Convergent synthesis of 6-substituted phenanthridines via anionic ring closure

Article abstract of DOI:10.1021/ol0170051

Chemical equation presented The addition of organometallic derivatives to the cyano group of 2-(2-fluorophenyl)benzonitrile followed by intramolecular nucleophilic substitution produces 6-substituted phenanthridines. Alkyllithiums, aryllithiums, and steri

Full text of DOI:10.1021/ol0170051

ORGANIC
LETTERS
2002
Vol. 4, No. 2
257-259
Convergent Synthesis of 6-Substituted
Phenanthridines via Anionic Ring
Closure
,†
Morten Lyse´n, Jesper L. Kristensen, Per Vedsø,* and Mikael Begtrup
The Royal Danish School of Pharmacy, Department of Medicinal Chemistry,
UniVersitetsparken 2, DK-2100, Copenhagen, Denmark
pV@dfh.dk
Received November 7, 2001
ABSTRACT
The addition of organometallic derivatives to the cyano group of 2-(2-fluorophenyl)benzonitrile followed by intramolecular nucleophilic substitution
produces 6-substituted phenanthridines. Alkyllithiums, aryllithiums, and sterically nondemanding lithium amides reacted at −78 °C to produce
the 6-substituted phenanthridines in 82−98% yield upon warming to room temperature. The addition of the corresponding Grignard reagents
requires an excess of the organometallic reagent and extented reaction times at elevated temperature.
The addition of organometallic species to cyano groups is a
fundamental transformation in organic synthesis.1 The result-
ing imine intermediates can be protonated and isolated at
the imine-stage or hydrolyzed to yield the corresponding
ketones.2 Alternatively, the intermediate imine anions can
be trapped with electrophiles.3 Protocols for the intra-
molecular trapping of imine-anions have also been devel-
oped. Thus, addition of Grignard reagents to the cyano group
of 4-chlorobutyronitriles and subsequent intramolecular
displacement of the chloride produces substituted pyrrolines.4
We now wish to report a new variant of this reaction, see
Scheme 1.5 Addition of an organometallic reagent to the
cyano group of 2-(2-fluorophenyl)benzonitrile (1) gives the
Scheme 1. 6-Substituted Phenanthridines via Anionic Ring
Closure
† Current address: Novo Nordisk A/S, Medicinal Chemistry Research,
DK-2760, Måløv, Denmark.
(1) Kharash, M. S.; Reinmuth, O. Grignard Reactions of Non-Metallic
Substances; Prentice Hall: New York, 1954; Chapter 10.
(2) (a) Wakefield, B. J. The Chemistry of Organolithium Compounds;
Pergamon Press Ltd.: Oxford, 1974; pp 116-121. (b) Wakefield, B. J.
Organomagnesium Methods in Organic Synthesis; Academic Press Lim-
ited: London, 1995; pp 101-108.
(3) (a) Chan, L. H.; Rochow, E. G. J. Organomet. Chem. 1967, 9, 231-
250. (b) Padwa, A.; Koehn, W. P. J. Org. Chem. 1975, 40, 1896-1902.
(c) Hose, D. R. J.; Mahon, M. F.; Molloy, K. C.; Raynham, T.; Wills, M.
J. Chem. Soc., Perkin Trans. 1 1996, 691-703. (d) Ortiz-Marciales, M.;
Tirado, L. M.; Colo´n, R.; Ufret, M. L.; Figueroa, R.; Lebro´n, M.; DeJesu´s,
M.; Mart´ınez, J.; Malave´, T. Synth. Commun. 1998, 28, 4067-4075.
(4) Demoen, P. J. A.; Janssen, P. A. J. Chem. Soc. 1959, 6281-6285
and references therein.
intermediate imine-anion (2). Subsequent intramolecular
nucleophilic aromatic substitution gives 6-substituted phenan-
thridines (3).
Substituted phenanthridines are of great interest for
medicinal chemistry applications and have a broad range of
biological activities.6 The Bischler-Napieralski cyclization
(5) We recently reported a similar approach to the synthesis of substituted
pyrazoloquinolines; see: Pawlas, J.; Vedsø, P.; Jakobsen, P.; Huusfeldt, P.
O.; Begtrup, M. J. Org. Chem. 2001, 66, 4214-4219.
10.1021/ol0170051 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/04/2002

