Photocyclization synthesis of phenanthridine and its derivatives under direct dehydrogenation conditions

Article abstract of DOI:10.1016/j.tetlet.2020.152734

A new method for synthesizing phenanthridines by photocyclization has been established. This method does not require inert gas protection, does not require transition metal catalysts and is environmentally friendly, efficient and convenient. It is proposed to use (E)-N,1-diphenylformimines as substrates to synthesize phenanthridine and its derivatives by ultraviolet light, which provides a new synthesis route for further research on the synthesis of phenanthridines by photocyclization. Eight new phenanthridine compounds were synthesized. The confirmation of their structures provides a material basis for further study of their properties and tapping of their potential for applications. The establishment of this method further broadens the synthetic pathways of phenanthridine compounds.

Full text of DOI:10.1016/j.tetlet.2020.152734

Tetrahedron Letters 64 (2021) 152734
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Tetrahedron Letters
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Photocyclization synthesis of phenanthridine and its derivatives under
direct dehydrogenation conditions
1
1
⇑
Wen-Qing Zhu , Jin Zhang , Pan Fan, Lan-Ting Shi, Hong Li, Min-Ge Yang, Yang Li
Xi’an Key Laboratory of Textile Chemical Engineering Auxiliaries, School of Enviromental and Chemical Engineering, Xi’an Polytechnic University, No. 19 Jinhua South Road,
710048 Xi’an, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method for synthesizing phenanthridines by photocyclization has been established. This method
does not require inert gas protection, does not require transition metal catalysts and is environmentally
friendly, efficient and convenient. It is proposed to use (E)-N,1-diphenylformimines as substrates to syn-
thesize phenanthridine and its derivatives by ultraviolet light, which provides a new synthesis route for
further research on the synthesis of phenanthridines by photocyclization. Eight new phenanthridine
compounds were synthesized. The confirmation of their structures provides a material basis for further
study of their properties and tapping of their potential for applications. The establishment of this method
further broadens the synthetic pathways of phenanthridine compounds.
Received 30 September 2020
Revised 29 November 2020
Accepted 30 November 2020
Available online 24 December 2020
Keywords:
Phenanthridine
Photocyclization reaction
Diphenylformimine
Tert-butanol
Ó 2020 Elsevier Ltd. All rights reserved.
Introduction
as the catalyst. However, the product yield in this work was not
very satisfactory [18]. Herein, we report novel metal-free method
Phenanthridines are an important group of natural alkaloids [1]
typified by trispheridine [2] decarine [3] and chelerythrine [4]
(Fig. 1). Many of them show a wide range of pharmacological prop-
erties, including antitumor, antileukemic, antifungal, and antiviral
activities [5]. Therefore, it is important to develop new methods for
the synthesis of these compounds [6]. Recent achievements
include palladium-catalyzed cascade reactions [7] annulations
employing arynes [8] aza-Wittig reactions [9] oxidative cyclization
of 2-isocyanobiphenyls [10] reactions of biaryl-2-carbonitriles
with organometallic reagents [11] transition-metal-catalyzed
cyclization of imines [12] anionic ring closure reactions [13] UV-
promoted phenanthridine syntheses from iminyl radicals [14] pho-
tochemical processes [15] and microwave-mediated cyclizations
[16]. Although great achievements have been made, further explo-
ration of convenient, efficient, and milder protocols is still signifi-
cant due to the broad application of phenanthridine derivatives.
Many useful molecular structures can be easily obtained
through photochemical organic conversion. Numerous approaches
to natural product synthesis have been reported in which a photo-
chemical transformation represents a key step [17]. In 1988,
Charles reported an example of photo-promoted imine cyclization
reaction to synthesize phenanthridine. The author used Lewis acid
using (E)-N,1-diphenylformimines as substrates to synthesize
phenanthridine and its derivatives by ultraviolet light (Scheme 1,
d). To the best of our knowledge, this is one of the few
Methods to synthesize phenanthridine by photocatalytic direct
dehydrogenation coupling, and the reaction does not require a
base. It is an environmentally friendly and atom-economical
reaction.
We selected (E)-N,1-diphenylmethanimine 1a (1.0 mmol) as the
substrate and reacted it in t-BuOH (250 mL) for 1 h under illumina-
tion by a high-pressure mercury lamp (UHP). The reaction temper-
ature was 45 °C. The target compound was obtained with an
isolated yield of 8% (Table 1, entry 1). Although this yield is very
low, it at least proves that this conversion can be achieved under
direct light conditions. Here, we carefully optimized the reaction
conditions. First, we investigated light sources with different pow-
ers, such as 300 W, 500 W, 1000 W, 2000 W, and 2500 W. We
found that the yield was the best at 2000 W, reaching 55%. When
the light source power was further increased, the yield decreased
(Table 1, entries 2–5); we think that a side reaction may have
occurred. Next, we conducted screening of many solvents for the
reaction, including MeOH, EtOH, DMF, CH3CN, 1.4-dioxane, etc.
Surprisingly, these solvents are not very suitable for this process
(Table 1, entries 6–11). We suspect that tert-butanol is involved
in the chemical reaction here. Therefore, t-BuOH is the best solvent
for the reaction. Next, we also investigated the reaction time, such
as 2 h and 4 h. We found that when the reaction time was more
⇑
Corresponding author.
E-mail address: liyang@xpu.edu.cn (Y. Li).
1
W.-Q. Zhu and J. Zhang contributed equally to this work.
https://doi.org/10.1016/j.tetlet.2020.152734
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

