Convenient One-Step Synthesis of Benzo[c]phenanthridines by Three-Component Reactions of Isochromenylium Tetrafluoroborates and Stilbenes in Acetonitrile

Article abstract of DOI:10.1021/acs.orglett.6b00010

A new type of three-component reaction of air-stable isochromenylium tetrafluoroborates with electron-rich stilbenes in acetonitrile has been developed under catalyst-free conditions in this work. This cascade multibond-formation reaction is initiated by an intermolecular oxa [4 + 2]-cycloaddition, relayed with a nucleophilic addition of acetonitrile, and terminated by an intramolecular Friedel-Crafts reaction, affording the corresponding benzo[c]phenanthridine analogues in one step.

Full text of DOI:10.1021/acs.orglett.6b00010

Letter
pubs.acs.org/OrgLett
Convenient One-Step Synthesis of Benzo[c]phenanthridines by
Three-Component Reactions of Isochromenylium Tetrafluoroborates
and Stilbenes in Acetonitrile
Gang-Gang Chen, Jun-Qiang Wei, Xiaoliang Yang,* and Zhu-Jun Yao*
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center
of Chemistry for Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu 210023, China
S
* Supporting Information
ABSTRACT: A new type of three-component reaction of air-
stable isochromenylium tetrafluoroborates with electron-rich
stilbenes in acetonitrile has been developed under catalyst-free
conditions in this work. This cascade multibond-formation
reaction is initiated by an intermolecular oxa [4 + 2]-
cycloaddition, relayed with a nucleophilic addition of
acetonitrile, and terminated by an intramolecular Friedel−
Crafts reaction, affording the corresponding benzo[c]-
phenanthridine analogues in one step.
he benzo[c]phenanthridine core commonly exists in
C-1 position19−22 or electron-rich olefins via [4 + 2]-
cycloaddition pathways23−26 under mild metal-free conditions.
In addition, three-component reactions of ICTBs, enols (in situ
derived from aliphatic aldehydes), and nitriles/aldehydes
provided various amino- and hydroxyl-functionalized tetrahy-
dronaphthalenes and dihydronaphthalenes.27 In this work, we
report a new three-component reaction28,29 of ICTBs, stilbenes,
and acetonitrile which delivers benzo[c]phenanthridines within
a single operation (Figure 2). This new method represents an
alternative convenient one-step entrance to the diverse
benzo[c]phenanthridine derivatives.
T
bioactive alkaloids1−4 and other related natural products,5
such as sanguinarine, chelerythrine, and chelamine6,7 (Figure
1). Because of these products’ diverse biological properties
Our previous work showed that stilbene 3a could react with
ICTB 1a (a representative isochromenylium tetrafluoroborate)
in MeCN at 80 °C to afford the dihydronaphthalene derivative
5a through formal [4 + 2]-cycloaddition and proton
elimination (Figure 2).16 On the basis of our understanding
Figure 1. Representative bioactive benzo[c]phenanthridine derivatives.
(especially antibiotic and antitumor8), great efforts have been
devoted to the synthesis of natural and unnatural benzo[c]-
phenanthridines using multistep approaches.9−13 Recently, the
Clement and Blache groups reported two concise syntheses of
this type of alkaloids and their derivatives, using strong base-
promoted condensation of 2-methylbenzonitrile with aromatic
aldehydes14 and Pd(OAc)2-catalyzed oxidative C−N bond
formation reaction,15 respectively.
Figure 2. New one-step synthesis of benzo[c]phenanthridines.
Received: January 3, 2016
Our recent investigations of isochromenylium tetrafluorobo-
rates (ICTBs),16,17 a class of air-stable reactive organic salts
having nonclassical Huckel aromaticity,18 have revealed that
̈
they were able to smoothly react with either nucleophiles at the
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00010
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Organic Letters
Letter
of the mechanism, immediate capture of the cationic
intermediate (after the [4 + 2]-cycloaddition) with an external
nucleophile would be a potential method to generate more
diverse products. It also would be a meaningful expansion of
the application scope of these air-stable ICTBs. Acetonitrile
(MeCN) is an economically available and widely applied polar
aprotic solvent. Since it contains a lone electron pair on its
nitrogen, acetonitrile has occasionally been applied as a weaker
nucleophile and nitrogen source in organic synthesis, such as
Ritter reactions.30 To favor the insertion of MeCN into the
above-mentioned ICTB reaction, proper adjustment of the
electronic density of the stilbene (to keep the cationic
intermediate in the reaction for a longer lifetime) was
considered. Therefore, the reaction behaviors of ICTB in
MeCN were examined through tuning the substituents of the
stilbenes (Scheme 1).