has been used extensively to synthesize phenanthridine
derivatives.7 It is usually performed in the presence of P4O10,
POCl3, or PCl5 at elevated temperature, thereby limiting the
kind of functional groups that can be tolerated. Many other
synthetic routes to phenanthridines have been developed.8
The key starting compound 1 required for the anionic ring
closure was accessed via a Suzuki cross-coupling reaction.9
The biphenyl could be prepared in two ways, see Scheme 2.
59% and 49% yields under similar conditions, whereas
p-tolylMgCl gave the desired product 3e in 81% yield after
3 h at 70 °C. The reaction with t-BuMgCl (entry 4) gave
complicated mixtures under several different conditions and
none of the desired product 3d could be isolated.
The addition to the cyano group appears to be the rate-
limiting step, as the imine-intermediate was not observed at
any time. In an attempt to speed up the reaction, the use of
the corresponding lithium reagents was investigated. The
addition to the cyano group proceeded at -78 °C, and
subsequent warming of the reaction mixture to room tem-
perature produced the desired 6-substituted phenanthridines;
see Table 1.
Scheme 2. Dual Synthesis of 1a
Yields were higher than with Grignard reagents, and only
1.05 equiv of the organolithium reagent was required to
obtain full conversion of 1. Notably, tert-butyllithium
produced the desired product 3d in 85% yield (entry 4).
Furthermore, higher yields were obtained when 1 was added
to a solution containing the lithium reagents. 6-Butylphenan-
thridine (3c) was isolated in 87% yield when 1 was added
to n-butyllithium at -78 °C, compared to 77% when the
order of addition was reversed.
a Key: (i) 3% Pd(PPh3)4, K2CO3, toluene/EtOH/H2O 6:1:1, 85
°C, 7 h.
This dual approach should offer the possibility of preparing
a wide selection of substituted derivatives of 1 using readily
available aryl halides and arylboronic acids and esters. The
arylboronic esters in Scheme 2 were prepared as previously
reported.10
In our initial experiment we focused on the Cu(I)-catalyzed
addition of Grignard reagents to 1.11 The reactions were very
sluggish and required heating for extended time (Table 1,
The protocol was extended to other aryllithium reagents;
see Table 2. The 6-aryl-substituted phenathridinines 3f-h
Table 2. Synthesis of 6-Substituted Phenanthridines via the
Addition of Aryllithium Reagents and Lithium Amides to 1
Table 1. Synthesis of 6-Substituted Phenanthridines via the
Addition of Grignard and Organolithium Reagents to 1
a Yields of chromatographically pure product.
a Yields of chromatographically pure product. b 3 equiv of RMgCl, 3%
CuI, reflux 20 h. c 1.05 equiv of RLi, -78 °C to room temperature.
d Experiment not performed. e Complex mixture. f Reflux for 3 h.
were isolated in 82-92% yield. 6-Aryl-substituted phenan-
thridines have been reported as potent DNA-intercalating
antitumor agents.6a Furthermore, sterically nondemanding
lithium amides reacted smoothly to give the corresponding
6-aminophenanthridines 3i-k in 88-98% yield.12 Recently,
entries 1-5). Furthermore, 3 equiv of Grignard reagent was
needed. Refluxing 1 with 1 equiv of i-PrMgCl in the presence
of 3% CuI for 20 h gave a 3:2 mixture of unchanged 1 and
the desired 6-substituted phenanthridine 3b. When 3 equiv
of i-PrMgCl was used, the desired product 3b was isolated
in 74% yield. MeMgCl and n-BuMgCl gave 3a and 3c in
(6) DNA-Intercalating antitumor agents: (a) Atwell, G. J.; Baguley, B.
C.; Denny, W. A. J. Med. Chem. 1988, 31, 774-779. 5-HT3 receptor
ligands: (b) Cappelli, A.; Anzini, M.; Vomero, S.; Mannuni, L.; Makovec,
F.; Doucet, E.; Hamon, M.; Bruni, G.; Romeo, M. R.; Menziani, M. C.;
258
Org. Lett., Vol. 4, No. 2, 2002

