A single step synthesis of 6-aminophenanthridines from anilines and 2-chlorobenzonitriles

Article abstract of DOI:10.1016/j.tet.2004.03.062

Biologically active 6-aminophenanthridines were prepared in a single step procedure: Metal amides in liquid ammonia promoted the condensation of anilines with 2-chloro-benzonitriles. 6-Aminophenanthridines were isolated in moderate yield.

Full text of DOI:10.1016/j.tet.2004.03.062

Tetrahedron 60 (2004) 4705–4708
A single step synthesis of 6-aminophenanthridines from anilines
and 2-chlorobenzonitriles
a
Fabienne Gug, St e´ phane Bach, Marc Blondel, Jean-Michel Vierfond, Anne-Sophie Martin
b
b
a
a
a,
and Herv e´ Galons
*
a
Laboratoire de Chimie Organique, Universit e´ Ren e´ Descartes, 4 avenue de l’Observatoire, 75006 Paris, France
C.N.R.S., Station Biologique, Cell Cycle Laboratory, place G. Teissier, 29680 Roscoff, Bretagne, France
b
Received 22 January 2004; revised 15 March 2004; accepted 19 March 2004
Abstract—Biologically active 6-aminophenanthridines were prepared in a single step procedure: Metal amides in liquid ammonia promoted
the condensation of anilines with 2-chloro-benzonitriles. 6-Aminophenanthridines were isolated in moderate yield.
q 2004 Elsevier Ltd. All rights reserved.
1
2
1
. Introduction
benzoates. After conversion of phenanthridinone into
1
3
6-chlorophenanthridines, 6-AP could then be obtained
upon reaction with ammonia.
1
4
Prion deseases are neurodegenerative pathologies that
include Creutzfeld–Jakob in human, bovine spongiform
encephalopathie in cattle and scrapie in sheep. All these
disorders are associated with an abnormal conformation of
Recently, a one step synthesis of 6-substituted-phenanthri-
dine has been described. It is based on the condensation of 2
arynes generated from fluoroarenes with one equivalent of
nitrile. However this approach does not allow the introduc-
tion of various groups on the benzene rings and cannot be
1
the normal host protein PrP.
Up to now no treatment has demonstrated clinical useful-
2
ness. Very recently, we have developed a rapid yeast-based
15
applied to the synthesis of unsubstituted 6-amino groups.
assay to screen for antiprion drugs, which led to the
discovery of phenanthridines as new prion inhibitors. In
particular, 6-aminophenanthridines (6-AP) displayed the
highest inhibition. In our test, 6-APs were found more
4
active than other previously reported inhibitors.
2. Results and discussion
3
2.1. Amination of 6-chlorophenanthridines
This prompts us to study the preparation of these
heterocycles. Phenanthridines can be obtained by cyclisa-
At the onset of our work, we tried to prepare 6-APs via
1
6
6-chlorophenanthridine using the above mentioned
previously reported procedure: 6-chlorophenanthridine
was obtained in an overall 48% yield from phenanthridine
but exposure to a methanolic solution of ammonia produced
only a minor trace of 6-AP. The amination was then
successfully achieved by hydrogenation of 6-benzylamino-
phenanthridine prepared by refluxing 6-chlorophenanthri-
dine in benzylamine (Scheme 1).
0
iodo-2-isocyanobiphenyle. Other syntheses include
5
tion of various biphenyles: 2-formyl-2 -nitrobiphenyle,
2
0
cyclisation of N-benzylanilides by reaction of hypervalent
6
7
iodine, condensation of Boc-aniline with 2-chlorobenzal-
8
dimines under basic conditions and annelation of tetra-
9
hydroquinolin-4-one.
In contrast to the numerous approaches to phenanthridines,
very few reports deal with 6-APs. The main routes start
from phenanthridinones. Phenanthridinones can be obtained
2.2. Cyclization of 2-chlorophenylbenzamidine
1
0
from phenanthridines via rearrangement of the N-oxide,
1
However, this classical approach was limited. We needed to
prepare functionalised 6-APs in order to establish
structure–activity relationships. This led us to investigate
other routes.
