Palladium-Catalyzed Nucleophilic Substitution/C-H Activation/Aromatization Cascade Reaction: One Approach to Construct 6-Unsubstituted Phenanthridines

Article abstract of DOI:10.1021/acs.joc.5b02145

A facile and practical palladium-catalyzed nucleophilic substitution/C-H activation/aromatization cascade reaction has been developed. A range of 6-unsubstituted phenanthridines could be obtained in moderate to good yields (31-85%) with readily prepared N-Ms arylamines and commercially available 2-bromobenzyl bromide derivatives as starting materials. The potential application of the protocol was also demonstrated by the expeditious synthesis of the natural alkaloid trisphaeridine.

Full text of DOI:10.1021/acs.joc.5b02145

Note
Palladium-Catalyzed Nucleophilic Substitution/C-
H Activation/Aromatization Cascade Reaction: One
Approach to Construct 6-Unsubstituted Phenanthridines
Wenyong Han, Xiaojian Zhou, Siyi Yang, Guangyan Xiang, Baodong Cui, and Yongzheng Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02145 • Publication Date (Web): 29 Oct 2015
Downloaded from http://pubs.acs.org on October 29, 2015
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Palladium-Catalyzed Nucleophilic Substitution/C-H
Activation/Aromatization Cascade Reaction: One Approach to
Construct 6-Unsubstituted Phenanthridines
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Wenyong Han,* Xiaojian Zhou, Siyi Yang, Guangyan Xiang, Baodong Cui,
and Yongzheng Chen*
School of Pharmacy, Zunyi Medical University, Zunyi, 563000, P. R. China
hanwy@zmc.edu.cn; yzchen@zmc.edu.cn
Table of Contents Graphic
ABSTRACT:
A
facile
and
practical
palladium-catalyzed
nucleophilic
substitution/C-H
activation/aromatization cascade reaction has been developed. A range of 6-unsubstituted
phenanthridines could be obtained in moderate to good yields (31–85%) with readily prepared
N-Ms arylamines and commercially available 2-bromobenzyl bromide derivatives as starting
materials. The potential application of the protocol was also demonstrated by the expeditious
synthesis of the natural alkaloid trisphaeridine.
The development of efficient methods to construct polycyclic aromatic hydrocarbons (PAHs)
has been attracting considerable interest due to the potential applications of this kind of
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compounds in organic materials1 and medicinal chemistry.2 In particular, phenanthridine has
emerged as an attractive synthetic motif since it is not only frequently found in natural products
(Figure 1) but also compounds incorporating such a motif possess several types of bioactivities
such as antimalarial, cytotoxicity, antimycobacterial, and anticancer et al.3,4 Thus, numerous
methodologies for the construction of phenanthridine scaffold have been established.5,6 And
therein, relatively few methods for the preparation of 6-unsubstituted phenanthridines were
reported. On the basis of an inspection into the literature data, it was found that the common
strategies for the generation of 6-unsubstituted phenanthridines include the photochemical
method,7 oxidation of 5,6-dihydrophenanthridine,8 microwave-assisted cyclization,9
intramolecular condensation,10 intramolecular biaryl-coupling,11 and hydride-induced anionic
cyclization.12 Some selected approaches to 6-unsubstituted phenanthridines were summarized in
Scheme 1. However, most of the approaches are mainly limited to the use of complex starting
materials, such as ortho-functionalized biaryls. Accordingly, the development of facile and
practical methods with easily accessible precursors for the construction of 6-unsubstituted
phenanthridine compounds is still desirable and valuable.
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Figure 1. Biologically active phenanthridines.
In recent years, transition-metal-catalyzed reactions have been well developed and used as a
powerful method for the construction of complex structural moleculars.13 Among them,
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palladium-catalyzed cascade reactions involving C-H activation, which provide a straightforward
and atom-economic approach to fused heterocyclic compounds, have also received increasing
attention.14,15 However, it should be noted that the synthetic methodology to access
6-unsubstituted phenanthridines through palladium-catalyzed cascade reaction is rare,8c,16
especially starting from readily accessible substrates.
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Scheme 1. Synthesis of 6-Unsubstituted Phenanthridines
Scheme 2. Synthesis of 2-Bromobenzyl Bromide Derivatives
Scheme 3. The Strategy of Our Proposed Methodology
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N-Ms arylamines17 and 2-bromobenzyl bromide derivatives,18 two kinds of readily accessible
precursors, have been broadly applied in organic synthesis, respectively. Generally, there were
two common methods for the synthesis of 2-bromobenzyl bromide derivatives: i) reduction of
ortho-bromoarylaldehydes followed by substitution using tribromophosphine gave 2-bromobenzyl
bromide derivatives [Scheme 2, Eq. (a)], and ii) substitution of ortho-bromomethylarenes with
N-bromosuccinimide using azobisisobutyronitrile as radical initiator gave 2-bromobenzyl bromide
derivatives [Scheme 2, Eq. (b)].19 Therefore, promoted by the importance of this phenanthridine
motif, and as our ongoing interest in the development of a facile and practical methodologies, we
report herein an unconventional strategy for the construction of 6-unsubstituted phenanthridines
from easily accessible precursors. Notably, this method is characterized by its easy accessibility of
the starting materials, as well as the high efficacy which is inherent to a palladium-catalyzed
cascade reaction sequence, involving the nucleophilic substitution/C-H activation/aromatization
(Scheme 3).
