Assembly of substituted phenanthridines via a cascade palladium-catalyzed coupling reaction, deprotection and intramolecular cyclization

Article abstract of DOI:10.1039/c6ra00249h

The discovery and development of a general method for the one-pot synthesis of substituted phenanthridines is presented. In the presence of Pd(PPh₃)₄, accessible precursors undergo a Suzuki cross-coupling reaction with 2-(Boc-amino)benzeneboronic acid pinacol ester and then spontaneously undergo deprotection and intramolecular condensation to form the corresponding phenanthridines in one step. This reaction has a wide range of substrates with various functional groups, and the corresponding products have been obtained in good yields.

Full text of DOI:10.1039/c6ra00249h

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Assembly of substituted phenanthridines via
a cascade palladium-catalyzed coupling reaction,
Cite this: RSC Adv., 2016, 6, 19571
deprotection and intramolecular cyclization†
ab
a
b
b
ab
Jun Ge,ab Xiaojian Wang,
*
*
Tianqi Liu, Zeyu Shi, Qiong Xiao and Dali Yin
The discovery and development of
a general method for the one-pot synthesis of substituted
phenanthridines is presented. In the presence of Pd(PPh3)4, accessible precursors undergo a Suzuki
cross-coupling reaction with 2-(Boc-amino)benzeneboronic acid pinacol ester and then spontaneously
undergo deprotection and intramolecular condensation to form the corresponding phenanthridines in
one step. This reaction has a wide range of substrates with various functional groups, and the
corresponding products have been obtained in good yields.
Received 5th January 2016
Accepted 11th February 2016
DOI: 10.1039/c6ra00249h
www.rsc.org/advances
synthesis of the substituted phenanthridine motif has spurred
vigorous research for the development of new methodologies.
Introduction
Traditionally, phenanthridines are synthesized by the Pictet–
Hubert reaction, which usually performed in the presence of
P4O10, POCl3, or PCl5 at elevated temperatures.18–21 The limita-
tion of functional group tolerance was observed in the Pictet–
Hubert reaction due to the harsh conditions. Besides the tradi-
tional methods, phenanthridines have recently been success-
fully prepared by transition metal catalyzed approaches,22–30
radical promoted cyclization,31–41 cycloaddition,42–45 and other
methods.46–48 The general synthetic approaches leading to phe-
nanthridines are summarized in Scheme 1. Although a number
of methods are available for the synthesis of these phenan-
thridines, many are limited because of the lack of generality,
limited functional group tolerance, and lengthy synthetic time.
Thus, a simple, efficient, and general method to synthesize
phenanthridines would be still attractive.
Substituted phenanthridines are an important class of hetero-
cyclic compounds in materials science and in medicinal
chemistry due to their signicant biological activities.1–3 Mole-
cules containing the phenanthridine core are the subject of
considerable interest as potent antitumor agents,4 anti-
tuberculosis agents,5,6 and antibacterial agents.7 Structures,
shown in Fig. 1, are representative examples of natural products
and biologically relevant compounds containing phenan-
thridine core structures.8–17 Because of these applications, the
Among synthesis methodology research towards phenan-
thridines, James and his coworker rst attempted to use
20-bromoacetophenone and (2-Boc-aminophenyl)boronic acid
to construct the phenanthridines scaffold using a stepwise
Fig.
1 Examples of natural products and biologically relevant
compounds.
aState Key Laboratory of Bioactive Substances and Functions of Natural Medicines,
Institute of Materia Medica, Peking Union Medical College, Chinese Academy of
Medical Sciences, Beijing 100050, P. R. China. E-mail: wangxiaojian@imm.ac.cn;
yindali@imm.ac.cn; Fax: +86 10 63165248; Tel: +86 10 63165248
bDepartment of Medicinal Chemistry, Beijing Key Laboratory of Active Substances,
Discovery and Drugability Evaluation, Institute of Materia Medica, Peking Union
Medical College, Chinese Academy of Medical Sciences, Beijing 100050, P. R. China
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra.
See DOI: 10.1039/c6ra00249h
Scheme 1 Synthetic approaches leading to phenanthridines.
