A mild acid-free one-pot reaction for synthesis of new phenanthridine dyes

Article abstract of DOI:10.1016/j.dyepig.2016.07.041

A series of new phenylphenanthridin dyes have been synthesized in the yields of 52–75% by a mild strategy in one-pot reaction. This is the first successful attempt to perform efficient soft acid-free reaction for phenanthridine ring construction. A large substrate scope was well demonstrated.

Full text of DOI:10.1016/j.dyepig.2016.07.041

Accepted Manuscript
A mild acid-free one-pot reaction for synthesis of new phenanthridine dyes
Xiaozhuan Qin, Ge Ding, Ziping Luo, Zhiyong Wang, Shengtao Zhang, Hongru Li,
Fang Gao
PII:
S0143-7208(16)30358-8
10.1016/j.dyepig.2016.07.041
DYPI 5375
DOI:
Reference:
To appear in: Dyes and Pigments
Received Date: 29 April 2016
Revised Date: 29 June 2016
Accepted Date: 31 July 2016
Please cite this article as: Qin X, Ding G, Luo Z, Wang Z, Zhang S, Li H, Gao F, A mild acid-free
one-pot reaction for synthesis of new phenanthridine dyes, Dyes and Pigments (2016), doi: 10.1016/
j.dyepig.2016.07.041.
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A mild acid-free one-pot reaction for synthesis of new phenanthridine dyes
Xiaozhuan Qin a, Ge Ding a, Ziping Luo a, Zhiyong Wang a*, b*, Shengtao Zhang a*, b*, Hongru Li a*, b*, Fang Gao a*, b*
a* College of Chemistry and Chemical Engineering, Chongqing University, Chongqing, China
b* National-municipal Joint Engineering Laboratory for Chemical Process Intensification and Reaction
Tel/Fax, 86-23-65678930, Emails, zwang@cqu.edu.cn, stzhang@cqu.edu.cn, hongruli1972@gmail.com, fanggao1971@gmail.com
Abstract
A series of new phenylphenanthridin dyes have been synthesized in the yields of 52~75% by a mild strategy
in one-pot reaction. This is the first successful attempt to perform efficient soft acid-free reaction for
phenanthridine ring construction. A large substrate scope was well demonstrated.
Keywords: Phenanthridine; Mild condition; Acid-free; One-pot reaction
1. Introduction
The phenanthridine family is widely found in medicinal chemistry and material science
because of the biological activity and the presence in a variety of significant natural products and
synthetic dye-stuffs [1]. So far, various synthetic strategies have been developed such as
Bischler–Napieralski cyclization and Heck cyclization for the robust synthesis of phenanthridines
[2]. However, the reported approaches remain the extreme difficulties including the multi-step
routes, the limited substrate scopes, the use of metal catalysts or the weak generalities/limited
diversities [3-5]. Therefore, there is a great demand to develop a simple, convenient protocol for
expeditious synthesis of phenanthridine derivatives.
Phenanthridine could be accessed by Pictet-Spengler reaction under various reaction
conditions such as Lewis acids [6], Bronsted acids [7], tandem threefold reaction condition [8]. In
2009, Youn and the coworker found the trifluoroacetic acid (TFA)-mediated coupling reaction of

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2-arylanilines with arylaldehydes for the synthesis of phenanthridines [9]. Some efforts were
devoted to improve the reaction conditions [10], however, strong acid catalysis was still required.
In this letter, we describe a new entry for the efficient synthesis of phenylphenanthridine dyes
by an acid-free one-pot reaction at room temperature under air atmosphere. In this way,
2'-amino-1,1'-biphenyl-3-ol reacts with different benzaldehydes to yield the target
phenylphenanthridine dyes. To the best of our knowledge, this is the first successful attempt to
perform one-pot reaction at mild acid-free conditions for synthesis of phenanthridine dyes.
2. Results and discussion
The substrate 1 (shown in Scheme 1) was obtained by directly condensing
3-hydroxyphenylboronic acid and 2-bromo aniline via Suzuki reaction without protecting amino
group in 90% isolated yield, which was used to undergo the reaction with benzaldehydes at room
temperature under air atmosphere. The isolated major products and the yields of the above
reactions are listed in Table 1. It is shown that phenanthridine dyes 2 are the major products with
the yields from 52% to 75% produced by various benzaldehydes, while the condensed products 3
could be isolated as the minor products (~ 10%) only in some reactions, such as
2'-amino-1,1'-biphenyl-3-ol reacted with the 2-methoxybenzaldehyde (Scheme 1(a)).
Insert Scheme 1
1
Figure 1(a) gives the representative H-NMR spectra of the phenanthridine dye P1. There
are two separated peaks at 8.615 ppm of 1H-NMR chemical shift, suggesting the absence of imino

