Synthesis of Phenanthridines through Palladium-Catalyzed Cascade Reaction of 2-Halo-N-Ms-arylamines with Benzyl Halides/Sulfonates

Article abstract of DOI:10.1002/ejoc.201601608

An efficient palladium-catalyzed nucleophilic substitution/C–H activation/aromatization cascade reaction between readily available 2-halo-N-Ms-arylamines (Ms = methanesulfonyl) and benzyl halides/sulfonates has been described. A wide variety of phenanthridines were synthesized in a one-pot fashion in moderate to high yields (37–86 %). Notably, this method provides a straightforward, facile approach for the synthesis of phenanthridines. The practicality was further substantiated by successfully carrying out a gram-scale preparation.

Full text of DOI:10.1002/ejoc.201601608

A Journal of
Accepted Article
Title: Synthesis of Phenanthridines via Palladium-Catalyzed Cascade
Reaction of 2-Halogeno-N-Ms-arylamines with Benzyl Halides/
Sulfonates
Authors: Wen-Yong Han, Si-Yi Yang, Ding-Lei Zhang, Xiao-Jian Zhou,
Mei Bai, Bao-Dong Cui, Nan-Wei Wan, Wei-Cheng Yuan, and
Yong-Zheng Chen
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601608
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601608
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10.1002/ejoc.201601608
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Synthesis of Phenanthridines via Palladium-Catalyzed Cascade
Reaction of 2-Halogeno-N-Ms-arylamines with Benzyl
Halides/Sulfonates
Si-Yi Yang,[a] Wen-Yong Han,*[a] Ding-Lei Zhang,[a] Xiao-Jian Zhou,[a] Mei Bai,[a] Bao-Dong Cui,[a] Nan-
Wei Wan,[a] Wei-Cheng Yuan,[b] and Yong-Zheng Chen*[a]
Abstract:
An
efficient
palladium-catalyzed
nucleophilic
harsh reaction conditions or complex starting materials
somewhat reduces the efficacy. From the atom- and step-
economy standpoints, to develop an efficient synthetic route
from simple and easily available starting materials for the
construction of phenanthridines for both academic and industrial
applications is highly desirable and valuable.
Given that the potential applications of palladium-catalyzed
cascade reaction involving C-H functionalization in the
construction of polycyclic aromatics,[12,13] we envisaged that the
phenanthridine scaffold could be easily constructed through
substitution/C−H activation/aromatization cascade reaction between
easily accessible 2-halogeno-N-Ms-arylamines and benzyl
halides/sulfonates has been disclosed.
A
wide variety of
phenanthridines were synthesized in one-pot fashion with moderate
to high yields (37–86%). Importantly, this methodology provided a
straightforward and facile approach to the synthesis of
phenanthridines, and the practicality was also further substantiated
by gram-scale preparation.
palladium-catalyzed
nucleophilic
substitution/C−H
functionalization/aromatization cascade from the following
starting materials: (1) easily accessible N-Ms arylamines and 2-
bromobenzyl bromide derivatives; (2) readily prepared 2-
halogeno-N-Ms-arylamines and benzyl halides/sulfonates/
acetate. Recently, we have developed a palladium-catalyzed
cascade reaction for the construction of phenanthridines from N-
Ms arylamines and 2-bromobenzyl bromide derivatives.[14]
Herein, we wish to report another promising alternative
approach using 2-halogeno-N-Ms-arylamines and benzyl
halides/sulfonates.
Introduction
Phenanthridines,
a
class of aza-polycyclic aromatic
hydrocarbons, are of high interest for the chemists because of
their prevalence in numerous natural products[1] and clinical
pharmaceuticals[2] as well as their versatile applications in
materials science.[3] Additionally, they could be served as a
valuable intermediate in the synthesis of many drug scaffolds
and natural products, including nitidine, fagaronine, bicolorine,
and NK 109.[4] Therefore, the development of new synthetic
strategies for such skeleton is always in demand. In the past
decades, a number of methodologies for the construction of
phenanthridines have been investigated.[5] Among the various
methods developed, major approaches include: (1) Pictet–
Hubert reaction from N-acyl-o-xenylamine,[6] (2) intramolecular
radical nucleophilic substitution from (2-halobenzyl)-N-
arylamines,[7] (3) radical isonitrile insertion reaction from 2-
isocyanobiphenyls,[8] (4) Fe(III)/photocatalyzed intramolecular N-
arylation from O-acyl oximes,[9] and (5) palladium-catalyzed
Suzuki coupling/condensation process from ortho-functionalized
organoboron compounds.[10] In addition, other methods to
construct phenanthridines have also been reported.[4,11] Despite
the elegance of the above approaches, the requirement of either
Results and Discussion
[a]
S.-Y. Yang, Prof. Dr. W.-Y. Han, D.-L. Zhang, X.-J. Zhou, Dr. M. Bai,
Prof. Dr. B.-D. Cui, Prof. Dr. N.-W. Wan, Prof. Dr. Y.-Z. Chen
Generic Drug Research Center of Guizhou Province, School of
Pharmacy
Scheme 1. Synthesis of Substrates.
Zunyi Medical University
Zunyi 563000 (China)
E-mail: hanwy@zmc.edu.cn; yzchen@zmc.edu.cn
Prof. Dr. W.-C. Yuan
National Engineering Research Center of Chiral Drugs, Chengdu
Institute of Organic Chemistry
Chinese Academy of Sciences
As shown in Scheme 1, all substrates could be obtained
according to the sophisticated literature procedures. 2-halogeno-
N-Ms arylamines (1a-o) could be readily synthesized from the
corresponding 2-halogeno-arylamines in good to high yields by
simple mesylation (Scheme 1a).[15] Benzyl bromide derivatives
(2a-h) could be easily available from cheap aryl aldehydes or
[b]
Chengdu 610041 (China)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201601608
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Table 1. Optimization of Reaction Conditions.[a]
Entry
[Pd]
Ligand
Base
Solvent
Yield (%)[b]
1
2
Pd(TFA)2
PPh3
PPh3
Cs2CO3
Cs2CO3
DMF
DMF
34
57
Pd(OTf)2(dippp)
3
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
Pd(OTf)2(dippp)
TFP
dppb
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
DMF
DMF
49
50
4
5
dpppe
DMF
47
6
JohnPhos
CyJohnPhos
BrettPhos
SPhos
DMF
46
7
DMF
38
8
DMF
38
9
DMF
45
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
RuPhos
XPhos
DMF
38
DMF
62
tBuXPhos
DavePhos
XantPhos
rac-BINAP
XPhos
DMF
44
DMF
43
DMF
10
DMF
16
DMF
trace
trace
trace
trace
trace
52
XPhos
DMF
XPhos
K3PO4
DMF
XPhos
NaOAc
NaOPiv
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
XPhos
DMF
XPhos
DMSO
NMP
XPhos
66
XPhos
mesitylene
1,4-dioxane
tAmOH
NMP/DMF
NMP/DMSO
8
XPhos
50
XPhos
46
XPhos
48[c]
77[c]
XPhos
XPhos
NMP/1,4-dioxane
64[c]
70[c]
XPhos
NMP/tAmOH
[a] Unless otherwise stated, all reactions were carried out with 1a (0.3 mmol), 2a (0.3 mmol) and base (4.0 equiv) in 2.0 mL of solvent with 5 mol% Pd-catalyst
and 20 mol% ligand under N2 atmosphere at 160 °C for 24 h. [b] Isolated yield. [c] Mixed solvents (1.0 mL/1.0 mL) were used.
