Synthesis of 6-acyl phenanthridines by oxidative radical decarboxylation-cyclization of α-oxocarboxylates and isocyanides

Article abstract of DOI:10.1039/c3cc49026b

A silver catalysed synthesis of 6-acyl phenanthridines by oxidative radical decarboxylation-cyclization of α-oxocarboxylates and isocyanides was developed. This reaction provided a novel method to realize C1 insertion via a radical process and various functional groups were well-tolerated. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc49026b

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Synthesis of 6-acyl phenanthridines by
oxidative radical decarboxylation–cyclization
of a-oxocarboxylates and isocyanides†
Cite this: Chem. Commun., 2014,
50, 2145
Received 26th November 2013,
Accepted 26th December 2013
Jie Liu,a Chao Fan,a Hongyu Yin,a Chu Qin,a Guoting Zhang,a Xu Zhang,a Hong Yia
and Aiwen Lei*ab
DOI: 10.1039/c3cc49026b
www.rsc.org/chemcomm
A silver catalysed synthesis of 6-acyl phenanthridines by oxidative
radical decarboxylation–cyclization of a-oxocarboxylates and iso-
cyanides was developed. This reaction provided a novel method to
realize C1 insertion via a radical process and various functional
groups were well-tolerated.
Radical chemistry has ushered in a new era in the development of
chemistry and it has become an important and effective tool in
organic synthesis in the past decades.1 Among a wide variety of
radical reactions, insertion reaction is one of the most useful
reactions in synthetic chemistry because the carbon chain of the
product can be extended.2 In general, there are two pathways
of insertion reactions for a carbon radical centre (Scheme 1(1)).
The first is C2 insertion (path A): the carbon radical reacts with
an acceptor to form a new b carbon radical centre thus leading to
an increase of two atoms in chain propagation. In C2 insertion
reactions, the acceptors mainly contain C–C multiple bonds like
alkenes and alkynes, C–N double bonds like imines and C–O double
Scheme 1 (1) Two pathways of insertions: C2 insertion (path A) and
C1 insertion (path B); (2) oxidative radical decarboxylation–cyclization
of a-oxocarboxylates and isocyanides.
Transition metal catalysed decarboxylation of carboxylic
bonds such as aldehydes, ketones and other carbonyl compounds. acids has become an important method to form C–C and
The other pathway is C1 insertion (path B): the carbon radical is C–hetero bond in recent years.9 For example, radical decarboxyl-
inserted by an acceptor to increase one carbon atom in chain ation of a-oxocarboxylic acids can also act as a powerful and
propagation and a new a carbon radical centre is formed. Among complementary synthetic method to provide an acyl radical,
various C1 insertion reactions, CO is one of the most common which presumably shows higher activity and more potential in
acceptor which reacts with a radical to generate a new acyl radical by acylation than traditional Friedel–Crafts acylation. Herein,
carbonylation.3 Similar to CO, isocyanides can also act as radical we envisioned to realize this radical decarboxylation by utilizing
acceptors to form imidoyl radicals, followed by bimolecular addition a-oxocarboxylic acids as the acyl radical resources to construct
or cyclization.4 However, only a few studies have been focused on 6-acyl phenanthridines, which demonstrate a plurality of bio-
this field and limited radical precursors were developed such as logical and photochemical activities and show great potential in
halides,5 boronic acids,6 CF3 reagents,7 aldehydes and diphenylphos- medical chemistry and materials applications.10 To the best of
phine oxide.8 Therefore, it is still necessary to develop more radical our knowledge, this is the first example for realizing isocyanide
precursors to realize isocyanide insertion via a radical process.
insertion by using an acyl radical via the oxidative radical
decarboxylation (Scheme 1(2)).
Initially, we started to evaluate the reaction parameters by
employing 2-isocyanobiphenyl (1a) and potassium oxophenylacetate
(2a) as model substrates. To our delight, the use of 10 mol%
Ag2CO3 as the catalyst and K2S2O8 as the oxidant in DMF at
100 1C could give the corresponding 6-benzoyl phenanthridine
(3a) in 47% yield (Table 1, entry 1).
a College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072,
P. R. China. E-mail: aiwenlei@whu.edu.cn; Tel: +86-27-68754672
b National Research Center for Carbohydrate Synthesis, Jiangxi Normal University,
Nanchang, 330022, P. R. China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc49026b
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Table 1 Optimization of conditions for the reaction of 2-isocyanobi-
phenyl (1a) and potassium oxophenylacetate (2a)a
Table 2 Scope of oxidative cyclization of different a-oxocarboxylates 2
and 2-isocyanobiaryls 1a
Entry
Catalyst
Oxidant
Solvent
Yieldb (%)
1
2
3
4
5
6
7c
8
9
Ag2CO3
Ag2O
AgOAc
AgNO3
—
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Na2S2O8
(NH4)2S2O8
O2
DMF
DMF
