An expeditious synthesis of 6-aminophenanthridines

Article abstract of DOI:10.1016/j.tetlet.2005.03.135

A simple synthesis of biologically active 6-aminophenanthridines was achieved by a Suzuki-Miyaura coupling reaction. Condensation of 2-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)aniline with 2-chlorobenzonitriles afforded 6-aminophenanthridines useful as prions inhibitors in a mild one-step procedure. The intermediate 2-amino-2′cyanobiphenyls could not be isolated.

Full text of DOI:10.1016/j.tetlet.2005.03.135

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3725–3727
An expeditious synthesis of 6-aminophenanthridines
Fabienne Gug,a Marc Blondel,b Nathalie Desban,b Serge Bouaziz,c
a
Jean-Michel Vierfond and Herve Galons
a,
*
´
a
´
´
Laboratoire de Chimie Organique, INSERM U 648, Universite Rene Descartes, 4, avenue de L’Observatoire, 75006 Paris, France
bAmyloid and Cell Cycle Group, Station Biologique du CNRS, place G. Teissier, 29680 Roscoff, Bretagne, France
´ ´
UPCG, INSERM U640, CNRS UMR 8151, Universite Rene Descartes, 4, avenue de L’Observatoire, 75006 Paris, France
c
Received 21 February 2005; accepted 21 March 2005
Available online 8 April 2005
Abstract—A simple synthesis of biologically active 6-aminophenanthridines was achieved by a Suzuki–Miyaura coupling reaction.
Condensation of 2-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)aniline with 2-chlorobenzonitriles afforded 6-aminophenanthridines
useful as prions inhibitors in a mild one-step procedure. The intermediate 2-amino-20cyanobiphenyls could not be isolated.
Ó 2005 Elsevier Ltd. All rights reserved.
N
1. Introduction
NH2
NH2
N
Prion related diseases or transmissible spongiform
encephalopathies form a group of neurodegenerative
diseases that includes scrapie (sheep), mad cow disease
and Creutzfeldt-Jacob disease in human. According to
the ꢀprotein onlyꢁ hypothesis formulated by Stanley
Prusiner, prions are infectious proteins.1 A high
throughput screening of anti-prions drugs based on the
inhibition of yeast prions replication has been developed
and allowed to select phenanthridine and some of its
derivatives as new prions inhibitors. In particular
6-aminophenanthridines (6APs) were found to be potent
inhibitors of yeast prions and, in addition, their activity
against mammalian prions were established in cell-based
assays.2
NaNH2
toluene
Cl
+
Cl
NaNH2
NH3
1. NaNH2
2. LiNH2
NH3
NH2
N
3a
Scheme 1. Condensation of 2-chlorobenzonitriles with anilines pro-
moted by alkali metals amides.
Indeed, the cyclisation of the intermediate amidine
requires an hydrogen ortho to the halogen as benzyne
are presumed intermediates. Also, para-substituted
2-chlorobenzonitriles failed to react under these
conditions.
Very few studies have been devoted to the preparation
of 6APs. We have previously reported a one step synthe-
sis of 6APs, which relies on the condensation of 2-chlo-
robenzonitriles on anilines via the formation of an
intermediate amidine (Scheme 1).3 This synthesis is
economical and allowed us to prepare very active com-
pounds. However, the yields were moderate or low
and the procedure requires the use of anhydrous liquid
ammonia as solvent. More importantly, derivatives
substituted in position 9 and 10 could not be obtained.
Structure–activity studies showed that derivatives bear-
ing various groups introduced in position 1–4 of the
6-AP reduced the activity whereas electron-withdrawing
groups (Cl or CF3) in position 8 increased the anti-prion
activity strongly suggesting the potential interest of
products substituted in positions 9 and 10.
Keywords: Phenanthridine; Prion; Suzuki coupling.
*
We now report a one step process to 6-APs based on a
Suzuki–Miyaura coupling.4 A large amount of work
Corresponding author. Tel.: +33 15373 9684; fax: +33 14329 0592;
e-mail: herve.galons@univ-paris5.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.135

3726
F. Gug et al. / Tetrahedron Letters 46 (2005) 3725–3727
has been devoted to the choice of the catalyst and reac-
tion conditions. Several directions have been pursued:
polymer supported,5 incarcerated6 or water soluble7
phosphine ligands have been proposed in various combi-
nation of base and solvent.8 Tetrapodal phosphines,
were particularly efficient exhibiting substrate–catalyst
ratios up to 100,000.9 Several attractive conditions,
which avoid the use of oxygen-sensitive phosphines have
also been found effective using primary,10 secondary,11
tertiary12 amines or ammonium13 ligands. Even palla-
dium on activated carbon was successfully used however
the reaction was conducted at high temperature.14
(Scheme 2) using various experimental conditions (Table
1). Palladium-tetrakistriphenylphosphine Pd[P(C6H5)3]4
was first used and compared with a series of reac-
tion conditions using Pd on carbon or palladium II
acetate.