toluene derivatives or direct commercial source (Schemes 1b
and 1c).[16] Starting from phenylmethanol under different reaction
conditions, benzyl chloride (2i), benzyl mesylate (2j), benzyl
tosylate (2k), and benzyl acetate (2l) could be obtained in 78%,
73%, 85%, and 89% yields, respectively (Scheme 1d).[17]
were initially employed to promote the reaction. To our delight,
the reaction proceeded smoothly to afford 3a in 34% yield (Table
1, entry 1). Encouraged by this preliminary result, a series of
palladium catalysts, including Pd(II) and Pd(0) species were
screened, which revealed that Pd(OTf)2(dippp) was the optimal
catalyst, delivering 3a in 57% yield (Table 1, entry 2).[18] Using
other monophosphine ligands, bidentate phosphine ligands, as
well as bulky biarylphosphine ligands resulted in low to
moderate yields (Table 1, entries 3–15) (Figure 1), and XPhos
Based on the successful development in the synthesis of
phenanthridines,[14] we further investigated the palladium-
catalyzed
cascade
reaction
using
N-(2-
bromophenyl)methanesulfonamide (1a) and benzyl bromide (2a)
as substrates. Empirical combination of Pd(TFA)2 and PPh3
(2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl)
was
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10.1002/ejoc.201601608
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proved to be the best choice (Table 1, entry 11). After
examination of some other inorganic bases, it was found that
Na2CO3, K2CO3, K3PO4, NaOAc, and NaOPiv were all ineffective
for this conversion (Table 1, entries 16–20). To promote the
efficacy, a survey of solvents revealed that NMP (N-methyl
pyrrolidone) was our choice (Table 1, entry 22). Finally, the yield
could be dramatically improved to 77% employing DMSO
(dimethyl sulfoxide) as a co-solvent (Table 1, entry 27).[19,20]
Table 2. The Substrate Scope of 2-Halogeno-N-Ms-arylamines.
N
Pd(OTf)2(dippp) (5 mol%)
XPhos (20 mol%)
Cs2CO3 (4.0 equiv)
NMP/DMSO (1.0 mL/1.0 mL)
N2, 160 oC, 24 h
Br
NHMs
Ar1
Ar1
+
H
X
X = Cl, Br, I
1a-o
2a
3a-m
Entry
Substrate
Product
Yield(%)[a]
1
2
3
1a, X = Br
1b, X = Cl
1c, X = I
3a
3a
3a
77
40[b]
80[b]
4
5
1d, R = Me
1e, R = OMe
3b
3c
82[b]
58
6
7
8
9
1f, R = Me
1g, R = OMe
1h, R = F
1i, R = Cl
1j, R = CF3
3d
3e
3f
3g
3h
72[b,c]
67
37[c,d]
38[b,c]
55[b,c]
10
11
80[b,c]
Figure 1. Various phosphine ligands studied for palladium-catalyzed cascade
reaction.
With the optimized reaction conditions in hand (Table 1, entry
27), we next explored the scope of 2-halogeno-N-Ms-arylamines
(1a-o) via a Pd(II)-catalyzed cascade reaction with benzyl
bromide (2a). As shown in Table 2, 2-chloride-N-Ms-
phenylamine (1b) and 2-iodide-N-Ms-phenylamine (1c) were
both effective substrates, in which lower yield (40%) and higher
yield (80%) were observed for chloride and iodide, respectively
(Table 2, entries 2 and 3). These results were consistent with
the reactivity of aryl halides.[21] The cascade reaction could be
extended to various 2-bromide-N-Ms-arylamines (1d-m) bearing
either electron-rich or electron-deficient substituents at the C3,
C4, C5, and C6 position on the phenyl ring, affording the
corresponding phenanthridines (3b-k) in 37−83% yields (Table 2,
entries 4–13). We also surveyed the reactivity of the
corresponding substrate involving sensitive functional group,
such as -CO2Me. However, the reaction was very complicated
as monitored by thin layer chromatography (TLC) analysis and
no desired product was observed (date was not given). In
general, functional groups, including methyl, methoxyl, fluoro,
chloro and trifluoromethyl, were all tolerated. Notably, the
products bearing halogens could be further functionalized for the
construction of other kinds of phenanthridines. N-(2-bromo-4,6-
dimethylphenyl) methanesulfonamide (1n) and N-(2-bromo-
12
13
1l, R = Me
1m, R = F
3j
3k
83[c]
78[b,c,d]
14
15
70
86[c]
[a] Isolated yields. [b] NMP (2.0 mL) was used as solvent. [c] Run for 48 h. [d]
Using PdCl2 and PPh3 instead of Pd(OTf)2(dippp) and XPhos, respectively.
naphthalen-1-yl)methanesulfonamide (1o) were also good
substrates for this reaction, and the desired products 3l and 3m
were obtained in 70% and 86% yields, respectively (Table 2,
entries 14 and 15). Furthermore, various benzylic
halides/sulfonates/acetate (2b-l) were examined subsequently
(Table 3). This reaction could proceed with ortho-, meta- and
para-substituted benzyl bromides, giving the corresponding
compounds (3n-q) in 50–57% yields (Table 3, entries 1–4).
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other kinds of substrates, such as benzyl chloride (2i), benzyl
mesylate (2j), benzyl tosylate (2k) and benzyl acetate (2l), were
further investigated. Although moderate yields were obtained,
the method was also compatible with compound 2i–k (Table 3,
entries 8–10). However, compound 2l was an ineffective
substrate for synthesis of phenanthridine, which was attributed
to the poor leaving ability of acetoxy group in 2l (Table 3, entry
11).
Table 3. The Substrate Scope of Benzylic Halides/Sulfonates/Acetate.
Entry
1
Substrate
Product
Yield(%)[a]
50[b]
2
3
51[b]
Scheme 2. Reaction on a Gram Scale.
52
2.7:1[c]
To demonstrate the utility of the current methodology, a
gram scale reaction was carried out under the almost identical
reaction conditions (Scheme 2). While a somewhat prolonged
reaction time (30 h) was required, the reaction proceeded well to
afford the corresponding product 3b in 79% isolated yield.
