[1]Benzopyrano[2,3,4-i,j]isoquinolines: A new, versatile route from 1-bromoxanthones

Article abstract of DOI:10.1016/S0040-4039(01)00983-2

[1]Benzopyrano[2,3,4-i,j]isoquinolines were synthesized from a bromoxanthone by assembly of the isoquinoline ring in three steps: vinylation, hydroamination and ring-closing reduction of the xanthone carbonyl.

Full text of DOI:10.1016/S0040-4039(01)00983-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5219–5221
[1]Benzopyrano[2,3,4-i,j ]isoquinolines: a new, versatile route
from 1-bromoxanthones
Alberto Garc´ıa and Domingo Dom´ınguez*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC, Facultad de Qu´ımica, Universidad de Santiago de Compostela,
15782 Santiago de Compostela, Spain
Received 8 March 2001; revised 6 June 2001; accepted 7 June 2001
Abstract—[1]Benzopyrano[2,3,4-i,j ]isoquinolines were synthesized from a bromoxanthone by assembly of the isoquinoline ring in
three steps: vinylation, hydroamination and ring-closing reduction of the xanthone carbonyl. © 2001 Elsevier Science Ltd. All
rights reserved.
In the course of research on tetracyclic xanthene deriva-
tives we planned the synthesis of tetrahydroderivatives
of [1]benzopyrano[2,3,4-i,j ]isoquinolines 1, to which
little attention has hitherto been paid in the literature.1
A classical approach to the isoquinoline ring is acid-cat-
alyzed cyclization of imino, alkylamino or sulfonamido
acetals derived from aminoacetaldehyde dimethylacetal;
the degree of oxidation of the final product being
determined by the type of compound subjected to
cyclization. In particular, the use of N-tosyl acetals2
delivers fully aromatized isoquinolines that can be
reduced to tetrahydroisoquinolines, with or without
prior N-alkylation. We therefore initially planned the
synthesis of benzopyranoisoquinoline 1 by electrophilic
cyclization of N-tosyl acetal 3.
afforded compound 3 in 28% overall yield (Scheme 1).
However attempts at cyclization using various acidic
conditions (6N aq. HCl, dioxane, reflux; PPA, 100°C;
TiCl4, CH2Cl2, −78°C; BF3·2AcOH) afforded only
products arising by nucleophilic displacement of the
sulfonamide and subsequent disproportionation of the
resulting xanthydrol, i.e. xanthene and xanthone.
The evident lability of the C9ꢀN bond of 3 under acidic
conditions prompted us to explore a route in which
C9ꢀN bond formation is the last step following intro-
duction of the aminoethyl subunit on C1. Given the
known hydroamination route from styrenes to
phenethylamines,5 the first step would be to obtain the
1-vinylxanthone derivative 5 (Scheme 2), which indeed
was envisaged as being a better substrate than styrene
for hydroamination because the electron-withdrawing
carbonyl group ortho to the vinyl group ought to
increase the electrophilicity of the double bond and
stabilize the benzylic anion generated during the amina-
tion process.
Reduction of the carbonyl group of xanthone 23 with
zinc powder in alkaline ethanol (92% yield),4 followed
by conversion of the resulting xanthydrol4b to the chlo-
ride (SOCl2, Et2O, reflux) and reaction with the sodium
salt of N-tosyl aminoacetaldehyde dimethyl acetal,2b
Scheme 1.
Keywords: Xanthones; vinylation; amination; isoquinolines.
* Corresponding author. Fax: +34-981-595012; e-mail: qomingos@usc.es
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00983-2

