Tert-Butyl peroxybenzoate (TBPB)-mediated 2-isocyanobiaryl insertion with 1,4-dioxane: Efficient synthesis of 6-alkyl phenanthridines via C(sp 3)-H/C(sp2)-H bond functionalization

Article abstract of DOI:10.1039/c4cc00743c

An efficient method for the construction of 6-alkyl phenanthridines by tert-butyl peroxybenzoate (TBPB)-mediated 2-isocyanobiaryl insertion with 1,4-dioxane was established. Two new C-C bonds were formed in this reaction via a sequential C(sp³)-H/C(sp²)-H bond functionalization under metal-free conditions. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00743c

Volume 50 Number 49 21 June 2014 Pages 6411–6544
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Shun-Yi Wang, Shun-Jun Ji et al.
tert-Butyl peroxybenzoate (TBPB)-mediated 2-isocyanobiaryl insertion with
1
,4-dioxane: efficient synthesis of 6-alkyl phenanthridines
3 2
via C(sp )–H/C(sp )–H bond functionalization

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tert-Butyl peroxybenzoate (TBPB)-mediated
-isocyanobiaryl insertion with 1,4-dioxane:
efficient synthesis of 6-alkyl phenanthridines
2
Cite this: Chem. Commun., 2014,
0, 6439
5
3
2
Received 28th January 2014,
Accepted 24th February 2014
via C(sp )–H/C(sp )–H bond functionalization†
Jia-Jia Cao, Tong-Hao Zhu, Shun-Yi Wang,* Zheng-Yang Gu, Xiang Wang and
Shun-Jun Ji*
DOI: 10.1039/c4cc00743c
www.rsc.org/chemcomm
An efficient method for the construction of 6-alkyl phenanthridines
by tert-butyl peroxybenzoate (TBPB)-mediated 2-isocyanobiaryl
insertion with 1,4-dioxane was established. Two new C–C bonds
3
2
were formed in this reaction via a sequential C(sp )–H/C(sp )–H
bond functionalization under metal-free conditions.
Over the past decades, significant attention has been focused on the
transformation of an unactivated C–H bond to C–C and C–X
1–3
bonds. In particular, great progress has been achieved with respect
3
2
to the functionalization of C(sp )–H bonds, especially the functio-
3–8
nalization of the C–H bonds of ethers. For example, Li et al.
reported iron/tert-butyl hydroperoxide (TBHP)-promoted C(sp )–H Scheme 1 6-Alkyl phenanthridine synthesis via somophilic isocyanide
3
functionalization of ethers to construct new C–N bonds in DCE at insertion.
4
5a
8
0 1C. Wan et al. demonstrated a novel Bu
4
NI-catalyzed C–O bond
3
formation protocol for the synthesis of a-acyloxy ethers via C(sp )–H
functionalization of ethers.
established a Cu(OAc) -catalyzed C–O bond formation protocol in (a)). However, there has been no report on the construction of
the reaction of ethers and b-ketoesters. Very recently, Yuan and 6-alkyl phenanthridines through the reaction of isocyanide with
5b
Reddy, Kappe and co-workers bromide for the synthesis of 6-alkyl phenanthridines (Scheme 1,
13
2
6
co-workers observed a C–S bond formation reaction of diaryl ethers. Herein, we report a TBPB-mediated 2-isocyanobiaryl insertion
disulfides with ethers using di-tert-butyl peroxide (DTBP) as the with ethers to access 6-alkyl phenanthridines under mild, metal-free
7
3
2
oxidant under metal-free conditions. Recently, Lei et al. described conditions via a consecutive C(sp )–H/C(sp )–H bond functionaliza-
a Ni/DTBP-mediated C–C bond formation reaction of arylboronic tion based on somophilic isocyanide insertion and the cascade HAS
8
3
2
acids and ethers. However, a sequential C(sp )–H/C(sp )–H bond strategy (Scheme 1, (b)).
9
functionalization of ethers gained less attention.
