Synthesis of Phenanthridine and Quinoxaline Derivatives via Copper-Catalyzed Radical Cyanoalkylation of Cyclobutanone Oxime Esters and Vinyl Azides

Article abstract of DOI:10.1002/cjoc.202100050

A copper-catalyzed radical cyclization of cyclobutanone oxime esters and vinyl azide is described. This method provides facile access to cyanoalkyl-substituted phenanthridines and quinoxalines with excellent isolated yields. Moreover, these reactions proceed under mild conditions with a board substrate scope and excellent functional group tolerance.

Full text of DOI:10.1002/cjoc.202100050

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Synthesis of Phenanthridine and Quinoxaline Derivatives via Copper-
Catalyzed Radical Cyanoalkylation of Cyclobutanone Oxime Esters and Vinyl Azides
Authors: Qi Liang, Long Lin, Guodong Li, Xianqiang Kong,* and Bo Xu*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2021, 39, 10.1002/cjoc.202100050.
The final Version of Record (VoR) of it with formal page numbers will soon be
published online in Early View: http://dx.doi.org/10.1002/cjoc.202100050.
ISSN 1001-604X • CN 31-1547/O6
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Xu Bo (Orcid ID: 0000-0001-8702-1872)
Cite this paper: Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
Synthesis of Phenanthridine and Quinoxaline Derivatives via Cop-
per-Catalyzed Radical Cyanoalkylation of Cyclobutanone Oxime
Esters and Vinyl Azides
Qi Liang, a† Long Lin, a† Guodong Li,a Xianqiang Kong,b,* and Bo Xua,*
a Key Laboratory of Science and Technology of Eco-Textiles, Ministry of Education, College of Chemistry, Chemical Engineering and Biotech-
nology, Donghua University, Shanghai 201620, China.
b School of Chemical Engineering and Materials, Changzhou Institute of Technology, No. 666 Liaohe Road, Changzhou 213032, China
†These authors contributed equally to this work.
E-mail: xianqiangk@sina.com (X. Kong); bo.xu@dhu.edu.cn (B. Xu).
Keywords
Copper | Radical | Cyanoalkylation | Vinyl Azides | phenanthridine
Main observation and conclusion
A copper-catalyzed radical cyclization of cyclobutanone oxime esters and vinyl azide is described. This method provides facile access
to the cyanoalkyl-substituted phenanthridines and quinoxalines with excellent isolated yields. Moreover, these reactions proceed un-
der mild conditions with a board substrate scope and excellent functional group tolerance.
Comprehensive Graphic Content
O
N
Ph
N3
O
R3
N3
R1
O
O
N
N3
mol%)
R2
N
R4
MeO
Cu(OTf)2 (10
DMSO, 14 100 o
h,
mol%)
Cu(OTf)2 (10
N
C,
mol%)
N
2
Cu(OTf)2 (10
DMSO, 14 100 o
N
h,
C,
DMSO, 14 100 o
2
h,
C,
2
R1
R2
R3
O
N
N
O
N
R4
CN
N
CN
CN
N
R3
R3
52-68%
≠
4-OCH3
(R4
15
)
8
56-78%
24
50-90%
examples,
examples,
examples,
O
*E-mail:
View HTML Article
Supporting Information
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/cjoc.202100050
This article is protected by copyright. All rights reserved.

First author et al.
Report
Background and Originality Content
Results and Discussion
Nitrogen-containing heterocycles, especially phenanthridine
and quinoxaline derivatives, had been applied extensively in phar-
maceuticals, materials, and organic synthesis.1-6 Therefore, the ex-
ploration of efficient and selective preparation methods for phe-
nanthridine and quinoxaline derivatives is of great significance.7 Da-
ting from 1896, Pictet and Hubert have already found that N-([1,1'-
biphenyl]-2-yl)acetamide can transform into 6-substituted phenan-
thridine with high temperature and low yield.8 Since then, many re-
searchers have begun to explore the efficient and selective prepa-
ration of phenanthridine9-14 and quinoxaline15-19 derivatives. Re-
cently, vinyl azides have become a class of versatile synthon for or-
ganic synthesis.20-25 And cyclization of vinyl azides utilizing radical
addition reaction provides a new method to prepare the phenan-
thridine and quinoxaline derivatives (Scheme 1a).26-33
Table 1. Optimization for synthesis 6-substituted phenanthridinesa
O
mol
10
% Catalyst
N
N
+
O
Ph
solvent, 14 100 o
h,
C
N3
CN
3a
1a
2a
Entry
Solvent
2a
Catalyst
Yield
1
2
1,4-dioxane
Toluene
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2.0
2.0
2.0
2.0
2.0
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuBr2
65
51
3
Diethyl Ether
THF
42
4
48
5
DMF
39
6
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
46
Iminyl Radical-triggered Intramolecular
a)
Cyclization
7
72
N
N
O
N
N
N3
8
54
R
Cyclization
or
R
R
R
Ar
9
CuI2
49
Ar
N2
10
11
12
Cu(OAc)2
Cu(CF3SO3)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
-
62
Iminyl Radical-triggered C-C Bond Cleavage
b)
67
87 (83c)
LG
N
N
C-C bond
Cleavage
acceptor
radical
13d DMSO
54
SET
NC
NC
R
14e
15f
16
DMSO
DMSO
DMSO
75
R
R
R
79
work
This
c)
trace
N
O
R4
a Reaction conditions: 1a (0.2 mmol), 2a, 10% mmol catalyst, N2, solvent
(2 mL) at 100 oC, 14 h. b Yields were determined by 1H-NMR. c Isolated
O
N
CN
CN
yield. Temperature: 60 oC. Temperature: 80 oC. Temperature: 120
d
e
f
R3
R3
N3
N
≠
4-OCH3
Ph
10
O
(R4
)
oC.