1
from fluorenones by the Schmidt reaction and by Suzuki
coupling of 2-Bocaminophenylboronic acid with 2-bromo-
Keywords: Amidine; Prions; Phenanthridine; Heterocyclisation.
*
Taking into account that potassium amide in liquid
ammonia allowed the cyclisation of the imine of
Corresponding author. Tel.: þ33-1-5373-9684; fax: þ33-1-4329-0592;
e-mail address: herve.galons@univ-paris5.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.062

4706
F. Gug et al. / Tetrahedron 60 (2004) 4705–4708
Similarly, naphthylamine reacted with 2-chlorobenzonitrile
to afford the benzo[c]phenanthridine 3j (Scheme 4).
Scheme 4. Preparation of benzo[c]phenanthridine.
3. Conclusion
Scheme 1. Amination of 6-chlorophenanthridine.
Although the isolated yields of 6-APs were moderate, the
presented procedure is simple to carry out, it allowed us to
prepare a series of diversely substituted 6-APs, bearing
either electro-donating or electro-attractive groups on the
aromatic rings.
2
-chlorobenzaldehyde with naphthylamine into benzo[c]-
1
7
phenanthridine, we have experimented the cyclisation of
N-phenyl-2-chlorobenzamidine 4. Addition of the amidine 4
to a sodium amide suspension in liquid ammonia led to the
formation of 6-AP 3a which was separated from unreacted 4
by column chromatography (Scheme 2).
Efforts are underway to use these easily obtainable 6-APs as
synthetic intermediates to prepare other biologically active
phenanthridines. Further, the obtention of compound 3j
illustrate the potency of the approach in the preparation of
benzophenanthridines which display a broad range of
1
9–21
pharmacological activities.
4. Experimental
Scheme 2. Cyclisation of 2-chlorophenylbenzamidine.
4.1. General
2
2
.3. Direct condensation of arylamines with
-halonitriles
All the starting material used were commercially available
except 6-chlorophenanthridine prepared from phenanthri-
dine. H and C NMR were recorded on a Bruker 400 MHz
spectrometer. Structural assignments were achieved by 1D
and 2D methods.
1
13
In order to get the target compounds in a one step procedure,
we have studied the condensation of 2-halobenzonitriles
with aryl amines in the presence of several combination of
bases: The use of a mixture of sodium and lithium amide
was found the most efficient providing single step access to
4.1.1. 6-Benzylaminophenanthridine (2) from 6-chloro-
phenanthridine (1). A solution of 6-chlorophenanthridine 1
(4.5 g, 21.1 mmol) in benzylamine 15 mL and tributylamine
6
2
-APs. An attempt to use 2-fluorobenzonitrile instead of
-chlorobenzonitrile was unsuccessful (Scheme 3, Table 1).
2
mL was refluxed 3 h. After concentration under reduced
pressure, the residue was chromatographed on silica gel
using CH Cl containing 0.1% NEt as eluent.
2
2
3
1
Yield 86%; mp 99 8C; H NMR (CDCl ) d 4.97 (s, 2H,
3
CH –C H ); 5.6 (br s, 1H, NH); 7.35 (t, 1H, 2-H); 7.32 (t,
2
6 5
1H, H-8); 7.4 and 7.55 (2m, 5H, C H ); 7.58 (t, 1H,); 7.62
6 5
(
1
t,); 7.78 (t, 1H,); 7.82 (t, 1H,); 7.85 (d, 1H, 7-H); 8.37 (d,
H, 1-H); 8.55 (d, 1H, 10-H). Analysis: calculated for
C H N : C, 84.48; H 5.67%; N 9.85%; found: C, 84.35; H
Scheme 3. Condensation of anilines with 2-chlorobenzonitriles.
Table 1. Phenanthridines produced via Scheme 3
2
0 16 2
5
.81%; N 10.02%.
