Synthesis of polysubstituted phenanthridines via ligand-free copper-catalyzed annulation

Article abstract of DOI:10.1021/ol502237a

A novel procedure for the cascade reaction of the addition of a Grignard reagent to a nitrile with a copper-catalyzed C-N bond coupling was developed, which afforded various polysubstituted phenanthridines in moderate to good yields with tolerance for a wide variety of substrates. Experimental data demonstrated that the reaction proceeded more likely through a Cu(I/III) catalytic cycle.

Full text of DOI:10.1021/ol502237a

Letter
pubs.acs.org/OrgLett
Synthesis of Polysubstituted Phenanthridines via Ligand-Free
Copper-Catalyzed Annulation
Yan-Fu Chen and Jen-Chieh Hsieh*
Department of Chemistry, Tamkang University, New Taipei City, 25137, Taiwan
S
* Supporting Information
ABSTRACT: A novel procedure for the cascade reaction of the addition of a
Grignard reagent to a nitrile with a copper-catalyzed C−N bond coupling was
developed, which afforded various polysubstituted phenanthridines in moderate to
good yields with tolerance for a wide variety of substrates. Experimental data
demonstrated that the reaction proceeded more likely through a Cu(I/III) catalytic
cycle.
henanthridine derivatives are important compounds for
organic synthesis since they were often discovered in a
Scheme 1. Cyclization via Iminyl and Imidoyl Radicals
P
wide variety of natural alkaloids,1 bioactive compounds, and
pharmaceuticals.2 In addition, some structures also possess
electronic and optical properties.3 Therefore, numerous
methods were developed to prepare phenanthridine fragments
such as transition-metal-catalyzed imine cyclization,4 oxidation
of 5,6-dihydrophenanthridine,5 cyclization of aryne,6 [2 + 2 +
2] cycloaddition,7 aza-Wittig reaction,8 intramolecular con-
densation of 2′-aminobiphenyl-2-carbaldehyde,9 modified
Pictet−Spengler10/Bischler−Napieralski11 reactions, anionic
ring closure reaction,12 and stepwise addition of Grignard
reagents to a nitrile with copper-catalyzed oxidative C−N
coupling.13 However, these strategies could only be applied to
some specific phenanthridines with limitation of the substrate
scope.
Syntheses of phenanthridines through cyclization reactions of
iminyl and imidoyl radicals are the most common methods and
have been developed over two decades.14−21 Besides
photolysis,14,15 current development has progressed to
oxidant-induced16 and transition-metal-mediated generation of
imidoyl or iminyl radicals. For example, Mn,17 Ag,18 Fe,19 Co,20
and Cu13,21 have been successfully applied to generate the
corresponding iminyl or imidoyl radicals which then cyclize to
form the desired phenanthridines.
Although strategies for the syntheses of phenanthridines are
dominated by using an iminyl or imidoyl radical as a key
intermediate, the difficulty in controlling the steric position of
2-/4- or 7-/9-substituents after cyclization was often observed
(Scheme 1). Therefore, development of novel methods to
provide the corresponding products with a clearly steric
position such as the coupling reaction through the cleavage
of a carbon−halide bond is still desirable.
The copper-catalyzed carbon−heteroatom coupling reaction
can be an alternative approach for phenanthridines with the
advantages of low cost, air stability, and easy operation.
Although this Ullmann type reaction was developed and widely
applied for over than one century, the mechanism still exists big
dispute. Until recently, direct evidence for the oxidative
addition of Cu(I) to aryl halides and formation of Ar−
Cu(III)−Br was first revealed by Ribas.22 Many research groups
supported the Cu(I/III) catalytic cycle and provided more
evidence to advocate this mechanism.23 Our experience in the
copper catalytic coupling reactions and the reactions involving a
nitrile24 encouraged us to explore the possibility for the
synthesis of phenanthridines via a copper-catalyzed annulation
reaction with a nitrile. Herein, we report the first example for
the synthesis of phenanthridines through the Cu(I/III) catalytic
cycle.
Our initial studies used 2′-bromo-[1,1′-biphenyl]-2-carbo-
nitrile (1a) as a model substrate (Table 1, entry 1), which was
treated with 5 mol % Cu(OAc)2 and 2 equiv of EtMgBr in 0.5
mL of benzene at 100 °C for 18 h; the corresponding 6-
ethylphenanthridine (3a) was obtained in 61% NMR yield.
1
Product 3a was confirmed by the H NMR, 13C NMR, and
HRMS analysis. We also observed some undefined side
products and substrate after working up the reaction.
