Practical Synthesis of Phenanthridinones by Palladium-Catalyzed One-Pot C-C and C-N Coupling Reaction: Extending the Substrate Scope to o-Chlorobenzamides

Article abstract of DOI:10.1002/ejoc.201501170

A highly efficient construction of phenanthridinone derivatives from o-halobenzamides was developed by using a phosphine-free palladium catalyst in N,N-dimethylacetamide. The domino reaction proceeds through a sequential C-C and C-N bond-formation process in one pot. This protocol exhibits broad substrate scope and affords a series of phenanthridinones in up to 93 % yield. Importantly, the protocol could also be applied for the less reactive o-chlorobenzamides. The approach constitutes the first example of the synthesis of phenanthridinones from this kind of substrate. Moreover, the success of a gram-scale reaction demonstrated that this operationally simple process is scalable.

Full text of DOI:10.1002/ejoc.201501170

DOI: 10.1002/ejoc.201501170
Full Paper
Deamidation Coupling
Practical Synthesis of Phenanthridinones by Palladium-
Catalyzed One-Pot C–C and C–N Coupling Reaction: Extending
the Substrate Scope to o-Chlorobenzamides
Hailong Liu,[a] Weibiao Han,[a] Chun Li,[a] Zhiyong Ma,[a] Ruixiang Li,[a] Xueli Zheng,[a]
Haiyan Fu,*[a] and Hua Chen*[a]
Abstract: A highly efficient construction of phenanthridinone ones in up to 93 % yield. Importantly, the protocol could also
derivatives from o-halobenzamides was developed by using a be applied for the less reactive o-chlorobenzamides. The ap-
phosphine-free palladium catalyst in N,N-dimethylacetamide. proach constitutes the first example of the synthesis of phen-
The domino reaction proceeds through a sequential C–C and anthridinones from this kind of substrate. Moreover, the success
C–N bond-formation process in one pot. This protocol exhibits of a gram-scale reaction demonstrated that this operationally
broad substrate scope and affords a series of phenanthridin- simple process is scalable.
Introduction
phenanthridinones and their derivatives has been an area of
intense research. The conventional synthetic methods usually
require multiple steps or harsh reaction conditions.[2] Therefore,
an efficient and practical protocol for the preparation of
phenanthridinones remains in demand. In recent years, palla-
dium-mediated coupling reactions have developed into one of
the most powerful tools in organic synthesis because of its high
efficiency in the assembly of new compounds. In this context,
a palladium-catalyzed approach has been developed to provide
an alternative access to phenanthridinones.[3,4] For instance,
palladium-catalyzed intramolecular direct arene arylation,[3b]
Suzuki–Miyaura cross-coupling of (2-aminophenyl)boronic acid
with o-halobenzoate,[3l] decarboxylative coupling of 2-(2-
bromo-N-methylbenzamido)benzoic acid,[3m] double or multi-
ple C–H activation starting from N-methoxybenzamide and aryl
iodide or simple arenes have been reported.[3p,3q] Readily avail-
able o-halobenzamide derivatives have frequently been used
as starting materials. These compounds can be annulated by
arynes[3k] or cyclized with ortho-substituted iodoarenes in the
presence of norbornene[3a] to afford the phenanthridinones. Re-
cently, important studies reported by Catellani, Kan, and Porée
revealed that two molecules of o-halobenzamide could be cou-
pled to form phenanthridinone by palladium-catalyzed C–N de-
amidation and C–C coupling reaction involving ipso-substitu-
tion, respectively.[3f–3j] However, these reaction systems require
either air-sensitive phosphine ligands or malodorous nor-
bornene as additives. Furthermore, the scope of the reactions
is usually limited to o-bromo(iodo)benzamides (Scheme 2); the
use of more challenging but less expensive o-chlorobenz-
amides as substrates have not been reported. These problems
stimulated us to find alternative catalytic systems for the syn-
thesis of phenanthridinone derivatives. Herein, we report a
phosphine-free palladium-catalyzed system for the construction
of the phenanthridinone derivatives from o-bromo(chloro)-
benzamides.