4
57
With the above-mentioned results in hand, we further
compared the current approach with our previously reported
alternative method for the same products (Table 4).[14]
Employing previous method, phenanthridine (3a) was
synthesized in 80% yield from N-phenylmethanesulfonamide
(4a) and 2-bromobenzyl bromide (5a). In comparison, the
substrate scope in our present approach for phenanthridine (3a)
was obviously more general (Table 4, entry 1). More importantly,
3b and 3i could be selectively constructed with high yields in
present work only by switching the position of the methyl group
in 2-bromide-N-Ms-arylamines (1d and 1k); however, the
regioselectivity issue was inevitably involved in previous process
using N-meta-tolylmethanesulfonamide (4b), affording two
unseparated isomers (3i/3b) in 31% overall yield with a 6.1:1
ratio. But regioselectivity was also observed with meta-methyl-
benzyl bromide (2d) using current method (Table 3, entry 3).
Therefore, these two strategies provided complementary
protocols toward the synthesis of phenanthridine analogues,
especially for the ones concerning a regioselectivity issue.
5
6
7
56
46[b]
45
8
9
10
11
2i, Y = Cl
3a
3a
3a
3a
51
46
53
0
2j, Y = OMs
2k, Y = OTs
2l, Y = OAc
To gain more insight into the palladium-catalyzed cascade
reaction mechanism, three control experiments have been
carried out. As shown in Scheme 3, the nucleophilic substitution
between 1d and 2a proceeded smoothly in the absence of
palladium catalyst and ligand, leading to compound 6b in 97%
yield (Scheme 3a). Subsequently, compound 7b was obtained in
90% yield from 6b via an intramolecular C−H arylation process
(Scheme 3b). After heating of compound 7b in NMP at 160 °C
for 10 h, aromatized product 3b could be isolated in 92% yield
(Scheme 3c). From these results, compound 6b and 7b are
proven to be two possible intermediates for the cascade reaction.
Based on the above results and previous study on Pd(II)-
catalyzed nucleophilic substitution/C-H activation/aromatization
cascade reaction,[14] a plausible mechanism is proposed in
Scheme 4. The nucleophilic substitution of benzyl
[a] Isolated yields. [b] NMP (2.0 mL) was used as solvent. [c] The ratio of
regioisomers (3p/3p') was determined by 1H NMR of the mixture.
Among them, meta-methyl benzyl bromide (2d) gave a mixture
of regioisomers in a 2.7:1 ratio and 52% overall yield (3p/3p′)
(Table 3, entry 3). Interestingly, starting from N-(2-
bromophenyl)methanesulfonamide (1a) and 1-(bromomethyl)-2-
fluorobenzene (2b), 7-(methyl- sulfonyl)phenanthridine (3n) was
obtained in 50% yield (Table 3, entry 1). In addition, the reaction
was also compatible with disubstituted benzyl bromides bearing
electron-donating or -withdrawing substituents at different
positions on the phenyl ring, affording the corresponding
compounds (3r-t) in 45–56% yields (Table 3, entries 5-7). Lastly,
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Table 4. The Substrate Scope of Benzylic Halides/ Sulfonates/Acetate.
Entry
Previous method[a]
Current method
1
2
[a] The results refer to being obtained with palladium-catalyzed cascade reaction from N-Ms arylamines and 2-bromobenzyl bromide derivatives in ref 14.
halides/sulfonates (2) with 2-halogeno-N-Ms-arylamines (1)
produces compound 6 in the presence of inorganic base. Next, a
catalytic cycle is initiated by oxidative addition of compound 6 to
the Pd0 species forming the intermediate A. Subsequently, the
intermediate A undergoes an intramolecular C−H arylation
affording palladacycle B, which undergoes reductive elimination
to bring about the cyclized compound 7 and regenerates the Pd0
species. Lastly, aromatization process promoted by base and
high temperature is occurred on the N-heterocycle of compound
7 to generate the title compound 3.
Conclusions
In conclusion, a facile and efficient palladium-catalyzed cascade
reaction involving nucleophilic substitution/C−H activation/
aromatization sequence for the construction of phenanthridines
has been explored. By using easily available 2-halogeno-N-Ms-
arylamines (1a-o) and benzyl halides/sulfonates (2a-l) as
partners, a broad array of phenanthridines (3a-t) were obtained
in moderate to high yields (37−86%). Remarkably, this
methodology represents a straightforward and practical protocol
for building rather simple aza-polycyclic aromatic hydrocarbons
from simple and easily available starting materials, and they will
provide a valuable synthetic tool for the discovery of drugs and
functional materials.
Scheme 3. Control Experiments for Mechanistic Studies.
Experimental Section
General methods: All commercially available reagents were used
without further purification. Column chromatography was performed on
silica gel (200-400 mesh). 1H NMR (400 MHz) chemical shifts were
reported in ppm (δ) relative to tetramethylsilane (TMS) with the solvent
Scheme 4. Proposed Mechanism.
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10.1002/ejoc.201601608
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resonance employed as the internal standard. Data were reported as
follows: chemical shift, multiplicity (s = singlet, d = doublet, dd = doublet
of doublets, t = triplet, q = quartet, m = multiplet), coupling constants (Hz)
and integration. 13C NMR (100 MHz) chemical shifts were reported in
ppm (δ) from tetramethylsilane (TMS) with the solvent resonance as the
internal standard. Melting points were uncorrected. N-Ms arylamines (1a-
o), benzyl chloride (2i), benzyl mesylate (2j), benzyl tosylate (2k), and
benzyl acetate (2l) were prepared according to the reported
procedures.[15,17] Unless otherwise stated, other substrates (2a-h) were
purchased from commercial suppliers.
Hz, 1C), 141.0 (d, J = 1.6 Hz, 1C), 132.2 (d, J = 9.2 Hz, 1C), 132.1, 131.3,
129.0, 128.3, 126.3, 125.6 (d, J = 9.1 Hz, 1C), 122.1, 117.7 (d, J = 24.2
Hz, 1C), 107.3 (d, J = 23.1 Hz, 1C).
2-Chlorophenanthridine (3g). White solid, 24.4 mg, yield 38%, mp
154.9−157.0 °C (lit.[14] 155.8−157.2 °C); 1H NMR (400 MHz, DMSO-d6) δ
9.38 (s, 1H), 8.89−8.87 (m, 2H), 8.25 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.8
Hz, 1H), 7.97 (t, J = 7.6 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.80 (d, J = 8.8
Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 154.1, 142.5, 132.0, 131.7,
131.6, 130.8, 129.1, 128.9, 128.7, 126.1, 125.0, 122.7, 122.5.
2-(Trifluoromethyl)phenanthridine (3h). White solid, 40.8 mg, yield
55%, mp 96.7−99.2 °C (lit.[4c] 98–100 °C); 1H NMR (400 MHz, DMSO-d6)
δ 9.51 (s, 1H), 9.17 (s, 1H), 9.01 (d, J = 8.4 Hz, 1H), 8.31−8.27 (m, 2H),
8.07−8.00 (m, 2H), 7.89 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz, DMSO-
d6) δ 156.2, 145.6, 132.1, 131.4, 131.0, 129.2, 128.9, 127.4 (q, J = 31.7
Hz, 1C), 126.3, 124.4 (q, J = 271.0 Hz, 1C), 124.6 (q, J = 3.2 Hz, 1C),
123.6, 122.8, 121.0 (q, J = 3.9 Hz, 1C). HRMS (ESI-TOF) Calcd. for
C14H9F3N [M+H]+: 248.0682; found: 248.0682.