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1
group. The H-NMR spectral integration area ratio of different hydrogen atoms is consistent with
that of the numbers of hydrogen atoms.
Insert Figure 1
The molecular structures of the yielded phenanthridine dyes were further confirmed by single
crystals obtained by the vapor diffusion of n-hexane into the solution in dichloromethane. The
typical X-ray single crystal diffraction of P1 shows the presence of phenanthridine ring, which is
defined by the small torsion angle of C6-C7-C8-C13 (1.06°). Hence, the fused three aromatic
rings (A, B, C) are almost in a plane. In addition, we notice a dihedral angle of 58.95° between the
fused three aromatic rings (A, B, C) and aromatic ring D (Figure 2(a)).
Insert Figure 2
Table 1 shows that the main target phenanthridine dyes and the yields are not greatly varied
by different electron-rich or -deficient benzaldehydes. The unhydrogenated phenanthridines are
the major products while the aromatic aldehydes are substituted by electron-donating groups. In
addition, the substituted positions of the groups in the benzaldehydes caused negligible effects on
the reaction (Table 1, P2, P3, P10).
It is noticed that the hydrogenated phenanthridines become the predominant products as the
benzaldehydes carry the strong electron-withdrawing groups such as nitro and cyano groups,
while the unhydrogenated phenanthridines are the minor products (Scheme 1(b), Table 1). On the
other hand, the hydrogenated phenanthridines can be converted into unhydrogenated

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phenanthridines as the temperature was raised (under reflux), which indicates the presence of a
large reaction energy barrier.
Insert Table 1
1
The chemical structures of the hydrogenated phenanthridines were identified by H &
13C-NMR spectra. As shown in Figure 1(b), the 1H-NMR chemical shifts of 5.565 ppm and 6.712
ppm in P11 can be assigned to -NH- and its adjacent -CH- groups, respectively. X-ray single
crystal diffraction of P11 further confirms the structures of hydrogenated phenanthridines (Figure
2(b)).
It is found that the phenanthridine dyes could be produced by this reaction in a variety of
organic solvents. However, a much longer reaction time (75 hr) was required in aprotic solvents
such as benzene, tetrahydrofuran and acetonitrile, which only produced a dramatic low yields of
phenanthridines (< 10%), and a higher yields of the main condensed products (60~75%).
As discussed, a shorter time (18 hr) and a higher yield of the reaction were found in alcoholic
solvents, particularly in methanol and ethanol solvents. However, the phenanthridine dyes were
obtained in lower yields in n-propanol and n-butyl alcohol solvents (30~40%). Furthermore, the
yields of phenanthridine dyes reached ~30% as the reaction was performed in mixed solvents of
methanol or ethanol and tetrahydrofuran (1:1, v:v) with a longer time (46 hr).
In addition, the reaction time could be reduced by the increase of the reaction temperature,
while the yields of the phenanthridine dyes were not increased remarkably. It is further observed
that the same reaction occurred under oxygen or argon atmosphere in ethanol or methanol. It is
also found that the target phenanthridine dyes were produced as well in toluene containing

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trifluoroacetic acid under the reflux for 2 hr.
Insert Scheme 2
In light of these experimental results, we propose a tentative mechanism for an acid free
one-pot reaction using 3-hydroxybiphenyl-2-amine as the substrate (Scheme 2). Firstly, the amine
and the aldehyde are easily condensed to yield the imine product, followed by the attack of the
double bond to the protonated imine, and rearrangement occurred, towards cyclization leading to
dihydrophenanthridines, which is followed by deprotonation and oxidation to yield the final
phenanthridine dyes. It is worthy pointing out that the cyclization may also go through the
different mechanisms, for instance, 6pi-electrocyclization with subsequent oxidation.
3. Conclusions
To be closing, we present an acid free one-pot reaction under the mild conditions for the
efficient synthesis of a variety of phenanthridines. The molecular structures of the yielded
1
phenanthridines were characterized by H & 13C NMR spectroscopy, MS, IR spectra as well as
X-ray diffraction analyses. Further work is being performed in our laboratory to investigate the
new interesting intriguing biological and optical activities of these dye molecules and will be
reported in due course.
Supplementary date