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A. Garc´ıa, D. Dom´ınguez / Tetrahedron Letters 42 (2001) 5219–5221
Scheme 2.
Table 1. Yields for hydroamination and ring closure
References
Compound
R
6 (%)
7 (%)
1. Hara, H.; Kishigami, M.; Endoh, M.; Kaneko, K.;
Hoshino, O. Heterocycles 1992, 33, 219–228.
2. (a) Birch, A. J.; Jackson, A. H.; Shanon, P. V. R. J.
Chem. Soc., Perkin Trans. 1 1974, 2185–2190; (b) Boger,
D. L.; Brotherton, C. E.; Kelley, M. D. Tetrahedron
1981, 37, 3977–3980; (c) Garc´ıa, A.; Dom´ınguez, D.;
Castedo, L. Synlett 1993, 271–272.
a
b
c
Bu
Bn
Allyl
69
77
85
72
86
83
3. Galt, R. H. B.; Horbury, J.; Matusiak, Z. S.; Pearce, R.
J.; Shaw, J. S. J. Med. Chem. 1989, 32, 2357–2362.
4. (a) Breazu, D.; Kovendi, A.; Szasz, D.; Radu, A.;
Dasoveanu, M. L.; Damnariu, M.; Poppa, V. I. Chem.
Abstr. 1988, 108, 77612g; (b) Filippatos, E.; Papadaki-
Valiraki, A.; Roussakis, Ch.; Verbist, J. F. Arch. Pharm.
(Weinheim Ger.) 1993, 326, 451–456.
5. (a) For the base-catalyzed hydroamination of styrenes,
see: Beller, M.; Breindl, C. Tetrahedron 1998, 54, 6359–
6368; (b) For the stoichiometric addition of amides, see:
Seijas, J. A.; Va´zquez-Tato, M. P.; Entenza, C.; Mar-
t´ınez, M. M.; Onega, M. G.; Veiga, S. Tetrahedron Lett.
1998, 39, 5073–5076.
Compound 5 was prepared in high yield by Stille
coupling between vinyltributyltin and 1-bromoxan-
thone 4,6 which had been obtained regioselectively by
bromination (Br2, AcOH, NaOAc, 55°C, 88%) of 4-
methoxyxanthone (2).7,8 When compound 56 was
reacted in THF with the lithium salt of a primary
amine,9 the corresponding phenethylamine 6 (Table 1)
was obtained in good yield.6 NaBH4 reduction of the
keto group of 6 in PrOH gave what H NMR showed
to be a 2:1 mixture of cyclized (7) and uncyclized
(9-hydroxy) compounds, which upon treatment with
glacial AcOH (rt, 60 min) afforded the isoquinoline 7 in
good yield (Table 1).6,10
i
1
6. All new compounds were fully characterized spectroscop-
ically and had satisfactory elemental analyses or HRMS
data.
For the synthesis of 7d, deallylation11 of 6c to the
aminoethylxanthone 8 was followed by reduction with
NaBH4 in MeOH, which gave a 73% overall yield of
the required product.6
7. 4-Methoxyxanthone was prepared as described in Ref.
4b.
8. The starting 4-methoxyxanthone was chosen in order to
allow for the regioselective bromination at the required
C1-position. For the synthesis of isoquinolines with a
different substitution pattern than 7a–d, the present syn-
thesis depends on the availability of the corresponding
starting haloxanthone in order to allow for the vinylation
at C1.
In this way, 1,2,3,11b-tetrahydro-6-methoxy-[1]benzo-
pyrano[2,3,4-i,j ]isoquinolines 7a–d, which have not
previously been described in the literature, were synthe-
sized in three steps and good overall yields from 1-
bromo-4-methoxyxanthone.
9. Experimental procedure for 6b: 1.6 M nBuLi (0.67 mL,
0.97 mmol) was added to a solution of benzylamine (0.10
g, 0.97 mmol) in 3 mL of dry THF at 0°C and the
mixture was stirred for 5 min, treated with a solution of
5 (0.10 g, 0.39 mmol) in 2.5 mL of dry THF, left standing
overnight without refrigeration and quenched with aq.
NH4Cl. After conventional work-up, chromatography of
the solid residue on silica gel with 90/10 CH2Cl2/MeOH
as eluent afforded 0.11 g (77%) of 6b as a yellowish solid;
mp 144–146°C; 1H NMR (CDCl3): l 8.28 (dd, J=7.8 and
Acknowledgements
Support of this work by grants from the Spanish Min-
istry of Education (Project PB98-0606) and from
Janssen-Cilag S.A. is gratefully acknowledged.

