Synthesis of phenanthridine derivatives via cascade annulation of diaryliodonium salts and nitriles

Article abstract of DOI:10.1039/c4ob01504e

A cascade coupling reaction toward a variety of phenanthridine derivatives has been developed. This cascade transformation proceeds via the copper-catalyzed coupling reaction of diaryliodonium salts and nitriles, and undergoes cyclization into the phenanthridine core.

Full text of DOI:10.1039/c4ob01504e

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Synthesis of phenanthridine derivatives via
cascade annulation of diaryliodonium salts
and nitriles †
Cite this: Org. Biomol. Chem., 2014,
12, 7904
Received 17th July 2014,
Jian Li,*a,b Hongni Wang,a,b Jiangtao Sun,a,b Yang Yangc and Li Liuc
Accepted 28th August 2014
DOI: 10.1039/c4ob01504e
www.rsc.org/obc
A cascade coupling reaction toward a variety of phenanthridine of new reaction methods in a step-economical fashion that
derivatives has been developed. This cascade transformation allow for the rapid construction of many complex com-
proceeds via the copper-catalyzed coupling reaction of diaryl- pounds.5 In 2008, Gaunt’s group developed a site-selective
iodonium salts and nitriles, and undergoes cyclization into the Cu(II)-catalyzed C–H bond functionalization process that can
phenanthridine core.
selectively arylate indoles at either the C3 or C2 position with
diaryliodonium salts under mild conditions; they proposed
the mechanism of the arylation reaction via a highly electro-
philic aryl-Cu(III) species, which would enable a mild arylation
process.6 Recently, MacMillan’s group reported an enantio-
selective arylation–cyclization cascade using a combination of
diaryliodonium salts and chiral copper catalysis. They postu-
lated that the aryl-Cu(III) could form and serve as a platform
for pyrroloindoline construction via an enantioselective aryla-
tion–cyclization cascade process using indole-based nucleo-
philes.7 Very recently, Chen and co-workers demonstrated a
regioselective [2 + 2 + 2] cyclization approach to the nitrogenous
hetero-arenes with diaryliodonium salts and nitriles catalyzed
by Cu(OTf)2.8 The reaction proceeded via a series of electro-
philic reactions and a key intermediate was the N-aryl nitrilium
cation generated in situ by the reaction of nitrile and iodonium
salt in the presence of Cu(OTf)2 via the same aryl-Cu(III) process.
Inspired by the aryl-Cu(III) activation mode, combined with
our ongoing interest in developing application of diaryl-
iodonium salts via transition metal catalysis,9 we developed an
efficient cascade coupling reaction toward a variety of phen-
anthridine derivatives; this cascade transformation proceeds
via the copper-catalyzed coupling reaction of diaryliodonium
salts and nitriles, and undergoes cyclization into the phen-
anthridine core. Our design plan is outlined in Scheme 1.
We proposed that the key intermediate N-aryl nitrilium cation
Introduction
The synthesis of substituted phenanthridines is of consider-
able interest in the fields of organic and pharmaceutical chem-
istry, since this basic skeleton is an important unit due to its
involvement in pharmaceuticals and biologically active natural
compounds, such as antiviral, antiprotozoal, antitumor
agents, and functional materials.1 Therefore, substantial
efforts have been focused on the synthetic methods of phen-
anthridines, and a number of well-established methods are
now available involving transition-metal-catalyzed, microwave-
assisted, benzyne-mediated and hypervalent iodine-promoted
reactions.2 All these approaches have provided powerful
methods for the selective assembly of phenanthridine.
However, the challenges such as multistep synthetic reactions
and limited substrate scope are still present. To meet the high
demand of the efficient synthesis of phenanthridines, it is
imperative to develop more general and convenient methods
with a new strategy.
On the other hand, diaryliodonium salts,3 as highly elec-
tron-deficient and environmentally benign reagents with low
toxicity, have emerged as attractive and versatile arylating
agents in the synthesis of arylated compounds.4 In this
context, Gaunt has made seminal contributions to the design
aSchool of Pharmaceutical Engineering & Life Sciences, Chang Zhou University,
Changzhou, 213164, P. R. China
bKey Laboratory of Advanced Catalytic Materials and Technology,
Chang Zhou University, Changzhou, 213164, P. R. China
cSchool of Petrochemical Engineering, Chang Zhou University, Changzhou, 213164,
P. R. China. E-mail: lijianchem@gmail.com; Fax: +86 519 86330224
†Electronic supplementary information (ESI) available: Experimental proce-
dures, all of the spectral data of the compounds. CCDC 981367. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob01504e
Scheme 1 Synthesis of phenanthridine derivatives via cascade annula-
tion of diaryliodonium salts and nitriles.
