Metal-free radical oxidative decarboxylation/cyclization of acyl peroxides and 2-isocyanobiphenyls

Article abstract of DOI:10.1039/c4cc10015h

A metal-free radical oxidative decarboxylation/cyclization of acyl peroxides and 2-isocyanobiphenyls was achieved, leading to 6-aryl phenanthridines as well as 6-alkyl phenanthridines in moderate to good yields. The procedure featured simple conditions and was metal-free and base free. It represents a practical approach to access 6-aryl/alkyl phenanthridines.

Full text of DOI:10.1039/c4cc10015h

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ARTDIOCI: 1L0.1E039/TC4YCC1P00E15H
Metal-free radical oxidative decarboxylation/cyclization of
acylperoxides and 2-isocyanobiphenyls
Changduo Pan, Honglin Zhang, Jie Han, Yixiang Cheng and Chengjian Zhu*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A metal-free radical oxidative decarboxylation/cyclization of
Scheme 1. Transformations based on aryl radical
acylperoxides and 2-isocyanobiphenyls was achieved, leading
to 6-arylphenanthridines as well as 6-alkylphenanthridines in
moderate to good yields. The procedure was featured with
10 simple condition, metal-free and base free. It represents a
practical approach to access 6-aryl/alkyl phenanthridines.
R2
R2
Mn(acac)3 (3 equiv)
R1
R1
eq. 1
ArB(OH)2
NC
toluene
N
Ar
N
The oxidative coupling methodology involving C–H
functionalization has established as a powerful and efficient
strategy for organic synthesis due to the avoidance of pre-
15 functionalization process.1 The radical-driven oxidative coupling
has lately emerged as a promising approach in this area.2 Most
recently, radical oxidative cyclization of 2-isocyanobiphenyls
with different radical precursors to provide 6-substituted
phenanthridines which are widely present in natural,
20 pharmaceutical and bioactive compounds3 has been developed.
For example, Chatani reported the first oxidative cyclization of 2-
isocyanobiphenyls by aryl/alkyl boronic acid as radical
precursors to synthesize 6-aryl/alkyl phenanthridines (Scheme 1,
N
O
Ar
H
Pd-catalyzed
eq. 2
O
Ar
Ar
O
-CO2
O
R2
R2
O
eq. 3
O
R
R1
R1
R
O
PhCF3
-CO2
H
O
N
R
NC
metal-free
base-free
This work
50
Table 1. Screening the optimal conditions
5
eq. 1).4 Subsequently, we and other groups6 developed the
25 radical isonitrile insertion reaction with various radical precursors
toward a series of 6-substituted phenanthridines. However, more
environmentally friendly method such as metal-free and base-free
for such transformation is still highly desired.
O
O
Ph
Ph
O
O
NC
N
Ph
2a
1a
3aa
Metal-catalyzed decarboxylative arylations started from
30 carboxylic acids has been established as a powerful tool for
carbon–carbon or carbon–heteroatom bonds formation.7 However,
in most cases, noble metals were always required with high
reaction temperatures. Aryl radicals could generate from the
decarboxylation of arylcarboxyl radicals that produced from
35 homolytic O-O bond cleavage of aryl acylperoxides under mild
condition.8 In 2009, Yu demonstrated the first Pd-catalzyed
decarboxylative ortho-arylation of 2-phenylpyridines with
benzoyl peroxides via radical pathway (Scheme 1, eq. 2).9
Inspired by these works, we envision that intermolecular addition
40 of aryl radicals that derived from thermal decomposition of aryl
acylperoxides to isonitrile of 2-arylphenylisonitrile to produce the
imidoyl radical, followed by intramolecular aromatic homolytic
substitution, could lead to 6-aryl phenanthridines. Herein, aryl
acylperoxides are demonstrated as a good aryl radical precursor
45 to react smoothly with 2-isocyanobiaryls to access 6-aryl
phenanthridines without the assistance of transition metal or base
(Scheme 1, eq. 3).
Entry
Solvent
Yield(%)
1
2
3
4
5
6
7
MeCN
DCE
32
20
69
23
76
80
0
PhCl
toluene
PhF
PhCF3
DMSO
Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol) and solvent (2 mL),
100 oC, 10 h, N2.
55
Initially, the reaction of 2-isocyanobiphenyl (1a) with benzoyl
peroxide (2a) in CH3CN was investigated. To our delight, the
desired product 3aa was obtained in 32% yield (Table 1, entry 1).
Next, other solvents were screened. Among the solvents screened,
60 PhCF3 performed best efficiency, providing 80% yield of the
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product (Table 1, entry 6). The reaction did not provide any
Next, various aryl acylperoxides were examined for this