Received: July 29, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502237a | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
,b
Table 1. Optimization of Reaction Conditions
Scheme 2. Scope of Grignard Reagents
b
entry
[Cu]
n
solvent
benzene
temp (°C) yield (%)
1
Cu(OAc)2
Cu(TFA)2
Cu(OTf)2
CuI
2
100
100
100
100
100
100
100
100
100
100
80
61
52
49
69
76
89
92
31
19
11
6
2
2
benzene
benzene
benzene
benzene
benzene
toluene
xylene
3
2
4
2
5
CuBr
2
6
Cu2O
2
7
Cu2O
2
8
Cu2O
2
9
Cu2O
2
hexane
10
11
12
13
Cu2O
2
THF
Cu2O
2
DME
c
Cu2O
2
polar solvent
toluene
toluene
toluene
toluene
toluene
100
100
120
80
0
d
Cu2O
1.3
1.3
1.3
1.3
1.3
95 (86)
96
84
81
13
e
14
Cu2O
f
15
g
Cu2O
16
Cu2O
100
100
17
none
a
Reactions were carried out using 0.1 mmol (1.0 equiv) of 2′-bromo-
a
[1,1′-biphenyl]-2-carbonitrile (1a) with 5 mol % [Cu] and EtMgBr
Reactions were carried out using 0.4 mmol (1.0 equiv) substrate 1a
with 5 mol % Cu2O, 1.3 equiv RMgBr (2) in 2.0 mL toluene at 100 °C
b
(2a, n equiv) in 0.5 mL of solvent at t °C for 18 h. 1H NMR yield
c
b
c
based on internal standard mesitylene. DMF, DMSO, and NMP were
used. Isolated yield in 0.4 mmol scale. 10 h. 28 h. Under air.
for 24 h. Isolated yield. RMgCl was used.
d
e
f
g
the thiophenyl group (3o) were also well tolerated, and the
desired products were afforded in high yields. The reaction for
the 6-phenylphenanthridine (3g) proceeded very smoothly and
gave an excellent yield. However, the yields were slightly lower
when there were heteroatoms on the para position of aryl
Grignard reagents (3h−3k). When 1a was treated with 4-
(TMS)2NPhMgBr (2j), the two TMS groups were lost in the
workup procedure, and 4-(phenanthridin-6-yl)aniline (3j) was
isolated. When more hindered aryl groups such as o-tolyl,
mestyl, and 1-naphthyl were introduced into the reaction, the
yields of corresponding products (3l−3n) remained high. The
stereo effect of the Grignard reagents appeared to not
significantly affect the cyclization reaction. The 6-phenylethynyl
substituted product (3p) was also obtained by using 5.0 equiv
of 2p at 90 °C. It is noteworthy that product 3p is a very
unique and challenging compound; the phenanthridine with
the 6-ethynyl group was not yet reported by any literature
related to the catalytic reaction.
The developed protocol allowed the reaction to be carried
out with various substrates 1, and the results are shown in
Scheme 3. We first investigated the effect of electron density on
the moiety of benzonitrile and of aryl bromide by using EtMgBr
with various substrates 1. It was found that the electron density
of both the benzonitrile and aryl bromide moieties significantly
affected the reactions. Reactions utilizing the substrate with an
electron-withdrawing group on the moiety of aryl bromide
afforded their corresponding products (3A−3C) in better
yields than in the case with an electron-donating group (3D). A
similar tendency was also observed for the effect of electron
density on the moiety of benzonitrile (3E−3H). When an
electron-rich substrate was introduced into the reaction, a
homocoupling compound of the Grignard reagent was often
detected. This catalytic reaction could well tolerate heterocyclic
To optimize the reaction conditions, the effect of solvents,
amount of EtMgBr, reaction temperatures, and copper sources
were investigated (Table 1). We first examined the copper
source for this reaction (entries 2−6). Among the various
copper sources employed, Cu2O was found to be the most
effective catalyst, providing an 89% NMR yield of the desired
product 3a (entry 6). The effect of solvent is very significant,
and it was found that only nonpolar solvents such as benzene,
toluene, xylene, and hexane allowed the reaction to proceed
(entries 6−9), but the reactions in polar solvents gave <10% of
the product (entries 10−12). A slightly excess amount (1.3
equiv) of EtMgBr was found to be sufficient for this cyclization
(entry 13). The reaction proceeded smoothly at 80 to 120 °C
with different reaction times (entries 13−15). However, the
reaction could not proceed when the reaction temperature was
lower than 80 °C. If the reaction temperature was higher than
120 °C, the reaction became very complicated and provided 3a
in a lower yield. The copper catalytic cyclization could also
proceed under air with a lower yield (entry 16). This is
probably due to the moisture interference in the reaction.
