Palladium-mediated total synthesis of 2-styrylbenzoic acids: A general route to 2-azachrysenes

Article abstract of DOI:10.1016/S0040-4039(02)00731-1

We describe a new total synthesis of 2-styrylbenzoic acids by Heck coupling of methyl o-iodobenzoates to styrenes. Additionally, in the first general synthesis of naphtho[2,1-f]isoquinolines, these acids were transformed into phenanthrenoic acids and then

Full text of DOI:10.1016/S0040-4039(02)00731-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4551–4553
Palladium-mediated total synthesis of 2-styrylbenzoic acids: a
general route to 2-azachrysenes†
Carme Pamp´ın, Juan C. Este´vez, Luis Castedo and Ramo´n J. Este´vez*
Departamento de Qu´ımica Orga´nica and Unidade Asociada (C.S.I.C.), Universidade de Santiago, 15782 Santiago de Compostela,
Spain
Received 6 March 2002; accepted 10 April 2002
Abstract—We describe a new total synthesis of 2-styrylbenzoic acids by Heck coupling of methyl o-iodobenzoates to styrenes.
Additionally, in the first general synthesis of naphtho[2,1-f ]isoquinolines, these acids were transformed into phenanthrenoic acids
and thence into the target compounds by a six-step sequence including a Bischler–Napieralski cyclization. © 2002 Elsevier Science
Ltd. All rights reserved.
Polycyclic aromatic hydrocarbons (PAHs) are wide-
spread pollutants produced in the combustion of
organic matter.1,2 Some PAHs, such as chrysene (9a),
are potent carcinogens, possibly because their rigid
planar embedded 2-phenylnaphthalene subunit may
facilitate interaction of their diol epoxide derivatives
with DNA.3,4 It has been suggested that structural
modifications of PAHs may afford antineoplastic com-
pounds. This is supported, for example, by the power-
ful anticancer activity of benzo[c]phenanthridines (9,
Y=CH, Z=N-Me), such as nitidine and fagaronine,
cases in which this activity has been attributed to
perturbation of the charge distribution in the tetracyclic
system of 9a by the introduction of a nitrogen atom.5
The introduction of alkoxy substituents at strategic
positions may also interfere with the processes involved
in the carcinogenic activity of 9a. Although 2-azachry-
senes (9, Y=N, Z=CH) have a structural relationship
to chrysene that is similar to that of benzo[c]-
phenanthridines, and therefore, like the latter,
might show antineoplastic activity, the synthesis of
these compounds has been almost completely over-
looked,6 and investigation of their properties7 has prac-
tically been limited to studies on pollution by
2-azachrysene (9d). We report here a new, simple,
efficient synthetic approach to 2-azachrysenes, starting
from o-styrylbenzoic acids (4) and involving sequential
construction of C and A rings of their tetracyclic
framework.
Heck coupling8 of methyl o-iodobenzoate 2a9 to styrene
afforded the E isomer of o-styrylbenzoic acid (4a),
together with a small amount of the corresponding
a-coupling product 3a (global yield 89%; a/b ratio 1:17)
(Scheme 1). Subsequent photocyclization10 of 4a in 95:5
ether–dichloromethane containing 1 equiv. of iodine
gave the phenanthrene ring system of the desired
phenanthrenoic acid ester 5a,11 and the heterocyclic
ring of 2-azachrysene was then added in five steps12 as
follows. Reduction of 5a with LiAlH4, followed by
oxidation of the resulting phenanthrenylmethyl alcohol
with MnO2 afforded phenanthrene aldehyde 5b. Reac-
tion of compound 5b with malonic acid gave phenan-
threnyl acrylic acid 6a, which upon treatment with
ClCO2Et and then with NaN3 afforded the correspond-
ing acylazide 6b. When a solution of 6b in Ph2O
containing Bu3N was refluxed for 1 h, the naphthoiso-
quinoline-1-one 8a was obtained in 78% yield as a
result of isomerization with respect to the double bond
of 6b, conversion of the resulting acylazide 7a into the
isocyanate 7b, and Bischler–Napieralski cyclization of
the latter. Finally, treatment of naphthoisoquinolinone
8a with POCl3 and subsequent removal of the chlorine
atom of 1-chloronaphthoisoquinoline 9c with Zn and
AcOH gave the desired compound, 9d.
* Corresponding author. Tel.: +34-981-563100, extension 14242; fax:
+34-981-591014; e-mail: qorjec@usc.es
†
Preparation of an o-styrylbenzoic acid by Heck coupling reaction of
The utility of this sequence was supported by the
analogous synthesis of dimethoxylated 2-azachrysene 9f
from o-styrylbenzoic acid 4b, via compounds 5c, 5d, 6c,
6d, 8b and 9e.
iodobenzene to o-vinylbenzoic acid has recently been carried out by
Kim, B. M.; Park, J. K. Bull. Korean Chem. Soc. 1999, 20, 744. As
far as we know, neither nor any other o-styrylbenzoic acids have
been obtained by similar procedures: see Refs. 12 and 13.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00731-1

