Palladium-catalyzed synthesis of o-acetylbenzoic acids: A new, efficient general route to 2-hydroxy-3-phenyl-1,4-naphthoquinones and indolo[2,3-b]naphthalene-6,11-diones

Article abstract of DOI:10.1016/S0040-4039(02)00990-5

We describe here a new, efficient general synthesis of o-acetylbenzoic acids by Heck palladium-catalyzed arylation of n-butyl vinyl ether with o-bromobenzoic acid esters and the use of these compounds as starting materials for the synthesis of 3-benzylideneisochroman-1,4-diones, which readily rearrange to 2-hydroxy-3-phenyl-1,4-naphthoquinones. The application of this strategy to the synthesis of indolo[2,3-b]naphthalene-6,11-diones is also described.

Full text of DOI:10.1016/S0040-4039(02)00990-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5141–5144
Palladium-catalyzed synthesis of o-acetylbenzoic acids: a new,
efficient general route to 2-hydroxy-3-phenyl-1,4-naphthoquinones
and indolo[2,3-b]naphthalene-6,11-diones
Jose´ C. Barcia, Jacobo Cruces, Juan C. Este´vez, Ramo´n J. Este´vez* and Luis Castedo
Departamento de Qu´ımica Orga´nica and Unidade Asociada (C.S.I.C.), Universidade de Santiago, 15782 Santiago de Compostela,
Spain
Received 4 April 2002; accepted 21 May 2002
Abstract—We describe here a new, efficient general synthesis of o-acetylbenzoic acids by Heck palladium-catalyzed arylation of
n-butyl vinyl ether with o-bromobenzoic acid esters and the use of these compounds as starting materials for the synthesis of
3-benzylideneisochroman-1,4-diones, which readily rearrange to 2-hydroxy-3-phenyl-1,4-naphthoquinones. The application of this
strategy to the synthesis of indolo[2,3-b]naphthalene-6,11-diones is also described. © 2002 Elsevier Science Ltd. All rights reserved.
Naphthoquinones are of perennial chemical interest on
account of their biological properties, their industrial
applications and their potential as intermediates in the
synthesis of heterocycles.1–3 For example, 3-hydroxy-2-
phenyl-1,4-naphthoquinones have been used as syn-
thetic precursors of antibiotic and antitumoral
quinonoid compounds,4 including 5H-benzo[b]carba-
zole-6,11-diones (indolonaphthoquinones)—a class
of indoles that became important synthetic targets
when it was proposed that kinamycin antibiotics5
were N-cyano-5H-benzo[b]carbazole-6,11-diones and,
more recently, when the antineoplastic activity of
these compounds was established.6 Antineoplastic
activity is also shown by structurally related pyrido-
[b]carbazoles7 such as elliptinium, which have well-
documented antitumor properties. The antineoplastic
activity of these compounds has been attributed to
their ring systems, which contain an embedded 2-
preliminary results on a new, general synthesis of 3-
hydroxy-2-phenyl-1,4-naphthoquinones. The approach
is based on the rearrangement of 3-benzylideneisochro-
man-1,4-diones resulting from isochroman-1,4-diones,
which in turn are easily prepared from 2-acetylbenzoic
acids. This route also allowed us to develop a general
synthesis of indolonaphthoquinones (12).
Taking into account our previous efficient synthesis of
o-acetylphenylacetic acids by Heck coupling of n-butyl
vinyl ether (BVE) and 2-bromophenylacetates,4a we rea-
soned that a similar Heck coupling reaction might give
easy access to o-acetylbenzoic acids. This was confi-
rmed when the reaction of BVE with methyl o-bro-
mobenzoate (1a, R=H), under conditions used by
Cabri et al.14 (Scheme 1, Table 1, entry 1), produced the
desired a-arylated compound 2a (a-selectivity being
attributed to the inclusion of TlOAc and a chelating
phosphine in the reaction medium). Compound 2a was
directly treated with 10% aq. HCl in THF at room
temperature for 1 h to produce an almost quantitative
yield of ketoester 3a.15 Formation of the b-arylated
product expected for classical Heck conditions (no
phenylnaphthalene-like
structure
in
a
planar
conformation.8
We recently described several syntheses of 3-hydroxy-2-
phenylnaphthoquinones9 and some of these routes were
simpler and more efficient than previous10 and more
recent11 syntheses. However, the general applicability of
these routes is limited by the methods used to prepare
starting materials (Friedel–Crafts12,13 acylation or Bich-
ler–Napieralski cyclization9a,b). We report here our
1
TlOAc) was not detected by H NMR spectroscopy.
Coupling of BVE to the electron-rich bromobenzoate
1b (R=OMe) gave a lower yield of 3d even when a
longer reaction time was used (Table 1, entry 2),
although regioselectivity was again total in this case.
Similar regiochemical purities were obtained when these
reactions were carried out using classical Heck condi-
tions,16,17 which require longer reaction times but have
the advantage of not involving the use of Tl salts and
expensive phosphines (Table 1, entries 3 and 4).
* Corresponding author. Tel.: +34-981-563100, ext. 14242; fax: +34-
981-591014; e-mail: qorjec@usc.es
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00990-5