Initial studies were focused on the model reaction of 2-isocyano-
The phenanthridines have attracted much research attention biphenyl (1a) and 1,4-dioxane (2a) in the presence of a catalytic
because they are key skeleton compounds, which show several amount of AgNO and different oxidants under argon atmosphere
3
biological activities, such as antibacterial, antitumor and cytotoxic (Table 1, entries 1–9). It was found that 6-(1,4-dioxan-2-yl)phenan-
1
0
11
activity. Recently, the somophilic isocyanide insertion strategy
has been successfully applied to construct a series of 6-substituted and 2a under a AgNO
phenanthridines through the homolytic aromatic substitution (HAS) (Table 1, entry 5). The structure of 3a was confirmed by IR and NMR
thridine (3a) could be obtained in a 70% LC yield by the reaction of 1a
3
(20 mol%)/TBPB (2.0 equiv.) catalytic system
1
2
process. More recently, Yu, Zhang and co-workers have reported spectroscopy and HRMS. To our delight, the LC yield of 3a could be
photoredox neutral isocyanide insertions with functionalized alkyl increased to 75% when the reaction was mediated by TBPB (2.0 equiv.)
only, without any metal salt (Table 1, entry 10). Further screening
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
regarding the amount of TBPB used, the reaction temperature and the
reaction time established the optimized conditions as follows:
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
China. E-mail: shunyi@suda.edu.cn, shunjun@suda.edu.cn;
2
1
-isocyanobiphenyl (1a) and 1,4-dioxane (2a) in the presence of a
.0 equiv. of TBPB under reflux conditions. 3a couldbeobtainedinan
88% LC yield (89% isolated yield) (Table 1, entry 17).
Fax: +86-512-65880307; Tel: +86-512-65880307
Electronic supplementary information (ESI) available: Experimental section, spectro-
†
scopic data and other supplementary information. See DOI: 10.1039/c4cc00743c
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a
Table 1 Screening of reaction conditions
b
Entry
Cat. (mol%)
Oxidant (equiv.)
(2)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
AgNO
AgNO
AgNO
AgNO
AgNO
AgNO
AgNO
AgNO
AgNO
—
3
3
3
3
3
3
3
3
3
(20)
(20)
(20)
(20)
(20)
(20)
(20)
(20)
(20)
2
K S
2
O
8
3
3
3
3
3
3
3
3
3
3
3
3
3
3
2
4
3
3
18
O
2
(1 atm)
Trace
39
TBHP (2)
DTBP (2)
TBPB (2)
CHP (2)
DDQ (2)
21
70
38
Scheme 2 The reaction of 1i and 1j with 2a.
Trace
28
Trace
75
PhI(OAc)
2
(2)
(2)
Cu(OAc)
TBPB (2)
TBPB (1)
TBPB (3)
TBPB (1)
TBPB (1)
TBPB (1)
TBPB (1)
TBPB (1)
TBPB (1)
2
(
1d) with 2a also proceeded smoothly, which furnished the desired
10
11
12
13
14
15
16
17
18
0
0
—
—
—
—
—
—
—
—
79
74
35
4
product 3d in a 68% yield. When 1-(2 -isocyano-[1,1 -biphenyl]-4-
yl)ethanone (1e) containing an electron-withdrawing group was sub-
jected to the reaction, the desired product 3e could also be obtained in
a 47% yield. It should be noted that the reaction of 2-isocyano-3 -
methyl-1,1 -biphenyl (1g) proceeded well to afford two regioisomers 3g
c
d
0
54
72
0
e
f
88 (89 )
36
0
g
and 3g in yields of 51% and 24%, respectively.
Next, we explored the reaction of 1i and 1j with 2a. It was found
that the reaction could be extended to 2-(2-isocyanophenyl)-
naphthalene (1i) with 2a, furnishing the desired product 3i in a
a
Reaction conditions: 1a (0.2 mmol), 2a (2 mL), under argon atmo-
b
sphere and reflux conditions. Yields were determined through LC
analysis with an internal standard (benzophenone) by calculating the
ratio between the formed products and the initial amount of the 38% yield. Unfortunately, only a trace amount of product 3j was
c
d
e
limiting reactant 1a. At 90 1C. At 80 1C. 1a (0.5 mmol), 2a (3 mL).
detected when 9-(2-isocyanophenyl)phenanthrene (1j) was used in
the reaction (Scheme 2).
f
g
Isolated yield. 1a (0.5 mmol), 2a (10 mmol) in 2 mL EtOAc. DTBP =
di-tert-butyl peroxide, CHP = cumene hydroperoxide.