General procedure for the synthesis of phenanthridines (3a-t) To a 4
mL flame-dried vial equipped with a stir bar was successively added 2-
halogeno-N-Ms-arylamines (1) (0.3 mmol), benzyl halides/sulfonates (2)
(0.3 mmol), Pd(OTf)2(dippp) (12.3 mg, 0.015 mmol), XPhos (28.6 mg,
0.06 mmol), Cs2CO3 (391.0 mg, 1.2 mmol), and dry NMP/DMSO (1.0
mL/1.0 mL). The vial was flushed with nitrogen for 30 s, sealed, and then
immersed into an oil bath (160 °C). The reaction mixture was vigorously
stirred at 160 °C for 24-48 h. After cooling to room temperature, brine
(10.0 mL) was added, and the mixture was extracted with EtOAc (5 × 10
mL). The combined organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated by rotary evaporation. The residue was purified
by flash chromatography on silica gel (petroleum ether/ethyl acetate =
5:1) to afford the corresponding phenanthridines (3).
3-Methylphenanthridine (3i). Light yellow solid, 46.4 mg, yield 80%, mp
1
66.9−68.7 °C; H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.76 (d, J =
8.4 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.93−7.89
(m, 2H), 7.75 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 2.55 (s, 3H);
13C NMR (100 MHz, DMSO-d6) δ 153.5, 144.2, 138.6, 131.8, 131.3,
129.1, 128.8, 128.7, 127.4, 125.7, 122.7, 122.0, 121.3, 21.1. HRMS (ESI-
TOF) Calcd. for C14H12N [M+H]+: 194.0964; found: 194.0964.
4-Methylphenanthridine (3j). White solid, 48.1 mg, 83% yield, mp
93.5−95.6 °C (lit.[14] mp 93.1−94.6 °C); 1H NMR (400 MHz, DMSO-d6) δ
9.37 (s, 1H), 8.77 (d, J = 8.4 Hz, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.19 (d, J
= 8.0 Hz, 1H), 7.93−7.89 (m, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.63−7.57 (m,
2H), 2.78 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 152.3, 142.6, 137.0,
132.1, 131.2, 129.4, 128.7, 127.7, 126.8, 125.7, 123.4, 122.4, 120.6,
18.2.
4-Fluorophenanthridine (3k). White solid, 46.1 mg, 78% yield, mp
93.6−96.4 °C (lit.[7b] mp 94−98 °C); 1H NMR (400 MHz, CDCl3) δ 9.28 (s,
1H), 8.50 (d, J = 8.2 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 7.8 Hz,
1H), 7.84 (s, 1H), 7.70 (s, 1H), 7.58 (s, 1H), 7.41 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 158.8 (d, J = 253.1 Hz, 1C), 153.7, 134.0 (d, J = 11.0 Hz,
1C), 132.0, 131.6, 129.1, 128.2, 127.1 (d, J = 8.4 Hz, 1C), 126.5, 126.1,
122.3, 117.9 (d, J = 4.4 Hz, 1C), 113.8 (d, J = 19.4 Hz, 1C). HRMS (ESI-
TOF) Calcd. for C13H9FN [M+H]+: 198.0714; found: 198.0744.
2,4-Dimethylphenanthridine (3l). Light yellow solid, 43.5 mg, 70% yield,
mp 116.5−118.8 °C (lit.[14] mp 117.0−118.5 °C); 1H NMR (400 MHz,
CDCl3) δ 9.23 (s, 1H), 8.57−8.51 (m, 1H), 8.19−8.15 (m, 1H), 8.02−7.98
(m, 1H), 7.82−7.77 (m, 1H), 7.68−7.62 (m, 1H), 7.41 (s, 1H), 2.85 (s, 3H),
2.56 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 151.3, 141.5, 137.3, 136.5,
132.7, 131.4, 130.7, 128.7, 127.2, 126.3, 123.9, 122.1, 119.8, 22.0, 18.7.
Benzocphenanthridine (3m). Light yellow solid, 59.2 mg, 86% yield, mp
132.8−134.9 °C (lit.[14] mp 133.5−135.1 °C); 1H NMR (400 MHz, DMSO-
d6) δ 9.60 (s, 1H), 9.32 (d, J = 8.4 Hz, 1H), 8.94 (d, J = 8.4 Hz, 1H), 8.82
(d, J = 8.8 Hz, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.12
(d, J = 7.6 Hz, 1H), 8.01 (t, J = 7.6 Hz, 1H), 7.87−7.73 (m, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 152.3, 140.6, 132.9, 132.1, 131.4, 131.3, 128.8,
127.9, 127.8, 127.7, 127.5, 127.1, 126.6, 124.2, 122.7, 120.7, 120.6.
7-(methylsulfonyl)phenanthridine (3n). Yellow solid, 38.6 mg, 50%
yield, mp 173.8−175.6 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H),
9.30 (d, J = 8.4 Hz, 1H), 8.93 (d, J = 8.4 Hz, 1H), 8.41 (d, J = 7.6 Hz, 1H),
8.22−8.15 (m, 2H), 7.91 (t, J = 7.6 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 3.54
(s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 148.2, 143.4, 137.9, 133.3,
130.6, 130.0, 129.7, 129.6, 128.9, 128.2, 123.4, 122.8, 121.2, 45.0.
HRMS (ESI-TOF) Calcd. for C14H12NO2S [M+H]+: 258.0583; found:
258.0584.
Phenanthridine (3a). White solid, 41.4 mg, yield 77%, mp
105.9−107.8 °C (lit.[14] mp 106.8-108.2 °C); 1H NMR (400 MHz, CDCl3) δ
9.40 (s, 1H), 8.64−8.59 (m, 2H), 8.20 (dd, J = 0.8, 8.0 Hz, 1H), 8.07 (d, J
= 8.0 Hz, 1H), 7.90−7.86 (m, 1H), 7.76−7.70 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 153.7, 144.5, 132.7, 131.2, 130.2, 128.9, 128.8, 127.7, 127.3,
126.5, 124.3, 122.4, 122.0.
1-Methylphenanthridine (3b). Yellow solid, 47.5 mg, yield 82%, mp
70.2−72.6 °C; 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.82 (d, J = 8.4
Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.82 (t, J = 7.6
Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 7.2
Hz, 1H), 3.07 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.5, 145.9, 135.5,
133.8, 131.3, 130.5, 129.2, 129.0, 127.9, 127.5, 126.8, 126.5, 123.8,
26.8. HRMS (ESI-TOF) Calcd. for C14H12N [M+H]+: 194.0964; found:
194.0962.