Table 1. Optimization of Reaction Conditions of ICTB 1a
with Stilbene 2a
b
2a
(equiv)
temp
(°C)
concn
(M)
time
(h)
4a
a
entry
solvent
(%)
c
1
THF
1.0
1.0
1.0
1.0
1.0
1.5
2.0
1.5
1.5
60
60
25
40
80
80
80
80
80
0.1
48
48
36
24
18
12
10
9
NR
NR
NR
trace
39
c
2
DCE
0.1
3
4
5
6
7
8
9
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
0.05
0.05
0.05
0.05
0.05
0.025
0.1
64
65
57
15
46
a
b
All reactions were performed under nitrogen atmosphere. Isolated
c
yields. MeCN (5.0 equiv of 1a) was used as a reagent.
the most suitable solvent. In other words, MeCN played dual
roles as both a reactant (the nitrogen source) and the solvent in
the reaction. Higher temperature could accelerate the reaction
and improve the efficiency (entries 3−5). Raising the amounts
of substrate 2a (based on 1 equiv of ICTB 1a) also favored this
reaction, and 1.5 equiv of 2a was considered to be a suitable
and economic choice (entries 5−7). The best reaction
concentration was proven to be 0.05 M (entries 6, 8, and 9).
Finally, entry 6 (1.5 equiv of 2a, 0.05 M in MeCN, 80 °C) was
selected as the standard conditions for further study.
Scheme 1. Examination of the Reactions of ICTB 1a with
Stilbenes 2a,p,r and 3b
Under the optimized conditions, a variety of additional
stilbenes 2b−s were examined (Table 2). Most of the reactions
could take place smoothly and afforded moderate to satisfactory
yields of expected products when the phenyl ring B of substrate
2 has one or two electron-donating substituent(s). Compared
with that of stilbene 2f having one methoxyl substituent (giving
Table 2. Reactions of ICTB 1a with Stilbenes 2 in MeCN
The reaction of ICTB 1a and stilbene 3b was carried out in
MeCN at 80 °C, affording a dihydronaphthalene derivative 5b
in 63% yield, and the expected tricyclic product 5b′ was not
detected16 (Scheme 1). Clearly, acetonitrile could not take part
in this reaction, while the reaction of stilbene 2p, in which the
benzene ring A was equipped with two electron-donating
methoxyl groups, provided the expected product 4p in 48%
yield under the same conditions. It indicated that the more
electron-rich phenyl ring A of the stilbene substrate favored
trapping acetonitrile into the reaction. With 3,5-dimethoxyl
groups fixed on the phenyl ring A of the stilbenes, additional
reactions were investigated by varying the substituent(s) of
phenyl ring B. The reaction with stilbene 2r (having an
electron-withdrawing cyano group on ring B) did not take
place, while the reaction with 2a (bearing an electron-donating
methoxyl group) smoothly afforded the corresponding product
4a. According to this evidence, we speculate that electron-rich
characters of both phenyl rings A and B of the stilbene are
crucial to favor the three-component reaction.
a
b
entry
2
time (h)
4 (%)
1
2b (R1 = H, R2 = 4-Me)
2c (R1 = H, R2 = 4-Cl)
2d (R1 = 3-Me, R2 = 5-Me)
2e (R1 = 3-OMe, R2 = 5-OMe)
2f (R1 = H, R2 = 3-OMe)
2g (R1 = H, R2 = 3-Me)
2h (R1 = H, R2 = 3-Cl)
2i (R1 = 2-Me, R2 = 3-Me)
2j (R1 = H, R2 = 2-OMe)
2k (R1 = H, R2 = 2-Me)
2l (R1 = H, R2 = 2-Cl)
2m (R1 = 2-Me, R2 = 4-Me)
2n (R1 = 3-OMe, R2 = 4-OMe)
2o (R1 = 3-Me, R2 = 4-Me)
2q (R1 = H, R2 = 4-NO2)
2s (R1 = H, R2 = 4-CF3)
10
14
17
12
7
4b (57)
4c (43)
4d (66)
4e (78)
4f (67)
4g (58)
4h (45)
4i (63)
4j (66)
4k (55)
4l (40)
4m (60)
4n (75)
4o (62)
NR
2
3
4
5
6
10
12
16
8
7
8
9
10
11
12
13
14
15
16
11
15
13
11
18
48
48
Next, the reaction between ICTB 1a and stilbene 2a was
applied as a platform for optimization of the conditions. Owing
to the poor solubility of 1a in either THF or DCE, the reaction
did not happen, even with small amounts of MeCN as the
cosolvent (Table 1, entries 1 and 2). MeCN was proven to be
NR
a
Reaction conditions: 1a (1.0 mmol) and 2 (1.5 mmol) in anhydrous
CH3CN (20 mL) under nitrogen atmosphere at 80 °C. Isolated
b
yields.
B
DOI: 10.1021/acs.orglett.6b00010
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Organic Letters
Letter
67% yield of product 4f, entry 5), reaction with 2e with two
methoxyl substituents on ring B afforded compound 4e in 78%
yield (entry 4). This clearly indicated that more EDGs on ring
B of 2 favored this type of three-component reaction. The
reactions were also found to tolerate a halogen substituent on
ring B, though lower yields of the products were given (entries
2, 7, and 11). However, when phenyl ring B of stilbene 2 has an
electron-withdrawing group (such as nitro and CF3 groups),
the cascade reaction could not proceed (entries 15 and 16).