The use of a bulky21 primary amine: adamantanamine
(simply added as the commercially available hydrochlo-
ride) afforded 3b in good yield upon heating in 1,2-
dimethoxyethane or dioxane.
The selected conditions were then used to prepare other
derivatives (e.g., unknown 9- and 10-substituted 6-amino-
phenanthridines) (Table 1, entries 10–13).20 It can be no-
ticed that phenanthridines22 and phenanthridinones23
have been previously obtained by Suzuki coupling using
2-Bocaminophenylboronic acid. Acidic cleavage of the
Boc group was required to allow cyclisation.
All these studies have been achieved with boronic acids,
which are considered more reactive than boronic
esters.15,16 We envisioned to prepare 6-APs starting
from commercially available 2-chlorobenzonitriles and
2-aminophenylboronic esters.17 Very few reports have
detailed the influence of base and catalyst when Suzuki
coupling are conducted with boronic esters. However,
on a practical point of view, the use of boronic esters
offers several advantages. In particular, they are soluble
and stable in organic solvents,18 they were stored in
organic solutions, which facilitated the optimisation
studies and, when unreacted, they can be recovered by
column chromatography. We focused our attention on
the preparation 6-amino-8-chloro-phenanthridine 3b
one of the most active inhibitor to date. The conden-
sation of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)aniline with 2,5-dichlorobenzonitrile was studied
2. Conclusion
A simple access to biologically active 6-APs is described.
Among the newly prepared compounds, 6-amino-9-flu-
orophenanthridine 3d was found slightly more active
than 3b. In all cases under study the intermediate biphen-
yls could not be isolated in the reaction mixture. More
generally optimised cross-coupling conditions described
herein could be useful for the condensation of other
sterically hindered boronic esters and arylchlorides.
NH2
N
5
6
NH2
N
4
6a
7
9
4a
O
Catalyst
3
1a
10a
10
8
B
Cl
+
R
Base, solvent
R
O
2
1
1
2
3
Scheme 2. Condensation of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline with 2-chlorobenzonitriles.
Table 1. 6-Aminophenanthridines prepared
Entry
Conditions: catalyst (mol equiv), solvent, ligand (mol equiv), base (mol equiv),a temp, time
3
R
Yieldb (%)
1
Pd[P(C6H5)3]4 (0.03), dimethoxyethane, 2 N Na2CO3 (2), 80 °C, 12 h
Pd–C (0.01), N-methylpyrrolidone, 2 N Na2CO3 (2), 100 °C, 16 h
Pd(OAc)2 (0.05), dimethoxyethane, 2 N Na2CO3 (2), 80 °C, 16 h
3b
3b
3b
3b
3b
3b
3b
3b
3a
3c
3d
3e
3f
8-Cl
8-Cl
25
0
Traces
2
3
8-Cl
8-Cl
4
Pd(OAc)2 (0.05), THF, 2 N Na2CO3 (2.2),eAdNH2ÆHCl (0.2), 70 °C, 16 h
Pd(OAc)2 (0.05), dimethoxyethane, Cs2CO3 (2.2), AdNH2ÆHCl (0.2), 90 °C, 16 h
Pd(OAc)2 (0.05), dioxane, Cs2CO3 (2.2), AdNH2ÆHCl (0.2), 100 °C, 16 h
Pd(OAc)2 (0.05), dioxane, 2 N Cs2CO3 (2.2), AdNH2ÆHCl (0.2), 100 °C, 16 h
Pd(OAc)2 (0.05), dioxane, Cs2CO3 (2.2), AdNH2ÆHCl (0.2), 20 °C, 48 h
Pd(OAc)2 (0.05), dioxane, Cs2CO3 (2.2), AdNH2ÆHCl (0.2), 100 °C, 16 h
Pd(OAc)2 (0.05), dioxane, Cs2CO3 (2.2), AdNH2ÆHCl (0.2), 100 °C, 16 h
Pd(OAc)2 (0.05), dioxane, Cs2CO3 (2.2), AdNH2ÆHCl (0.2), 100 °C, 16 h
Pd(OAc)2 (0.05), dioxane, Cs2CO3 (2.2), AdNH2ÆHCl (0.2), 100 °C, 16 h
Pd(OAc)2 (0.05), dioxane, Cs2CO3 (2.2), AdNH2ÆHCl (0.2), 100 °C, 16 h
5
63
5
8-Cl
8-Cl
6
73, 69,c 45d
7
8-Cl
8-Cl
60
0
8
9
H
65
52
77
81
76
10
11
12
13
9-O-CH2C6H5
9-F
9-Cl
10-Cl
a Other bases (t-BuOK, K2CO3) were used without success.