We further explored the effects of different substituents on
With the optimal conditions in hand, we investigated the the aromatic ring bearing the isocyano group. The results are
0
substrate scope using various 1-isocyano-2-arylbenzene derivatives. summarized in Table 3. 2-Isocyano-5-methyl-1,1 -biphenyl (1k)
0
The results are listed in Table 2. The utilization of 2-isocyano-4 - showed good applicability to this reaction, which afforded
0
methoxy-1,1 -biphenyl (1b) bearing an electron-donating group results the desired product 3k in an 86% yield. The reactions of the
0
in the formation of 6-substituted phenanthridine 3b in an 81% yield. halide-substituted 5-fluoro-2-isocyano-1,1 -biphenyl (1l) and
The reaction of halide-substituted 4 -fluoro-2-isocyano-1,1 -biphenyl 5-chloro-2-isocyano-1,1 -biphenyl (1m) led to the formation of
the phenanthridines 3l and 3m in 61% and 70% yields,
0
0
0
0
a
respectively. 2-Isocyano-4-methoxy-1,1 -biphenyl (1o) bearing a
Table 2 The reaction of 1a–h with 2a
methoxy group also successfully underwent the reaction to
afford 3o in a 66% yield. The reaction of 2-isocyano-5-nitro-
0
1
,1 -biphenyl 1n did not proceed under identical conditions.
In order to expand the applicability of this reaction, we tried
reacting 1a with 2b. However, no desired products was observed
Table 3 The reaction of 1k–o with 2a
a
Reaction conditions: 1 (0.5 mmol) in 3 mL 1,4-dioxane (2a) under
argon atmosphere and reflux conditions.
6
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In conclusion, we have developed an efficient method to
construct 6-alkyl phenanthridines by a tert-butyl peroxybenzo-
ate (TBPB)-mediated 2-isocyanobiaryl insertion reaction with
1
,4-dioxane. Two new C–C bonds were formed in this reaction
3
2
via cascade C(sp )–H/C(sp )–H bond functionalization under
metal-free conditions.
Scheme 3 The reaction of 1a with 2b.
We gratefully acknowledge the Natural Science Foundation
of China (No. 21172162, 21372174), the PhD Programs Foundation
of Ministry of Education of China (2013201130004), the Young
National Natural Science Foundation of China (No. 21202111),
the Young Natural Science Foundation of Jiangsu Province
Scheme 4 Control experiment.
(
BK2012174), the Key Laboratory of Organic Synthesis of Jiangsu
Province (KJS1211), PAPD, and Soochow University for financial
and only the phenanthridine 4a was obtained in 47% yields support.
(Scheme 3).
To understand the mechanism of this reaction, a control
Notes and references
experiment reacting 1a with 2a in the presence of TEMPO was
carried out. As expected, the desired product 6-(1,4-dioxan-2-yl)-
phenanthridine (3a) was not detected; instead, only the formation
of a TEMPO-1,4-dioxane (5) adduct was observed (Scheme 4). This
result indicated that TBPB-mediated 2-isocyanobiaryl insertion with
1
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plausible mechanism is proposed in Scheme 5. Firstly, TBPB
decomposes to a tert-butoxyl radical and a benzoate radical.
Then, the tert-butoxyl radical reacts with 1,4-dioxane to activate
the C–H bond adjacent to the oxygen atom, furnishing the
active intermediate I, which can be trapped by TEMPO to give 5.
Addition of I to 1a affords the imidoyl radical intermediate II.
The intermediate IV and benzoate are formed by the subsequent
intramolecular aromatic substitution of II and further oxidation
by the benzoate radical. Finally, the desired phenanthridine is
delivered after deprotonation.
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