O
R3
Cu(OTf)2
O
N
mol
%,
R4
N
DMSO
N
Vinyl azide 1a and cyclobutanone O-benzoyl oxime 2a were
chosen as model substrates to optimize the reaction conditions (Ta-
ble 1). Initially, Cu(OTf)2 was evaluated as the catalyst. As expected,
=
4-OCH3
(R4
)
O
N
O
o
1a can be successfully transformed to 3a with 65% yield at 100 C
R1
R2
N
O
R1
R2
Ph
10
using 1,4-dioxane as the solvent (Table 1, entry 1). Different sol-
vents were examined (Table 1, entries 2-7), and DMSO was the op-
timal solvent (72% yield). A variety of CuII catalysts was investigated
as well (Table 1, entries 8-11). However, they were less effective.
The use of a larger amount of cyclobutanone O-benzoyl oxime (2a)
led to a higher chemical yield (83%) (Table 1, entry 12). Modification
of temperature (60 oC, 80 oC, 120 oC) could not improve the reac-
tion (Table 1, entries 13-15). Finally, a control experiment revealed
that only a trace amount of 3a was formed in the absence of CuII
catalyst.
R3
N3
mol
%,
Cu(OTf)2
DMSO
CN
R3
Scheme 1. Literature background.
Cyanoalkyl moieties are of wide appearance in modern phar-
maceuticals and bioactive compounds.34-38 Cyano groups could also
be converted to many other common functional groups conven-
iently.39-41 Therefore, a wide variety of methods have been devel-
oped for cyanoalkylation.42,43 Traditionally, cyanoalkyl is usually pre-
pared using inorganic cyanides and alkyl halides. Inorganic cyanides
are highly toxic, and the preparation of alkyl halides may also need
extra steps. Recently, the C-C bond cleavage of cyclic iminyl radicals
has been successfully applied to synthesizing alkyl nitriles (Scheme
With the optimized reaction conditions in hand (Table 1, entry
12), we then explored the scope and functional group tolerance of
the phenanthridine synthesis (Table 2). First, we evaluated the ef-
fects of R2 functional group. The substitution pattern (meta, para)
and electronic properties of aromatic substituents (electron defi-
cient or rich) of R2 played a small role; good yields were obtained
regardless (Table 2, 3b-3d, 3e-3f). The halogen (Table 2, 3g, 3h, 3j),
alkyl (Table 2, 3i, 3j), even naphthalene (Table 2, 3k) groups were
well-tolerated. Then, the effect of R1 functional groups was also
investigated: a very wide range of substituents were all suitable for
this transformation (Table 2, 3m-3r, 3t), furnishing the correspond-
ing products in good yields. Also, 3-substituted substrates were also
converted into the desired products (Table 2, 3u−3x) in 55−64%
yields.
2b).44-53And cyclobutanone oxime esters have become important
54-59
raw materials for organic synthesis.
Especially, cyanoalkyl can
be introduced to the nitrogen-containing heterocycles by using cy-
clo ketone oxime esters.60,61 For example, the group of Guo has re-
ported a metal-catalyzed radical cyclization of cyclobutanone oxime
esters and vinyl azides to synthesize cyanoalkyl-substituted phe-
nanthridines.62,63 Besides, the group of Li64 and our group65 have
described visible-light-driven cyanoalkylation of quinoxalinones.
Herein, we are glad to report radical cyclization of cyclobutanone
oxime esters and vinyl azides to synthesize cyanoalkyl-substituted
phenanthridine and quinoxaline derivatives by using inexpensive
Cu(II) as the catalysts (Scheme 1c).
