Copper-catalyzed synthesis of phenanthridine derivatives under an oxygen atmosphere starting from biaryl-2-carbonitriles and grignard reagents

Article abstract of DOI:10.1021/ol101490n

A copper-catalyzed synthesis of phenanthridine derivatives was developed starting from biaryl-2-carbonitriles and Grignard reagents. The present transformation is carried out by a sequence of nucleophilic addition of Grignard reagents to biaryl-2-carbonitriles to form N-H imines and their Cu-catalyzed C-N bond formation on the aromatic C-H bond, where molecular oxygen is a prerequisite to achieve the catalytic process.

Full text of DOI:10.1021/ol101490n

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3682-3685
Copper-Catalyzed Synthesis of
Phenanthridine Derivatives under an
Oxygen Atmosphere Starting from
Biaryl-2-carbonitriles and Grignard
Reagents
Line Zhang, Gim Yean Ang, and Shunsuke Chiba*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637371, Singapore
shunsuke@ntu.edu.sg
Received June 29, 2010
ABSTRACT
A copper-catalyzed synthesis of phenanthridine derivatives was developed starting from biaryl-2-carbonitriles and Grignard reagents. The present
transformation is carried out by a sequence of nucleophilic addition of Grignard reagents to biaryl-2-carbonitriles to form N-H imines and their
Cu-catalyzed C-N bond formation on the aromatic C-H bond, where molecular oxygen is a prerequisite to achieve the catalytic process.
Phenanthridines and their derivatives are of great interest in
medicinal chemistry and material science due to their potent
biological activities1 and optoelectronic properties.2 Although
diverse approaches toward the construction of a phenanthri-
dine skeleton have been reported so far,3 versatile and
efficient methodologies to synthesize phenanthridines with
selective control of substitution patterns using readily ac-
cessible building blocks are still needed. Herein we wish to
report a copper-catalyzed synthesis of phenanthridine deriva-
tives under an oxygen atmosphere starting from biaryl-2-
(3) For recent reports on the synthesis of substituted phenanthridines
and their derivatives, see: (a) Bude´n, M. E.; Dorn, V. B.; Gamba, M.; Pierini,
A. B.; Rossi, R. A. J. Org. Chem. 2010, 75, 2206. (b) Youn, S. W.; Bihn,
J. H. Tetrahedron Lett. 2009, 50, 4598. (c) Kohno, K.; Azuma, S.; Choshi,
T.; Nobuhiro, J.; Hibino, S. Tetrahedron Lett. 2009, 50, 590. (d) Candito,
D. A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 6713. (e) Gerfaud,
T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48, 572. (f) Portela-
Cubillo, F.; Scanlan, E. M.; Scott, J. S.; Walton, J. C. Chem. Commun.
2008, 4189. (g) Mandadapu, A. K.; Saifuddin, M.; Agarwal, P. K.; Kundu,
B. Org. Biomol. Chem. 2009, 7, 2796. (h) Yanada, R.; Hashimoto, K.;
Tokizane, R.; Miwa, Y.; Minami, H.; Yanada, K.; Ishikura, M.; Takemoto,
Y. J. Org. Chem. 2008, 73, 5135. (i) Bowman, W. R.; Lyon, J. E.; Gareth,
J. P. Synlett 2008, 14, 2169. (j) Sripada, L.; Teske, J. A.; Deiters, A. Org.
Biomol. Chem. 2008, 6, 263. (ii) Sanz, R.; Ferna´ndez, Y.; Castroviejo, M. P.;
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D.; Daugulis, O. J. Org. Chem. 2007, 72, 7720. (l) Wang-Ge, S.; Yun-
Yun, Y.; Yan-Guang, W. J. Org. Chem. 2006, 71, 9241. (m) Alonso, R.;
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Banwell, M. G.; Lupton, D. W.; Ma, X.; Renner, J.; Sydnes, M. O. Org.
Lett. 2004, 6, 2741. (o) Mehta, B. K.; Yanagisawa, K.; Shiro, M.; Kotsuki,
H. Org. Lett. 2003, 5, 1605. (p) Pawlas, J.; Begtrup, M. Org. Lett. 2002, 4,
2687. (q) Lyse´n, M.; Kristensen, J. L.; Vedsø, P.; Begtrup, M. Org. Lett.
2002, 4, 257. (r) Moreno, I.; Tellitu, I.; Etayo, J.; San Mart´ın, R.;
Dominguez, E. Tetrahedron 2001, 57, 5403.
(1) (a) Bernardo, P. H.; Wan, K. F.; Sivaraman, T.; Xu, J.; Moore, F. K.;
Hung, A. W.; Mok, H. Y. K.; Yu, V. C.; Chai, C. L. L. J. Med. Chem.
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L. F.; LaVoie, E. J. Bioorg. Med. Chem. 2005, 13, 6782. (c) Lewis, W. G.;
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M. A.; Duval, O.; Sukhanova, A.; Devy, J.; MacKay, S. P.; Waigh, R. D.;
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M.; Vomero, S.; Mannuni, L.; Makovec, F.; Doucet, E.; Hamon, M.; Bruni,
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10.1021/ol101490n  2010 American Chemical Society
Published on Web 07/16/2010