b Determined by HPLC, mean of at least two experiments.
c Isolated by column chromatography.
d Isolated by crystallisation.
e AdNH2ÆHCl = adamantanamine hydrochloride. Compounds 2 were commercially available except 2-chloro-4-benzyloxy-benzonitrile19 used in the
synthesis of 3c.

F. Gug et al. / Tetrahedron Letters 46 (2005) 3725–3727
3727
19. Prepared in 66% yield from 2-chloro-4-hydroxybenzonit-
rile: by a Mitsunobu procedure, crystallisation from
cyclohexane. Mp: 98–100 °C. 1H NMR (CDCl3): d 5.11
(s, 2H); 6.94 (dd, 1H); 7.10 (d, 1H); 7.40 (br s, 5H); 6.55 (d,
1H).
Acknowledgements
We are grateful to Alexis Leclaire for performing the
HPLC, Crystel Beaufils who achieved the NMR studies,
Sophie Mairesse-Lebrun who did the microanalysis
and Trevor Arends (Steraloids) for his help during the
preparation of the manuscript.
20. Typical procedure for the synthesis of 6APs (entries 6, 8–
13). Solvents were deaerated with nitrogen and a slow
bubbling of nitrogen was maintained throughout the
reaction. Pd(OAc)2 (0.112 g, 0.5 mmol) was added to a
solution of 2-chlorobenzonitriles 2 (10 mmol) in dioxane
(75 mL). After stirring for 5 min at rt 1-adamantanamine
hydrochloride (0.76 g, 4 mmol), 2-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)aniline (2.39 g, 11 mmol) and
Cs2CO3 (0.7 g, 22 mmol) were added. The reaction was
stirred 16 h at 100 °C. After cooling to rt the mixture was
concentrated in vacuo to half of its initial volume and
partitioned between CH2Cl2 and water. The aqueous
phase was extracted twice with CH2Cl2. The combined
organic phases were washed with brine, dried over Na2SO4
and evaporated until dryness. The mixture was chromato-
graphed on silica gel using CH2Cl2–EtOH 0.5–
>5% + NEt3 0.5%.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.03.135. Analytical data of new compounds.
References and notes
1. Soto, C.; Castilla, J. Nat. Med. 2004, 10, S63–S67.
2. Bach, S.; Talarek, N.; Vierfond, J.-M.; Mettey, Y.;
Galons, H.; Meijer, L.; Cullin, C.; Blondel, M. Nat.
Biotechnol. 2003, 1075–1081.
3. Gug, F.; Bach, S.; Blondel, M.; Vierfond, J.-M.; Martin,
A.-S.; Galons, H. Tetrahedron 2004, 60, 4705–4708.
4. (a) Suzuki, A. J. Orgamet. Chem. 1999, 576, 147–168; (b)
Kotha, S.; Kakali, L.; Kashinath, D. Tetrahedron 2002,
58, 9633–9695; (c) Bellina, F.; Carpita, A.; Rossi, R.
Synthesis 2004, 2419–2440.
5. Parrish, C. A.; Buchwald, S. L. J. Org. Chem. 2001, 66,
3820–3827.
6. Okamoto, K.; Akiyama, R.; Kobayashi, S. Org. Lett.
2004, 6, 1987–1990.
7. Moore, L. R.; Shaughnessy, K. H. Org. Lett. 2004, 6, 225–
228.
8. Navarro, O.; Oonishi, Y.; Kelly, R. A.; Stevens, E. D.;
Briel, O.; Nolan, S. P. J. Organomet. Chem. 2004, 3722–
3727.
Compound 3a: mp (AcOEt) 186–188 °C, lit.3 189 °C.
Compound 3b: mp (AcOEt) 177–181 °C, lit.3 180 °C.
Compound 3c: mp (AcOEt) 112–115 °C; 1H NMR
(CDCl3): d 5.40 (s, 2H, CH2); 6.3 (br s, 2H, NH2); 7.32
(dd, J8–7 = 8.1 Hz, J10–8 = 2 Hz, 1H, 8-H); 7.39 (t, 1H,
J2–1 = J2–3 = 8.3 Hz, 2-H); 7.44 (m, 5H, C6H5); 7.58
(t, 1H, J3–4 = 8.3 Hz, 3-H); 7.72 (d, 1H, 4-H); 7.96 (d,
1H, 10-H); 8.10 (d, 1H, 7-H); 8.26 (d, 1H, 1-H).