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Running title
Chin. J. Chem.
a Reaction conditions: 4 (0.2 mmol), 2 (0.24 mmol), Cu(OTf)2 (10 mol%), N2,
Table 2. Synthesis of phenanthridine derivatives.a
solvent (2 mL) at 100 oC, 14 h. All yields are isolated yields.
R1
OBz
R1
N
After completion of phenanthridine synthesis, we turned our
attention to the quinoxalinone synthesis (Table 3). When we ex-
posed 2-azido-N-methyl-N-phenylacrylamide 4a as our radical ac-
ceptor to our standard conditions, the quinoxaline product 5a was
isolated in a slightly lower yield (62%), possibly due to the fact that
2-azido-N-methyl-N-phenylacrylamide 4a is an electron-poorer al-
kene than 2-(1-azidovinyl)-1,1'-biphenyl 1a. Subsequently, the sub-
strate scope was explored by using various quinoxalinones and dif-
ferent 3-substituted cyclobutanone oxime esters. Methyl, chloro,
bromo, trifluoromethyl, and cyano groups on the benzene ring were
well-tolerated under the standard conditions, and the correspond-
ing products were isolated in good yields (Table 3, 5b−5h). We
found that cyclobutanone oxime esters bearing the bulky groups
(Table 3, 5i-5o), even the 3-N-substituted cyclobutanone oxime es-
ter (Table 3, 5i), and the cyclobutanone oxime ester substituted
with ester group, all were suitable substrates.
mol
10
%
Cu(OTf)2
N
+
DMSO, 12 100 o
h,
C
CN
N3
R2
R2
R3
R3
1
2
3
N
N
N
Cl
CN
CN
CN
=
=
=
=
=
R
3a
83%
74%
82%
(R H),
(R F),
(R Cl),
3b
3c
3d
3e
3f
=
69%
R
3g
3i
(R Cl),
(R Me),
=
90%
3h
58%
,
R
CF 79%
(
3),
78%
(R Me),
=
OMe), 69%
(R
R
N
F
N
N
CN
CN
CN
69%
80%
CF 70%
COOMe), 51%
75%
=
3l
(R Cl),
=
3m
3n
3o
3j
(R F),
52%
,
3k
Table 4. Synthesis of spiro-cyclic compound 6a
83%
,
=
=
=
(R
(R
3),
OBz
3p
3q
(R CN),
OMe
O
O
OMe), 76%
N
(R=
N
Cu(OTf)2
O
O
O
DMSO, 12 100 o
C
N
N
R3
h,
NC
N3
R3
N
O
N
N
2
4
6
CN
CN
CN
O
O
3s'
3r
3s
43%
N
50%
43%
,
,
N
N
,
O
O
N
NC
O
N
Boc
6a
78%
,
6b 57%
,
NC
N
N
CN
N
O
CN
O
CN
N
O
N
O
R
3t
61%
,
3x 57%
,
O
N
N
O
N
O
=
3u
3v
3w
55%
COOMe),
60%
(R
Boc
6c
69%
,
=
6d
(R CN),
(R= Ph),
CN
O
73%
O
,
CN
64%
O
N
N
a Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Cu(OTf)2 (10 mol%), N2,
O
O
O
N
O
N
solvent (2 mL) at 100 oC, 14 h. All yields are isolated yields.
6e 71%
,
6f
68%
,
CN
CN
Table 3. Synthesis of quinoxalinone derivatives.a
O
N
N
OBz
N
O
CN
65%
N
O
N
N
O
O
N3
R4
mol
10
DMSO, 12 100 o
%,
Cu(OTf)2
C
N
O
N
6g
,
6h
56%
,
CN
CN
R4
h,
R3
R3
5
4
2
a Reaction conditions: 4 (0.2 mmol), 2 (0.24 mmol), Cu(OTf)2 (10 mol%), N2,
=
5b
5d
5f
5g
5h
61%
62%
62
(R Me),
solvent (2 mL) at 100 oC, 14 h. All yields are isolated yields.
N
N
O
N
N
O
=
(R Cl),
=
(R Br),
=
=
R
R
CF 59%
CN
(
(
3),
R
CN
We found that spiro-cyclic compound 6 was isolated synthe-
sized with the starting material 2-azido-N-(4-methoxyphenyl)-N-
methylacrylamide (Table 4). 3-Ester-, 3-oxybenzyl-, and 3-phenyl
substituted cyclobutanone oxime esters were suitable substrates,
affording the corresponding products good yields (65−73%)(Table 4,
6d−6g). The 3,3-disubstituted substrates were also converted into
the desired products 6c in 57% yields. Surprisingly, the 2,3-disubsti-
tuted substrates were well-tolerated in this transformation (Table 4,
6h).