1-Methoxyphenanthridine (3c). Light yellow solid, 36.4 mg, yield 58%,
mp 102.5−104.2 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.45 (d, J = 8.0 Hz,
1H), 9.33 (s, 1H), 8.22 (s, 1H), 7.93−7.91 (m, 1H), 7.80−7.72 (m, 3H),
7.34 (s, 1H), 4.12 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 158.0, 154.2,
146.1, 131.3, 131.2, 128.8, 128.6, 127.2, 127.1, 126.5, 122.3, 113.8,
108.7, 56.1. HRMS (ESI-TOF) Calcd. for C14H12NO [M+H]+: 210.0913;
found: 210.0913.
2-Methylphenanthridine (3d). Light yellow solid, 41.7 mg, yield 72%,
1
mp 81.6−91.8 °C (lit.[14] mp 90.1−91.3 °C); H NMR (400 MHz, CDCl3) δ
9.21 (s, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 8.08 (d, J = 8.4 Hz,
1H), 8.01 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.67 (t, J = 7.6 Hz,
1H), 7.56 (d, J = 8.4 Hz, 1H), 2.62 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
152.6, 142.6, 137.2, 132.4, 131.0, 130.5, 129.7, 128.8, 128.7, 127.5,
126.5, 124.0, 121.9, 22.1.
2-Methoxyphenanthridine (3e). White solid, 42.1 mg, yield 67%, mp
102.1−104.9 °C (lit.[14] 103.7−105.1 °C); 1H NMR (400 MHz, DMSO-d6) δ
9.21 (s, 1H), 8.85 (d, J = 8.4 Hz, 1H), 8.19−8.16 (m, 2H), 8.02 (d, J = 8.8
Hz, 1H), 7.91 (t, J = 7.6 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 8.8
Hz, 1H), 4.00 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 158.3, 150.8,
139.3, 131.4, 131.0, 130.8, 128.6, 127.9, 126.1, 124.9, 122.6, 118.9,
103.5, 55.8.
2-Fluorophenanthridine (3f). Light yellow solid, 21.9 mg, yield 37%, mp
129.6−131.7 °C (lit.[14] 130.8−132.5 °C); 1H NMR (400 MHz, CDCl3) δ
9.22 (s, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.19−8.12 (m, 2H), 8.04 (d, J = 8.0
Hz, 1H), 7.88−7.83 (m, 1H), 7.75−7.71 (m, 1H), 7.49−7.44 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 161.5 (d, J = 246.1 Hz, 1C), 152.7 (d, J = 2.6
7-(Difluoromethoxy)phenanthridine (3o). Yellow solid, 37.5 mg, 51%
yield, mp 126.5−128.1 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H),
8.83 (d, J = 8.0 Hz, 1H), 8.73 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H),
7.98 (t, J = 8.0 Hz, 1H), 7.85 (t, J = 7.2 Hz, 1H), 7.79 (t, J = 7.2 Hz, 1H),
7.58 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 73.2 Hz, 1H); 13C NMR (100 MHz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601608
European Journal of Organic Chemistry
FULL PAPER
DMSO-d6) δ 148.2 (t, J = 3.1 Hz, 1C), 146.6, 144.0, 133.5, 131.9, 129.7,
129.6, 127.8, 123.3, 122.7, 119.3, 117.7, 116.6 (t, J = 258.0 Hz, 1C),
115.5. HRMS (ESI-TOF) Calcd. for C14H10F2NO [M+H]+: 246.0725;
found: 246.0721.
8-Methylphenanthridine (3p, Major) and 10-methylphenanth-ridine
(3p', Minor). Yellow liquid, 30.1 mg, yield 52%; major: minor = 2.7:1; 1H
NMR (400 MHz, CDCl3) δ (major + minor) 9.24 (s, 0.27H), 9.22 (s,
0.73H), 8.85 (d, J = 8.2 Hz, 0.27H), 8.53 (d, J = 8.2 Hz, 0.73H), 8.49 (d, J
= 8.2 Hz, 0.73H), 8.25 (d, J = 8.0 Hz, 0.27H), 8.18 (d, J = 8.0 Hz, 0.73H),
7.93 (d, J = 8.0 Hz, 0.27H), 7.81 (s, 0.73H), 7.77-7.59 (m, 3.27H), 3.12 (s,
0.81H), 2,59 (H, 2.19H); 13C NMR (100 MHz, CDCl3) δ (major + minor)
154.6, 153.4, 145.7, 144.1, 137.7, 135.3, 133.0, 132.0, 130.6, 130.5,
130.0, 128.4, 128.3, 128.0, 127.2, 127.1, 126.7, 126.6, 126.5, 125.8,
Synthesis of compound 7b (Scheme 3b). A 4 mL flame-dried vial with
a
stir bar was charged with N-benzyl-N-(2-bromo-3-methylphenyl)
methanesulfonamide (6b) (106.3 mg, 0.3 mmol), Cs2CO3 (146.6 mg, 0.45
mmol), Pd(OTf)2(dippp) (12.3 mg, 0.015 mmol), and XPhos (28.6 mg,
0.06 mmol) in 2.0 mL of dry N-Methyl pyrrolidone under nitrogen
atmosphere at 160 °C for 36 h. After cooling to room temperature, brine
(10.0 mL) was added, and the mixture was extracted with EtOAc (5 × 10
mL). The combined organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated by rotary evaporation. The residue was purified
by flash chromatography on silica gel (petroleum ether/ethyl acetate =
5:1) to afford the product 7b as a white solid (73.8 mg, 90%). White solid,
mp 98.3−100.2 °C; 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.6 Hz, 1H),
7.58−7.55 (m, 1H), 7.44−7.40 (m, 1H), 7.39−7.33 (m, 2H), 7.27−7.26 (m,
2H), 4.69 (s, 2H), 2.69 (s, 3H), 2.07 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 137.6, 135.5, 134.4, 131.7, 131.0, 129.9, 128.1, 128.0, 127.9, 127.8,
126.3, 125.6, 50.4, 38.0, 22.8. HRMS (ESI-TOF) Calcd. for
124.3, 122.2, 121.9, 26.7, 21.7. HRMS (ESI-TOF) Calcd. for C14H12
[M+H]+: 194.0964; found: 194.0967.
N
9-Methylphenanthridine (3q). Yellow solid, 33.0 mg, 57% yield, mp
81.1−83.7 °C (lit.[10c] mp 82−86 °C); 1H NMR (400 MHz, DMSO-d6) δ 9.29
(s, 1H), 8.76−8.72 (m, 1H), 8.59(s, 1H), 8.09 (s, 1H), 8.07 (s, 1H),
7.77−7.68 (m, 2H), 7.62−7.58 (m, 1H), 2.60 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ 153.1, 144.1, 141.6, 131.8, 129.5, 129.4, 129.0, 128.6,
126.9, 124.2, 123.5, 122.8, 121.6, 21.9. HRMS (ESI-TOF) Calcd. for
C15H15NNaO2S [M+Na]+: 296.0716; found: 296.0713.