1
2
3
4
5
Entry Compounds 3
R
R
X
R
R
R
Yield (%)
4.1.2. Debenzylation of 6-benzylaminophenanthridine
2) into 6-aminophenanthridine (3a). To a solution of
-benzylaminophenanthridine 2 (2.84 g, 10 mmol) in
EtOH–AcOH (100 mL, 95:5) was added 5% Pd–C
0.1 g). The mixture was hydrogenated under vigorous
stirring (5 atm, 40 8C) for 3 h. After removal by filtration of
the catalyst, the solution was concentrated under reduced
pressure, diluted in 100 mL H O, brought to pH 10 with
2
(
6
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
F
H
H
H
F
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
42
39
52
44
38
36
62
17
33
H
H
H
Cl
OCH
H
3
(
H
H
CF
H
3
OCH
H
3
Cl OCH
3
Cl
Cl
H
H
H
Cl
saturated NaHCO3 and extracted with CH Cl . The
2
2
F
remaining solid crystallized upon trituration with AcOEt.

F. Gug et al. / Tetrahedron 60 (2004) 4705–4708
4707
1
Yield 19%; mp 187–189 8C; H NMR (CDCl ) d 7.40 (t,
3
9-H); 7.85 (d, 1H, 7-H); 7.94 (dd, 1H, 1-H); 8.35 (d, 1-H,
10-H). Analysis: calculated for C H FN : C, 73.57%; H,
4.27%; N, 13.20%; found: C, 73.76%; H, 4.12%; N,
13.31%.
1
H, J1 – 2¼J ¼8.6 Hz, 2-H); 7.58 (t, 1H, J
2 – 3
¼
7 – 8
13
9
2
J8–9¼8.5 Hz, 8-H); 7.64 (t, 1H, J ¼8.6 Hz, 3-H); 7.72
3–4
(
d, 1H, 4-H); 7.82 (t, 1H, J9–10¼8.5 Hz, 9-H); 7.95 (d, 1H,
7-H); 8.38 (d, 1H, 1-H); 8.56 (d, 1H, 10-H) Analysis:
calculated for C H N : C, 80.39%; H 5.19%; N 14.42%;
found: C, 80.09%; H 5.31%; N 14.56%.
4.2.2. 6-Amino-2-methoxyphenanthridine (3c). Mp 165–
1
1
3 10 2
167 8C; H NMR (CDCl ) d 3.90 (s, 3H, OCH ); (5.20 (br s,
3
3
2
H, NH ); 7.12, dd, J ¼8.5 Hz, J ¼2 Hz, 3-H); 7.60 (t,
2
3–4
1–3
4
used by Daoust and Lessard
.1.3. N-Phenyl-2-chlorobenzamidine (4). The method
8
1H, 8-H); 7.66 (d, 1H, 1-H); 7.69 (d, 1H, 4-H); 7.80 (t, 1H,
9-H); 7.95 (d, 1H, 7-H); 8.42 (d, 1H, 10-H). Analysis:
calculated for C H N O: C, 74.98%; H, 5.39%; N,
1
for the synthesis of
phenylbenzamidine was slightly modified: To a solution
1
4 12 2
aniline in 20 mL, toluene, NaNH (0.39 g, 10 mmol) was
2
12.49%; found: C, 74.81%; H, 5.45%; N, 12.77%.
added. After 1h stirring at 50 8C, 2-chlorobenzonitrile was
added and the mixture brought to reflux for 2 h. After
cooling to 0 8C, NH Cl, then water 100 mL were added
4
4.2.3. 6-Amino-3-fluorophenanthridine (3d). Mp 182–
1
183 8C; H NMR (CDCl ) d 5.75 (br s, 2H, NH ); 7.15, (td,
3
2
carefully and the mixture extracted with 3£100 mL CH Cl .