The investigation began with the optimization of several reaction conditions for the synthesis
of 5-(methylsulfonyl)-5,6-dihydrophenanthridine (3a) using N-phenylmethanesulfonamide (1a)
and 1-bromo-2-(bromomethyl)benzene (2a) as model substrates (Table 1). After an initial screen
of palladium catalysts in the presence of PPh3 using Cs2CO3 as base in DMF at 140 °C for 10 h
(Table 1, entries 1–4), the annulated product 3a could be obtained in 66% yield by using
Pd(TFA)2 as a catalyst (Table 1, entry 4). Several other ligands were also screened (Table 1,
entries 5–7), it revealed that DPPB, BINAP, and Xantphos were inferior to PPh3 for the reaction
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(Table 1, entry 4). Using other inorganic bases led to no improvement in the reaction performance
(Table 1, entries 8–11). A survey of solvents revealed that DMF was the best solvent (Table 1,
entry 4 vs entries 12–14). Furthermore, we investigated the effect of the loading of Pd(TFA)2 and
PPh3 (Table 1, entries 15–16), and 5 mol % of Pd(TFA)2 and 20 mol % of PPh3 were proven to be
a good choice for the cascade process (Table 1, entry 16 vs entries 4 and 15). To our delight, the
fused heterocyclic compound 4a was obtained in 16% yield performing at 160 °C, suggesting that
the aromatization process would readily proceed in high temperature (Table 1, entry 17).
Surprisingly, extending the reaction time from 10 to 24 h led to 4a in an improved yield (40%)
(Table 1, entry 18). Afterward, increasing the equivalent of Cs2CO3 from 2.5 to 4.0, substrates 1a
and 2a were completely converted into 4a in 80% yield (Table 1, entry 19).
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Table 1. Optimization of Reaction Conditionsa
yield (%)b
entry
[Pd]/ligand
base
solvent
3a
16
34
35
66
36
18
13
48
10
50
4a
<5
<5
<5
<5
<5
<5
<5
<5
0
1
2
Pd(PPh3)4/PPh3
Pd2(dba)3/PPh3
Pd(OAc)2/PPh3
Pd(TFA)2/PPh3
Pd(TFA)2/DPPB
Pd(TFA)2/BINAP
Pd(TFA)2/Xantphos
Pd(TFA)2/PPh3
Pd(TFA)2/PPh3
Pd(TFA)2/PPh3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
K3PO4
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
3
4
5
6
7
8
9
10
<5
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Pd(TFA)2/PPh3
NaOPiv
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
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15
39
41
26
65
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44
0
0
Pd(TFA)2/PPh3
Pd(TFA)2/PPh3
Pd(TFA)2/PPh3
Pd(TFA)2/PPh3
Pd(TFA)2/PPh3
Pd(TFA)2/PPh3
Pd(TFA)2/PPh3
Pd(TFA)2/PPh3
DMSO
mesitylene
t-Amylol
DMF
<5
<5
<5
<5
<5
16
40
80
13
14
15c
16d
17de
18def
19defg
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DMF
DMF
DMF
DMF
a
Unless otherwise noted, all reactions were carried out with 1a (0.3 mmol), 2a (0.3 mmol) and
base (2.5 equiv.) in 2.0 mL of solvent with 10 mol % Pd-catalyst and 20 mol % ligand under N2
atmosphere at 140 °C for 10 h. b Isolated yield. c 5 mol % Pd(TFA)2 and 10 mol % PPh3 were used.
d 5 mol % Pd(TFA)2 and 20 mol % PPh3 were used. e The reaction was performed at 160 °C. f The
reaction was performed for 24 h. g 4.0 equiv. Cs2CO3 was used.
With the optimal reaction conditions in hand (Table 1, entry 19), the generality of this
palladium-catalyzed cascade reaction was subsequently investigated. As shown in Scheme 4, all
substrates could be smoothly transformed into the corresponding 6-unsubstituted phenanthridines
in moderate to good yields. Whether substituent group is an electron–donating or –withdrawing at
the ortho position on the N-Ms arylamines, the reactions proceeded smoothly and gave the
corresponding products 4b-4e in good yields (73–82%). However, meta-substituted N-Ms
arylamine, such as N-meta-tolylmethanesulfonamide, gave two unseparated isomers in a 6.1:1
ratio and 31% overall yield (4f/4f'). For the para position, N-Ms arylamines bearing the
electron-rich substitutes provided good yields (4g and 4h), whereas the electron-deficient groups
led to a slightly lower yields (4i and 4j). Moreover, this cascade process can be extended to
disubstituted N-Ms arylamines at different positions on the phenyl ring, giving the corresponding
compounds in 56–85% yields (4k–4n). To our delight, the method was compatible with polycyclic
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Scheme 4. Substrate Scope.a
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a The reactions were carried out with 1 (0.3 mmol), 2 (0.3 mmol), Cs2CO3 (4.0 equiv.), Pd(TFA)2
(5 mol %), and PPh3 (20 mol %) in 2.0 mL of DMF under N2 atmosphere at 160 °C for specified
reaction time. Isolated yields were given. b Using PdCl2 instead of Pd(TFA)2 at 120 °C.
