A new synthetic approach to 7-hydroxynitidine

Article abstract of DOI:10.1016/j.tetlet.2008.06.108

Benzo[c]phenanthridine alkaloid, 7-hydroxynitidine, was synthesized from readily available 2-benzyloxy-6-bromo-3,4-dimethoxybenzaldehyde 5 and napthylamine 6 using reductive amination followed by radical cyclization in eight steps. This method is highly e

Full text of DOI:10.1016/j.tetlet.2008.06.108

Tetrahedron Letters 49 (2008) 5262–5264
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Tetrahedron Letters
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A new synthetic approach to 7-hydroxynitidine
b
Prasanna Ramani a, , Gabriele Fontana
*
a Centre for biomolecular Interdisciplinary Studies and Industrial applicaitions (CISI), University of Milan, Via G. Fantoli 16/15, Milan 20138, Italy
b Indena S.p.a., Via Ortles 19, Milan, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Benzo[c]phenanthridine alkaloid, 7-hydroxynitidine, was synthesized from readily available 2-benzyl-
oxy-6-bromo-3,4-dimethoxybenzaldehyde 5 and napthylamine 6 using reductive amination followed
by radical cyclization in eight steps. This method is highly efficient and better way to synthesize fully
aromatized benzo[c]phenanthridine compounds.
Received 28 May 2008
Revised 22 June 2008
Accepted 24 June 2008
Available online 28 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Benzo[c]phenanthridine alkaloids
7-Hydroxynitidine
Microwave irradiation
Radical cyclization
Benzo[c]phenanthridines are naturally occurring isoquinoline
alkaloids with various biological activities.1–3 Sanguinarine 1a
shows antibacterial4 and antifungal5 activities, while nitidine 1b
and fagaronine 1d have been investigated as potential anti-tumor
and antiviral agents.6 Hence, more attention has been given to
the development of a facile synthetic methodology of benzo[c]phe-
nanthridines.7–9 7-Hydroxynitidine 1c (see Fig. 1), a modified
benzo[c]phenanthridine alkaloid, was shown to have strong cyto-
toxic activity against HeLa S3 cells.10 The presence of the 7-hydro-
xy group enhances anti-tumor activity.
hyde 2 undergoes Baeyer–Villiger oxidation by the treatment with
performic acid and the resulting formate ester was hydrolyzed
with aqueous KOH to give the corresponding phenol 3.
Ortho formylation12 of the latter to 4 followed by O-protection
with benzyl bromide afforded aldehyde 5. The aldehyde 5 and nap-
thylamine 6, which was synthesized from 2,3-dihydroxynaptha-
lene,13 were condensed in toluene to obtain the Schiff base
simply by using microwave irradiation at 140 °C. The imine was
reduced with dimethylamine borane14 to obtain 7 (Scheme 3).
This reaction by using microwave irradiation gave a better
yield15 in shorter time with higher purity when compared to the
classical reaction under reflux conditions (3 days, 25% yield). The
subsequent radical cyclization using 2,20-azobis(2-methylbutyro-
nitrile) (AMBN) and tributyltin hydride gave 8.11 This radical cycli-
zation led to good purity and fairly high yield16 (55%) compared to
the reported cyclization reaction through a benzyne intermediate
which gave rise to many unknown side products and a very low
yield10 (5–10%). Compound 7 was purified by using Biotage SP4
purification system17 followed by recrystallization from ethanol.
Nakanishi and Suzuki10 attempted, unsuccessfully, to synthe-
size 6-bromo derivative, 5, in various ways in order to make the
synthesis of 7-hydroxynitidine easier. This Letter describes a sim-
ple and efficient synthetic way to synthesize the title compound
(Scheme 1). NK109 was synthesized using the same strategy.11
The 2-(benzyloxy)-6-bromo-3,4-dimethoxybenzaldehyde 5,
required for the synthesis of 7-hydroxynitidine was obtained from
the commercially available 5-bromo-2,3-dimethoxy benzaldehyde
2 in three steps and 41% yield as described in Scheme 2. Thus, alde-
Figure 1. Structures of benzo[c]phenanthridine alkaloids.
* Corresponding author. Tel.: +39 0250320928; fax: +39 0250320945.
E-mail addresses: prasanna.ramani@unimi.it, prasanna.ramani@gmail.com (P. Ramani).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.108