Moreover, when the copper source was absent, product 3a
could be afforded in low yield via anionic ring closure reaction
(entry 17).
This copper-catalyzed annulation reaction was successfully
extended to various Grignard reagents (2), and the results are
listed in Scheme 2. For most cases, the reaction required at least
24 h to fully consume the substrates (1). As indicated, reactions
worked well for both alkyl and aryl Grignard reagents. Primary
(3b and 3c), secondary (3d and 3e), and tertiary (3f) alkyl
groups were all well tolerated, but secondary and tertiary alkyl
groups provided their corresponding products in lower yields.
Aryl groups (3g−3n) and a heterocyclic aromatic group such as
B
dx.doi.org/10.1021/ol502237a | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
,b
Scheme 3. Scope of Polysubstituted Phenanthridines
Scheme 4. Control Experiments
a
Determined by GC−MS.
That means TEMPO as a radical scavenger is functionless in
this copper catalysis. In addition, the reaction rate for the iodo
compound 1b was compared as well. The reaction rates
between 1a and 1b at low temperature were very different.
These results do not support the formation of radicals by the
homolysis of aryl halide.23c,25
According to the above results and previous reports, a
tentative mechanism can be proposed (Scheme 5).22−25 The
Scheme 5. Proposed Mechanism
a
Reactions were carried out using 0.4 mmol (1.0 equiv) of substrate 1
with 5 mol % Cu2O, and 1.3 equiv of RMgBr (2) in 2.0 mL of toluene
b
at 100 °C for 24 h. Isolated yield.
aromatic substrates as well, and the corresponding products 3I
and 3J could be obtained in good yields. Moreover, because of
the natural limitation of Grignard reagents, various subunits
except the electrophilic substituents could be freely combined
to provide a wide scope of polysubstituted phenanthridines.
Thus, products with an extended ring system or complicated
structures can be established in moderate to good yields (3K−
3R). It is very important to understand that products 3E−3G
and 3J−3Q could not be obtained in a regiochemically pure
form via an imidoyl radical pathway, and products 3K, 3L, and
3P were very difficult to afford in a single isomer by the existing
radical procedures (Scheme 1).
To study the reaction mechanism, some control experiments
were conducted to understand the reaction pathway (Scheme
4). We utilized additional TEMPO and found that when 1.0
equiv of TEMPO was introduced into the reaction, the reaction
was only slightly influenced and product 3a was provided in
74% yield. However, when the amount of TEMPO was
increased to 2.0 equiv, we could only detect a trace amount of
3a by GC-MS and the major product was found to be the
coupling product of TEMPO with EtMgBr (4a). If the amount
of EtMgBr was increased to 3.3 equiv, we could again isolate 3a
in 63% yield. Upon further reaction in a stepwise process, we
observed that the yield of 3a did not significantly reduce after
completing the addition of the Grignard reagent to the nitrile.
catalytic reaction is likely to be initiated by the nucleophilic
addition of a Grignard reagent to the nitrile of compound 1
(complex A). The following transmetalation of the Mg(II) to
Cu(I) complex then occurs to generate MgBr2 and complex B.
Oxidative addition of complex B in an intramolecular manner
takes place to form a Cu(III) species (complex C). The
subsequent reductive elimination provides compound 3 and
regenerates the Cu(I) species.
In conclusion, we have developed a novel method for the
copper-catalyzed annulation reaction involving the addition of
the Grignard reagent to the nitrile and C−N bond coupling.
This method efficiently provides polysubstituted phenanthri-
dines in moderate to good yields with tolerance for a very wide
variety of substrates. The mechanism study demonstrated that
the reaction is more likely via an oxidative addition of Cu(I) to
aryl halide, but not a radical pathway. Further studies to explore
the possibility for the synthesis of natural alkaloids are currently
underway.
C
dx.doi.org/10.1021/ol502237a | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization, spectral data, and
copies of all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
́
(12) (a) Lysen, M.; Kristensen, J. L.; Vedsø, P.; Begtrup, M. Org. Lett.
AUTHOR INFORMATION
Corresponding Author
■
2002, 4, 257. (b) Pawlas, J.; Begtrup, M. Org. Lett. 2002, 4, 2687.
(c) Gug, F.; Bach, S.; Blondel, M.; Vierfond, J.-M.; Martin, A.-S.;
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Desban, N.; Bouaziz, S.; Vierfond, J.-M.; Galons, H. Tetrahedron Lett.
2005, 46, 3725.
*E-mail: jchsieh@mail.tku.edu.tw.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the Ministry of Science and Technology of Republic
of China (MOST 103-2113-M-032-009-MY2) for financial
support of this research.
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