arylamine,
such
as
N-(pyren-1-yl)methanesulfonamide
and
N-(naphthalen-1-yl)methanesulfonamide, affording the corresponding fused heterocyclic
compounds 4o and 4p in 65% and 78% yields, respectively.20 For 2-bromobenzyl bromide
derivatives 2, the substrates bearing electron-donating or –withdrawing group at the C4 position
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on the phenyl ring, the desired products 4q–t were obtained in 42–68% yields. Ultimately,
1-bromo-2-(bromomethyl)naphthalene was also proved to be good candidate for this
transformation, the expected product 4u could be obtained in 53% yield.
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Scheme 5. Larger than the Other Reactions and the Synthetic Application
To evaluate the practicability of the established methodology, the palladium-catalyzed cascade
process was conducted on a larger than the other reactions. As shown in Scheme 5, the reaction
proceeded well to afford the corresponding product 4b in a slightly downward isolated yield (78%
yield) [Scheme 5, Eq. (a)]. This method was also successfully applied to the synthesis of natural
alkaloid trisphaeridine in 55% yield, which represented the shortest route for trisphaeridine
starting from commercially available materials to date.7a,7c,7e,10a,11,12,21 In addition, it was worth
emphasizing that trisphaeridine can be converted into two other alkaloids bicolorine and
5,6-dihydrobicolorine in light of the reported procedures [Scheme 5, Eq. (b)].12
Scheme 6. Preliminary Mechanism Studies
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NHMs
Br
Ms
N
Cs2CO3
(1.2 equiv.)
Br
+
(a)
DMF (2.0 mL)
70 oC, 3 h
Br
1a
0.3 mmol
5a
2a
0.3 mmol
7
88.8 mg, 87% yield
Ms
N
8
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Pd(TFA)2 (5 mol %)
PPh3 (20 mol %)
Ms
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N
(b)
(c)
Cs2CO3 (1.5 equiv.)
DMF (2.0 mL)
N2, 160 oC, 10 h
Br
5a
0.3 mmol
3a
56.0 mg, 72% yield
Ms
N
N
Cs2CO3 (1.2 equiv.)
DMF (2.0 mL), 160 C, 12 h
4a
3a
0.3 mmol
49.5 mg, 92% yield
In order to understand the reaction mechanism of this sequential nucleophilic substitution, C-H
activation and aromatization process, some control experiments were carried out. When the
reaction of 1a and 2a was carried out in the absence of Pd(TFA)2 and PPh3, substituted product 5a
was obtained in 87% yield [Scheme 6, Eq. (a)]. Starting from 5a, palladium-catalyzed
intramolecular C-H arylation could take place, giving the corresponding annulated product 3a in
72% yield [Scheme 6, Eq. (b)]. And then, treatment of 3a with 1.2 equiv. of Cs2CO3 in DMF at
160 °C for 12 h led to aromatized product 4a in 92% yield [Scheme 6, Eq. (c)]. These results
suggest that compound 5a and 3a are possible reaction intermediates for the formation of 4a.
While a precise mechanism awaits further study, a possible catalytic cycle for the cascade
reaction is proposed in Scheme 7. Firstly, the base promoted the nucleophilic substitution between
N-Ms arylamines (1) and 2-bromobenzyl bromide derivatives (2) producing compound 5. Then
the oxidative addition of 5 to in-situ generated Pd0 species, followed by the intramolecular C-H
activation to form the intermediate B. Subsequent reductive elimination occurred to afford the
annulated product 3, while Pd0 species were regenerated to complete the catalytic cycle. Further
aromatization of 3 occurred to deliver the fused heterocycles 4 at high temperature in the presence
of base.
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Scheme 7. Proposed Catalytic Cycle
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In summary, we have developed an efficient palladium-catalyzed sequential nucleophilic
substitution/C-H activation/aromatization process, providing a variety of 6-unsubstituted
phenanthridine compounds in moderate to good yields (31–85%). Moreover, natural alkaloid
trisphaeridine could be efficiently synthesized in only one step using the present methodology.
Notably, this work represents a facile and practical protocol leading to 6-unsubstituted
phenanthridines from readily prepared N-Ms arylamines and commercially available
2-bromobenzyl bromide derivatives. Additionally, the developed protocol will open up a
straightforward way to access 6-unsubstituted phenanthridines.