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Table 1 Screening of the reaction conditionsa
Entry
X
Catalyst
Ligand
Base
Solvent
Yieldb
1
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
dppp
dppp
dppp
dppf
Cs2CO3
NaOAc
Et3N
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
Glycol
Glycol
Glycol
Glycol
Glycol
Glycol
Glycol
Glycol
Glycol
Glycol
Glycol
Glycol
EtOH
DMF
44%
0
10%
37%
14%
17%
73%
80%
76%
67%
75%
71%
6%
Scheme
2
Strategies
for
the
construction
substituted
phenanthridines.
strategy by a Suzuki cross-coupling reaction, followed by acid-
catalyzed N-Boc removal, intramolecular cyclization and basi-
cation.49 Subsequently, Marko published the synthesis
method of a lycobetaine–tortuosine analogue, which also
included the metal catalyzed coupling and acid hydrolysis
steps.50 Obviously, amide or ester substituted materials were not
tolerated during the second acid work up step. Additionally,
Graham also mentioned a Suzuki coupling/ring closure to
prepare the norallonitidine and nornitidine. However, the
reactions were claimed to be sluggish and the products were
achieved with low yields.51 Recently, Dhara also reported
a method to synthesize substituted phenanthridines using
substituted aromatic ortho-bromoaldehydes and ortho-amino-
benzeneboronic acid as starting substrates.52 In our
previous studies, we showed a new approach for constructing
1-substituted-4-methylisoquinolines via a cascade Pd-catalyzed
Heck reaction, intramolecular cyclization and isomerization.53
In order to extend our study about synthetic methodology of
heterocyclic compound,54–57 we applied this strategy to the
construction of phenanthridines (Scheme 2).
9
I
I
10
11
12
13c
14
K3PO4
OTf
Br
I
Na2CO3
Na2CO3
Na2CO3
Na2CO3
I
20%
a
All reactions were conducted using 1a (1 mmol, 1.0 equiv.), 2 (1.2
mmol, 1.2 equiv.), base (2 mmol, 2.0 equiv.), Pd catalyst (3 mmol%),
b
solvent (3.0 mL), stirred at 120 ꢀC for 2 h under argon. Isolated
yields. c The reaction was conducted at 85 ꢀC for 4 h under argon.
Na2CO3, K2CO3 and K3PO4 were examined subsequently
(Table 1, entries 8–10). The results showed that carbonates were
better than K3PO4, but there was little difference among
Na2CO3, K2CO3 and Cs2CO3. We also investigated the effect of
reactive group X in substrates. It was found that Br and OTf gave
a similar performance as I (Table 1, entries 11 and 12). Varying
the solvents proved glycol to be optimal (Table 1, entries 8, 13
and 14). Consequently, we decided to use entry 8 as the optimal
condition to investigate the application of this transformation.
Aer the optimized reaction condition was established, we
then attempted to apply it to synthesize a series of 6-alkylphe-
nanthridines. As shown in Table 2, when R1 were electron-
Results and discussion
Initially, 2-iodoacetophenone (1a) and 2-(Boc-amino) donating groups such as alkyl and alkoxyl as well as electron-
benzeneboronic acid pinacol ester (2) were chose as the withdrawing groups like uoro, triuoromethyl, substituted
model substrates to explore the possible formation of 6-methyl 6-methylphenanthridines were successfully obtained in good
phenanthridine (3a) and the results were summarized in yields (Table 2, 3b–3f). We were pleased to nd that amide
ꢀ
Table 1. The reaction proceeded in glycol at 120 C for 2 hours group, sensitive to acid condition, was observed to tolerate this
with Pd(OAc)2 as the catalyst, 1,3-bis(diphenylphosphine) condition (Table 2, 3g). A chloro group substituent of aceto-
propane (dppp) as the ligand, Cs2CO3 as the base. To our phenone had a negative effect on this reaction (Table 2, 3h).