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Table 2 The synthesis of phenanthridine 3 from various nitriles 2 a,b,c
generated in situ by the reaction of nitrile and iodonium salt
in the presence of Cu(OTf)2.10 Subsequent intramolecular
cyclization would then yield the desired phenanthridine.
Results and discussion
At the outset of our studies, [1,1′-biphenyl]-2-yl(mesityl)iodo-
nium (1a) derived from 2-iodo-1,1′-biphenyl11 and benzonitrile
(2a) were selected as model substrates to commence this
project. The blank experiments (in the absence of a catalyst) of
1a and 2a were investigated in DCE at 80 °C and 130 °C for
20 h, respectively, no desired compound was detected (Table 1,
entries 1 and 2). Interestingly, the reaction produced the 6-phenyl-
phenanthridine 3a in 31% yield in the presence of 10 mol%
of Cu(OTf)2 (Table 1, entry 3). To optimize reaction conditions,
different copper based catalysts were examined, the screening
results indicated that Cu(OTf)2 was the most effective catalyst
for this transformation (Table 1, entries 4–8). To further
improve the efficiency of the reaction, several frequently used
aprotic polar solvents were also examined. However, the reac-
tion did not work well (Table 1, entries 9–12). Further study
was thus carried out about the temperature, to our delight, sig-
nificant improvement was achieved at 150 °C and 80% yield
was obtained (Table 1, entry 13). The thermal stability test of
1a (1.0 mol) in DCE (2.0 mL) proceeded at 150 °C; 14% of 1a
was decomposed after 20 h. Moreover, under microwave
irradiation the reaction occurred to afford 3a in 43% yield in
2 hours at 150 °C (Table 1, entry 14).
With the optimized reaction conditions in hand, we probed
the scope of different aryl nitriles (Table 2). A variety of
a Standard reaction conditions: 1a (1.0 mmol), 2 (2.0 mmol), Cu(OTf)2
(10 mol%), DCE (2.0 mL) were heated in a sealed tube, 20 h. b Be
cautious of potentially hazardous high temperature. c Isolated yield.
Table 1 Optimization of reaction conditions for the preparation of 3aa
different groups at the aromatic moiety of benzonitrile, such
as halogen, nitro, methyl and aniline, were well tolerated in
this transformation. The nitrile substrates bearing an electron-
donating group were found suitable than an electron-with-
drawing group to afford the final products (Table 2, 3d–3h).
Moreover, a range of meta- and ortho-substituted aryl nitriles
with steric and electronic properties can be readily exploited
(Table 2, 3i–3m). Further exploration of the substrate scope
involved heterocyclic nitrile derivatives. It was found that the
reaction successfully provided 6-(thiophen-2-yl)phenanthridine
3n in 41% yield.
Next we turned our attention to the scope of the diaryl-
iodonium salt coupling partner. As revealed in Table 3, the current
catalytic system exhibited good reactivity for various sub-
stituted diaryliodonium salts. A range of unsymmetrical
[Ar-I-Mes]OTf salts were tested and we were pleased to find that
the salts were all readily converted to the corresponding substi-
tuted phenanthridines in moderate to good yields via this reac-
tion (42–78% yields). The diaryliodonium salts bearing an
electron-donating group on the 1′-benzene ring (Table 3, 1b, 1c)
resulted in better yields than that bearing an electron-withdrawing
Yield (%)b
3a
Entry
Catalyst
T (°C)
Solvent
1
2
3
4
5
6
7
8
—
—
80
130
130
130
130
130
130
130
130
130
130
130
150
150
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DMSO
DMF
Toluene
PhCl
DCE
—
—
Cu(OTf)2
CuI
CuBr
CuCl
CuBr2
31
13
9
11
Trace
—
Trace
—
15
7
CuCl2
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
10
11
12
13
14c
80
43
DCE
a Standard reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), catalyst
(10 mol%), solvent (2.0 mL) were heated in a sealed tube, 20 h.
b Isolated yield. c Heated with microwave, 2 h.