EXPERIMENTAL SECTION
General experimental information
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 resonance employed
as the internal standard. Data were reported as follows: chemical shift, multiplicity (s = singlet, d
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= doublet, t = triplet, q = quartet, td = triplet-doublet, 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-phenylmethanesulfonamide (1a), 1-bromo-2-(bromomethyl)benzene (2a), 1-bromo-2-
(bromomethyl)-4-methoxybenzene (2b), 1-bromo-2-(bromomethyl)-4-chlorobenzene (2c),
1-bromo-2-(bromomethyl)naphthalene (2d) and 5-bromo-6-(bromomethyl)benzo[d][1,3]dioxole
(2e) were purchased from commercial suppliers. Other N-Ms arylamines were prepared according
to the reported procedures.17
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General procedure for the synthesis of phenanthridines 4a-4u. A 4 mL flame-dried vial with a
stir bar was charged with N-Ms arylamines (1) (0.3 mmol), 2-bromobenzyl bromide derivatives
(2) (0.3 mmol), Cs2CO3 (391.0 mg, 1.2 mmol), Pd(TFA)2 (5.0 mg, 0.015 mmol), and PPh3 (15.7
mg, 0.06 mmol) in 2.0 mL of dry DMF under nitrogen atmosphere at 160 °C for 24-48 h. After the
completion of the reaction detected by thin layer chromatography (TLC), brine (10.0 mL) was
added, and the mixture was extracted with EtOAc (5 x 10 mL). The combined organic layer was
dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation. The residue was
purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) to
afford the desired product 4a-4u.
Phenanthridine (4a). White solid, 43.0 mg, yield 80%, mp 106.8-108.2 °C (lit.7b mp
104-106 °C); 1H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.60-8.53 (m, 2H), 8.20 (d, J = 8.0 Hz,
1H), 8.01 (d, J = 8.0 Hz, 1H), 7.84-7.80 (m, 1H), 7.77-7.71 (m, 1H), 7.69-7.64 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 153.6, 144.5, 132.6, 131.1, 130.2, 128.8, 128.7, 127.5, 127.1, 126.4, 124.2,
122.3, 121.9; HRMS (ESI-TOF) Calcd. for C13H10N [M+H]+: 180.0808; found: 180.0803.
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4-Methylphenanthridine (4b) Light yellow solid, 47.0 mg, 81% yield, mp 93.1-94.6 °C (lit.7a mp
6
7
1
94.2-95.4 °C); H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.56 (d, J = 8.0 Hz, 1H), 8.41 (d, J =
8
9
8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.69-7.65 (m, 1H), 7.61-7.53 (m, 2H),
2.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 152.2, 143.3, 137.8, 132.9, 131.0, 129.6, 128.7, 127.3,
126.7, 126.2, 124.0, 122.1, 120.2, 18.8; HRMS (ESI-TOF) Calcd. for C14H12N [M+H]+: 194.0964;
found: 194.0958.
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4-Ethylphenanthridine (4c)8c. Light yellow oil, 51.0 mg, 82% yield; H NMR (400 MHz,
CDCl3) δ 9.31 (s, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.43-8.41 (m, 1H), 8.02 (d, J = 8.0 Hz, 1H),
7.82-7.78 (m, 1H), 7.68-7.64 (m, 1H), 7.63-7.59 (m, 2H), 3.40 (q, J = 7.6 Hz, 2H), 1.45 (t, J = 7.6
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 152.2, 143.7, 142.7, 133.0, 130.8, 128.7, 127.9, 127.3,
126.9, 126.2, 124.1, 122.1, 120.1, 25.3, 15.6; HRMS (ESI-TOF) Calcd. for C15H14N [M+H]+:
208.1121; found: 208.1120.
4-Ethoxyphenanthridine (4d). White solid, 52.9 mg, 79% yield, mp 73.4-74.8 °C; IR (KBr) ν
(cm−1) 3414, 2927, 1620, 1528, 1352, 1258, 1092, 750; 1H NMR (400 MHz, DMSO-d6 + CDCl3)
δ 9.12 (s, 1H), 8.39 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H),
7.67-7.63 (m, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 4.16
(q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO-d6 + CDCl3) δ 154.9,
151.7, 135.1, 132.0, 130.6, 128.3, 127.3, 127.0, 126.0, 124.9, 122.0, 113.5, 109.0, 64.0, 14.5;
HRMS (ESI-TOF) Calcd. for C15H14NO [M+H]+: 224.1070; found: 224.1070.
4-Chlorophenanthridine (4e). Light yellow solid, 46.7 mg, 73% yield, mp 101.1-102.4 °C (lit.8c
mp 98-100 °C); 1H NMR (400 MHz, CDCl3) δ 9.37 (s, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.46 (d, J =
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= 1.6, 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 154.2, 140.8, 134.4, 132.4, 131.6, 129.2, 129.1,
128.3, 127.1, 126.4, 126.0, 122.2, 121.3; HRMS (ESI-TOF) Calcd. for C13H9ClN [M+H]+:
214.0418; found: 214.0419.