delight, 3a was obtained in 44% yield (Table 1, entry 1), indi- This observation, combined with the fact that some aryl chlo-
cating that it was feasible to construct the phenanthridine rides failed to be compatible well with palladium-catalyzed
scaffold based on our hypothesis. However, changing the base coupling reaction.58,59
Cs2CO3 to NaOAc or organic base Et3N failed to show any
On the other hand, the R2 substitution effect of phenones
improvement (Table 1, entries 2–3). When ligand dppp was was then investigated in reactions with 2. The ethyl, isopropyl
replaced with 1,10-bis(diphenylphosphino)ferrocene (dppf), the and cyclohexyl substituted phenones reacted efficiently,
result was similar to dppp with a yield of 37% (Table 1, entry 4). affording corresponding phenanthridine derivatives in yields
We then screened catalysts such as Pd(PPh3)2Cl2, Pd2(dba)3, and ranging from 58 to 77% (Table 2, 3i–3k). Interestingly, when R2
Pd(PPh3)4 (Table 1, entries 5–7).
was triuoromethyl group, the corresponding product was ob-
The results showed that Pd(PPh3)4 displayed the highest tained in 67% yield (Table 2, 3l). Additionally, pyridine fused
catalytic activity toward the formation of 3a in 80% yield. phenanthridine was also constructed in the current reaction
Keeping the Pd(PPh3)4 as the catalyst, other bases such as system and obtained with 55% yield (Table 2, 3m).
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Table 2 Synthesis of 6-alkylphenanthridinesab
Table 3 Synthesis of 6-unsubstituted phenanthridinesab
a
All reactions were conducted using 4a–d (1 mmol, 1.0 equiv.), 2 (1.2
mmol, 1.2 equiv.), base (2 mmol, 2.0 equiv.), Pd(PPh3)4 (3 mmol%),
solvent (3.0 mL), stirred at 120 ꢀC for 2 h under argon. b Isolated yields.
Table 4 Synthesis of 6-arylphenanthridinesab
a
All reactions were conducted using 1a–l (1 mmol, 1.0 equiv.), 2 (1.2
mmol, 1.2 equiv.), base (2 mmol, 2.0 equiv.), Pd(PPh3)4 (3 mmol%),
solvent (3.0 mL), stirred at 120 ꢀC for 2 h under argon. b Isolated yields.
Next, we turned our attention to explore whether substituted
bromobenzaldehyde could work well in this reaction system. It
was found that substrate bearing an electron-donating group
smoothly afforded the corresponding phenanthridines in good
yield (Table 3, 5b). Moreover, triuoromethyl group substituted
phenanthridine was obtained in 63% yield (Table 3, 5c). Tri-
sphaeridine,
a natural product isolated from plants of
Amaryllidaceae, was then synthesized through this method with
85% yield (Table 3, 5d).8
In light of the above results, 2-OTf/halide substituted
benzophenones were then subjected to the same conditions to
test the scope of the reaction. o-Bromobenzophenones
reacted smoothly with 2 affording corresponding phenyl-
phenanthridines in good to excellent yields. In general,
electron-donating and electron-withdrawing groups were found
to be compatible on both the A and B phenyl rings. For A phenyl
ring, aer two monosubstituted-6-phenyl-phenanthridines
were obtained (Table 4, 7b–7c), the 8,9-dimethoxy-6-phenyl-
phenanthridine was also obtained in 60% yield (Table 4, 7d).
With respect to halide-substituted substrate, the chloro-
a
All reactions were conducted under argon using 6a–k (1 mmol,
1.0 equiv.), 2 (1.2 mmol, 1.2 equiv.), Pd(PPh3)4 (3 mmol%), Na2CO3
(2 mmol, 2.0 equiv.), solvent (3.0 mL), stirred at 120 ꢀC for 2 h under
argon. b Isolated yields.
substituted substrate afforded the product in a lower yield at the para-position of B phenyl ring were methyl, nitrile and
than the corresponding uoro-substituted substrate (Table 4, triuoromethyl groups, the corresponding substituted phe-
7e–7f), which was consistent with our previous nding. More- nanthridines were obtained in good yields (Table 4, 7h, 7j–7k).
over, 3-nitro-6-phenylphenanthridine was also successfully ob- However, when the R3 group of B phenyl ring was methoxy
tained in 80% yield (Table 4, 7g). When the substituted groups group, the yield was only 59% (Table 4, 7i). Noticeably, changing
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