Photoredox Catalysis: Construction of Polyheterocycles via Alkoxycarbonylation/Addition/Cyclization Sequence

Article abstract of DOI:10.1021/acs.orglett.7b01553

A novel visible-light-induced cascade reaction for the preparation of ester-functionalized polyheterocycles was developed under metal-free conditions, which was initiated by an intermolecular radical addition to a carbon-carbon double bond of N-arylacrylamide derivatives using alkyl carbazate as the ester source followed by cyano-mediated cyclization. The desired phenanthridine derivative products were isolated in moderate to high yields with broad substrate scope.

Full text of DOI:10.1021/acs.orglett.7b01553

Letter
pubs.acs.org/OrgLett
Photoredox Catalysis: Construction of Polyheterocycles via
Alkoxycarbonylation/Addition/Cyclization Sequence
Xuanxuan Li, Xinxin Fang, Shengyi Zhuang, Ping Liu, and Peipei Sun*
School of Chemistry and Materials Science, Jiangsu Provincial Key Laboratory of Material Cycle Processes and Pollution Control,
Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Nanjing Normal University, Nanjing 210023, China
S
* Supporting Information
ABSTRACT: A novel visible-light-induced cascade reaction for the preparation of ester-functionalized polyheterocycles was
developed under metal-free conditions, which was initiated by an intermolecular radical addition to a carbon−carbon double
bond of N-arylacrylamide derivatives using alkyl carbazate as the ester source followed by cyano-mediated cyclization. The
desired phenanthridine derivative products were isolated in moderate to high yields with broad substrate scope.
he importance of heterocyclic compounds in organic and
functionalized polycyclic heterocycles. In this letter, we wish to
Tpharmaceutical chemistry is undoubted, thus the synthesis report a novel visible-light-induced cascade alkoxycarbonyla-
tion/addition/cyclization to obtain tetracyclic compounds 2-(5-
oxo-5,6-dihydro-4H-pyrido[4,3,2-gh]phenanthridin-6-yl)-
acetates, in which cyano acted as the key mediator.
of these molecules is one of the most important works for organic
chemists, and many efforts have been made for this purpose over
the course of a century.1 Visible-light-induced radical reactions
have aroused more and more attention in recent years because of
their simplicity, efficiency, and unique activation, as well as atom
economy.2 This strategy has been successfully used for the
synthesis of heterocycles,3 and a series of pioneering and
significant methods were developed in this field. Many of these
heterocyclization reactions were initiated via the addition of
radicals to carbon−carbon double bonds. For example, by the
addition of several radicals to N-acryloyl benzamides, isoquino-
line-1,3(2H,4H)-diones were synthesized;4 the addition to N-
arylacrylamides generated oxoindoles;5 the addition to cinna-
mamides resulted in quinolone-2-ones or 1-azaspiro[4.5]-
decanes;6 intramolecular oxy- and aminoarylation of alkenes
with a aryl radical produced tetrahydrofuran and pyrrolidine
derivatives;7 the difunctionalization of styrenes using ammonium
thiocyanate yielded 1,3-oxathiolanes.8 The radical addition plays
an increasingly significant role in the synthesis of heterocyclic
compounds.