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3-Methylphenanthridine (4f, major)22d and 1-Methylphenanthridine (4f', minor). Light
yellow oil, 18.0 mg, 31% yield; major : minor = 6.1 : 1; 1H NMR (400 MHz, CDCl3): δ (major +
minor) 9.26 (s, 1H), 8.89 (d, J = 9.2 Hz, 0.14H), 8.57 (d, J = 8.0 Hz, 0.86H), 8.46 (d, J = 8.0 Hz,
0.86H), 8.12-8.07 (m, 0.28H), 8.03 (d, J = 8.0 Hz, 0.86H), 7.98 (s, 0.86H), 7.86-7.82 (m, 1H),
7.70-7.66 (m, 1.14H), 7.51 (d, J = 8.0 Hz, 1H), 3.13 (s, 0.42H), 2.60 (s, 2.58H); 13C NMR (100
MHz, CDCl3): δ (major + minor) 153.6, 144.6, 139.1, 132.8, 131.4, 131.2, 130.6, 129.7, 129.3,
129.0, 128.9, 128.0, 127.2, 126.9, 126.6, 126.2, 122.2, 121.9, 121.8, 26.9, 21.7; HRMS (ESI-TOF)
Calcd. for C14H12N [M+H]+: 194.0964; found: 194.0958
2-Methylphenanthridine (4g). Light yellow solid, 45.2 mg, 78% yield, mp 90.1-91.3 °C (lit.7a
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mp 90.1-91.1 °C); H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.34 (s,
1H), 8.08 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.84 (td, J = 1.2, 7.6 Hz, 1H), 7.69 (td, J =
1.2, 7.6 Hz, 1H), 7.57 (dd, J = 1.2, 8.4 Hz, 1H), 2.63 (s, 3H).13C NMR (100 MHz, CDCl3) δ 152.7,
142.8, 137.1, 132.4, 130.9, 130.5, 129.9, 128.8, 127.4, 126.6, 124.0, 121.9, 22.1. HRMS
(ESI-TOF) Calcd. for C14H12N [M+H]+: 194.0964; found: 194.0962.
2-Methoxyphenanthridine (4h). White solid, 39.5 mg, 63% yield, mp 103.7-105.1 °C (lit.22b mp
89-90 °C); 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 9.2
Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 2.8 Hz, 1H), 7.75 (d, J = 7,6 Hz, 1H), 7.62 (d, J =
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7,6 Hz, 1H), 7.32 (dd, J = 2.4, 8.8 Hz, 1H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.4,
151.0, 139.7, 132.0, 131.4, 130.5, 128.6, 127.5, 126.5, 125.1, 121.8, 118.5, 103.0, 55.6; HRMS
(ESI-TOF) Calcd. for C14H12NO [M+H]+: 210.0913; found: 210.0912.
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2-Fluorophenanthridine (4i). Light yellow solid, 35.5 mg, 60% yield, mp 130.8-132.5 °C; IR
(KBr) ν (cm−1) 3446, 3059, 2925, 1618, 1495, 1445, 1187, 864, 751; 1H NMR (400 MHz, CDCl3)
δ 9.23 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.19-8.15 (m, 2H), 8.05 (d, J = 8.4 Hz, 1H), 7.89-7.85 (m,
1H), 7.76-7.73 (m, 1H), 7.51-7.45 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 161.5 (d, J = 245.8 Hz,
1C), 152.9 (d, J = 2.7 Hz, 1C), 141.4, 132.4 (d, J = 9.2 Hz, 1C), 132.1 (d, J = 4.3 Hz, 1C), 131.2,
128.6 (d, J = 66.1 Hz, 1C), 126.5, 125.7, 125.6, 122.2, 117.7 (d, J = 24.1 Hz
, 1C), 107.3 (d, J =
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1C). HRMS (ESI-TOF) Calcd. for C13H9FN [M+H]+: 198.0714; found: 198.0713.
2-Chlorophenanthridine (4j). White solid, 32.7 mg, 51% yield, mp 155.8-157.2 °C (lit.7b mp
154-157 °C); 1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 8.43-8.42 (m, 2H), 8.07 (d, J = 8.4 Hz,
1H), 8.00 (d, J = 8.4 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.63 (dd, J = 0.4,
8.4 Hz, 1H).13C NMR (100 MHz, CDCl3) δ 153.8, 142.8, 133.1, 131.6, 131.5, 131.3, 129.2, 128.9,
128.2, 126.5, 125.2, 122.0, 121.9; HRMS (ESI-TOF) Calcd. for C13H9ClN [M+H]+: 214.0418;
found: 214.0417.
1,3-Dimethylphenanthridine (4k). Light yellow solid, 34.8 mg, 56% yield, mp 141.9-143.3 °C
(lit.22a mp 142-143 °C); 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.85 (d, J = 8.4 Hz, 1H), 8.07
(d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.84 (td, J = 1.6, 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.37 (s,
1H), 3.10 (s, 3H), 2.56 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.8, 141.6, 138.0, 135.3, 134.0,
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133.1, 130.5, 129.3, 128.8, 127.4, 126.4, 126.3, 26.7, 21.3; HRMS (ESI-TOF) Calcd. for C15H14N
[M+H]+: 208.1121; found: 208.1119.