Wen-Qing Zhu, J. Zhang, P. Fan et al.
Tetrahedron Letters 64 (2021) 152734
Scheme 1. Examples of natural products and alkaloids containing a phenanthridine core and general photochemical synthesis routes.
than 2 h, the yield began to decrease, and some by-products with
uncertain structure have increased a lot (Table 1, entries 12–13).
Here, we choose 2 h as the best reaction time. Finally, we also
investigated the amount of solvent, and we observed that the ini-
tially used low concentration is suitable for the reaction. When
the amount was reduced, the reaction yield decreased by 20%
(Table 1, entry 14), and there was no significant increase in the
yield when the reaction concentration was increased. Thus far,
we have determined the best conditions for the reaction to be as
follows: substrate (1.0 mmol), UHP (2000 W), t-BuOH (250 mL),
reaction temperature of 45 °C, and reaction time of 2 h.
After obtaining the optimal reaction conditions, we investigated
the suitability of the reaction substrate. Here, we employed a vari-
ety of different substituents, including electron-deficient and elec-
tron-rich substituents. First, we tried to use imine substrates with
a single electron-rich substituent, and we saw that they could all
be converted into corresponding phenanthridines (Table 2, entries
2–7). In the second step, we made many attempts to use disubsti-
tuted imines. It can be seen that when the electron-deficient and
electron-rich substituents are located on different benzene rings,
this conversion can also proceed smoothly, but the separation
yields are medium (Table 2, entries 8–10). When the double sub-
stituents are all electron-rich substituents, such as methyl-methyl,
Table 1
Selected results for the optimal reaction conditions.[a]
Entry
Light Source
Temperature (oC)
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
UHP (300 W)
UHP (500 W)
UHP (1000 W)
UHP (2000 W)
UHP (2500 W)
UHP (300 W)
UHP (2000 W)
UHP (2000 W)
UHP (2000 W)
UHP (2000 W)
UHP (2000 W)
UHP (2000 W)
UHP (2000 W)
UHP (2000 W)
45
45
45
45
45
45
45
45
45
45
45
45
45
45
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
MeOH
EtOH
DMF
CH3CN
DMSO
8
15
53
55
51
<5
<5
<5
<5
<5
<5
75
68
55
9
10
11
12[c]
13[d]
14[e]
dioxane
t-BuOH
t-BuOH
t-BuOH
aReaction conditions: 1a (1.0 mmol), light source (UHP), solvent (250.0 mL), 45 °C
for 1 h, under air in pressure tubes;
matography;
[b]
Yields of isolated products after chro-
[c]
[d]
[e]
2 h;
4 h;
t-BuOH (25.0 mL).
2

Wen-Qing Zhu, J. Zhang, P. Fan et al.
Tetrahedron Letters 64 (2021) 152734
Table 2
methyl-methoxy, and methoxy-methoxy, the target product can be
obtained in a higher yield (Table 2, entries 11–14). This result once
again confirmed that electron-rich substrates show good applica-
bility for the reaction.
Substrates scope.[a]
.
According to the experimental results, combined with related
literature [19,20], the following possible mechanism is proposed
for this reaction (Scheme 2, taking the 1a reaction to produce 2a
as an example): First, imine compound 1a undergoes cis–trans iso-
merization under the action of light. It is isomerized to compound
A. At the same time, tert-butanol decomposes under light to pro-
duce tert-butoxy radicals and hydrogen radicals. Tert-butoxy radi-
cals abstract the benzylic hydrogen atom of compound A to form
free radical intermediate B and tert-butanol. Free radical interme-
diate B undergoes 1,3-migration to generate intermediate C, and C
undergoes two possible processes to produce cyclohexadiene rad-
ical D. One is the process of 6-exo cyclization (path 1) to directly
generate D; the other (path 2) is that the radical attack on the aro-
matic ring directly connects N to the ipso position of the benzene
ring to induce 5-exo cyclization to form spiro ring free radical E,
and subsequently, the spirocyclic radical E rearranges to produce
cyclohexadiene radical D. Cyclohexadienyl radicals lose hydrogen
atoms under the action of tert-butoxy to generate tert-butanol
and the final product phenanthridine 2a.
We have established a new method to synthesize phenan-
thridine and its derivatives via a photocyclization reaction. First,
using substituted benzaldehyde and substituted aniline as raw
materials, (E)-N,1-diphenylformimine compound intermediates
are obtained through dehydration, and then, phenanthridine com-
pounds are synthesized by photocyclization reaction under mer-
cury lamp irradiation. This method was used to synthesize
around 20 kinds of phenanthridine compounds, and their possible
reaction mechanism was proposed. Compared with traditional
methods for synthesizing phenanthridine and its derivatives, this
method has the following advantages: (1) No metal catalyst is
required, and the substrate does not need to be prefunctionalized.
(2) The reaction conditions are mild, and the reaction time is short.
(3) The method exhibits functional group tolerance, good perfor-
mance and high atom economy. (4) t-BuOH as a solvent is green
and environmentally friendly. The synthesis method provides a
Entry
1
Product
Yield (%)b
75
2
79
3
4
71
81
5
6
78
72
7
8
69
45
9
62
10
11
12
56
85
74
13
14
62
80
aReaction conditions: 1 (0.4 mmol), light source (UHP), t-BuOH (0.004 M), 45 °C for
[b]
2
h, under air in pressure tubes;
Yields of isolated products after
Scheme 2. A plausible mechanism.
chromatography.
3

Wen-Qing Zhu, J. Zhang, P. Fan et al.
Tetrahedron Letters 64 (2021) 152734
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pounds and lays a material foundation for the application of such
compounds in the fields of medicines and materials.
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(c) M. Tobisu, A. Kitajima, S. Yoshioka, I. Hyodo, M. Oshita, N. Chatani, J. Am.
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We are grateful for the financial support from the National Nat-
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and the Doctoral Scientific Research Foundation of Xi’an Polytech-
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