Based on the previous reports, a possible mechanism is pro-
posed (Scheme 2). Initially, iminyl radical A is generated from the
decomposition of cyclobutanone oxime ester catalyzed by copper
catalysts and rearranges to cyanoalkyl radical B by C−C bond cleav-
age. The addition of radical B to the double bond in starting material
1 to give iminyl radical C with the generation of N2 gas. Cyclization
of iminyl radical C to generate radical D, which is re-oxidized by the
copper to give cation E. After deprotonation, cation E is converted
to final product 5.
5a
68%
CN),
62%
,
N
O
N
N
N
N
CN
N
CN
N
CN
R
O
5j
O
N
O
O
O
O
51%
,
=
5c
5e
55%
61%
(R Me),
=
5i
53%
,
(R Cl),
N
CN
N
N
N
N
CN
CN
O
O
O
O
O
O
O
N
Boc
5m
61%
,
5l
51%
,
5k
52%
,
N
N
CN
O
O
5n
55%
Ph
,
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de

First author et al.
Report
Scheme 2. Plausible reaction mechanism.
octahydrobenzo[j]phenanthridine-7,12-diones as new leads against
Mycobacterium tuberculosis. J. Med. Chem. 2014, 57, 2895-2907.
N
N
O
(4)
Naidu, K. M.; Nagesh, H. N.; Singh, M.; Sriram, D.; Yogeeswari,
CN
5
P.; Gowri Chandra Sekhar, K. V. Novel amide and sulphonamide derivatives
of 6-(piperazin-1-yl)phenanthridine as potent Mycobacterium tuberculosis
H37Rv inhibitors. Eur. J. Med. Chem. 2015, 92, 415-426.
R
O
HOBz
N
O
2
R
(5)
Liu, R.; Huang, Z.; Murray, M. G.; Guo, X.; Liu, G. Quinoxalin-
OBz
N
N
O
2(1H)-one derivatives as inhibitors against hepatitis C virus. J. Med. Chem.
2011, 54, 5747-5768.
[Cu]
CN
N
H
R
E
+
OBz
(6)
Hussain, S.; Parveen, S.; Hao, X.; Zhang, S.; Wang, W.; Qin, X.;
R
A
Yang, Y.; Chen, X.; Zhu, S.; Zhu, C.; Ma, B. Structure-activity relationships
studies of quinoxalinone derivatives as aldose reductase inhibitors. Eur. J.
Med. Chem. 2014, 80, 383-392.
R
[Cu]+
CN
N
N
N
O
B
O
(7)
Ke, Q.; Yan, G.; Yu, J.; Wu, X. Recent advances in the direct
CN
Ph
H
D
R
functionalization of quinoxalin-2(1H)-ones. Org. Biomol. Chem. 2019, 17,
N3
N2
CN
5863-5881.
R
O
(8)
(9)
Pictet, A.; hubert, A. Ber. Dtsch. Chem. Ges. 1896, 29, 1182.
N
N
C
Guo, W. S.; Dou, Q.; Hou, J.; Wen, L. R.; Li, M. Synthesis of 6-
Phosphorylated Phenanthridines by Mn(II)-Promoted Tandem Reactions of
2-Biaryl Isothiocyanates with Phosphine Oxides. J. Org. Chem. 2017, 82,
7015-7022.
Conclusions
In summary, we have developed an efficient method of radical
cyclization of cyclobutanone oxime esters and vinyl azides using an
accessible and inexpensive Cu(II) catalyst. Using this uncomplicated
method, we were able to synthesize cyanoalkyl-substituted phe-
nanthridine and quinoxaline derivatives from readily available and
safe starting materials under mild conditions.
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The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2021xxxxx.
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oxidative decarboxylation/cyclization of acyl peroxides and 2-
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Acknowledgment
We are grateful to the National Science Foundation of China
(NSFC-21871046).
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Manuscript received: XXXX, 2021
Manuscript revised: XXXX, 2021
Manuscript accepted: XXXX, 2021
Accepted manuscript online: XXXX, 2021
Version of record online: XXXX, 2021
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www.cjc.wiley-vch.de
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Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
Entry for the Table of Contents
Title
Author, Corresponding Author,* Author
Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
R3
O
CN
R4
N
N
O
N3
O
N
or
N
CN
O
N
R3
)
R4
N
R4 4-OCH3
≠
Ph
10
O
(when
R1
O
R3
Cu(OTf)2
R4 4-OCH3
=
(when
)
R1
R2
mol
%,
DMSO
N
N3
CN
R2
R3
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de