3k and analogues thereof were reported to have high affinity
for the 5-HT3 receptor.6b Our approach provides a rapid and
convergent access to this class of compounds.
In conclusion, we have developed a rapid and convergent
synthesis of 6-substituted phenanthridines proceeding in two
steps from readily available starting materials. The addition
of alkyllithiums, aryllithiums and lithium amides to 2-(2-
fluorophenyl)benzonitrile (1) produces the corresponding
6-substituted phenanthridines 3a-k via an intramolecular
anionic ring closure.13 We are currently exploring the scope
of the reaction with respect to substituted derivatives of 1
and the application of other nucleophiles.
Supporting Information Available: Detailed experi-
mental procedures and characterization for compounds 1 and
3a-k. This information is available free of charge via the
Internet at http://pubs.acs.org.
Benedetti, P. G.; Langer, T. J. Med. Chem. 1998, 41, 728-741. Topo-
isomerase inhibitors: (c) Janin, Y. L.; Croisy, A.; Riou, J.-F.; Bisagni, E.
J. Med. Chem. 1993, 36, 3686-3692. (d) Lynch, M. A.; Duval, O.;
Sukhanova, A.; Devy, J.; MacKay, S. P.; Waigh, R. D.; Nabiev, I. Bioorg.
Med. Chem. Lett. 2001, 11, 2643-2646. Positive ionotropic activity: (e)
Heber, D.; Ju¨rgens, J.; Ravens, U.; Schumann, J. Arch. Pharm. (Weinheim,
Ger.) 1988, 321, 787-792. Antituberculosis activity: (f) Ishikawa, T. Med.
Res. ReV. 2001, 21, 61-72.
(7) (a) Mamalis, P.; Petrow, V. J. Chem. Soc. 1950, 703-711. (b) Buu-
Ho¨ı, N. P.; Jaquignon, P.; Long, C. T. J. Chem. Soc. 1957, 505-509.
(8) For a comprehensive list of references see Patra, P. K.; Suresh, J.
R.; Ila, H.; Junjappa, H. Tetrahedron 1998, 54, 10167-10178.
(9) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(10) Kristensen, J.; Lyse´n, M.; Vedsø, P.; Begtrup, M. Org. Lett. 2001,
3, 1435-1437.
(11) Weiberth, F. J.; Hall, S. S. J. Org. Chem. 1987, 52, 3901-3904.
(12) Attempted addition of lithium diisopropylamide to 1 led to a complex
mixture, presumably due to competing ortho-lithiation.
OL0170051
(13) Representative Procedure. 6-Piperidyl-phenanthridine (3j). Pi-
peridine (91 mg, 1.05 mmol) was dissolved in THF (4 mL) under N2 and
cooled to -10 °C. n-Butyllithium (1.6 M in hexanes, 1.05 mmol) was added,
and stirring was continued for 10 min. The mixture was cooled to -78 °C
before 2-(2-fluorophenyl)benzonitrile (1) (1.00 mmol) dissolved in THF
(2 mL) was added dropwise, and stirring was continued for 15 min. The
dry ice bath was removed, and the mixture was stirred at room temperature
for 20 min. The reaction was quenched with saturated NH4Cl (10 mL),
extracted with CH2Cl2 (3 × 20 mL), and dried (Na2SO4), and the solvent
was evaporated giving the crude product, which was purified by flash
chromatography yielding 246 mg (94%) of 3j as colorless crystals, mp 86
°C, reported mp 82-83 °C. Keene, B. R. T.; Turner, G. L. Tetrahedron
1971, 27, 3405-3416.
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