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1,4-Dimethylphenanthridine (4l). Light yellow solid, 50.4 mg, 81% yield, mp 86.7-88.2 °C; IR
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(KBr) ν (cm−1) 3451, 2964, 1585, 1448, 1246, 811, 750; H NMR (400 MHz, CDCl3) δ 9.29 (s,
1H), 8.88 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.86-7.82 (m, 1H), 7.71 (td, J = 0.8, 7.6 Hz,
1H), 7.52 (d, J = 7.4 Hz, 1H), 7.42 (d, J = 7.4 Hz, 1H), 3.09 (s, 3H), 2.86 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 152.3, 144.7, 136.0, 134.2, 133.1, 130.8, 130.2, 129.1, 128.9, 127.5, 126.7, 126.6,
123.8, 26.9, 19.4. HRMS (ESI-TOF) Calcd. for C15H14N [M+H]+: 208.1121; found: 208.1121.
2,4-Dimethylphenanthridine (4m). Light yellow solid, 51.6 mg, 83% yield, mp 117.0-118.5 °C
(lit.8c mp 117-118 °C); 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.16
(s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.41 (s, 1H),
2.85 (s, 3H), 2.56 (s, 3H).13C NMR (100 MHz, CDCl3) δ 151.3, 141.6, 137.3, 136.4, 132.6, 131.3,
130.6, 128.6, 127.1, 126.3, 123.9, 122.1, 119.7, 22.0, 18.7. HRMS (ESI-TOF) Calcd. for C15H14N
[M+H]+: 208.1121; found: 208.1121.
3,4-Dimethylphenanthridine (4n). Light yellow solid, 52.9 mg, 85% yield, mp 145.1-146.4 °C
(lit.8c mp 90-91 °C); 1H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.29 (d,
J = 8.4 Hz, 1H), 7.99 (d, J = 8.0 Hz,1H), 7.78 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.46 (d,
J = 8.4 Hz, 1H), 2.83 (s, 3H), 2.53 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 152.1, 143.2, 136.9,
135.5, 133.0, 130.7, 129.3, 128.6, 126.9, 125.7, 122.0, 121.9, 119.2, 20.8, 14.0; HRMS (ESI-TOF)
Calcd. for C15H14N [M+H]+: 208.1121; found: 208.1119.
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Phenaleno[1,9-bc]phenanthridine (4o). Yellow solid, 59.2 mg, 65% yield, mp 273.8-275.6 °C;
IR (KBr) ν (cm−1) 3444, 3038, 1620, 1238, 867, 747; 1H NMR (400 MHz, DMSO-d6 + CDCl3) δ
9.61-9.58 (m, 2H), 9.51 (s, 1H), 9.12 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 9.2 Hz, 1H), 8.36-8.31 (m,
2H), 8.29-8.24 (m, 2H), 8.19-8.13 (m, 1H), 8.09-8.02 (m, 2H), 7.86 (t, J = 7.6 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6 + CDCl3) δ 153.0, 138.2, 132.5, 131.7, 131.5, 131.1, 130.1, 129.3, 128.9,
128.6, 128.3, 128.2, 128.1, 127.0, 126.5, 126.1, 125.7, 124.3, 123.9, 123.1, 121.6, 119.1; HRMS
(ESI-TOF) Calcd. for C23H14N [M+H]+: 304.1121; found: 304.1119.
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Benzo[c]phenanthridine (4p). Light yellow solid, 53.7 mg, 78% yield, mp 133.5-135.1 °C (lit.8c
mp 126-129 °C); 1H NMR (400 MHz, CDCl3) δ 9.48 (s, 1H), 9.42 (d, J = 8.0 Hz, 1H), 8.65 (d, J =
8.0 Hz, 1H), 8.52 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 7.2 Hz, 1H), 8.03-7.98 (m, 2H), 7.87 (t, J = 6.8
Hz, 1H), 7.79 (t, J = 7.2 Hz, 1H), 7.74-7.67 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 152.1, 141.6,
133.4, 132.9, 132.1, 130.9, 128.8, 128.0, 127.8, 127.5, 127.2, 127.1, 127.0, 124.8, 122.3, 121.2,
120.0; HRMS (ESI-TOF) Calcd. for C17H12N [M+H]+: 230.0964; found: 230.0965.
8-Methoxyphenanthridine (4q). Yellow solid, 42.7 mg, 68% yield, mp 109.1-110.5 °C; IR (KBr)
ν (cm−1) 3444, 2952, 1614, 1460, 1366, 1241, 1031, 837, 756; 1H NMR (400 MHz, CDCl3) δ 9.23
(s, 1H), 8.52-8.48 (m, 2H), 8.17 (d, J = 8.0 Hz, 1H), 7.71-7.64 (m, 2H), 7.50-7.47 (m, 1H), 7.38 (s,
1H), 3.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.0, 152.9, 143.7, 130.2, 127.8, 127.3, 127.1,
124.4, 123.7, 122.2, 121.9, 108.1, 55.7; HRMS (ESI-TOF) Calcd. for C14H12NO [M+H]+:
210.0913; found: 210.0917.