Synthesis of compound 3b starting from compound 7b (Scheme 3c).
A 4 mL flame-dried vial with a stir bar was charged with 1-methyl-5-
(methylsulfonyl)-5,6-dihydrophenanthridine (7b) (82.0 mg, 0.3 mmol),
and Cs2CO3 (117.3 mg, 0.36 mmol) in 2.0 mL of dry N-Methyl pyrrolidone
at 160 °C for 10 h. After cooling to room temperature, brine (10.0 mL)
was added, and the mixture was extracted with EtOAc (5 × 10 mL). The
combined organic layer was dried over anhydrous Na2SO4, filtered, and
concentrated by rotary evaporation. The residue was purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) to
afford the product 3b as a yellow solid (53.3 mg, 92%).
C
14H12N [M+H]+: 194.0964; found: 194.0990.
8,10-Dimethylphenanthridine (3r). Light yellow solid, 34.8 mg, 56%
yield, mp 138.7−140.9 °C (lit.[22] mp 149–150 °C); 1H NMR (400 MHz,
DMSO-d6) δ 9.24 (s, 1H), 8.84 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.0 Hz,
1H), 7.88 (s, 1H), 7.78−7.69 (m, 2H), 7.65 (s, 1H), 3.05 (s, 3H), 2.52 (s,
3H); 13C NMR (100 MHz, DMSO-d6) δ 154.2, 145.0, 136.9, 136.8, 134.8,
130.0, 128.6, 127.8, 127.6, 127.3, 126.6, 126.4, 125.0, 25.8, 20.7. HRMS
(ESI-TOF) Calcd. for C15H14N [M+H]+: 208.1121; found: 208.1121.
10-Fluoro-7-methoxyphenanthridine (3s). Yellow solid, 31.4 mg, yield
1
46%, mp 149.0−151.8 °C; H NMR (400 MHz, CDCl3) δ 9.63 (d, J = 2.8
Hz, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.77 (t, J = 7.6
Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.42 (dd, J = 12.8, 8.8 Hz, 1H), 6.92 (dd,
J = 8.8, 3.2 Hz, 1H), 4.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.2 (d,
J = 245.8 Hz, 1C), 153.7 (d, J = 2.61 Hz, 1C), 147.4 (d, J = 1.6 Hz, 1C),
143.8, 129.43 (d, J = 2.0 Hz, 1C), 129.2, 127.8 (d, J = 2.2 Hz, 1C), 127.2
(d, J = 22.0 Hz, 1C), 122.5 (d, J = 11.5 Hz, 1C), 121.6 (d, J = 5.2 Hz, 1C),
118.2 (d, J = 25.3 Hz, 1C), 117.9 (d, J = 3.8 Hz, 1C), 107.0 (d, J = 8.5 Hz,
1C), 56.3. HRMS (ESI-TOF) Calcd. for C14H11FNO [M+H]+: 228.0819;
found: 228.0815.
7-Fluoro-8-methylphenanthridine (3t). Brown solid, 28.5 mg, yield 45%,
mp 106.2−108.1 °C; 1H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.52−8.48
(m, 1H), 8.27−8.20 (m, 2H), 7.77−7.63 (m, 3H), 2.49 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 157.9 (d, J = 251.7 Hz, 1C), 146.3 (d, J = 7.3 Hz,
1C), 143.9, 134.4 (d, J = 6.1 Hz, 1C), 132.3 (d, J = 2.9 Hz, 1C), 130.2,
128.9, 127.5, 123.4 (d, J = 2.4 Hz, 1C), 122.3, 122.0 (d, J = 15.8 Hz, 1C),
117.2 (d, J = 4.7 Hz, 1C), 116.0 (d, J = 14.7 Hz, 1C), 14.4 (d, J = 3.8 Hz,
1C). HRMS (ESI-TOF) Calcd. for C14H11FN [M+H]+: 212.0870; found:
212.0868.
Synthesis of compound 6b (Scheme 3a) A 4 mL vial with a stir bar was
charged with N-(2-bromo-3-methylphenyl)methanesulfonamide (1d) (79.2
mg, 0.3 mmol), (bromomethyl)benzene (2a) (51.3 mg, 0.3 mmol), and
Cs2CO3 (117.3 mg, 0.36 mmol) in 2.0 mL of dry N-Methyl pyrrolidone at
70 °C for 3 h. After cooling to room temperature, brine (10.0 mL) was
added, and the mixture was extracted with EtOAc (5 × 10 mL). The
combined organic layer was dried over anhydrous Na2SO4, filtered, and
concentrated by rotary evaporation. The residue was purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) to
afford the product 6b as a white solid (103.1 mg, 97%). White solid, mp
80.1−82.7 °C; 1H NMR (400 MHz, CDCl3) δ 7.26−7.22 (m, 5H), 7.18 (dd,
J = 0.8, 8.0 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.90 (dd, J = 1.6, 8.0 Hz,
1H), 5.11 (d, J = 14.8 Hz, 1H), 4.54 (d, J = 14.8 Hz, 1H), 3.04 (s, 3H),
2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 140.3, 137.5, 136.0, 131.5,
131.1, 129.5, 128.5, 128.1, 127.4, 127.0, 54.5, 41.6, 24.1. HRMS (ESI-
TOF) Calcd. for C15H16BrNNaO2S [M+Na]+: 375.9977; found: 375.9980.
Acknowledgements
We are grateful for financial support from the Education
Department of Guizhou Province (QJHKYZ-2016-081 and
QJHRCTDZ-2012-03), Science and Technology Department of
Guizhou Province (2015GZ18284, QKHRC-2016-4029, and
QKHRCTD-2014-4002), and New Century Excellent Talent of
the Ministry of Education (NCET-13-1069).
Keywords: phenanthridine • C−H activation • cascade reaction •
2-halogeno-N-Ms-arylamines • benzyl halides/sulfonates
[1]
[2]
a) R. T. Boulware, F. R. Stermitz, J. Nat. Prod. 1981, 44, 200–205; b) T.
Nakanishi, M. Suzuki, A. Saimoto, T. Kabasawa, J. Nat. Prod. 1999, 62,
864–867; c) Z. Jin, Nat. Prod. Rep. 2011, 28, 1126–1142.
a) M. Cushman, P. Mohan, E. C. R. Smith, J. Med. Chem. 1984, 27,
544–547; b) Y. L. Janin, A. Croisy, J. F. Riou, E. Bisagni, J. Med. Chem.
1993, 36, 3686–3692; c) G. Y. Park, J. J. Wilson, Y. Song, S. J. Lippard,
Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 11987–11992; d) E. Dubost, N.
Dumas, C. Fossey, R. Magnelli, S. Butt-Gueulle, C. Ballandonne, D. H.