Phenanthridinones composed of three fused six-membered
rings are the key motifs of Amaryllidaceae alkaloids, which have
potent biological activity, including antitumor and antivirus ac-
tivities, and acetylcholinesterase inhibition (Scheme 1).[1] The
development of synthetic methods for the construction of
Scheme 1. Selected examples of phenanthridinone derivatives as natural pro-
ducts or key skeleton of bioactivity.
[a] Key Laboratory of Green Chemistry & Technology, Ministry of Education,
College of Chemistry, Sichuan University
Chengdu, People's Republic of China
E-mail: scuhchen@scu.edu.cn
scufhy@scu.edu.cn
http://chem.scu.edu.cn/test/jiaoshi/FuHaiYan
http://chem.scu.edu.cn/test/jiaoshi/ChenHua
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501170.
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Table 1. Optimization of Pd catalyst.[a]
Entry
Pd source
Yield of 1b [%][b]
1
2
3
4
5
PdClC3H5dppb
Pd2(dba)3
PdCl2
Pd(OAc)2
PdCl2(PhCN)2
56
55
35
37
58
[a] Reaction conditions: Pd catalyst (2 mol-%), 1a (0.5 mmol, 1 equiv.), K2CO3
(3 equiv.), DMAc (2 mL), 140 °C, 24 h. [b] Detected by NMR spectroscopic
analysis using an internal standard.
Table 2. Optimization of the reaction conditions.[a]
Entry
Base (equiv.)
Additive (μL)
Solvent
Yield of 1b [%][b]
Scheme 2. Palladium-catalyzed C–N deamidation coupling reaction and C–C
coupling reaction.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17[c]
18[d]
K2CO3 (3)
KOAc (3)
K3PO4 (3)
KF (3)
–
–
–
–
–
–
–
–
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
xylene
NMP
58
9
62
66
71
48
85
48
78
92
88
34
32
61
42
72
68
80
CsF (3)
CsF (2)
CsF (4)
CsF (5)
CsF (4)
CsF (4)
CsF (4)
CsF (4)
CsF (4)
CsF (4)
CsF (4)
CsF (4)
CsF (4)
CsF (4)
Results and Discussion
Initially, we carried out the reaction in N,N-dimethylacetamide
(DMAc) at 140 °C, in the presence of 2 mol-% of PdClC3H5dppb
and K2CO3, in an attempt to construct azepinone, a seven-mem-
bered lactam, from compound 1a by Pd-catalyzed direct intra-
molecular C–H arylation.[5] However, possibly due to the ex-
tremely low reactivity of the furan C3–H group,[6] no expected
azepinone was detected. Instead, phenanthridinone derivative
1b was obtained in 56 % yield (Table 1, Entry 1). The result
turned our focus towards developing an efficient way to synthe-
size phenanthridinone derivatives. The optimization of reaction
conditions are shown in Tables 1 and 2.
H2O (1)
H2O (2)
H2O (3)
H2O (4)
H2O (2)
H2O (2)
H2O (2)
H2O (2)
H2O (2)
H2O (2)
diglyme
DMF
DMAc
DMAc
[a] Reaction conditions: PdCl2(PhCN)2 (2 mol-%), 1a (0.5 mmol, 1 equiv.), sol-
vent (2 mL), 140 °C, 24 h. [b] Based on NMR spectroscopic analysis using an
internal standard. [c] 120 °C. [d] 160 °C.
Upon testing several other Pd salts, it was found that
Pd(OAc)2 and PdCl2 gave much lower yields (Table 1,
Entries 3 and 4), whereas the use of Pd2(dba)3 or PdCl2(PhCN)2
resulted in comparable yields (Entries 2 and 5). Therefore, we
the presence of water has a great influence on the yield. A
detailed investigation on the effect of the amount of water re-
vealed that 2 μL of water is optimal, improving the yield to
92 % (Entry 9). Solvent screening and temperature variation ex-
periments showed that the best solvent was DMAc, and the
best temperature was 140 °C. Consequently, the catalytic sys-
tem was established as: 2 mol-% of PdCl2(PhCN)2 and 4.0 equiv.