8-Methoxy-2,4-dimethylphenanthridine (4r). Light yellow solid, 38.4 mg, 54% yield, mp
140.8-142.1 °C; IR (KBr) ν (cm−1) 3437, 2923, 1616, 1458, 1369, 1209, 1028, 827; 1H NMR (400
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MHz, CDCl3) δ 9.19 (s, 1H), 8.48 (d, J = 9.2 Hz, 1H), 8.12 (s, 1H), 7.44 (dd, J = 2.0, 9.2 Hz, 1H),
7.38 (s, 1H), 7.34 (d, J = 2.0 Hz, 1H), 3.98 (s, 3H), 2.84 (s, 3H), 2.57 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.7, 150.6, 140.9, 137.3, 136.6, 130.5, 127.7, 127.2, 124.2, 123.9, 121.9, 119.3, 107.7,
55.7, 22.1, 18.7; HRMS (ESI-TOF) Calcd. for C16H16NO [M+H]+: 238.1226; found: 238.1225.
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8-Methoxy-3,4-dimethylphenanthridine (4s). Light yellow solid, 39.9 mg, 56% yield, mp
146.3-147.3 °C; IR (KBr) ν (cm−1) 3450, 2924, 1614, 1471, 1258, 1203, 1023, 840, 756; 1H NMR
(400 MHz, CDCl3) δ 9.22 (s, 1H), 8.46 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 7.47-7.42 (m,
2H), 7.34-7.33 (m, 1H), 3.98 (s, 3H), 2.82 (s, 3H), 2.53 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
158.5, 151.4, 142.5, 135.9, 135.4, 129.5, 127.6, 127.0, 123.7, 122.2, 122.0, 118.8, 107.7, 55.7,
20.8, 14.0; HRMS (ESI-TOF) Calcd. for C16H16NO [M+H]+: 238.1226; found: 238.1226.
8-Chlorophenanthridine (4t). White solid, 26.9 mg, 42% yield, mp 97.5-99.9 °C (lit.16d mp
96.5-97.2 °C); 1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.56-8.53 (m, 2H), 8.20 (d, J = 8.0 Hz,
1H), 8.03 (s, 1H), 7.83-7.76 (m, 2H), 7.73-7.69 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 152.4,
144.5, 133.5, 131.8, 131.1, 130.4, 129.2, 127.9, 127.7, 127.3, 123.9, 123.7, 122.3; HRMS
(ESI-TOF) Calcd. for C13H9ClN [M+H]+: 214.0418; found: 214.0410.
Benzo[k]phenanthridine (4u). Light yellow solid, 36.5 mg, 53% yield, mp 108.7-110.1 °C
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(lit.9a mp 108-110 °C); H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 9.18-9.12 (m, 1H), 9.08-9.03
(m, 1H), 8.32 (dd, J = 1.2, 8.0 Hz, 1H), 8.05-8.02 (m, 1H), 7.98-7.95 (m, 1H), 7.91-7.87 (m, 1H),
7.81-7.77 (m, 1H), 7.73-7.70 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 152.7, 146.6, 135.2, 131.2,
130.3, 129.0, 128.8, 128.3, 128.2, 127.9, 127.1, 127.0, 126.9, 125.3, 125.1, 124.7; HRMS
(ESI-TOF) Calcd. for C17H12N [M+H]+: 230.0964; found: 230.0962.
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Large preparation of compound 4b [Scheme 5, Eq. (a)]. A 50 mL flame-dried flask with a stir
bar was charged with N-o-tolylmethanesulfonamide (1b) (555.0 mg, 3.0 mmol),
1-bromo-2-(bromomethyl)benzene (2a) (750.0 mg, 3.0 mmol), Cs2CO3 (3909.8 mg, 12.0 mmol),
Pd(TFA)2 (49.9 mg, 0.15 mmol), and PPh3 (157.4 mg, 0.6 mmol) in 20.0 mL of dry DMF under
nitrogen atmosphere at 160 °C for 24 h. After the completion of the reaction detected by thin layer
chromatography (TLC), brine (100.0 mL) was added, and the mixture was extracted with EtOAc
(5 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and
concentrated by rotary evaporation. The residue was purified by flash column chromatography on
silica gel (petroleum ether/ethyl acetate = 5:1) to afford the desired product 4b as a light yellow
solid (452.2 mg, 78%).