carbonitriles and Grignard reagents. The present transfor-
mation is carried out by a sequence of addition of Grignard
reagents to biaryl-2-carbonitriles to form N-H imines and
their Cu-catalyzed intramolecular cyclization including C-N
bond formation on the aromatic C-H bond, where molecular
oxygen is a prerequisite to achieve the catalytic process.
We have recently reported generation of iminyl copper
species from R-azido carbonyl compounds and their copper-
catalyzed C-C bond cleavage under an oxygen atmosphere,
where nitriles were synthesized.4,5 During the course of the
study, it was found that a reaction of ethyl 2-azido-2-
(biphenyl-2-yl)acetate (1) provided the desired biphenyl-2-
carbonitrile (2a) in 46% yield along with 50% yield of
phenanthridine 3, which might be formed via aromatic C-H
bond functinalization/C-N bond formation of the iminyl
copper species (Scheme 1).
N-H imines with a catalytic amount of Cu salts under an
oxygen atmosphere would give iminyl copper species B,6
which could lead to formation of phenanthridines 4.
On the basis of this hypothesis, the formation of phenan-
thridines was investigated using biphenyl-2-carbonitrile (2a)7
and p-tolylmagnesium bromide, and Table 1 lists the represen-
Table 1. Optimization of Reaction Conditions
yield (%)a
entry
metal salts
time (h)
4a
5a
Scheme 1. Copper-Catalyzed Reaction of Ethyl
2-Azido-2-(biphenyl-2-yl)acetate (1)
1
2
3
4
Cu(OAc)2
CuCl2
Cu(OTf)2
CuCl
26
19
19
18
18
65
24
24
24
24
91
88
93
89
90
21
2
1
2
0
0
6
0
0
2
36
72
99
83
71
5
CuTC
6b
7
Cu(OAc)2
Pd(OAc)2
Co(OAc)2
Mn(OAc)3
FeCl3
8
9
10
a Isolated yields. b The reaction was carried out using 1 equiv of
Cu(OAc)2 under an N2 atmosphere using degassed DMF. Tol ) 4-meth-
ylphenyl; CuTC ) copper(I) thiophene-2-carboxylate.
To explore an efficient synthetic method of phenan-
thridines via the iminyl copper species, we planned to use
biaryl-2-carbonitriles and organometallic reagents as shown
in Scheme 2, which commences with nucleophilic addition
tative data. Addition of p-tolylmagnesium bromide to nitrile
2a occurred smoothly in Et2O at 60 °C (in sealed tube). After
protonation with MeOH,8 DMF (diluted to 0.1 M) and metal
salts (10 mol %) were subsequently added, and the reaction
mixture was stirred at 80 °C under an oxygen atmosphere (1
atm). It was found that several copper salts, either Cu(I) or
Cu(II), exhibited good catalytic activity toward the formation
of phenanthridine 4a (entries 1-5). In contrast, the reaction
using a stoichiometric amount of Cu(OAc)2 without oxygen
(under a N2 atmosphere) provided phenanthridine 4a in only
21% yield along with 36% yield of N-H imine 5a, suggesting
that molecular oxygen plays a vital role to achive the catalytic
C-N bond formation process (entry 6).9 Other metal complexes
such as Pd(II), Co(II), Mn(III), and Fe(III) were not viable
catalysts for this transformation (entries 7-10).
Scheme 2. Synthetic Plan of Phenanthridines from
Biaryl-2-carbonitriles and Organometallic Reagents
By utilizing Cu(OAc)2 as the catalyst (entry 1 in Table
1), we examined the generality of this catalytic method for
synthesis of substituted phenanthridines. First, scope of
Grignard reagents were examined using biphenyl-2-carbo-
nitrile (2a) (Table 2). Sterically hindered 2-methyl- and 2,6-
dimethylphenyl moieties as well as an electron-deficient
4-chlorophenyl part could be installed with good to excellent
of R-[M] to biaryl-2-carbonitriles to afford N-H imines A
after proper protonation. Consecutive treatment of resulting
(4) Chiba, S.; Zhang, L.; Ang, G. Y.; Hui, B. W.-Q. Org. Lett. 2010,
12, 2052
.
(5) For a report on copper-catalyzed synthesis of azaspirocyclohexadi-
enones from R-azido-N-arylamides under an oxygen atmosphere via iminyl
peroxycopper(III) intermediates, see: Chiba, S.; Zhang, L.; Lee, J.-Y. J. Am.
(6) For a report on formation of iminyl rhodium(I) complexes from N-H
diarylimines, see: Zhao, P.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127,
11618.
Chem. Soc. 2010, 132, 7266
.
Org. Lett., Vol. 12, No. 16, 2010
3683