1H, J2-F¼10.2 Hz, J2–4¼2.7 Hz, 2-H); 7.4 (dd,1H,
2
2
The organic solution was washed with water, dried
(Na SO ) and concentrated under reduce pressure. The
amidine crystallized from Et O as a dark brown solid. Yield
J4-F¼10.2 Hz, 4-H); 7.65 (t, 1H, J ¼J ¼8.2 Hz, 8-H);
7–8
8–9
7.84 (t, 1H, J
9–10
¼8.2 Hz, 9-H); 7.94 (d, 1H, 7-H); (8.35,
1–3
2
4
1
3
dd, J1–2¼8.9 Hz, J ¼1 Hz, 1-H); 8.48 (d, 1H, 10-H). C:
2
1
5
6
7
5%; mp 170 8C; H NMR (CDCl ) d 4.80 (br s, 1H, NH);
3
111.5 (d, J ¼23.3 Hz, C-3); 112.4 (d, J ¼23.4 Hz, C-2);
3-F
2-F
.95 (m, 3H, Aro); 7.40 (m, 5H, Aro); 7.45 (d, 1H, Aro);
þ
123.10, C-10; 123.9, C-7, 124.27 (d, J ¼8 Hz); 127.51,
1
-F
.60 (br s, 1H, NH). MS (ES ) C H N Cl requires 230
1
C-7); 131.40, C-9; 147 (d, JC–F¼12 Hz, C –C–N) 155.89,
3
11
2
4
þ
and 232 found: 231, 233 (MþH , 100%).
C-2; 163.22 (d, J3-F¼243 Hz, C-3). Analysis: calculated for
C H FN : C, 73.57%; H, 4.27%; N, 13.20%; found: C,
1
3
9
2
4
.1.4. Aminophenanthridine 3a from 4. In a flask
73.41%; H, 4.38%; N, 13.43%.
connected with an efficient condenser, ammonia (100 mL)
was introduced followed by Fe(NO ) (0.02 g) and piece by
4.2.4. 6-Amino-8-chlorophenanthridine (3e). Mp 175–
1
3
3
piece Na (1.15 g, 50 mmol). The solution was stirred for
.5 h during this period, the initial blue colour of the
solution of Na gradually turned to grey indicating the
180 8C; H NMR (CDCl ) d 6.60 (br s, 2H, NH ); 7.35 (t,
2
3
0
1H, J2–1¼J ¼8.4 Hz, 2-H); 7.55 (t, 1H, 3-H); 7.65 (d,
2–3
1H, J3–4¼8.4 Hz, H-4); 7.72 (dd, 1H, J
¼8 Hz,
9–10
complete conversion into NaNH . N-Phenyl-2-chloro-
2
benzamidine 4 was introduced. After 2 h stirring, NH Cl
4
J7–9¼2 Hz, 9-H); 8.18 (d, 1H, 7-H); 8.32 (d, 1H, 1-H);
8.65 (d, 1H, 10-H). Analysis: calculated for C H ClN : C,
13
9
2
(
5 g) was added gradually and the mixture was left
68.28%; H, 3.97%; N, 12.25%; found: 68.44%; H, 4.11%;
N, 12.35%.
overnight. Water was added and the mixture was extracted
with CH Cl . The organic layer was washed with water,
2
2
dried and evaporated. The mixture was applied to a silica gel
column and eluted with CH Cl then CH Cl –MeOH (99:1)
containing 0.5% NEt as eluent. Unreacted 4 (yield: 22%)
4.2.5. 6-Amino-8-trifluoromethylphenanthridine (3f).
1
Mp 146–149 8C; H NMR (CDCl ) d 6.60 (br s, 2H,
3
2
2
2
2
NH ); 7.35 (t, 1H, J ¼J ¼8.3 Hz, 2-H); 7.55 (t, 1H,
3
2
1–2
2–3
was eluted first followed by 3a (yield 56%).
J3–4¼8.3 Hz, 3-H); 7.65 (d, 1H, 4-H); 7.95 (dd, J ¼2 Hz,
7–9
1
H, 9-H); 8.15 (d, 1H, J ¼2 Hz, H-7); 8.32 (d, 1H, 1-H);
7
–9
4.2. Preparation of 6-aminophenanthridines (3) from
arylamines and 2-halonitriles
8.65 (d, 1H, 10-H). Analysis: calculated for C H F N : C,
14 9 3 2
64.12%; H, 3.46%; N, 10.68%; found C, 64.10%; H, 3.31%,
N, 10.81%.