A. Garc´ıa, D. Dom´ınguez / Tetrahedron Letters 42 (2001) 5219–5221
5221
1.5 Hz, 1H), 7.71 (td, J=7.5 and 1.5 Hz, 1H), 7.58 (dd,
J=7.5 and 1.2 Hz, 1H), 7.40–7.20 (m, 6H), 7.15 (d,
J=8.2 Hz, 1H), 7.12 (d, J=8.2, 1H), 4.01 (s, 3H), 3.85 (s,
2H), 3.50 (t, J=7.2 Hz, 2H), 2.95 (t, J=7.2 Hz, 2H); 13C
NMR (CDCl3): l 178.9 (C), 155.4 (C), 148.3 (C), 147.6
(C), 140.8 (C), 134.8 (CH), 134.2 (C), 128.7 (2×CH),
128.5 (2×CH), 127.1 (CH), 127.0 (CH), 126.1 (CH), 124.3
(CH), 122.9 (C), 122.8 (C), 118.1 (CH), 115.1 (CH), 56.7
(OCH3), 54.2 (CH2), 51.2 (CH2), 35.7 (CH2); MS (m/z):
359 (M+, 10), 340 (14), 268 (49), 240 (100), 225 (95), 120
(82), 91 (97). HRMS calcd for C23H21NO3: 359.1534.
Found: 359.1521.
AcOH and stirred at rt for 1 h. Toluene (20 mL) was
added and the solvents evaporated to leave a solid, which
was triturated with Et2O and filtered to afford 0.33 g
(86%) of 7b as a brownish solid; mp 134–136°C; IR (CsI):
1
3030–2830, 1573, 1496, 1456, 1438, 1271, 1239 cm−1; H
NMR (CDCl3): l 7.82 (d, J=7.9 Hz, 1H), 7.43–7.12 (m,
8H), 6.86 (s, 2H), 5.34 (s, 1H), 3.97 (s, 3H), 3.71 (d,
J=13.5 Hz, 1H), 3.24–3.18 (m, 2H), 3.21 (d, J=13.5 Hz,
1H), 3.08–2.94 (m, 1H), 2.65–2.55 (dt, J=16 and 3.5 Hz,
1H); 13C NMR (CDCl3): l 152.1 (C), 146.0 (C), 140.5
(C), 139.9 (C), 128.9 (2×CH), 128.7 (2×CH), 128.6 (CH),
127.7 (CH), 127.3 (CH), 127.0 (C), 123.8 (CH), 122.9
(CH), 121.5 (C), 118.8 (C), 117.5 (CH), 111.1 (CH), 56.7
(OCH3), 54.6 (CH), 49.8 (CH2), 46.2 (CH2), 21.6 (CH2);
MS (m/z): 343 (M+, 9), 342 (8), 252 (14), 224 (93), 209
(100), 91 (52). Anal. calcd for C23H21NO3: C, 80.40; H,
6.16; N, 4.08. Found: C, 80.06; H, 6.30; N, 4.13%.
11. Laguzza, B. C.; Ganem, B. Tetrahedron Lett. 1981, 22,
1483–1486.
10. Experimental procedure for cyclization: NaBH4 (excess)
was added to a solution of 6b (0.40 g, 1.11 mmol) in 30
mL of isopropanol and the mixture was refluxed for 5 h.
The solvent was partially evaporated, an aqueous satu-
rated solution of NH4Cl was slowly added at 0°C to
destroy excess NaBH4 and, after conventional work-up,
the organic residue (0.38 g) was dissolved in 5 mL glacial
.