A novel C-N cleavage in isoquinolines allowing the first direct transformation of 1-benzylisoquinolines into benzo[c]phenanthridines and a new route to 2-phenyl-1,4-naphthoquinones

Article abstract of DOI:10.1016/S0040-4039(00)01052-2

Treatment of N-carbethoxy-1-benzylideneisoquinolines with LDA gives N-ethoxycarbonyl-1-amino-1-(2-vinylphenyl)-2-phenylethylenes, which can easily be transformed into N-carbethoxy-1-amino-2-phenyl-naphthalenes. Bichler-Napieralski reaction of these latter compounds affords the corresponding benzo[c]-phenanthridines, while their hydrolysis and subsequent oxidation constitutes a route to 2-phenyl-1,4-naphthoquinones. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01052-2

Tetrahedron Letters 41 (2000) 6351±6353
A novel C±N cleavage in isoquinolines allowing the ®rst
direct transformation of 1-benzylisoquinolines into
benzo[c]phenanthridines and a new route to
2-phenyl-1,4-naphthoquinones
Monica Treus, Juan C. Estevez, Luis Castedo and Ramon J. Estevez*
Â
Departamento de Quõmica Organica e Unidade Asociada (CSIC), Universidade de Santiago,
Â
15706 Santiago de Compostela, Spain
Received 11 February 2000; accepted 20 June 2000
Abstract
Treatment of N-carbethoxy-1-benzylideneisoquinolines with LDA gives N-ethoxycarbonyl-1-amino-1-
(2-vinylphenyl)-2-phenylethylenes, which can easily be transformed into N-carbethoxy-1-amino-2-phenyl-
naphthalenes. Bichler±Napieralski reaction of these latter compounds a€ords the corresponding benzo[c]-
phenanthridines, while their hydrolysis and subsequent oxidation constitutes a route to 2-phenyl-1,4-
naphthoquinones. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: alkaloids; antitumour compounds; cleavage reactions; isoquinolines; quinones.
1-Benzylisoquinolines have received considerable chemical attention because they are the
biogenetic precursors of a great variety of natural compounds of pharmacological interest,1
including protoberberines, which are transformed into benzo[c]phenanthridines2 such as fagaronine
and nitidine; the considerable antileukemic activity of the latter3 has been attributed to their
conformationally rigid embedded 2-phenylnaphthalene subunit.4 A number of syntheses of
benzo[c]phenanthridines have been developed, including a biomimetic preparation from 1-benzyl-
isoquinolines via protoberberines,5,6 but no direct transformation of 1-benzylisoquinolines into
benzo[c]phenanthridines has been hitherto described. Here we brie¯y sketch the ®rst, which
proceeds by an approach that is based on a novel C±N bond cleavage and provides a new route
to 2-phenyl-1,4-naphthoquinones.
Treatment of the readily prepared N-ethoxycarbonylbenzylideneisoquinoline 1a7 for 30 min
with LDA at 0ꢀC resulted in cleavage of C3±N bond, giving the styrylurethane 2a8 (easily identi-
* Corresponding author. Tel: +34 981 563100, ext. 14242; fax: +34 981 591014; e-mail: qorjec@uscmail.usc.es
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01052-2

6352
®ed from its analytical and spectroscopic data) (Scheme 1). Thermal electrocyclization of 2a
a€orded the 2-phenylnaphthalene derivative 3a, Bichler±Napieralski cyclization of the N-
methyl derivative of which (3b) gave the expected benzo[c]phenanthridine 4a. A similar
sequence led to the tetrasubstituted benzo[c]phenanthridine 4b via 2b, 3c and 3d.
Scheme 1. Compounds 1, 2, 4 and 5: (a) R=H; (b) R=OMe; compound 3: (a) R=R0=H; (b) R=H, R0=Me; (c)
R=OMe, R0=H; (d) R=OMe, R0=Me; compound 6: (a) R=X=H; (b) R=H, X=OH; (c) R=OMe, X=H; (d)
R=OMe, X=OH. Conditions: (i) LDA, THF, 0ꢀC, 30 min±1 h (100% yield); (ii) (a) 10% Pd±C, o-xylene, re¯ux, 3±6
days (35±50% yield); (b) NaH, THF, rt, 30 min, MeI, rt, 40 min±1 h (74±75% yield); (iii) P2O5, POCl3, re¯ux, 1.5±2.5 h
(58±66% yield); (iv) KOH aq., EtOH, re¯ux, 14±19 h (93±100% yield); (v) (a) Fremy's salt, KH2PH4, 2:1 acetone:water,
rt, 2 h (65% yield); (b) NaOH, 4:1 methanol:water, 4.5 h (90% yield)
In addition, hydrolysis of urethane 3a gave 2-phenyl-1-amino naphthalene 5a, which was easily
and eciently transformed into 2-phenyl-1,4-naphthoquinone 6a by oxidation with Fremy's salt.
Final treatment of 6a with aq. sodium hydroxide easily gave the corresponding 3-hydroxy-2-
phenyl-1,4-naphthoquinone 6b, a member of a class of compounds that have received considerable
attention9 on account of their chemical and biological properties. The utility of this sequence was
supported by the analogous transformation of urethane 3c into hydroxynaphthoquinone 6d via
5b and 6c.
A systematic study of this promising new C±N bond cleavage, including optimization of the
new route to benzo[c]phenanthridines, is now in progress. Additionally, we are studying an
application of the new direct route to naphthoquinones 6 to the preparation of derivatives of
pharmacological interest, including 6,11-dihydrobenzo[b]naphtho[2,3-d]furan-6,11-diones, 7,12-
dihydro-5H-dibenzo[c,g]chroman-5,7,12-triones and other similar antitumoral compounds.
Acknowledgements
We thank the Ministry of Education and Culture (DGES) and the Xunta de Galicia for
®nancial support.