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Synthesis of trisphaeridine (4v) [Scheme 5, Eq. (b)]. A 10 mL flame-dried vial with a stir bar
was charged with N-phenylmethanesulfonamide (1a) (154.1 mg, 0.9 mmol),
5-bromo-6-(bromomethyl)benzo[d][1,3]dioxole (2e) (264.5 mg, 0.9 mmol), Cs2CO3 (1173.0 mg,
3.6 mmol), Pd(TFA)2 (15.0 mg, 0.045 mmol), and PPh3 (47.2 mg, 0.18 mmol) in 6.0 mL of dry
DMF under nitrogen atmosphere at 160 °C for 24 h. After the completion of the reaction detected
by thin layer chromatography (TLC), brine (30.0 mL) was added, and the mixture was extracted
with EtOAc (5 x 30 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered,
and concentrated by rotary evaporation. The residue was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) to afford trisphaeridine (4t) as a
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(400 MHz, CDCl3) δ 9.09 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H),
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7.71-7.67 (m, 1H), 7.65-7.61 (m, 1H), 7.34 (s, 1H), 6.17 (s, 2H); C NMR (100 MHz, CDCl3) δ
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HRMS (ESI-TOF) Calcd. for C14H10NO2 [M+H]+: 224.0706; found: 224.0706.
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Synthesis of compound 5a [Scheme 6, Eq. (a)]. A 4 mL vial with a stir bar was charged with
N-phenylmethanesulfonamide (1a) (51.4 mg, 0.3 mmol), 1-bromo-2-(bromomethyl)benzene (2a)
(75.0 mg, 0.3 mmol), and Cs2CO3 (117.3 mg, 0.36 mmol) in 2.0 mL of dry DMF at 70 °C for 3 h.
After the completion of the reaction detected by thin layer chromatography (TLC), brine (10.0
mL) was added, and the mixture was extracted with EtOAc (5 x 10 mL). The combined organic
layer was dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation. The
residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate
= 5:1) to afford the desired product 5a as a white solid (88.8 mg, 87%). White solid, mp
112.3-113.8 °C; IR (KBr) ν (cm−1) 3470, 2931, 1632, 1403, 1337, 1153, 1027, 959, 757; 1H NMR
(400 MHz, CDCl3) δ 7.57 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.40-7.34 (m, 4H),
7.30-7.26 (m, 2H), 7.10 (t, J = 7.6 Hz, 1H), 5.05 (s, 2H), 3.02 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 139.1, 135.3, 132.7, 130.3, 129.4, 129.2, 128.3, 128.1, 127.6, 123.3, 54.3, 37.9; HRMS
(ESI-TOF) Calcd. for C14H14BrNNaO2S [M+Na]+: 361.9821; found: 361.9816.
Synthesis of compound 3a starting from compound 5a [Scheme 6, Eq. (b)]. A 4 mL
flame-dried vial with
a
stir bar was charged with N-(2-bromobenzyl)-N-
phenylmethanesulfonamide (5a) (102.1 mg, 0.3 mmol), Cs2CO3 (146.6 mg, 0.45 mmol),
Pd(TFA)2 (5.0 mg, 0.015 mmol), and PPh3 (15.7 mg, 0.06 mmol) in 2.0 mL of dry DMF under
nitrogen atmosphere at 160 °C for 10 h. After the completion of the reaction detected by thin layer
chromatography (TLC), brine (10.0 mL) was added, and the mixture was extracted with EtOAc (5
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x 10 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and
concentrated by rotary evaporation. The residue was purified by flash column chromatography on
silica gel (petroleum ether/ethyl acetate = 5:1) to afford the desired product 3a as a white solid
(56.0 mg, 72%). White solid, mp 73.2-74.8 °C (lit.22c mp 73-74 °C); 1H NMR (400 MHz, CDCl3)
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δ 7.85-7.80 (m, 2H), 7.71-7.69 (m, 1H), 7.46-7.31 (m, 5H), 4.83 (s, 2H), 2.27 (s, 3H); C NMR
(100 MHz, CDCl3) δ 135.9, 132.2, 131.3, 129.9, 129.0, 128.9, 128.7, 128.0, 127.7, 126.2, 124.2,
123.8, 49.6, 37.8; HRMS (ESI-TOF) Calcd. for C14H13NNaO2S [M+Na]+: 282.0559; found:
282.0554.
Synthesis of compound 4a starting from compound 3a [Scheme 6, Eq. (c)]. A 4 mL
flame-dried vial with a stir bar was charged with 5-(methylsulfonyl)-5,6-dihydrophenanthridine
(3a) (77.8 mg, 0.3 mmol), and Cs2CO3 (117.3 mg, 0.36 mmol) in 2.0 mL of dry DMF at 160 °C
for 12 h. After the completion of the reaction detected by thin layer chromatography (TLC), brine
(10.0 mL) was added, and the mixture was extracted with EtOAc (5 x 10 mL). The combined
organic layer was dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation.
The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl
acetate = 5:1) to afford the desired product 4a as a white solid (49.5 mg, 92%).
Supporting Information Available NMR spectra, X-ray crystal structure and the CIF file of 4p.
This material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgements
We are grateful for financial support from Science and Technology Department of Guizhou
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Province (No. 2015GZ18284 and QKHRCTD-2014-4002), Education Department of Guizhou
Province (QJHRCTDZ-2012-03), and New Century Excellent Talent of the Ministry of Education
(NCET-13-1069). Special thanks are expressed to Prof. Zeli Yuan (Zunyi Medical University) for
his help of single crystal analysis.
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Notes and References
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(20) See Supporting Information for the details of X-ray structures of product 4p.
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