P. Ramani, G. Fontana / Tetrahedron Letters 49 (2008) 5262–5264
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Scheme 1. Reterosynthesis of 7-hydroxynitidine.
Scheme 2. Synthesis of 6-bromoaldehyde unit.
Scheme 3. Microwave irradiation and radical cyclization to obtain cyclized product 8.
Scheme 4. Synthesis of 7-hydroxynitidine.
With methyl o-nitrobenzenesulfonate 10,18 compound 8 was
successfully methylated to benzo[c]phenanthridinium 9 (Scheme
4). Reagent 10 was easily prepared from o-nitrobenzenesulfonyl
chloride and sodium methoxide in methanol. Since the resulting
benzo[c]phenanthridinium o-nitrobenzensulfonate 9 is barely sol-
uble in toluene, it was gradually precipitated and centrifuged after
completion of the reaction.
deprotection of benzyl group of compound 11 was carried out by
using 6 N H2SO4 at 80 °C to obtain 7-hydroxynitidine 1c as hydro-
gen sulfate salt.
In summary, this synthetic pathway emphasizes the use of
microwave irradiation for the formation of Schiff base and the rad-
ical cyclization for the easy synthesis of 7-hydroxynitidine. Thus,
we have synthesized the benzo[c]phenanthridine alkaloid,
7-hydroxynitidine, in eight steps with an overall yield of 14.3%.
This radical cyclization method is an efficient procedure for the
Compound 9 was neutralized with sodium hydroxide in ethanol
to remove the acid residue and gave the pseudobase 11.19 The

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P. Ramani, G. Fontana / Tetrahedron Letters 49 (2008) 5262–5264
13. (a) Stermitz, F. R.; Gillespie, J. P.; Amoros, L. G.; Romero, R.; Stermitz, T. A. J.
Med. Chem. 1975, 18, 708–713; (b) Clark, J. H.; Holland, H. L.; Miller, J. M.
Tetrahedron Lett. 1976, 41, 3361–3364.
formation of benzo[c]phenanthridine framework and provides a
facile access in multi-gram scale.
14. Billman, J. H.; McDowell, J. W. J. Org. Chem. 1961, 26, 1437–1440.
15. Compounds 5 (500 mg, 1.42 mmol) and 6 (399 mg, 2.14 mmol) were dissolved
in toluene and subjected to microwave irradiation for 4 h at 140 °C. After the
Acknowledgments
amination was over, the solution was transferred to
a single neck flask,
The authors wish to acknowledge scientific counsel on this
work by Professor Carlo Scolastico. This work was supported by
‘Associazione Fondazione Renato Dulbecco’. P.R. was a recipient
of ICTP Programme for Training and Research in Italian Laborato-
ries, Trieste, Italy.
dimethylamine borane (102 mg) and acetic acid (1 mL) were added at 20 °C
slowly. The reaction was stirred at room temperature for 1 h. The reaction
mixture was quenched with 1 N HCl and stirred for 30 min and neutralized
with 5 N NaOH. The organic layer was separated and aqueous phase was
reextracted with toluene (2 ꢀ 50 mL). The organic layers were combined,
washed with water, dried (Na2SO4) and concentrated in vacuum. The crude
product was purified by using Biotage SP4 purification system17 followed by
recrystallization from ethanol to give 7 (590 mg, 66%) as a white solid. Mp:
136–138 °C. 1H NMR (CDCl3) d: 3.91 (s, 3H), 3.93 (s, 3H), 4.46 (s, 2H), 5.13 (s,
2H), 6.01 (s, 2H), 6.78 (d, 1H), 6.9 (s, 1H), 7.1 (d, 1H), 7.2 (d, 2H), 7.29–7.38 (m,
5H), 7.383–7.88, (m, 2H); MS (m/z) 522(M+), 524 (M+ (Br isotope)).
16. A solution of 7 (406 mg, 0.78 mmol) in toluene (87 mL) was heated to 110 °C. A
solution of Bu3SnH (0.840 mL, 3.1 mmol) and AMBN (600 mg, 3.1 mmol) in
toluene (87 ml) was added to the reaction mixture. After 1 h, the mixture was
cooled to room temperature, MnO2 (0.5 g, 5.5 mmol) was added, and the
resulting solution was stirred for 1 h. After oxidation was complete, the
reaction mixture was filtered through a thin Celite bed and the filtrate was
concentrated in vacuum to obtain thick oil. The product 8 (190 mg, 55.6%) was
obtained as a colourless solid by precipitation using diethyl ether at 10–15 °C.
Mp: 174–175 °C. 1H NMR (DMSO-d6) d: 4.0 (s, 3H), 4.1 (s, 3H), 5.3 (s, 2H), 6.1 (s,
2H), 7.2 (s, 1H), 7.28–7.4 (m, 2H), 7.40–7.44 (m, 2H), 7.6 (m, 1H), 7.7 (m, 1H),
8.24 (d, 1H), 8.7 (s, 1H), 9.6 (s, 1H). MS m/z 440 (M+1).
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