6353
References
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8. All new compounds gave satisfactory analytical and spectroscopic data. Selected physical and spectroscopic data
are as follows: Compound 2a: Mp 106±109ꢀC (ethyl ether); H NMR (ꢀ, ppm, Cl3CD): 1.10 (m, 3H, ±CH3), 3.85
1
(s, 3H, ±OCH3), 3.91 (s, 3H, ±OCH3), 4.01 (q, J=6.8 Hz, 2H, ±OCH2±), 5.13 (d, J=11 Hz, 1H, ±CˆCH2), 5.57 (d,
J=17.5 Hz, 1H, ±CˆCH2), 5.90 (s, 1H, ±N±CˆCH±), 6.65 (bs, 1H, ±NH±), 6.90 (s, 1H, Ar±H), 7.02 (dd, J=11
and 17.5 Hz, 1H, ±CH±CH2), 7.04 (s, 1H, Ar±H), 7.21 (t, J=7.5 Hz, 1H, Ar±H), 7.34 (t, J=7.5 Hz, 2H, 2ÂAr±H),
7.41 (d, J=7.5 Hz, 2H, 2ÂAr±H); MS (m/z, %): 353 (M+, 22.97), 264 (100). Compound 2b: mp 137±139ꢀC
(methanol); 1H NMR (ꢀ, ppm, Cl3CD): 1.11 (t, J=7.07 Hz, 3H, ±CH3), 3.87 (s, 3H, ±OCH3), 3.88 (s, 3H, ±OCH3),
3.90 (s, 3H, ±OCH3), 3.93 (s, 3H, ±OCH3), 4.04 (q, J=7.07 Hz, 2H, ±OCH2±), 5.14 (d, J=11 Hz, 1H, ±CˆCH2),
5.56 (d, J=17.4 Hz, 1H, ±CˆCH2), 5.86 (s, 1H, ±N±CˆCH±), 6.45 (bs, 1H, ±NH±), 6.81±6.88 (m, 2H, 2ÂAr±H),
6.97±7.05 (m, 4H, 3ÂAr±H and Ar±CHˆCH2); MS (m/z, %): 413 (M+, 35.88), 262 (100). Compound 4a: mp 193±
195ꢀC (methanol). 1H NMR (ꢀ, ppm, Cl3CD): 4.00 (s, 3H, ±CH3), 4.01 (s, 3H, ±CH3), 4.02 (s, 3H, ±CH3), 7.13 (s,
1H, Ar±H), 7.51±7.57 (m, 3H, 3ÂAr±H), 7.69±7.76 (m, 1H, Ar±H), 8.04 (d, J=8.8 Hz, 1H, Ar±H), 8.20 (d, J=8.8
Hz, 1H, Ar±H), 8.52 (dd, J=7.9 Hz, J=1.4 Hz, 1H, Ar±H); MS (m/z, %): 319 (M+, 100). Compound 4b: mp 220±
250ꢀC (acetonitrile, decomposition); 1H NMR (ꢀ, ppm, Cl3CD): 4.04 (s, 9H, 3±CH3), 4.05 (s, 3H, ±CH3), 4.10 (s,
3H, ±CH3), 7.17 (s, 1H, Ar±H), 7.56±7.59 (m, J=8.75 Hz, 3H, 3ÂAr±H), 7.90 (s, 1H, Ar±H), 7.98 (d, J=8.75 Hz,
1H, Ar±H); MS (m/z, %): 379 (M+, 100).
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