The preparation of the NaNH suspension was carried out as
2
described above. To a suspension of NaNH in liquid NH
2
4.2.6. 6-Amino-2,4-dimethoxyphenanthridine (3g). Mp
1
3
(
10 mmol, 100 mL) the arylamines 1 in anhydrous Et O
2
138–141 8C; H NMR (CDCl ) d 4.00 and 4.05 (2s, 2£3H,
3
(
10 mmol, 30 mL) were added droplet. The mixture was
2OCH ); 5.5 (br s, 2H, NH ); 6.70 (d, 1H, J ¼2 Hz, 3-H);
3
2
1–3
stirred for 0.5 h. After this time, 2-halobenzonitriles were
gradually added. In most cases, the 2-chlorobenzonitriles
were added as solids, (2-chlorobenzonitrile was added in
7.38 (d, 1H, 1-H); 7.69 (t, 1H; J7–8¼J ¼8.4 Hz, 8-H);
8–9
7.82 (t, 1H, 9-H); 8.02 (d, 1H, 7-H) 8.50 (d, 1H, H-10).
Analysis: calculated for C H N O : C, 70.85%; H, 5.55%;
N, 11.02%, found: C, 70.65%; H, 5.45%; N, 10.78%.
1
5 14 2 2
anhydrous Et O). The mixture was then stirred for 2 h and
2
lithium (0.14 g, 20 mmol) was added in two pieces. The
mixture was stirred an additional 2 h, NH Cl (2 g) was then
4.2.7. 6-Amino-7-chlorophenanthridine (3h). Mp 156–
1
4
added carefully. The reaction was left overnight. After
evaporation of ammonia, work up and purification were
performed as described above. 6-APs were easily distin-
guished from benzimidine by their stronger UV absorption
on tlc plates. Products 3 were crystallized from AcOEt.
157 8C; H NMR (CDCl ) d 6.37 (br s, 2H, NH ); 7.37 (t,
3
2
1H, J2–1¼J ¼8.3 Hz, 2-H); 7.60 (t, 1H, 3-H); 7.65 (m,
2–3
3H, 4-Hþ8-Hþ9-H); 8.31 (d, 1H, 1-H); 8.54 (m, 1H, 10-H).
Analysis: calculated for C H ClN : C, 68.28%; H, 3.97%;
1
3
9
2
N, 12.25%; found: C, 68.44%; H, 4.19%; N, 12.17%.
4
1
1
.2.1. 6-Amino-2-fluorophenanthridine (3b). Mp 132–
1
4.2.8. 6-Amino-8-chloro-2-fluorophenanthridine (3i). Mp
1
34 8C; H NMR (CDCl ) d 5.70 (br s, 2H, NH ); 7.3 (dd,
3
187–189 8C; H NMR (CDCl ) d 5.70 (br s, 2H, NH ); 7.30
3
2
2
H, J3-F¼10.1 Hz, J ¼2.5 Hz, 3-H); 7.65 (t, 1H,
1–3
(dd, 1H, J2-F¼10 Hz, J ¼8 Hz, 2-H); 7.55 (dd, 1H, 4-H);
2–1
J8–9¼J
¼8.5 Hz, 8-H) 7.68 (t, 1H, 3-H); 7.75 (t, 1H,
7.67 (td, 1H, 9-H); 7.87 (d, 1H, J¼2 Hz, 7-H) 7.98 (dd,
9–10

4708
F. Gug et al. / Tetrahedron 60 (2004) 4705–4708
1-H); 8.35 (d, 1H, 10-H). Analysis: calculated for
C H ClFN : C, 63.30%; H, 3.27%; N, 11.36%; found C,
7. Moreno, I.; Tellitu, I.; Etayo, J.; SanMartin, R.; Dominguez, E.
Tetrahedron 2001, 57, 5403–5411.