Compound 3d: mp (AcOEt) 142–145 °C; 1H NMR
(CDCl3): d 5.55 (s large, 2H, NH2); 7.42 (t, 1H, J6–7
J7–8 = 8.2 Hz, 7-H); 7.45 (t, 1H, J2–1 = J2–3 = 8.23 Hz,
=
2-H); 7.65 (t, 1H, 3-H); 7.75 (d, 1H, 4-H); 7.97 (dd, 1H, J8-F
10 Hz, 8-H); 8.17 (d, 1H, J10-F = 9.9 Hz, 10-H).
=
Compound 3e: mp (AcOEt) 131–133 °C; 1H NMR
(CDCl3): d 5.55 (br s, 2H, NH2); 7.43 (td, 1H, J1–2 =
J2–3 = 8.2 Hz, J2–4 = 1.0 Hz, 2-H); 7.60 (d, 1H, 8-H); 7.65
(td, 1H, 3-H); 7.74 (dd, 1H, 4-H); 7.92(d, 1H, J7–8
8.53 Hz, 7-H); 8.30 (dd, 1H, 1-H); 8.51 (d, 1H, J8–10
=
=
9. Berthiol, F.; Kondolff, I.; Doucet, H.; Santelli, M. J.
Organomet. Chem. 2004, 689, 2786–2798.
10. Tao, B.; Boykin, D. W. J. Org. Chem. 2004, 69, 4330–
4335.
11. Tao, B.; Boykin, D. W. Tetrahedron Lett. 2003, 44, 7993–
7996.
12. Li, J.-H.; Liu, W.-J. Org. Lett. 2004, 6, 2809–2811.
1.71 Hz, 10-H). 13C NMR (CDCl3): 116.8 (6a-C); 120
(1a-C); 122.1 (1-C); 122.6 (10-C); 123.7 (2-C); 125.1 (7-C);
126.1 (4-C); 127.7 (8-C); 129.9 (3-C); 135.6 (10a-C); 137.0
(9-C); 144.0 (4a-C); 154.2 (6-C).
Compound 3f: mp (AcOEt) 127–129 °C; 1H NMR
(CDCl3): d 5.5 (br s, 2H, NH2); 7.43 (t, 1H, J1–2
=
¨
13. Ozdemir, I.; Alici, B.; Gurbuˆz, N.; C¸ etinkaya, E.; C¸ etin-
¨
J2–3 = 8.19 Hz, 2-H); 7.56 (t, 1H, J7–8 = J8–9 = 7.51 Hz,
8-H); 7.64 (t, 1H, 3-H); 7.76 (d, 1H, 4-H); 7.92 (d, 1H,
9-H); 7.98 (br d, 1H, J7–8 = 6.14 Hz, 7-H); 9.6 (d, 1H,
1-H). 13C NMR (CDCl3): 121.3 (1a-C); 122.8 (7a-C); 123
(7-C); 123 (2-C); 126.6 (4-C); 127 (8-C); 127.1 (1-C); 129.7
(3-C); 131.3 (10a-C); 132 (10-C); 135.2 (9-C); 144 (4a-C);
154.0 (6-C).
kaya, B. J. Mol. Catal. A 2004, 217, 37–40.
14. Gruber, M.; Chouzier, S.; Koehler, K.; Djakovitch, L.
Appl. Catal. A: Gen. 2004, 265, 161–169.
15. Satoh, Y.; Gude, C.; Chan, K.; Firooznia, F. Tetrahedron
Lett. 1997, 38, 7645–7648.
16. Prieto, M.; Zurita, E.; Rosa, M. L.; Lloyd-Williams, P.;
Giralt, E. J. Org. Chem. 2004, 69, 6812–6820.
21. The bulk of the electron-rich ligands is regularly consid-
ered to facilitate Suzuki coupling.
´
´
17. Baudouin, O.; Cesario, M.; Guenard, D.; Gueritte, F.
J. Org. Chem. 2002, 67, 1199–1207.
22. Siddiqui, M. A.; Snieckus, V. Tetrahedron Lett. 1988, 29,
5463–5466.
23. Lamba, J. J. S.; Trost, J. M. J. Am. Chem. Soc. 1994, 116,
11723–11736.
18. The chemistry of functionalised boronic esters have been
reviewed: Matteson, D. S. J. Organomet. Chem. 1999, 581,
51–65.