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Table 3 The synthesis of phenanthridine 3 from various diaryliodonium
triflates 1 a,b,c
Fig. 1 The X-ray diffraction pattern of compound 1f.
a Standard reaction conditions: 1 (1.0 mmol), 2 (2.0 mmol), Cu(OTf)2
(10 mol%), DCE (2.0 mL) were heated in a sealed tube, 20 h.
b Be cautious of potentially hazardous high temperature. c Isolated yield.
Scheme 2 Plausible mechanism for the reaction.
group (Table 3, 1f). The structure of compound 1f was unequi-
vocally confirmed by single-crystal X-ray diffraction analysis
(Fig. 1).12
The catalytic system tolerated valuable electrophilic func-
tional groups, such as fluoro and chloro substituents (Table 3,
1d, 1e and 1g). Moreover, 1-benzene substituted diaryl-
iodonium salts 1h, 1i and 1j were also suitable substrates
for the cyclization, and led to the corresponding products in
42%–51% yields.
Scheme 3 Mechanism experiment catalyzed by Cu(I) in situ.
A plausible mechanism for the reaction between diaryliodo-
nium salts and aryl nitriles is illustrated in Scheme 2. First,
Cu(I) was formed from Cu(OTf)2 by either a reduction or dis-
proportionation.7b,8 Next, oxidative insertion of Cu(OTf)2 into a
suitable diaryliodonium salt 1 would result in a highly electro-
philic Ar-Cu(III) species 4,7 which acts as carbocation equi-
valents; subsequent addition of the aryl nitrile 2 would produce
the key intermediate N-aryl nitrilium cation 6 8,10 while recon-
stituting the catalyst. The resonance occurs between N-phenyl-
In order to prove the reaction process via Cu(I) catalysis,
AgOTf and CuI were utilized as catalysts for this transform-
ation (Scheme 3). It was found that 61% of the desired phen-
anthridine 3a was formed smoothly in the presence of AgOTf
and CuI, which could produce Cu(I) species in situ.
Conclusions
nitrilium 6 and intermediate 7, which undergoes an electro- In conclusion, we have demonstrated a cascade coupling reac-
philic annulation to afford phenanthridine 3.
tion toward a variety of phenanthridine derivatives. This
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cascade transformation proceeds via the copper-catalyzed
coupling reaction of diaryliodonium salts and nitriles, under-
goes cyclization into the phenanthridine core. The reaction
outcomes provide a new strategy for synthetically and medicin-
ally phenanthridine derivatives. Further studies to extend the
scope and synthetic utility for the synthesis of substituted
phenanthridines are in progress in our laboratory.
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General experimental methods
All experiments were conducted under an air atmosphere.
Flasks were flame dried and cooled under nitrogen before use.
All solvents were dried appropriately. For column chromato-
graphy, 200–300 mesh silica gel was employed. 1H NMR and
13C NMR were recorded on a 300 MHz, 400 MHz or 500 MHz
spectrometer in CDCl3 solution and the chemical shifts were
reported in parts per million (δ) relative to the internal stan-
dard TMS (0 ppm). For HRMS measurements, the mass ana-
lyzer is GC-TOFMS. Unless otherwise noted, materials obtained
from commercial suppliers were used without further
purification.
General procedure for cascade annulation of diaryliodonium
salts and nitriles. A solution of diaryliodonium salts
1
(1 mmol), nitriles 2 (2.0 mmol) and Cu(OTf)2 (36 mg,
0.1 mmol) in DCE (2 mL) was stirred at 150 °C for 20 h. After
completion of the reaction (observed on TLC), the solvent was
evaporated under reduced pressure to obtain the crude
mixture. The residues were purified by silica-gel column
chromatography (ethyl acetate–petroleum ether = 1/10–1/4) to
afford the pure product 3. The obtained product was analyzed
by 1H NMR, 13C NMR and HRMS.
Acknowledgements
We are grateful to the Natural Science Foundation of Jiangsu
(BK20140259), the Priority Academic Program Development of
Jiangsu Higher Education Institutions and Jiangsu Key Labora-
tory of Advanced Catalytic Materials and Technology for gener-
ous financial support for our research.
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