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The synthesis and characterization of the major products including NMR spectral data, IR
spectral data, elementary analysis as well as high resolution mass spectral data
(HRMS) of the products (P1~P13) are provide in the Supplementary date, and the
document is available free of charge from the website of this journal.
The supplementary crystallographic data for this work are contained in file numbered by
1472575-1472576, which are free available http://www.ccdc.cam.ac.uk/conts/retrieving.html or
from the Cambridge crystallographic data center, 12, Union Road, Cambridge CB2 1EZ, UK; fax:
44-1223-336033. The crystallographic data are also provided in the Supplementary date.
Acknowledgements
The authors greatly appreciate Chongqing Natural Science Foundation CSTC2012jjB50007
and CSTC2010BB0216. H. Li is grateful to the Postdoctoral Science Foundation of China for
financial supporting (Grant No. 22012T50762 & 2011M501388). This work was also supported
by the Graduate Student Innovation Foundation of Chongqing University (CDJX11131146).
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The captions of Figures 1~2
Figure 1 1H-NMR spectra of P1 and P11
Figure 2 An ORTEP (30% thermalellipsoids) plot of P1 and P11 with the numbering
The captions of Schemes 1~2
Scheme 1 Synthesis of phenanthridine dyes with different electron donating or accepting substrates by one-pot
reaction
Scheme 2 Postulated mechanism of a mild acid-free one-pot reaction
The caption of Table 1
Table 1 The one-pot synthesis results of phenanthridine dyes.a

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Figures
Figure 1
Figure 2

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Schemes
Scheme 1
(a)
HO
HO
R3 HO
R1
R2
R3
R2
EtOH
rt
R2
NH2
OHC
R3
+
+
N
N
R1
.
R1
3
2
1
(minor)
(major)
P1:R1=R2=R3=-H
P6:R1=R2=-H, R3=-N(Me)2
P7:R1=R2=-H, R3=-N(Et)2
P8:R1=R2=-H, R3=-F
P9:R1=R2=-H, R3=-Cl
P10:R2=R3=-H, R1=-OCH3
P2:R1=R2=-H, R3=-OCH3
P3:R1=R3=-H, R2=-OCH3
P4:R1=-H, R2=R3=-OCH3
P5:R3=-H, R1=R2=-OCH3
(b)
HO
HO
R3 HO
R2
R3
R1
R2
EtOH
rt
R2
NH2
OHC
R3
+
+
NH R1
N
R1
4
1
(major)
(minor)
reflux
P11:R1=R2=-H, R3=-NO2
P12:R1=R2=-H, R3=-CN
P13:R1=R3=-H, R2=-NO2
Scheme 2
HO
R CHO
HO
HO
HO
HO
H
R
O
R
EtOH
-
H
R
R
N
NH2
NH
N
N
H

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Tables
Table 1
Entry
P1
Aldehyde
Product
Yield(%)
75%
Entry
P8
Aldehyde
Product
Yield(%)
54%
PhCHO
4-FC6H4CHO
HO
HO
F
N
N
P2
P3
P4
P5
P6
P7
4-MeOC6H4CHO
70%
68%
67%
72%
63%
62%
P9
4-ClC6H4CHO
52%
65%
68%
55%
60%
HO
HO
HO
HO
HO
Cl
HO
HO
HO
HO
OCH3
N
N
3-MeOC6H4CHO
P10
P11
P12
P13
2-MeOC6H4CHO
4-NO2C6H4CHO
4-CNC6H4CHO
3-NO2C6H4CHO
OCH3
N
N
N
N
OCH3
2,3-
NO2
MeOC6H4CHO
OCH3
OCH
3
NH
3,4-
CN
OCH3
OCH3
MeOC6H4CHO
NH
4-
HO
N
(Me)2NC6H4CHO
NO2
NH
N
4-(Et)2NC6H4CHO
HO
N
N
[a] Performed under the experimental conditions: 1 (1 equiv.), aromatic aldehyde (1.05 equiv.) in ethanol at 25°C,
18 hr under air atmosphere.

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Highlights
ꢀ
ꢀ
ꢀ
The mild acid-free one-pot reaction strategy for efficient synthesis of phenanthridines dyes
A large scope of the substrates well used for this approach
The chemical structures of the yielded phenanthridines well identified by various
characterizations
ꢀ
The roles of alcoholic solvents well demonstrated by the experiments