4552
C. Pamp´ın et al. / Tetrahedron Letters 43 (2002) 4551–4553
Scheme 1. (i) Pd(OAc)2 (5% molar), Ph3P, Et3N, MeCN, argon, 80°C, 24 h. (ii) UV light, I2, Et2O, rt, 3 h. (iii) (a) LiAlH4, THF,
rt, 1.5 h; (b) MnO2, CHCl3, 40°C, 24 h. (iv) CH2(CO2H)2, piperidine, pyr., 80°C, 2 h, then reflux, 1 h. (v) (a) ClCO2Et, Et3N,
acetone, 0°C, 45 min; (b) NaN3, H2O, 0°C, 30 min. (vi) Bu3N, Ph2O, reflux, 1 h. (vii) POCl3, reflux, 3 h. (viii) Zn, AcOH, reflux,
2 h.
To sum up, we describe here the first total synthesis of
2-azachrysenes, which includes new general syntheses of
2-styrylbenzoic acids and phenanthrenylbenzoic acids
that are simpler and more efficient than previous
ones.13,14 Optimization of this route is now in progress
in order to obtain a panel of 2-azachrysenes for a
systematic study of their chemical and biological prop-
erties, antineoplastic activity included.
4. Cheng, C. C. In Progress in Medicinal Chemistry; Ellis,
G. P.; West, G. B.; Eds. Structural aspects of antineo-
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Vol. 25, pp. 35–83.
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Acknowledgements
We thank the Ministry of Education and Culture
(DGES) and the Xunta de Galicia for financial support.
6. (a) Whaley, W. M.; Meadow, M. J. Org. Chem. 1954, 19,
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C. Pamp´ın et al. / Tetrahedron Letters 43 (2002) 4551–4553
4553
11. (a) All new compounds gave satisfactory analytical and
spectroscopic data. Selected physical and spectroscopic
data follow. Compound 4a. 1H NMR (l, ppm, CDCl3):
3.78 (s, 3H, -CO2CH3), 6.92 (d, J=16.3 Hz, 1H,
-CHꢀCH-), 7.17–7.35 (m, 5H, 5×Ar-H), 7.47–7.51 (m,
2H, 2×Ar-H), 7.58 (d, J=7.7 Hz, 1H, Ar-H), 7.86 (dd,
J=7.8 and 1.3 Hz, 1H, Ar-H), 8.02 (d, J=16.3 Hz, 1H,
-CHꢀCH-). MS (m/z, %): 238 (M+, 79), 178 (100). Com-
pound 5a. 1H NMR (l, ppm, CDCl3): 4.04 (s, 3H,
-CO2CH3), 7.64–7.70 (m, 3H, 3×Ar-H), 7.87 (d, J=9.4
Hz, 1H, Ar-H), 7.93 (d, J=7.4 Hz, 1H, Ar-H), 8.22 (d,
J=7.4 Hz, 1H, Ar-H), 8.70 (d, J=7.9 Hz, 1H, Ar-H),
8.78 (d, J=9.4 Hz, 1H, Ar-H), 8.92 (d, J=8.4 Hz, 1H,
Ar-H). MS (m/z, %): 236 (M+, 100). Compound 4b. Mp
86–88°C (MeOH). 1H NMR (l, ppm, CDCl3): 3.87 (s,
3H, -CO2CH3), 3.89 (s, 3H, -OCH3), 3.94 (s, 3H, -OCH3),
6.89 (d, J=16.2 Hz, 1H, -CHꢀCH-), 7.10 (s, 1H, Ar-H),
7.22–7.36 (m, 3H, 3×Ar-H), 7.44 (s, 1H, Ar-H), 7.51–7.54
(m, 2H, 2×Ar-H), 8.07 (d, J=16.2 Hz, 1H, -CHꢀCH-).
MS (m/z, %): 298 (M+, 100). Compound 5b. Mp 109–
-OCH3), 4.25 (s, 3H, -OCH3), 7.68–7.74 (m, 2H, 2×Ar-H),
7.98–8.01 (m, 2H, 2×Ar-H), 8.45–8.46 (m, 1H, Ar-H),
8.63 (d, J=9.0 Hz, 1H, Ar-H), 8.77 (bs, 1H, Ar-H), 9.69
(bs, 1H, Ar-H), 9.77 (d, J=8.3 Hz, 1H, Ar-H). MS (m/z,
%): 289 (M+, 2), 58 (100).
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13. For previous syntheses of o-styrylbenzoic acids, see Ref.
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1
111°C (AcOEt). H NMR (l, ppm, CDCl3): 3.97 (s, 3H,
-CO2CH3), 4.02 (s, 3H, -OCH3), 4.06 (s, 3H, -OCH3),
7.60–7.65 (m, 2H, 2×Ar-H), 7.69 (d, J=9.3 Hz, 1H,
Ar-H), 7.84–7.88 (m, 1H, Ar-H), 7.92 (s, 1H, Ar-H), 8.65
(d, J=9.3 Hz, 1H, Ar-H), 9.62–9.66 (m, 1H, Ar-H). MS
(m/z, %): 296 (M+, 100). Compound 9f. Mp 152–154°C
(MeOH). 1H NMR (l, ppm, CDCl3): 4.04 (s, 3H,