of CsF, with 2 μL of water as additive in DMAc. These conditions
were used to investigate the scope of the reaction.
subsequently used
a phosphine-free palladium catalyst
PdCl2(PhCN)2 for further optimization. The nature of the base
was also found to be important for the reaction. Although it
was shown by other groups that the carbonate base was neces-
sary for the reaction to proceed,[3i,3j] our base screening investi-
gation demonstrated that CsF and K3PO4 were also suitable for
our system, affording 1b in 71 and 62 % yield, respectively. The
yield was further enhanced to 85 % by using 4.0 equiv. CsF
(Table 2, Entry 6). The reason why CsF is so effective might be
Under the optimized reaction conditions, we set out to test
that it enhances deprotonation of the N–H group by hydrogen- the scope of the reaction with respect to amides (Table 3). A
bond formation. Further optimization led to the discovery that diverse range of N-heteroaromatic, N-aromatic and N-alkyl-o-
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Table 3. Scope of the reaction with respect to bromo-substituted substrate.[a]
bromoarylamides were found to be suitable substrates. When
the N-substituted groups of R were heteroaromatics (1b–9b),
good yields (81–90 %) were obtained. Notably, the thiophene-
substituted substrates, which contain a sulfur atom, did not ap-
pear to poison the palladium catalyst (6b–9b). N-Benzylaryl-
amides provided the corresponding phenanthridinone deriva-
tives 10b–19b in 63–93 % isolated yields. N-Phenyl- and N-alk-
ylarylamides also reacted smoothly and gave the product in
excellent yields (20b–27b). The electron nature of the aromatic
ring in o-bromobenzamide affected the outcome of the reac-
tion to a certain extent. Electron-neutral and electron-deficient
substrates all afforded the expected products in high yields
(1b–3b, 5b, 7b–13b, and 15b–27b).[7] In the case of the elec-
tron-rich substrates (e.g., R2 = CH3), an increase in the amount
of catalyst to 4 mol-% was required to achieve good yields (4b,
6b, and 14b). This phenomenon differed from the previously
reported results, for which the reaction efficiency depended
strongly on the electronic nature of the substrates, and the
scope of the reaction was limited to electron-rich o-bromobenz-
amides.[3g,3i,3j] In contrast, electron-withdrawing groups such as
F and CF3 were compatible with our system. To our surprise,
when F was present ortho to the bromine atom, good results
could still be obtained despite the increased steric hindrance
(3b, 9b, and 12b). We expect that this catalytic system will be
an effective complementary approach to existing processes.
Aryl chlorides remain an uncommon reagent in Pd-catalyzed
coupling reactions because of the low reactivity of the relatively
inert C–Cl bond. However, because of their lower cost and
wider diversity, aryl chlorides are always attractive substrates in
place of their bromo counterparts. We were pleased to find that
o-chlorobenzamide derivatives were also reactive under the es-
tablished catalytic conditions, albeit requiring a higher catalyst
loading of 4 mol-% (Table 4). To our knowledge, the use of
chlorobenzamide as substrate to construct phenanthridinone
by Pd-catalyzed aryl–aryl and N–aryl coupling has not been re-
ported. Selected examples are outlined in Table 4.
N-Substituted o-chlorobenzamides were investigated to
study the effect of the R group on the reaction. Both benzyl and
phenyl groups afforded the corresponding products in good to
excellent yields (Table 4; 10b vs. 20b). The amide core can be
electron-neutral and electron-deficient. For example, both
benzamide and arylamides containing a fluoro, methylsulfonyl,
or trifluoromethyl group generated the corresponding products
in good yields (71–84 %). Interestingly, even N-benzyl-2-chloro-
3-(trifluoromethyl)benzamide, bearing a sterically demanding 3-
CF3 substituent, resulted in a 78 % yield of 28b. In contrast,
substrate N-benzyl-2-chloro-3-methylbenzamide, bearing
a
weak electron-donating 3-CH3 group, gave the corresponding
desired product 30b in only 25 % yield. The use of PCy3·HBF4
as a promoter, which is a popular ligand,[8] greatly improved
the yield of 30b to 86 %. In contrast to the result obtained with
o-bromo-N-heteroaromatic-substituted substrates, relatively
low yields were induced when the o-chloro derivative had a
heteroaryl group attached to the N atom, which led mainly to
recovery of starting material. However, it is notable that the
reaction proceeded with moderate yields in the presence of the
PCy3 ligand (1b and 7b).
