
+
a
( )
CHO
1a
2a
, 0.3 mmol
A
, 35%
B
3aa
, 0%
, 0.2 mmol
, 20%
O
Cl
N
Cl
standard conditions
(b)
B
3aa
, 0%
, 0.2 mmol
O
CHO
Cl
N
Cl
Cl
standard conditions
competitive reaction for C-H arylation
+
Cl
CHO
I
Cl
Pd(OAc)2 (10 mol%)
c
(
)
B
3aa
, 25%
, 57%
92%
0%
A
, 0.2 mmol
L-tert-leucine (1 eq)
KH/KD = 3.7
+
without Pd(OAc)2 and AgTFA
without Pd(OAc)2 and MnO2
0%
d
(
)
CHO
AgTFA (2 eq), AcOH (4 eq)
HFIP (0.2 M), 110 oC, 3 h
H3/D3
H4/D4
0%
e
)
(
MnO2 (2 eq)
L-tert-leucine (1 eq)
Cl
Cl
N
Cl
Cl
CHO
Cl
NH
A
A
/[D3]-
1a
1a
2a
, 1.5 eq
/[D4]-
f
( )
AcOH (4 eq), HFIP, 110 o
C
+
parallel reaction for C-H arylation
12 h
D
Cl
A
A
3aa
, 80%
C
detected by GC-MS
Cl
D
CHO
, 0.2 mmol
,
I
Pd(OAc)2 (10 mol%)
L-tert-leucine (1 eq)
CHO
N
AcONH4 (1 eq)
D
CHO
+
AcOH (4 eq), HFIP, 110 o
24 h
C
AgTFA (2 eq), AcOH (4 eq)
HFIP (0.2 M), 110 oC, 3 h
D
D
D
D
3aa
, 0.2 mmol
A
[D3]- , 5%
1a
[D4]-
2a
, 1.5 eq
g
(
h
(
)
)
with MnO2
without MnO2
90%
0%
KH/KD = 4.2
I
Pd(OAc)2 (10 mol%)
L-tert-leucine (1 eq)
Cl
Cl
CHO
MnO2 (2 eq)
L-tert-leucine (1 eq)
CHO
Cl
Cl
N
Cl
Cl
+
CHO
i
( )
AgTFA (2 eq), AcOH (4 eq)
HFIP (0.2 M), 110 oC, 3 h
AcOH (4 eq), HFIP, 110 o
24 h
C
1a
2a
A
, 21%
, 1.5 eq
A
3aa
, 0.2 mmol
, 0%
TEMPO or BHT (2.0 eq)
MnO2 (2 eq)
AcONH4 (1 eq)
H/D exchange reaction
CHO
N
j
( )
D
Cl
D
D
Cl
AcOH (4 eq), HFIP, 110 o
24 h
C
Pd(OAc)2 (10 mol%)
L-tert-leucine (1 eq)
D
CHO
D
CHO
3% H
A
3aa
, 0%
, 0.2 mmol
TEMPO (2.0 eq)
AgTFA (2 eq), AcOH (4 eq)
HFIP (0.2 M), 110 oC, 24 h
D
D
D/H
Scheme 4 Control experiments
1a
[D4]- , > 99% D
1a
[D4]- , 97% D
To gain insight into the mechanistic details, a series of
control experiments were conducted (Scheme 4). In the
absence of MnO2, the reaction of 1a and 2a could only
generated 3-chloro-[1,1'-biphenyl]-2-carbaldehyde (A) and 1-
chloro-9H-fluoren-9-one (B) without the observation of
phenanthridine 3aa (Scheme 4, a). Next, the further
investigation of A and B was carried out under the varied
reaction conditions. It was found that A could transform to the
desired product 3aa in 57% yield under the standard reaction
conditions while B was not reactive at all (Scheme 4, b and c).
Moreover, with MnO2 as the sole oxidant, compound 3aa
could be produced from A in an excellent yield, while no
reaction took place in the absence of MnO2. These results
competitive reaction for annulation
MnO2 (2 eq)
L-tert-leucine (1 eq)
Cl
N
Cl
CHO
D4/H4
D5H5
KH/KD = 1.5
AcOH (4 eq), HFIP (0.2 M)
110 oC, 3 h
A
/[D5]-
A
3aa/
3aa
[D4]-
Scheme 5 Deuteration studies
Based on the experimental research above and previous
literatures, a plausible reaction mechanism was proposed
(Scheme S1 in the Supporting Information). Firstly, by use of
amino acid as the transient directing group, the palladium
catalysed C-H arylation of aldehydes was achieved to furnish
the
biaryl
aldehyde
A.11
Meanwhile,
a
decarboxylation/oxidation cascade of amino acid took place to
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Y. X. Wang, J. H. Wang, G.-X. Li, G. He and G. Chen, Org. Lett.,
yield the corresponding imine intermediate VII. While the
hydrolysis of VII could give ammonia,13 the over-oxidation
reaction would deliver the nitrile compound which was
observed by GC-MS analysis (see details in the Supporting
Information). Subsequently, the condensation of A and
ammonia would form the crucial imine intermediate C, which
was oxidized by MnO2 to produce the imine radical cation D.14
Finally, D underwent intramolecular radical cyclization and the
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5
6
sequential
phenanthridine product 3.
In conclusion, the expeditious and novel access to
phenanthridines via Pd/MnO2-mediated C-H
oxidation/aromatization
to
furnish
the
arylation/oxidative annulation cascade involving aldehydes
and aryl Iodides is developed, in which amino acid serve as
both the directing group and nitrogen source. The reaction
proceeds with the well tolerance of a variety of functional
groups and could be readily scalable. Moreover, the
mechanistic studies evidenced a radical pathway for the MnO2
promoted cyclization of imine to construct phenanthridine
core. And broad applications of this catalytic system for the
synthesis of diverse valuable heterocycles and ligands are
ongoing in our laboratory.
7
(a) B. Niu, K. Yang, B. Lawrence and H. Ge, ChemSusChem,
2019, 12, 2955; (b) P. Gandeepan and L. Ackermann, Chem,
2018, 4, 199; (c) W. Liu, J. Zheng, Z. Liu, W. Hu, X. Wang and
Y. Dang, ACS Catal., 2018, 8, 7698.
8
9
F.-L. Zhang, K. Hong, T.-J. Li, H. Park and J.-Q. Yu, Science,
2016, 351, 252.
Funding from the National Natural Science Foundation of China (No.
21702237, and 21272004) is acknowledged.
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Conflicts of interest
There are no conflicts of interest to declare.
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