stirring for 36 h (entry 4). When 2-thienylmagnesium
bromide was utilized, the desired phenanthridine 4d and
biphenyl-2-carbonitrile (2a) were isolated in 54% and 41%
yields, respectively, although nitrile 2a was once consumed
by the reaction with the Grignard reagent (entry 5). It was
speculated that regeneration of nitrile 2a might proceed via
C-C bond cleavage of 2-thenyliminocopper species (see
Supporting Information for more detail). Alkyl Grignard
reagents also could be used, affording phenanthridines 4 in
good yields (entries 6 and 7).
Next, various biaryl-2-carbonitriles 2 were utilized to
prepare substituted phenanthridines (Scheme 3). By varying
substituent R2 on C(3) of phenanthridine 4, both electron-
donating and -withdrawing groups could be installed (for
4i-4m). Several substituents such as F, CF3, and Me were
also successfully introduced at the C(7), C(8), and C(9) of
phenanthridines (for 4n-4q).
Table 2. Reaction Scope of Grignard Reagentsa
entry
R1
time (h)
yield (%)b
4b, 99
4c, 88
4d, 91
4e, 5 (5e, 90)
4f, 54 (2a, 41)
4g, 76
1
2
3
4
2-Me-C6H4
2,6-Me2-C6H3
4-Cl-C6H4
4-MeO-C6H4
2-thienyl
19
20
32
36
60
31
22
5
6c
7d
CH2CH2Ph
i-Pr
4h, 67
a Unless otherwise noted, reactions were carried out using 0.5 mmol of
biaryl-2-carbonitriles 2a with 1.3 equiv of Grignard reagents in Et2O (0.5
mL) at 60 °C (sealed tube) for 2 h followed by addition of MeOH (60 µL),
DMF (4 mL), and Cu(OAc)2 (10 mol %); the mixture was stirred at 80 °C
under an O2 atmosphere. b Isolated yields. c The reaction of 2a with
Ph(CH2)2MgBr was completed in 24 h at 60 °C. d The reaction of 2a with
i-PrMgBr (2 equiv) was carried out at 80 °C for 24 h.
This catalytic method allowed accessing polycyclic aza-
aromatic hydrocarbons (aza-PAHs)10 (Table 3). The reaction
Table 3. Synthesis of Polycyclic Aza-Aromatic Compounds
(aza-PHAs)a
yields (entries 1-3). An electron-donating group such as
methoxy on the benzene ring retarded the present cyclization,
affording the corresponding phenanthridine 4e in only 5%
yield along with 90% yield of N-H imine 5e even after
Scheme 3. Reaction Scope on Substituents of
Biaryl-2-carbonitriles 2a b
,
a Reactions were carried out using 0.5 mmol of biaryl-2-carbonitriles 6
with 1.3 equiv of p-tolylmagnesium bromide in Et2O (0.5 mL) at 60 °C
(sealed tube) for 2 h followed by addition of MeOH (60 µL), DMF (4 mL),
and Cu(OAc)2 (10 mol %); the mixture was stirred at 80 °C under an O2
atmosphere. b Reaction times on copper-catalyzed cyclization. c Isolated
yields. d The reaction of 6d (0.3 mmol) with p-tolylmagnesium bromide (2
equiv) was carried out in toluene (1 mL) at 80 °C (sealed tube) for 2 h
followed by addition of MeOH (60 µL), DMF (4 mL), and Cu(OAc)2 (20
mol %); the mixture was stirred at 120 °C under an O2 atmosphere.
a Unless otherwise noted, reactions were carried out using 0.5 mmol of
biaryl-2-carbonitriles 2 with 1.3 equiv of p-tolylmagnesium bromide in Et2O
(0.5 mL) at 60 °C (sealed tube) for 2 h followed by addition of MeOH (60
µL), DMF (4 mL), and Cu(OAc)2 (10 mol %), and the mixture was stirred
at 80 °C under an O2 atmosphere. b Isolated yields and reaction times on
copper-catalyzed cyclization are recorded in parentheses. c 20 mol % of
Cu(OAc)2 was used.
of 1-phenyl-2-naphthonitrile (6a) with p-tolylmagnesium
bromide provided tetracyclic benzo[k]phenanthridine 7a
in good yield (entry 1). Aza-chrysene (benzo[c]phenan-
3684
Org. Lett., Vol. 12, No. 16, 2010

