Cascade approach to substituted 6-aryl-phenanthridines from aromatic aldehydes, anilines, and benzenediazonium-2-carboxylate

Article abstract of DOI:10.1021/jo061648i

(Chemical Equation Presented) Aromatic aldehydes reacted with anilines and benzenediazonium-2-carboxylate to afford 6-aryl-phenanthridines. The reaction furnishes a rapid and direct construction of substituted phenanthridine rings from readily available starting materials via a one-pot cascade process.

Full text of DOI:10.1021/jo061648i

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bonds in one operation without isolating the intermediates and
adding further reagents and has exhibited high efficiency in the
synthesis of complex organic building blocks from easily
available starting materials.6 Herein, we report a new cascade
reaction of benzyne with aromatic aldehydes and anilines, which
furnishes a rapid and versatile synthesis of 6-aryl-phenan-
thridines.
Cascade Approach to Substituted
6-Aryl-phenanthridines from Aromatic
Aldehydes, Anilines, and
Benzenediazonium-2-carboxylate
Wang-Ge Shou, Yun-Yun Yang, and Yan-Guang Wang*
Department of Chemistry, Zhejiang UniVersity, Hangzhou
Benzynes are highly reactive intermediates that have found
numerous applications in organic synthesis.7 The dienophilic
nature of the benzynes has been exploited in [2 + 2] and [4 +
2] cycloaddition reactions with enes and dienes.8 It is reported
that the reaction between benzyne and imines, such as N-
benzylideneanilines, gave 1,2-diarylbenzazetidenes,9 N-(o-anili-
nobenzhydryl)-aniline, and 5,6-dihydro-5,6-diphenylphenan-
thridines10 as well as acridines11 via [2 + 2] and/or [4 + 2]
cycloaddition reactions. In our initial experiment, we found that
the in situ generated benzyne from benzenediazonium-2-
310027, People’s Republic of China
orgwyg@zju.edu.cn
ReceiVed August 8, 2006
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Aromatic aldehydes reacted with anilines and benzenedia-
zonium-2-carboxylate to afford 6-aryl-phenanthridines. The
reaction furnishes a rapid and direct construction of substi-
tuted phenanthridine rings from readily available starting
materials via a one-pot cascade process.
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Substituted phenanthridines are an important class of hetero-
cyclic compounds in material science1 and in medicinal
chemistry due to their significant biological activities.2 The
Bischler-Napieralski cyclization has been used extensively to
synthesize phenanthridine derivatives.3 It is usually performed
in the presence of P4O10, POCl3, or PCl5 at elevated tempera-
tures, thereby limiting the kind of functional groups that can
be tolerated. Although several other synthetic routes to substi-
tuted phenanthridines have been developed, most of them require
multi-step syntheses, strictly anhydrous conditions, and/or metal
catalysts.4 Thus, there is a need for more efficient, versatile,
and simpler synthetic methods of creating phenanthridines. As
one promising approach, we were particularly interested in
cascade reactions5 since this methodology can form several
* Corresponding author. Tel: +86-571-87951512. Fax: +86-571-87951512.
(1) (a) Zhang, J.; Lakowicz, J. R. J. Phys. Chem. B 2005, 109, 8701-
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10.1021/jo061648i CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/21/2006
J. Org. Chem. 2006, 71, 9241-9243
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TABLE 2. One-Pot Synthesis of 6-Arylphenanthridines 7 and 8
SCHEME 1. Three-Component Cascade Synthesis of
Phenanthridine 6a
entry
1
R
product
isolated yield (%)
H
7a
8a
7b
8b
44
1a
30
18
2
5-Br
TABLE 1. One-Pot Synthesis of 6-Arylphenanthridines 6
a Determined by GC/MS.
As shown in Table 1, aniline and the electron-rich anilines
afforded the desired 6-aryl-phenanthridines 6 in 31 to ∼95%
isolated yields (Table 1, entries 1 to ∼26), while the electron-
deficient anilines only gave trace products (Table 1, entry 27).
Presumably because of steric effects, the asymmetry 3,4-
dimethylaniline (3f) resulted in the less crowded compounds 7
as the major products (Table 2). Noteworthy, in all of our cases,
we did not isolate 1,2-diarylbenzazetidenes, which were previ-
ously reported to be the major products of [2 + 2] cycloaddion
reactions of N-arylimines with benzyne generated in situ from
benzenediazonium-2-carboxylate.9
entry
Ar
R
product isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
4-O2NC6H4 (2a)
2a
4-OEt (3a)
4-Me (3d)
H (3c)
3a
6a
6b
6c
6d
6e
95
75
65
35
31
32
38
40
45
78
75
65
62
66
64
58
59
43
94
54
55
58
57
65
67
43
trace
2a
C6H5 (2b)
3,4-Me2C6H3 (2c)
2c
4-BrC6H4 (2d)
4-ClC6H4 (2e)
4-FC6H4 (2f)
3a
4-OMe (3b) 6f
3d
3d
3d
6 g
6h
6i
6j
6k
6l
4-(EtO2C)C6H4 (2 g) 3a
Finally, the structures of products were characterized by IR,
1HNMR, 13CNMR, MS, and HRMS spectra. The structure of
compound 6d was unambiguously confirmed by X-ray crys-
tallopraphy (see Supporting Information).
2g
2f
2e
2f
2e
2d
2d
2b
3b
3b
3b
3a
3a
3b
3a
3b
3b
3a
3b
3a
3b
6 m
6n
6o
6p
6q
6r
6s
In conclusion, we have demonstrated that the reaction of
aromatic aldehydes with anilines and benzenediazonium-2-
carboxylate afforded 6-aryl-phenanthridine derivatives 6. This
three-component cascade reaction provides a rapid and direct
construction of substituted 6-arylphenanthridine rings. Our
method has several advantages including (1) a one-pot procedure
with high bond-forming efficiency, (2) simple and easily
available starting materials, and (3) metal-free and mild condi-
tions. The scope and synthetic applications of this method are
under investigation.
2a
2-naphthyl (2h)
6t
2h
6u
6v
6w
6x
6y
6z
2-HOC6H4 (2i)
2i
2-HO,5-BrC6H3 (2j) 3a
2j
2j
2b
3b
3d
4-Cl (3e)
Experiment Section
carboxylate (1)12 could react with 4-nitro-benzaldehyde (2a) and
4-ethyloxy-aniline (3a) to give 6-aryl-phenanthridine (6a) in a
one-pot process (Scheme 1). When the reaction was performed
in 1,2-dichoroethane (DCE) at 80 °C for 1 h, almost quantitative
conversion was obtained. The reaction is believed to involve a
cascade imine and benzyne formation/[4 + 2] cycloaddition/
dehydrogenation sequence as shown in Scheme 1.
With this result in hand, we went on to study the scope of
the methodology. Using the optimized reaction conditions, a
variety of aromatic aldehydes and anilines were investigated.
General Procedure for the Synthesis of 6-Aryl-phenanthri-
dine 6. To the solution of aromatic aldehyde 2 (1 mmol) and aniline
3 (1 mmol) in DCE (5 mL) was added a suspension of benzene-
diazonium-2-carboxylate11 (2 mmol) in DCE (30 mL) at 80 °C over
a period of 1 h. The solvent was evaporated in vacuum, and the
residue was purified by silica gel column chromatography using
hexane-EtOAc (15:1) as the eluant to afford pure 6, which was
rescrystallized from hexane-EtOAc.
2-Ethoxy-6-(4-nitrophenyl)phenanthridine (6a). Yellow crys-
tal; mp 176-177 °C; IR (KBr) 1620, 1602, 1595, 1561, 1519, 1497,
1
1258, 1204 cm-1; H NMR (500 MHz, CDCl3): δ 8.62 (d, J )
(12) (a) Friedman, L.; Logullo, F. M. J. Org. Chem. 1969, 34, 3089-
3092. (b) Logullo, F. M.; Seitz, A. H.; Friedman, L. Org. Synth. 1968, 48,
12.
8.2 Hz, 1 H), 8.39 (d, J ) 8.2 Hz, 2 H), 8.12 (d, J ) 8.9 Hz, 1 H),
7.96-7.93 (m, 2 H), 7.90 (d, J ) 8.2 Hz, 2 H), 7.85 (t, J ) 7.5
9242 J. Org. Chem., Vol. 71, No. 24, 2006

