Photocyclization of 1-(2-halophenyl)-3,4-dihydro-6,7- dimethoxyisoquinolines: A short and new synthesis of triclisine

Article abstract of DOI:10.1016/j.tetlet.2005.04.076

A short and new synthesis of the non-phenolic azafluoranthene alkaloid triclisine utilizing the photocyclization of 1-(2-halophenyl)-3,4-dihydro-6,7- dimethoxyisoquinolines as a key step has been described.

Full text of DOI:10.1016/j.tetlet.2005.04.076

Tetrahedron
Letters
Tetrahedron Letters46 (2005) 4385–4386
Photocyclization of
1-(2-halophenyl)-3,4-dihydro-6,7-dimethoxyisoquinolines:
a short and new synthesis of triclisine
M. M. V. Ramana,* R. H. Sharma and J. A. Parihar
Department of Chemistry, University of Mumbai, Vidyanagari, Santacruz (E), Mumbai 400 098, India
Received 19 February 2005; revised 12 April 2005; accepted 19 April 2005
Available online 5 May 2005
Abstract—A short and new synthesis of the non-phenolic azafluoranthene alkaloid triclisine utilizing the photocyclization of 1-(2-
halophenyl)-3,4-dihydro-6,7-dimethoxyisoquinolines as a key step has been described.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Table 1. Photolysis of 1-(2-halophenyl)-3,4-dihydro-6,7-dimethoxyiso-
quinolines 1a,b
Azafluoranthenes constitute a small group of isoquino-
line derived alkaloidsconitsing of the non-phenolic
bases triclisine, imeluteine and rufescine, and the pheno-
lic bases norrufescine and telitoxine. Synthetic ap-
proachestowardsthees alkaloidsinvolve either
Entry
Substrate
Time (h)
2 (%)
3 (%)
1
2
1a
1b
12
7
42
40
19
24
Pschorr or Pschorr-type cyclizations1–3 of the appropri-
ate arenediazonium precursors to build ring D, or selec-
tive controlled introduction of the azafluoranthene aryl
D ring by an inverse electron demand Diels–Alder reac-
tion of 3-carbomethoxy-2-pyrones.4 The Snieckusap-
proach,5 which allowed the simultaneous formation
of the B and C rings, is based on a metallation (ortho
and remote)-cross coupling process. Herein, we wish to
report a short synthesis of the non-phenolic azafluor-
anthene alkaloid triclisine utilizing the photocyclization
of 1-(2-halophenyl)-3,4-dihydro-6,7-dimethoxyisoquino-
linesasa key step.
these conditions for 7 h proceeded in an identical fash-
ion to give the cyclized product 2 in a 40% yield along
with the photoreduced product 3 in a 24% yield. The re-
sults obtained from these photolysis reactions of 1a,b
are summarized in Table 1. To the best of our knowl-
edge, thisphotolyisof 1-(2-halophenyl)-3,4-dihydro-
6,7-dimethoxyisoquinolines 1a,b hasbeen utilized for
the synthesis of 2,3-dihydroazafluoranthene 2 for the
first time. Dehydrogenation of 2 with 5% Pd–C at
250 ꢁC for 15 min gave the azafluoranthene alkaloid tri-
clisine 4 in a 52% yield (Scheme 1).
Towardsthisend, the photocyclization of 1-(2-halophen-
yl)-3,4-dihydro-6,7-dimethoxyisoquinolines 1a,b was
explored. Irradiation of a benzene solution of 1a
containing sodium thiosulfate with Vycor-filtered light
(ꢀ254 nm) for 12 h led to the formation of two products
identified asthe desired cyclized and photoreduced com-
pounds 2 and 3 in yieldsof 42% and 19%, respectively.
Photolysis of the iodo aromatic isoquinoline 1b under
In conclusion, this work provides a new synthesis of the
azafluoranthene alkaloid triclisine 4, which involves
photocyclization of 1a,b to give 2,3-dihydroazafluor-
anthene 2 as a key step and the subsequent dehydrogena-
tion of 2.
Typical procedure for Vycor-filtered irradiation of 1-(2-
halophenyl)-3,4-dihydroisoquinolines 1a,b: A solution of
1a,b (0.5 mmol) and Na2S2O3 (100 mg) in benzene
(75 mL) and H2O (1 mL) wasirradiated for 7–12 h
(Table 1). The benzene wasevaporated under reduced
pressure and the residue obtained was made alkaline
Keywords: Photolysis; Dehydrogenation; Triclisine.
*
Corresponding author. Tel.: +91 6526091x353; fax: +91 6528547;
e-mail: mmvramana@indiatimes.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.076

4386
M. M. V. Ramana et al. / Tetrahedron Letters 46 (2005) 4385–4386
MeO
MeO
MeO
MeO
N
N
N
MeO
MeO
hν
+
X
3
2
1a: X = Br
1b: X = I
5 % Pd-C
250 oC
MeO
B
A
N
MeO
C
D
4
Scheme 1. Synthesis of the non-phenolic azafluoranthene alkaloid triclisine.
with 10% aqueousammonium hydroxide oslution
(10 mL). It wasthen extracted with CHCl
CHCl3 (50:50)] to afford the azafluoranthene alkaloid
triclisine 4.
3
(3 · 15 mL). The combined CHCl3 layerswere wahs ed
with water (2 · 10 mL) and then dried (anhydrous
Na2SO4). Evaporation of the solvent gave a brown res-
idue, which waspurified by column chromatography
[alumina (neutral), hexane–CHCl3 (70:30)] to furnish
the photoreduced product 3 (Table 1). Further elution
with hexane–CHCl3 (50:50) followed by recovery of
the solvents gave the dihydroazafluoranthene 2 (Table
1).
1
The MP, IR and H NMR data of triclisine 4 were in
agreement with the reported data.7
References and notes
1. Cava, M. P.; Buck, K. T.; da Rocha, A. I. J. Am. Chem.
Soc. 1972, 94, 5931.
2. Banwell, M. G.; Hamel, E.; Ireland, N. K.; Mackay, M. F.;
Serelis, A. K. J. Chem. Soc., Perkin Trans. 1 1993, 1905–
1911.
3. Menachery, M. D.; Cava, M. P.; Buck, K. T.; Prinz, W. J.
Heterocycles 1982, 19, 2255–2257.
4. Boger, D. L.; Brotherton, C. E. J. Org. Chem. 1984, 49,
4050–4055.
5. Zhao, B.; Snieckus, V. Tetrahedron Lett. 1991, 32, 5277–5278.
6. Menachery, M. D.; Buck, K. T. Heterocycles 1985, 19,
2677–2679.
1H NMR data of 2,3-dihydro-5,6,-dimethoxyazafluor-
anthene 2 were in agreement with the reported data.6
Typical procedure for the dehydrogenation of 2: Dihydro-
azafluoranthene 2 (100 mg) washeated with 5% Pd–C
(50 mg) at 250 ꢁC for 15 min then extracted with hot
EtOAc (4 · 50 mL). The combined EtOAc extract was
filtered to remove catalyst traces. Evaporation of the
solvent gave a brown residue, which was purified by
column chromatography [alumina (neutral), hexane–
7. Menachery, M. D.; Cava, M. P. J. Nat. Prod. 1983, 46,
761–835.