Altering the position of substituent(s) on ring B of 2 did not
significantly affect the reaction behaviors, and the reactions of
substrates 2b, 2g, and 2k afforded similar yields of products 4b,
4g, and 4k (entries 1, 6, and 10). The relative configurations of
representative product 4b were determined by 1D and 2D
NMR experiments, and other products were elucidated by
spectral comparison accordingly.
Table 3. Reactions of ICTBs 1a−e with Stilbenes 2t−x
a
b
entry
1
2 (R =)
6 (yield, %)
1
2
1a
1a
2t (4-OH)
6t (R4 = R5 = OMe; R6 = Ph; R7 = 4-OAc; 55)
2u (3-OH) 6u (R4 = R5 = OMe; R6 = Ph; R7 = 3-OAc;
53)
3
4
5
6
1a
1a
1a
1b
2v (H)
2w (2-Cl)
2x (4-Cl)
2t
6v (R4 = R5 = OMe; R6 = Ph; R7 = H; 45)
6w (R4 = R5 = OMe; R6 = Ph; R7 = 2-Cl; 38)
6x (R4 = R5 = OMe; R6 = Ph; R7 = 4-Cl; 40)
A possible mechanism was suggested according to the
comprehensive analysis of the results from this work (Figure 3).
6bt (R4 = R5 = OMe; R6 = n-C6H13; R7 = 4-
OAc; 53)
7
8
9
1c
1d
1e
2t
2t
2t
6ct (R4, R5 = -OCH2O-; R6 = Ph; R7 = 4-OAc;
60)
6dt (R4 = OMe; R5 = OAc; R6 = Ph; R7 = 4-
OAc; 63)
6et (R4 = OAc; R5 = OMe; R6 = Ph; R7 = 4-
OAc; 56)
a
The procedure was described in the Supporting Information.
Isolated yields.
b
amount of DMAP in DCM, providing the corresponding
acetates 6. The results once again confirmed the above three-
component cascade transformations, which worked well with
various ICTBs 1a−e and stilbenes containing free phenolic
hydroxyl group(s). Slightly lower isolation yields in several
cases might be caused by the material loss of the highly polar
products on silica gel chromatography. The relative config-
urations of product 6t were further confirmed by the X-ray
single-crystal analysis (see the Supporting Information).
In summary, a new three-component cascade annulation of
isochromenylium tetrafluoroborates, electron-rich stilbenes,
and acetonitrile has been developed in this work, providing
the corresponding benzo[c]phenanthridine analogues in a
single operation with excellent diastereoselectivities. The
mechanism of this cascade reaction was also discussed and
proposed based on the results and experimental evidence. The
new methodology is advantageous in its ease of operation and
metal-free conditions and, thus, will be useful in future
applications to the synthesis of biologically important natural
and unnatural products having a benzo[c]phenanthridine core.
Figure 3. Proposed mechanism for the multistep cascade reaction.
At first, a [4 + 2]-cycloaddition (or a formal [4 + 2]-
cyclization) takes place between the electron-deficient 2-oxa
diene of the isochromenylium salt 1a and the electron-enrich
stilbene 2, giving a bridged oxonium intermediate 4B. This [4 +
2]-adduct is immediately attacked by the nitrogen atom of
acetonitrile from the less steric direction. The resulting
intermediate 4C is then slowly converted into its diastereomer
4D at reaction temperature (80 °C) to favor the subsequent
intramolecular Friedel−Crafts reaction, completing the closure
of the heterocycle. Final elimination of HBF4 from the
intermediate 4E affords the observed multi-ring product 4.
Based on our understanding of the above results, we further
expanded the reactions to more ICTBs 1 and several additional
electron-rich stilbenes containing free phenolic hydroxyl
group(s), including natural resveratrol (2t) and pinosylvin
(2u), in acetonitrile. Because of the high polarity of the
products, these reactions were conducted in a two-stage process
to improve the product purification (Table 3). The crude
products from the first step (the three-component reaction)
were fully acetylated with acetic anhydride, Et3N, and a catalytic
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00010.
Experimental procedure and physical characterizations of
the products; NMR copies of new compounds (PDF)
X-ray crystal data of 6t (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yxlnmr@nju.edu.cn.
*E-mail: yaoz@nju.edu.cn.
C
DOI: 10.1021/acs.orglett.6b00010
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(25) Zhang, H.; Zhu, L.; Wang, S.-Z.; Yao, Z.-J. J. Org. Chem. 2014,
79, 7063−7074.
Notes
The authors declare no competing financial interest.
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■
Financial support from the National Natural Science
Foundation of China (Nos. 21272112, 21472087, and
21532002) and the Ministry of Science and Technology of
the People’s Republic of China (No. 2013AA092903) is greatly
appreciated.
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