1
3
8
2
6
3.30%; H, 3.15%; N, 11.45%.
8. Reuter, D.; Flippin, L. A.; McIntosh, J.; Caroon, H. J.
Tetrahedron Lett. 1994, 35, 4899–4902.
4
1
.2.9. 8-Amino-benzo[c]phenanthridine (3j). Mp 145–
1
9. Patra, P. K.; Suresh, J. R.; Ila, H.; Junjappa, H. Tetrahedron
1998, 54, 10167–10178.
50 8C; H NMR (CDCl ) d 5.45 (br s, 2H, NH ); 7.50–8.00
3
2
(m, 7H); 8.30 (d, 1H); 8.70 (d, 1H); 9.20 (d, 1H). Analysis:
calculated for C H N : C, 83.58%; H, 4.95%; N, 11.47%;
found C, 83.33%; H, 5.12%; N, 11.23%.
10. DeRuiter, J.; Swearingen, B. E.; Wandrekar, V.; Mayfield,
C. A. J. Med. Chem. 1989, 32, 1033–1038.
1
7 12 2
11. Li;, J.-H.; Serdyuk, L.; Ferraris, D. V.; Tays, K. L.; Kletzly, P.;
Weixing, L.; Lautar, S.; Zhang, J.; Kalish, V. J. Bioorg. Med.
Chem. Lett. 2001, 11, 1687–1690.
Acknowledgements
12. Lamda, J. J. S.; Tour, J. M. J. Am. Chem. Soc. 1994, 116,
1
13. Arcus, C. L.; Coombs, M. M.; Evans, J. V. J. Chem. Soc. 1956,
1723–11736.
The authors thank Dr. T. Arends (Steraloids) for his help
during the preparation of the manuscript.
1498–1506.
4. Reese, C. B. J. Chem. Soc. 1958, 895.
1
1
5. Pawlas, J.; Begtrup, M. Org. Lett. 2002, 4, 2687–2690. Lysen,
M.; Kristensen, J. L.; Veds, P.; Begtrup, M. Org. Lett. 2002, 4,
References and notes
2
57–260.
1
2
. Dormont, D. FEBS Lett. 2002, 529, 17.
. Aguzzi, A.; Glatzel, M.; Montrasio, F.; Prinz, M.; Heppner,
F. L. Nat. Rev. Neurosci. 2001, 2, 745–749.
16. Currie, K. S.; Tenant, G. J. Chem. Soc. Chem. Commun. 1995,
22, 2295–2296.
17. Kessar, S. V.; Gupta, Y. P.; Balakrishman, P.; Sawal, K. K.;
Mohammad, T.; Dutt, M. J. Org. Chem. 1988, 53, 1708–1713.
18. Daoust, B.; Lessard, J. Can. J. Chem. 1995, 73, 362–374.
19. Yu, Y.; Singh, S. K.; Liu, A.; Li, T. K.; Liu, L. F.; LaVoie, E. J.
Bioorg. Med. Chem. 2003, 11, 1475–1491.
3
. Bach, S.; Talarek, N.; Vierfond, J.-M.; Mettey, Y.; Galons, H.;
Meijer, L.; Cullin, C.; Blondel, M. Nat. Biotechnol. 2003,
1075–1081.
4
5
6
. Korth, C.; May, B. C.; Cohen, F. E.; Prusiner, S. B. Proc. Natl.
Acad. Sci. 2001, 98, 9836–9841.
20. Sedo, A.; Malik, R.; Vicar, J.; Simanek, V.; Ulrichova, J.
Physiol. Res. 2003, 52, 367–372.
. Banik, B. K.; Indrani, H.; Hackfeld, L.; Becker, F. Hetero-
cycles 2002, 56, 467.
. Lenoir, I.; Smith, M. L. J. Chem. Soc. Perkin Trans. 1 2000,
21. Harayama, T.; Akiyama, T.; Nakano, Y.; Shibaike, K.;
Akamatsu, H.; Hori, A. H.; Takeuchi, Y. Synthesis 2002,
237–241.
641–644.