Table 1. Screening of Reaction Conditionsa
Scheme 1. Initial Test of Transition-Metal-Free Aryl Halide
Couplings Using Previously Known to Be Successful Additives
(Phen and DMEDA)
entry
L (mol %)
solvent
base
temp/°C %yieldb
1
L1 (40)
L2 (40)
L3 (40)
L4 (40)
benzene
benzene
benzene
benzene
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
120
120
120
120
120
120
120
120
120
120
120
120
120
100
80
7
important molecules.11 They have a wide range of biolo-
gical activities and applications, including antibacterial,
antiprotozoal, and anticancer agents.12 A well-known
member in the phenanthridine class is Ethidium, a common
and versatile DNA/RNA intercalator.13 Previous synthetic
methods for preparing phenanthridine scaffolds include
radical,14 benzyne-mediated,15 photochemical,16 hyperva-
lent iodine-promoted,17 and transition metal-catalyzed
approaches.18 Although a number of useful synthetic
methods are available, there remain limitations such as
multistep synthesis, limited substrate scope, and difficult
removal of transition metal impurities. In some cases,
harsh reaction conditions are also required. Thus, exploration
2
0
3
9
4
4
5
tBuOH (50) benzene
26
99
99
48
34
83
98
2
6
L5 (40)
L6 (40)
L7 (40)
L8 (40)
L6 (40)
L6 (40)
L6 (40)
L6 (10)
L6 (10)
L6 (10)
L6 (10)
nil
benzene
benzene
benzene
benzene
7
8
9
10
11
12
13
14
15
16
17
18
19
mesitylene KOt-Bu
toluene
DMF
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
Nil.
toluene
toluene
toluene
toluene
toluene
toluene
toluene
98 (96)
77
0
120
120
120
120
0
KOt-Bu
K2CO3
KOt-Bu
0
(9) For recent selected references on CÀC bond coupling using ArI and
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L6 (10)
L6 (2)
0
44
a Reaction conditions: 1 (1.0 mmol), L (mol % as indicated), KOt-Bu
(2.0 mmol), and solvent (8.0 mL) were stirred at specified reaction
temperature for 24 h. b Calibrated GC yields were reported using
dodecane as the internal standard. Isolated yield in parentheses.
for a milder and more convenient process from readily avail-
able building blocks (e.g., benzophenones and anilines) for the
synthesis of a phenanthridine moiety is imperative. In con-
tinuing our former focus on transition-metal-free DMEDA-
catalyzed CÀH arylation of benzene using aryl iodides5 and
arylation of heterocycles,19 herein we report the development
of an intramolecular CÀH arylation from aryl chlorides using
an ethylene glycol catalyzed system. This method provides a
simple synthesis of phenanthridine derivatives from readily
available components.
We embarked on this research by testing the feasibility
of aryl halide CÀH bond coupling for phenanthridine
synthesis, using either previously known successful DMEDA
or phenanthroline derivatives as promoters (Scheme 1).4À6
Disappointingly, apart from an aryl iodide/bromide, an
aryl chloride was found to be unsuccessful in this process.
In fact, other structurally similar diamines were also in-
ferior in this reaction (Table 1, entries 1À4). In an attempt
to make the aryl chloride coupling reaction viable, we sur-
veyed other simple organic molecules which are known to be
more effective for promoting aryl radical anion formation
(which is believed to be the key species in the homolytic
aromatic substitution8c /coupling process). Inspired by the
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