DMF
DMF
47
42
41
39
6
69
75(71)
37
Trace
DMF
DMSO
DMSO
DMSO
DMSO
a
Reaction conditions: 1a (0.375 mmol), 2a (0.25 mmol), catalyst (10 mol%),
oxidant (0.5 mmol), solvent (1.5 mL), 100 1C, N2, 6 h. b Yield determined by
GC analysis. c Yield in the parentheses is isolated yield.
Then we tried other silver salts, such as Ag2O, AgOAc and
AgNO3, and slightly lower yields were obtained (entries 2–4). It
is noteworthy that Ag salts might play a critical role in the blank
experiment (entry 5). When the solvent was changed to DMSO,
the yield was increased up to 69%. The reaction also proceeded
in the presence of various oxidants such as Na2S2O8, (NH4)2S2O8
and dioxygen (1 atm) (entries 7–9), and Na2S2O8 gave the best
result to promote this reaction.
With the optimal conditions established, various a-oxocarboxylates
2 were tested to react with 2-isocyanobiaryls 1 to form the corre-
sponding 6-acyl phenanthridines products 3 (Table 2). This reaction
was successfully amenable to a wide range of a-oxocarboxylates, and
moderate to good yields were achieved with substrates bearing various
functional groups such as Me (3b and 3c), OMe (3d and 3e) and F (3f).
In addition, heterocyclic a-oxocarboxylates like thiophene was found
to be favoured in this catalytic system to afford the corresponding
products (3g). It is noteworthy that aliphatic a-oxocarboxylates were
compatible in this reaction as well and gave moderate yields (3h).
Furthermore, the reactivities of different isocyanides were also inves-
tigated. Isocyanides bearing both electron-rich (3i to 3n) and -deficient
groups (3r) underwent this oxidative radical decarboxylation–
cyclization process smoothly to afford the desired products in
moderate to good yields. In addition, this transformation also
showed satisfactory tolerance with halogen groups (3o to 3q)
which provided useful handles for further transformations
through traditional cross coupling reactions.
a
Reaction conditions: 1 (0.75 mmol), 2 (0.5 mmol), Ag2CO3b(10 mol%),
Na2S2O8 (1.0 mmol), DMSO (3.0 mL), 100 1C, N2, 6 h. 0.5 mmol
CH3COCO2Na was used.
Table 3 Radical inhibiting experiments
Additive
Yield of 3a (%)
None
TEMPO (2 equiv.)
BHT (2 equiv.)
71
0
0
In order to gain insights into this novel oxidative decarboxylation–
cyclization, radical scavengers, such as TEMPO and BHT, were
employed in the reaction (Table 3). As a result, the reactions Therefore, we tried to use electron paramagnetic resonance (EPR) to
were completely shut down, which could indicate that this study this oxidative process. As shown in Fig. 1(a), no EPR signal was
transformation involved radical intermediates.
observed when AgOTf was tested alone in DMSO, 80 1C, N2 for
Moreover, although it is widely proposed that Ag(I) could be 2 hours.13 However, when a mixture of AgOTf and Na2S2O8 was used
easily oxidized to Ag(II) in the presence of persulfates as the under the same conditions, a strong EPR signal could been detected
oxidants according to related reports,11 recently Maiti’s group (Fig. 1(b)). According to related reports, we may ascribe this
has demonstrated a novel Ag(0)–Ag(I) catalytic circle in the obvious signal to Ag(II) species.14 Therefore, this oxidative radical
presence of persulfates from XPS.12 This result intrigued us to decarboxylation involved a Ag(I)–Ag(II) catalytic circle via a single
investigate the plausible oxidation state of Ag species in our reaction. electron transfer (SET) process.
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This work was supported by the 973 Program (2012CB725302),
the NSFC (21390400, 21025206, 21272180 and 21302148), the
Research Fund for the Doctoral Program of Higher Education of
China (20120141130002) and the Program for Changjiang Scholars
and Innovative Research Team in University (IRT1030).
Notes and references
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proposed mechanism is described in Scheme 2. In the presence
of Ag2CO3 and Na2S2O8, a-oxocarboxylates I underwent an oxidative
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The addition of the benzoyl radical to the isocyanide III
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arene to form cyclohexadienyl radical V. Subsequently, a single
electron transfer process happened between the cyclohexadienyl
radical V and Ag(II) which finally gave the desired product 6-acyl
phenanthridine VI.
In summary, we have demonstrated a novel approach for the
silver catalyzed synthesis of 6-acyl phenanthridines by oxidative
radical decarboxylation–cyclization of a-oxocarboxylates and
isocyanides. This reaction provides a complementary method to
realize C1 insertion via a radical process. In addition, this method
presented a variety of functional group tolerance and showed
promising potential in biological activities and pharmaceutical
applications. The EPR experiments provided information that this
reaction involved a Ag(I)–Ag(II) catalytic circle.
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Chem. Commun., 2014, 50, 2145--2147 | 2147