product in DMSO (Table 1, entry 7).
transformation. As shown in Figure 2, various functional groups
such as methoxy, trifluoromethyl, fluoro,DOchI:l1o0r.o103a9n/dC4CbrCo1m00o15H
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After the establishment of the optimal reaction condition, a
series of 2-isocyanobiaryl compounds were explored. As shown 30 groups were tolerated in this oxidative coupling reaction. Ortho-,
5
in Figure 1, various functional groups such as fluoro, chloro,
trifluoromethyl and trifluoromethoxy groups were tolerated well
affording the products in good yields. The reaction was not
significantly affected by the substituent on the aromatic ring
meta-, and para-substituted aryl acylperoxides all worked well in
the present system to afford the 6-arylphenanthridines in good
yields (Figure 2, 3ab-3aj). To further explore the scope of the
reaction, alkyl acylperoxides such as decanoic peroxyanhydride
attached to isocyanides, such as methyl, fluoro, chloro, 35 (2k), lauroyl peroxide (2l), stearic peroxyanhydride (2m) and 2-
10 trifluoromethyl groups, leading to the 6-arylphenanthridines 3ba–
3ga in good yields. Subsequently, the effect of substituents on 4-
position of the aromatic ring were surveyed. The isocyanides 1h-
1i bearing electron-donating groups gave the product in higher
yields than those of electron-withdrawing analogues 1j-1k. 2-
15 Isocyanobiphenyl bearing ortho substituent performed lower
reactivity due to the steric effect (Figure 1, 3la). To investigate
the regioselectivity of the cyclization, the 2-isocyanobiphenyl
bearing a meta-methyl (1o) was investigated resulting with a
mixture of two regioisomers in a ratio of 1:2 (Table 2, 3oa+3oa').
20 Notably, halogen groups were tolerable, which was suitable for
potential further functionalization.
ethylhexanoic peroxyanhydride (2n) were subjected to the
precedure. Delightedly, 6-alkylphenanthridines were provided
with good yields (Figure 2, 3ak-3an).
Figure 2. Scope of acylperoxides
O
O
R
R
O
PhCF3, 100 o
C
NC
1a
N
O
R
2
3
Me
Me
N
N
N
Figure 1. Scope of 2-isocyanobiphenylsa
Me
3ab, 77%
3ac, 75%
3ad, 73%
R2
R2
O
O
Ph
R1
R1
Ph
O
PhCF3, 100 o
C
N
NC
O
Ph
N
N
2a
1
N
3
3ag, 71%
OMe
Cl
3ae, 73%
3af, 81%
F
Me
Me
N
N
3aa, 80%
N
Cl
N
3ba, 75%
3ca, 77%
N
N
3ah, 68%
3ai, 66%
3aj, 70%
Br
CF3
Cl
F3CO
F
N
N
N
3fa, 83%
3ea, 74%
(CH2)9CH3
3da, 62%
(CH2)7CH3
(CH2)15CH3
N
N
N
Me
t-Bu
3al, 65%
3am, 63%
3ak, 58%
F3C
N
N
N
3ia, 68%
3ha, 70%
3ga, 78%
N
3an, 52%
Cl
40
Cl
F
Reaction conditions: 1a (0.2 mmol), 2 (0.6 mmol) and PhCF3 (2 mL), N2,
100 oC, 10 h.
N
N
N
3la, 66%
3ka, 82%
3ja, 76%
When 3.0 equiv of 2,2,6,6-tetramethylpiperidine oxide
Me
45 (TEMPO) was added as a radical inhibitor, the desired product
was not observed, providing evidence for the free radical
Ph
Me
mechanism. Based on the experimental result,
a possible
N
N
N
mechanism is illustrated in Scheme 2. Initially, the thermal
decomposition of benzoyl peroxide (2a) along with release of
50 CO2 produces the phenyl radical A.8 Then, the addition of radical
A to isonitrile of 2-isocyanobiaryl 1a forms the imidoyl radical B,
which upon intramolecular cyclization gives radical intermediate
C. Finally, hydrogen abstraction of radical intermediate C takes
place to provide the product 3aa.
N
3ma, 70%
3oa+3oa', 73% (ratio 1:2)b
3na, 74%
a Reaction conditions: 1 (0.2 mmol), 2a (0.6 mmol) and PhCF3 (2 mL), N2,
25 100 oC, 10 h. b the ratio was determined by 1H NMR.
2
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isocyanobiphenyls.
Through
this
radical
oxidative
75
80
decarboxylation/cyclization pathway under metal-free and
10 base free condition, 6-arylphenanthridines as well as 6-
alkylphenanthridines were obtained in moderate to good
yields. It represents
a practical approach to access 6-
substituted phenanthridines.
We gratefully acknowledge the National Natural Science
15 Foundation of China (21172106 and 21372114), the National
Basic Research Program of China (2010CB923303) and the
Research Fund for the Doctoral Program of Higher Education
of China (20120091110010) for their financial support. C. Pan
thanks the support of Natural Science Foundation of China
20 (21272178).
85
90
Notes and references
State Key Laboratory of Coordination Chemistry, School of Chemistry
and Chemical Engineering, Nanjing University, Nanjing 210093, P. R.
of China E-mail: cjzhu@nju.edu.cn
95
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