thridine) 7b could be accessed selectively from 2-(naph-
thalen-2-yl)benzonitrile (6b) (entry 2). Pentanuclear aza-
aromatic hydrocarbons, dibenzo[c,k]phenanthridine 7c and
dibenzo[c,i]phenanthridine (aza-picene) 7d, were also
synthesized starting from binaphthyl-2-carbonitriles 6c and
6d, respectively, although longer reaction time and higher
temperature (120 °C for 7d) were required (entries 3 and
4). In the cases of 6b, 6c, and 6d, C-H functionalization
occurred exclusively on the R-carbon (marked in blue)
of the naphthalene ring, which suggested that an electro-
philic aromatic substitution pathway11 might be involved
in the mechanism of the copper-catalyzed C-N bond
formation (see Supporting Information for putative reac-
tion mechanisms).12-14
In conclusion, a facile synthetic method of phenanthridine
derivatives has been developed starting from biaryl-2-
carbonitriles and Grignard reagents via Cu-catalyzed C-N
bond formation on the aromatic C-H bond under an O2
atmosphere. Continuous studies on the scope, mechanistic
evaluation, and synthetic applications of the present method
toward various polynuclear aza-aromatic hydrocarbons are
in progress.
Acknowledgment. This work was supported by funding
from Nanyang Technological University and Singapore
Ministry of Education.
Supporting Information Available: Experimental pro-
cedures and characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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(9) No C-N bond formation was observed without Cu catalysts.
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OL101490N
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Dodd, R. H.; Dauban, P. Chem. Commun. 2009, 5061. For a review on
copper-catalyzed aromatic C-H functionalization, see: Zhang, M. Appl.
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Org. Lett., Vol. 12, No. 16, 2010
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