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Hz, 1 H), 7.62 (d, J ) 7.5 Hz, 1 H), 7.40 (t, J ) 7.2 Hz, 1 H), 4.28
(q, J ) 6.8 Hz, 2 H), 1.54 (t, J ) 6.8 Hz, 3 H) ppm; 13C NMR
(125 MHz, CDCl3): δ 158.6, 156.1, 148.1, 146.5, 139.1, 133.2,
133.1, 131.1, 130.7, 128.0, 127.8, 125.3, 124.8, 123.8, 122.8, 119.6,
103.9, 64.2, 15.1 ppm; MS (ESI): m/z 345 ([M + H]+); HRMS
(ESI): m/z calcd for C21H17N2O3 ([M + H]+) 345.1234, found
345.1235.
2-Methyl-6-(4-nitrophenyl)phenanthridine (6b). Yellow solid;
mp 168-169 °C; IR (KBr) 1597, 1520, 1347, 1323 cm-1; 1H NMR
(500 MHz, CDCl3): δ 8.73 (d, J ) 8.3 Hz, 1 H), 8.43-8.41 (m,
3 H), 8.12 (d, J ) 8.3 Hz, 1 H), 7.96 (d, J ) 8.2 Hz, 1 H), 7.93-
7.90 (m, 2 H), 7.87-7.86 (m, 1 H), 7.63-7.61 (m, 2 H), 2.67 (s,
3 H), ppm; 13C NMR (125 MHz, CDCl3): δ 157.9, 148.2, 146.5,
142.1, 138.0, 133.5, 131.2, 131.1, 131.0, 130.4, 128.6, 127.6, 124.8,
124.0, 123.9, 122.8, 121.9, 22.3 ppm; MS (ESI): m/z 315 ([M +
H]+); HRMS (ESI): m/z calcd for (C20H14N2O2 + H) 315.1128,
found 315.1127.
Acknowledgment. This work was supported by the Special-
ized Research Fund for the Doctoral Program of Higher
Education (20050335101), the Natural Science Foundation of
Zhejiang Province (R404109), as well as the Teaching and
Research Award Program for Outstanding Young Teachers in
Higher Education Institutions of MOE, People’s Republic of
China.
Supporting Information Available: Experimental procedures;
spectral data for other products; copies of 1H and 13C NMR spectra
for all products; and X-ray structure details for compound 6d (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO061648I
J. Org. Chem, Vol. 71, No. 24, 2006 9243