Caignard, F. Dulin, J. Sopkova de-Oliveira Santos, P. Millet, Y. Charnay,
S. Rault, T. Cailly, F. Fabis, J. Med. Chem. 2012, 55, 9693–9707; e) H.
N. Nagesh, K. M. Naidu, D. H. Rao, J. P. Sridevi, D. Sriram, P.
Yogeeswari, K. V. Chandra Sekhar, Bioorg. Med. Chem. Lett. 2013, 23,
6805–6810; f) D. Castillo, M. Sauvain, M. Rivaud, V. Jullian, Planta
Med. 2014, 80, 902–906.
[3]
a) J. L. Vivero-Escoto, I. I. Slowing, V. S.-Y. Lin, Biomaterials 2010, 31,
1325–1333; b) C. Chen, G. Shang, J. Zhou, Y. Yu, B. Li, J. Peng, Org.
Lett. 2014, 16, 1872–1875; c) G. Zhao, C. Chen, Y. Yue, Y. Yu, J. Peng,
J. Org. Chem. 2015, 80, 2827–2834; d) M. T. Bakić, D. Jadreško, T.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601608
European Journal of Organic Chemistry
FULL PAPER
Hrenar, G. Horvat, J. Požar, N. Galić, V. Sokol, R. Tomaš, S. Alihodžić,
M. Žinić, L. Frkanec, V. Tomišić, RSC Adv. 2015, 5, 23900–23914; e) H.
Ma, B. Liu, B. Li, L. Zhang, Y.-G. Li, H.-Q. Tan, H.-Y. Zang, G. Zhu, J.
Am. Chem. Soc. 2016, 138, 5897–5903.
Haridharan, K. Muralirajan, C.-H. Cheng, Adv. Synth. Catal. 2015, 357,
366–370.
[12] For reviews, see: a) W. R. Gutekunst, P. S. Baran, Chem. Soc. Rev.
2011, 40, 1976–1991; b) H. Ohno, Asian J. Org. Chem. 2013, 2, 18–28;
c) Y. Yamamoto, A. I. Almansour, N. Arumugam, R. S. Kumar,
ARKIVOC 2016, 2, 9–41.
[4]
[5]
a) T. Nakanishi, M. Suzuki, Org. Lett. 1999, 1, 985–988; b) M. Blanchot,
D. A. Candito, F. Larnaud, M. Lautens, Org. Lett. 2011, 13, 1486–1489;
c) W.-L. Chen, C.-Y. Chen, Y.-F. Chen, J.-C. Hsieh, Org. Lett. 2015, 17,
1613–1616.
[13] For selected references, see: a) N. D. Ca', E. Motti, A. Mega, M.
Catellani, Adv. Synth. Catal. 2010, 352, 1451–1454; b) H. Ohno, M.
Iuchi, N. Kojima, T. Yoshimitsu, N. Fujii, T. Tanaka, Chem. - Eur. J.
2012, 18, 5352–5360; c) J. Zhao, K. Oniwa, N. Asao, Y. Yamamoto, T.
Jin, J. Am. Chem. Soc. 2013, 135, 10222–10225; d) G.-C. Ge, C.-H.
Ding, X.-L. Hou, Org. Chem. Front. 2014, 1, 382–385; e) M. Iwasaki, Y.
Araki, S. Iino, Y. Nishihara, J. Org. Chem. 2015, 80, 9247–9263; f) S. P.
Cooper, K. I. Booker-Milburn, Angew. Chem. 2015, 127, 6596–6600;
Angew. Chem. Int. Ed. 2015, 54, 6496–6500; (g) P. K. Gupta, N. Yadav,
S. Jaiswal, M. Asad, R. Kant, K. Hajela, Chem. - Eur. J. 2015, 21,
13210–13215; (h) M. Feng, B. Tang, H.-X. Xu, X. Jiang, Org. Lett. 2016,
18, 4352–4355; (i) D. N. Rao, S. Rasheed, P. Das, Org. Lett. 2016, 18,
3142–3145; (j) X. Li, J. Pan, S. Song, N. Jiao, Chem. Sci. 2016, 7,
5384–5389; (k) Ref 3b and 3c.
For reviews, see: a) L.-M. Tumir, M. R. Stojković, I. Piantanida,
Beilstein J. Org. Chem. 2014, 10, 2930–2954; b) B. Zhang, A. Studer,
Chem. Soc. Rev. 2015, 44, 3505–3521; c) X. Sun, S. Yu, Chin. J. Org.
Chem. 2016, 36, 239–247.
[6]
[7]
G. T. Morgan, L. P. Walls, J. Chem. Soc. 1931, 2447–2456.
For selected references, see: a) M. E. Budén, V. B. Dorn, M. Gamba, A.
B. Pierini, R. A. Rossi, J. Org. Chem. 2010, 75, 2206–2218; b) A. M.
Linsenmeier, C. M. Williams, S. Bräse, J. Org. Chem. 2011, 76, 9127–
9132; c) A. M. Linsenmeier, C. M. Williams, S. Bräse, Eur. J. Org.
Chem. 2013, 3847–3856; d) S. De, S. Mishra, B. N. Kakde, D. Dey, A.
Bisai, J. Org. Chem. 2013, 78, 7823–7844; e) L. E. Peisino, G. P.
Camargo Solorzano, M. E. Budén, A. B. Pierini, RSC Adv. 2015, 5,
36374–36384.
[14] W. Han, X. Zhou, S. Yang, G. Xiang, B. Cui, Y. Chen, J. Org. Chem.
2015, 80, 11580–11587.
[8]
For selected references, see: a) X. Li, M. Fang, P. Hu, G. Hong, Y.
Tang, X. Xu, Adv. Synth. Catal. 2014, 356, 2103–2106; b) C. Pan, H.
Zhang, J. Han, Y. Cheng, C. Zhu, Chem. Commun. 2015, 51, 3786–
3788; c) J.-W. Gu, X. Zhang, Org. Lett. 2015, 17, 5384–5387; d) Z.
Zhang, X. Tang, W. R. Dolbier, Jr, Org. Lett. 2015, 17, 4401–4403; e) S.
Lu, Y. Gong, D. Zhou, J. Org. Chem. 2015, 80, 9336–9341; f) S. Wang,
W.-L. Jia, L. Wang, Q. Liu, Eur. J. Org. Chem. 2015, 6817–6821; g) Y.
Zhou, C. Wu, X. Dong, J. Qu, J. Org. Chem. 2016, 81, 5202–5208; h)
W. Wan, G. Ma, J. Li, Y. Chen, Q. Hu, M. Li, H. Jiang, H. Deng, J. Hao,
Chem. Commun. 2016, 52, 1598–1601; i) Y. Xu, Y. Chen, W. Li, Q. Xie,
L. Shao, J. Org. Chem. 2016, 81, 8426–8435; j) J. Rong, L. Deng, P.
Tan, C. Ni, Y. Gu, J. Hu, Angew. Chem. 2016, 128, 2793–2797; Angew.
Chem. Int. Ed. 2016, 55, 2743–2747; k) L. Noël-Duchesneau, E.
Lagadic, F. Morlet-Savary, J.-F. Lohier, I. Chataigner, M. Breugst, J.