[a] Reaction conditions: PdCl2(PhCN)2 (2 mol-%), substrate (0.25 mmol,
1 equiv.), CsF (4 equiv.), DMAc (1 mL), H2O (1 μL), 140 °C, 24 h. Isolated yields.
[b] PdCl2(PhCN)2 (4 mol-%).
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Table 4. Scope of the reaction with respect to chloro-substituted substrates.[a] Experimental Section
General Remarks: All reactions were carried out in dried Schlenk
tubes under argon. Unless otherwise indicated, reagents obtained
from commercial sources were used without further purification.
DMAc, DMF, xylene and NMP were dried and distilled under re-
duced pressure and stored over molecular sieves (4 Å). NMR spectra
were recorded with a Bruker Avance II (400 MHz) spectrometer. HR
mass spectra (ESI) were recorded with a Waters Q-TOF Premier spec-
trometer.
General Procedure for the Synthesis of Substrates (Amides): 2-
Bromobenzoic acid (1 mmol, 201 mg, 1 equiv.) or its derivative was
dissolved in CH2Cl2 (5 mL); then Et3N (1.1 mmol, 154 μL, 1.1 equiv.)
was added dropwise followed immediately by the dropwise addi-
tion of isobutyl chloroformate (1.1 mmol, 143 μL, 1.1 equiv.) at 0 °C.
The mixture was stirred for 15 min; then amine (1.2 mmol,
1.2 equiv.) was added dropwise at 0 °C. The resulting mixture was
stirred at room temperature, and the progress of the reaction was
monitored by TLC. Upon complete consumption of 2-bromobenzoic
acid, the mixture was concentrated in vacuo, and the residue was
purified by column chromatography on silica gel (petroleum ether/
EtOAc/CH2Cl2, 5:1:2 or 9:1:2) to afford the desired compound.
Typical Procedure for the Palladium-Catalyzed C–N Deamid-
ation Coupling Reaction and C–C Coupling Reaction of 2-
Bromo-N-(furan-2-ylmethyl)benzamide
(1a):
PdCl2(PhCN)2
(0.01 mmol, 3.8 mg), 2-bromo-N-(furan-2-ylmethyl)benzamide (1a;
0.5 mmol, 140.1 mg), CsF (2 mmol, 304 mg), and H2O (2 μL,
0.11 mmol) were added to a Schlenk flask, and the mixture was
dissolved in anhydrous DMAc (2 mL) under nitrogen. The reaction
mixture was stirred at 140 °C for 24 h; then ethyl acetate was added
to dissolve the mixture as much as possible (except for inorganic
salts). Celatom was used to filter undissolved substances. The sol-
vent was then evaporated under vacuum, and the mixture was puri-
fied by column chromatography on silica gel (petroleum ether/
EtOAc/CH2Cl2, 5:1:2) to afford 1b (55.7 mg, 81 %) as a pale-yellow
solid.
[a] Reaction conditions: PdCl2(PhCN)2 (4 mol-%), substrate (0.25 mmol), CsF
(4 equiv.), DMAc (1 mL), H2O (1 μL), 140 °C, 24 h. Isolated yields. [b] PCy3·HBF4
(8 mol-%).
A scaled-up experiment (Scheme 3) was performed on a
gram-scale reaction of N-benzyl-2-chlorobenzamide under the
same conditions. Scaled up by 32 times to 8 mmol, the reaction
proceeded as expected to give the desired product 10b in 76 %
isolated yield, demonstrating the practicality of this method.
Acknowledgments
We appreciate the National Natural Science Foundation of
China (21202104) for financial support.
Keywords: Palladium · Domino reactions · C–C coupling · C–
N coupling · Synthetic methods
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Conclusions
We have reported a highly efficient system for the construction
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Received: October 9, 2015
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Published Online: November 25, 2015
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