Cyano is a versatile functional group in organic synthesis
because it can be used as an important precursor for a multitude
of transformations.9 Cyano-participated radical addition/cycliza-
tion for the formation of cyclic compounds has aroused much
interest in recent years. A series of reports involved the
application of a cyano group to be used as the carbonyl source
in the construction of various substituted quinoline diones10 and
some other cyclic ketones.11 Furthermore, several intramolecular
radical cascade cyclizations through the addition to a cyano
group to construct fused N-heterocyclic compounds were
developed.12 These significant approaches stimulated us to
further explore the application of this group in the synthesis of
Looking for appropriate reaction conditions, we selected N-(2-
cyano-[1,1′-biphenyl]-3-yl)-N-methylmethacrylamide (1a) and
methyl carbazate (2a) as the model substrates. Under the
irradiation of 5 W white LEDs, using eosin Y as photocatalyst and
in the presence of TBHP (tert-butyl hydroperoxide), the fused
heterocycle product methyl 2-(4,6-dimethyl-5-oxo-5,6-dihydro-
4H-pyrido[4,3,2-gh]phenanthridin-6-yl)acetate (3a) was ob-
tained in 48% yield after 16 h, whereas less than 10% byproduct
3a′ that was generated via a cyclization on the 6-position of the
benzene ring of 1a was observed. Encouraged by this result, we
optimized the reaction conditions (Table 1). Oxidants were first
screened. Without oxidant, no desired product 3a was obtained
(entry 2). Compared with TBHP, the oxidants H2O2, DTBP (di-
tert-butyl peroxide), TBPB (tert-butyl peroxybenzoate), and
DCP (dicumyl peroxide) showed lower efficiency for this
reaction (entries 3−6). Sequential screening of solvents found
that the highest yield of 57% was obtained when the reaction was
performed in DCM, whereas other solvents gave lower yields
(entries 7−11). In view of the important impact of the catalyst on
photoredox catalysis, we next examined several other photo-
catalysts such as eosin B, rhodamine B, acid red 94, fluorescein,
and Ru(bpy)3Cl2 (entries 12−16). Nevertheless, no results
better than those of eosin Y were observed. The experimental
results also revealed that a 2 mol % catalyst loading was
appropriate for this reaction (entries 17 and 18). In the dark, the
reaction could not take place at all (entry 19). The irradiation
Received: May 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01553
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Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 1. Synthesis of Pyrido[4,3,2-gh]phenanthridin-6-
a
yl)acetate Derivatives
3a yield
3a′ yield
entry
catalyst (mol %)
oxidant
TBHP
solvent
(%)
(%)
1
eosin Y (2)
eosin Y (2)
eosin Y (2)
eosin Y (2)
eosin Y (2)
eosin Y (2)
eosin Y (2)
eosin Y (2)
eosin Y (2)
eosin Y (2)
eosin Y (2)
eosin B (2)
rhodamine B (2)
acid red 94 (2)
fluorescein (2)
Ru(bpy)3Cl2 (2)
eosin Y (1)
eosin Y (3)
eosin Y (2)
eosin Y (2)
eosin Y (2)
eosin Y (2)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
48
0
<10
0
2
3
H2O2
38
42
46
0
0
4
DTBP
TBPB
BPO
<10
<10
0
5
6
7
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
55
57
40
32
20
trace
46
40
0
trace
trace
<10
<10
<10
0
8
DCM
9
acetone
DMSO
DMF
10
11
12
13
14
15
16
17
18
DCM
DCM
trace
0
DCM
DCM
0
DCM
41
42
55
0
<10
0
DCM
DCM
trace
0
b
19
DCM
c
20
d
DCM
54
43
75
trace
0
21
DCM
e
22
DCM
trace
a
Reactions conditions (unless otherwise specified): 1a (0.2 mmol), 2a
(0.4 mmol), catalyst (2 mol %), oxidant (4 equiv), and solvent (2 mL)
were placed in a sealed tube under Ar atmosphere upon irradiation of
b
c
d
5 W white LEDs for 16 h. In the dark. Using 5 W blue LEDs. Using
e
23 W CFL. The reaction time was 36 h.
with 5 W blue LEDs or 23 W CFL instead of 5 W white LEDs
provided lower yields of 3a (entries 20 and 21). Furthermore, the
yield could be increased to 75% when the reaction time was
extended to 36 h (entry 22).