Lalevée, A.-C. Gaumont, S. Lakhdar, Org. Lett. 2016, 18, 5900–5903; l)
P. Xiao, J. Rong, C. Ni, J. Guo, X. Li, D. Chen, J. Hu, Org. Lett. 2016,
18, 5912–5915; m) Y. Jin, H. Yang, H. Fu, Org. Lett. 2016, 18, 6400–
6403.
[15] A. R. O. Venning, P. T. Bohan, E. J. Alexanian, J. Am. Chem. Soc.
2015, 137, 3731–3734.
[16] a) Y. Dai, X. Feng, H. Liu, H. Jiang, M. Bao, J. Org. Chem. 2011, 76,
10068–10077; b) S. Rousseaux, J. Garcia-Fortanet, M. A. Del Aguila
Sanchez, S. L. Buchwald, J. Am. Chem. Soc. 2011, 133, 9282–9285; c)
S. E. Kiruthika, P. T. Perumal, Org. Lett. 2014, 16, 484–487; d) S. M. A.
Hussaini, P. Yedla, K. S. Babu, T. B. Shaik, G. K. Chityal, A. Kamal,
Chem. Biol. Drug Des. 2016, 88, 97–109.
[17] a) Condition A: SOCl2, Et2O, 25 ºC, 10 min; pyridine, reflux, 2 h. N.
Popoff, B. Macqueron, W. Sayhoun, J. Espinas, J. Pelletier, O. Boyron,
C. Boisson, N. Merle, K. C. Szeto, R. M. Gauvin, A. De Mallmann, M.
Taoufik, Eur. J. Inorg. Chem. 2014, 888–895; b) Condition B: MsCl,
Et3N, DCM, N2, -20 ºC, 2 h. X. Jiang, F.-L. Qing, Beilstein J. Org. Chem.
2013, 9, 2862–2865; c) Condition C: TsCl, K2CO3, KOH, 25 ºC, ground,
30 min. Q. Glenadel, M. Bordy, S. Alazet, A. Tlili, T. Billard, Asian J.
Org. Chem. 2016, 5, 428–433; d) Condition D: AgOTf, Ac2O, 60°C, 15
min. R. Das, D. Chakraborty, Synthesis, 2011, 1621–1625.
[9]
For selected references, see: a) R. Alonso, P. J. Campos, B. García, M.
A. Rodríguez, Org. Lett. 2006, 8, 3521–3523; b) R. Alonso, A.
Caballero, P. J. Campos, M. A. Rodríguez, Tetrahedron 2010, 66,
8828–8831; c) I. Deb, N. Yoshikai, Org. Lett. 2013, 15, 4254–4257; d)
X.-D. An, S. Yu, Org. Lett. 2015, 17, 2692–2695; e) H. Jiang, X. An, K.
Tong, T. Zheng, Y. Zhang, S. Yu, Angew. Chem. 2015, 127, 4127–
4131; Angew. Chem. Int. Ed. 2015, 54, 4055–4059.
[18] A series of palladium catalysts, including Pd(OAc)2, Pd(OPiv)2, PdCl2,
PdCl2(PPh3)2, Pd(OTf)2(dippp), [Pd(dppf)Cl2]2•DCM, [(cinnamyl)PdCl]2,
Pd(PPh3)4, Pd2(dba)3 and Pd(diphos)2 were screened for the model
reaction, affording 3a in 46%, 53%, 40%, 39%, 57%, 37%, 40%, 45%,
53% and 24% yields, respectively.
[19] Different ratios of NMP to DMSO were further examined for the model
reaction, but these results were inferior to NMP/DMSO (1.0 mL/1.0 mL).
[20] Other catalytic systems, including Pd(OPiv)2/PPh3 and Pd2(dba)3/PPh3,
were also investigated with the optimized mixed solvents. However, the
yield wasn’t further improved (dates were not given).
[10] For selected references, see: a) S. Dhara, M. Ghosh, J. K. Ray, Synlett.
2013, 24, 2263–2265; b) M. Ghosh, A. Ahmed, R. Singha, J. K. Ray,
Tetrahedron Lett. 2015, 56, 353–355; c) A. Borah, P. Gogoi, Eur. J. Org.
Chem. 2016, 2200–2206.
[21] For selected references, see: a) K. Kanagaraj, K. Pitchumani, Chem. -
Eur. J. 2013, 19, 14425–14431; b) S. J. Sabounchei, M. Hosseinzadeh,
J. Chem. Sci. 2015, 127, 1919–1926; c) S. Sobhani, Z. Zeraatkar, F.
Zarifi, New J. Chem. 2015, 39, 7076–7085; d) X.-D. Xiao, Y.-L. Bai, J.-
Q. Liu, J.-W. Wang, Tetrahedron Lett. 2016, 57, 3385–3388; e) A.
Naghipour, A. Fakhri, Catal. Commun. 2016, 73, 39–45.
[11] a) L. Sripada, J. A. Teske, A. Deiters, Org. Biomol. Chem. 2008, 6,
263–265; b) A. K. Mandadapu, M. Saifuddin, P. K. Agarwal, B. Kundu,
Org. Biomol. Chem. 2009, 7, 2796–2803; c) D. A. Candito, M. Lautens,
Angew. Chem. 2009, 121, 6841–6844; Angew. Chem. Int. Ed. 2009, 48,
6713–6716; d) Y. Hu, Y. Sun, J. Hu, T. Zhu, T. Yu, Q. Zhao, Chem. -
Asian J. 2011, 6, 797–800; e) W.-Y. Wang, X. Feng, B.-L. Hu, C.-L.
Deng, X.-G. Zhang, J. Org. Chem. 2013, 78, 6025–6030; f) X. Bao, W.
Yao, Q. Zhu, Y. Xu, Eur. J. Org. Chem. 2014, 7443–7450; g) R.
[22] R. A. Abramovitch, D. Newman, G. Tertzakian, Can. J. Chem. 1963, 41,
2390–2394.
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10.1002/ejoc.201601608
European Journal of Organic Chemistry
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Entry for the Table of Contents
FULL PAPER
Palladium-Catalyzed Cascade
Reaction
Si-Yi Yang, Wen-Yong Han,* Ding-Lei
Zhang, Xiao-Jian Zhou, Mei Bai, Bao-
Dong Cui, Nan-Wei Wan, Wei-Cheng
Yuan, Yong-Zheng Chen*
A facile and efficient palladium-catalyzed cascade reaction involving nucleophilic
substitution/C−H activation/aromatization sequence for the construction of
phenanthridines has been explored. Importantly, this work represents a facile and
practical protocol leading to phenanthridines from easily accessible 2-halogeno-N-
Ms-arylamines and benzyl halides/sulfonates.
Page No. – Page No.
Synthesis of Phenanthridines via
Palladium-Catalyzed Cascade
Reaction of 2-Halogeno-N-Ms-
arylamines with Benzyl
Halides/Sulfonates
This article is protected by copyright. All rights reserved.