With the optimized conditions in hand, the substrate scope in
this visible-light-induced alkoxycarbonylated cyclization was
investigated (Scheme 1). The effect of the substituents on the
benzene ring A of reactant 1 was first examined. As shown in
Scheme 1, for the substrates with both electron-donating groups
(alkyl, alkoxy, alkylthiol, etc.) and electron-withdrawing groups
(halogen, ester, sulfonyl, cyano, etc.) on the para-position of
benzene ring A, the reactions proceeded smoothly, and the yields
had no significant difference (3a−3m). The structure of the
product 3m was further confirmed by crystal X-ray diffraction
(CCDC number 1538715). In the presence of a strong electron-
withdrawing substituent, trifluoromethyl, a lower yield of 57%
was obtained (3n). The ortho-MeO- or Cl-substituted reactants
also gave high yields (3o and 3p), in which no steric hindrance
was observed. For the meta-methyl-substituted reactant (1q), a
mixture of the products 3q1 and 3q2 were separated from the
reaction mixture in a ratio of 5:1. The reaction could also take
place on the naphthalene ring, and the pentacyclic compounds
were obtained from this visible-light-induced cascade cyclization
(3r and 3s). For disubstituted substrates, the reaction gave
results similar to those of monosubstituted substrates (3t and
3u). The effect of different substituents on nitrogen was then
studied. The comparable yields were obtained from N-nbutyl
reactants (3w−3y), whereas N-isobutyl- or benzyl-substituted
a
Reactions conditions: 1 (0.2 mmol), 2 (0.4 mmol), eosin Y (2 mol
%), TBHP (4 equiv), and DCM (2 mL) were placed in a sealed tube
under Ar atmosphere upon irradiation of 5 W white LEDs for 36 h.
b
At 1 mmol scale.
derivatives gave the products in moderate yields (3v, 3z, and
3aa). It is worth mentioning that a thieno[3,2-c]isoquinoline
motif was constructed via the cyclization on the thiophene ring
(3ab), which demonstrated that this cascade cyclization was
appropriate for the synthesis of more types of fused heterocyclic
compounds. The reaction could still perform well when R3 was
phenyl, and the desired product 3ac with 60% yield was obtained
under the same conditions. In addition, when ethyl carbazate was
employed as the ester group source, the cascade cyclization
reaction also proceeded smoothly to afford product 3ad in 77%
yield.
To understand the reaction mechanism adequately, a control
experiment was carried out, as shown in Scheme 2. When 2 equiv
of radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy
B
DOI: 10.1021/acs.orglett.7b01553
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Organic Letters
Letter
Scheme 2. Control Experiment
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01553.
Experimental procedures, characterization data, and NMR
spectra for 1 and 3 (PDF)
X-ray data for 3m (CIF)
(TEMPO) was added to the reaction mixture of 1a under the
standard reaction conditions, the reaction was entirely sup-
pressed and no desired product 3a was found; the TEMPO−
COOCH3 adduct was detected by LC-MS, which indicated that
this reaction might proceed through a radical pathway.
On the basis of the above experimental results and previous
reports, a plausible mechanism for this transformation is
proposed in Scheme 3. Initially, the photocatalyst eosin Y was
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sunpeipei@njnu.edu.cn.
ORCID
Peipei Sun: 0000-0002-1716-2343
Notes
Scheme 3. Proposed Reaction Mechanism
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Projects 21672104 and 21502097), the
Natural Science Foundation of the Education Department of
Jiangsu province (15KJB150015), and the Priority Academic
Program Development of Jiangsu Higher Education Institutions.
The authors also thank Mr. Hailong Liu (School of Life Sciences,
Nanjing Normal University) for the determination of HRMS.
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Y*. Eosin Y* readily underwent a single electron transfer with
TBHP to give a tert-butoxyl radical, which captured a hydrogen
from methyl carbazate (2a) to give the nitrogen radical
intermediate A.13 The sequential dehydrogenation of A by
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photocatalyst eosin Y was regenerated to go to the next catalytic
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to electron-deficient ortho-carbon was unfavorable (path b).
In summary, we have developed a novel visible-light-induced
cascade cyclization reaction for the synthesis of ester-function-
alized pyrido[4,3,2-gh]phenanthridind derivatives using alkyl
carbazate as the ester source under metal-free conditions. The
process showed considerable advantages such as mild reaction
conditions, simplicity of the reaction procedure, and high atom
economy. This present work provides an efficient strategy for
constructing polycyclic heterocycles.
C
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