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J. C. Barcia et al. / Tetrahedron Letters 43 (2002) 5141–5144
Scheme 1. Reagents and conditions: (i) see Table 1. (ii) 10% aq. HCl, rt, 1 h. (iii) 20% aq. H2SO4, dioxane, reflux, 2 h. (iv) Br2,
AcOH:toluene (1:2), 60°C, 30 min. (v) NaOAc, EtOH, rt, 30 min. (vi) NH4OAc, AcOH, 60°C, 6 h. (vii) NaOMe, MeOH, rt, 24
h.
Table 1. Coupling of o-bromobenzoates to BVE
Entry
Compound
Catalyst
Additive
Solvent
Reaction time (h)
Reaction product (%)
1
2
3
4
1a (R=H)
1b (R=OMe)
1a (R=H)
Pd(OAc)2/DPPP (2.5 mol%)
Pd(OAc)2/DPPP (2.5 mol%)
Pd(OAc)2/Ph3P (7.5 mol%)
Pd(OAc)2/Ph3P (7.5 mol%)
TlOAc
TlOAc
–
–
DMF
DMF
CH3CN
CH3CN
2.5
3.5
4
3a (90)
3d (85)
3a (91)
3d (89)
1b (R=OMe)
16
The high a-regioselectivity achieved with classical Heck
conditions suggests that the carboxymethyl group of
aryl halides 1 interacts with the palladium complex to
give a chelate-facilitated a-arylation,18 a mechanism
different from the one hypothesized by Cabri et al.14 for
the arylation of BVE in the absence of TlOAc. As far
as we know, this is the second example in which Cabri
coupling conditions have facilitated the reaction but are
not necessary for a-selectivity.14
This easy and efficient method for the preparation of
2-hydroxy-3-phenyl-1,4-naphthoquinones allowed us to
develop a new, general synthesis of indolonaphtho-
quinones 12 (Scheme 2). Condensation of isochroman-
1,4-dione 4a with nitrobenzaldehyde gave the expected
nitrobenzylideneisochroman-1,4-dione 9a and subse-
quent treatment of this compound with sodium
methoxide in methanol afforded nitrophenylnaphtho-
quinone 10a. Compound 10a was converted, as
described previously,4a into indolonaphthoquinone 12a
by treatment with NaBH4 in isopropanol at rt, a pro-
cess that presumably takes place via the aminophenyl-
naphthoquinone intermediate 11a, with the amino
group attacking C4. The utility of this route was
demonstrated by the preparation of indolonaphtho-
quinones 12b, 12c and 12d. Dimethoxylated indolo-
naphthoquinone 12b was obtained from dimethoxylated
isochroman-1,4-dione 4b and o-nitrobenzaldehyde,
through nitrobenzylideneisochroman-1,4-dione 9b and
nitrophenylnaphthoquinone 10b, which has previously4a
been transformed into 12b. Secondly, isochroman-1,4-
dione 4a and dimethoxylated o-nitrobenzaldehyde 8b
were converted into nitrobenzylideneisochromanone 9c.
This compound was then converted into dimethoxyl-
ated nitrophenylnaphthoquinone 10c using a similar
route as for 12a. Finally, rearrangement of nitroben-
zylideneisochromanone 9d—resulting from condensa-
tion of dimethoxylated isochromanone 4b and
Next, methyl o-acetylbenzoates 3a and 3d were
hydrolyzed to the corresponding benzoic acids 3b and
3e, which were easily converted into 3-hydroxy-2-
phenyl-1,4-naphthoquinones 7a and 7b through ben-
zylideneisochroman-1,4-diones 5a and 5b, respectively.
Thus, when o-acetylbenzoic acid 3b was reacted with
bromine in acetic acid/toluene (1:2) at 60°C for 30 min,
the corresponding 2-bromoacetylbenzoic acid 3c was
obtained. This compound readily cyclizes under basic
conditions to give the isochroman-1,4-dione 4a.19 Con-
densation of 4a with benzaldehyde gave benzyli-
deneisochromanone 5a, which when stirred with
sodium methoxide in methanol at rt for 24 h rearranged
to 3-hydroxy-2-phenyl-1,4-naphthoquinone 7a, proba-
bly through benzoic acid ester 6a.20 Similarly, phenyl-
naphthoquinone 7b was obtained from dimethoxylated
o-acetylbenzoic acid 3d, through compounds 3e, 3f, 4b
and 5b.

J. C. Barcia et al. / Tetrahedron Letters 43 (2002) 5141–5144
5143
Scheme 2. Reagents and conditions: (i) NH4OAc, AcOH, 60°C, 6 h. (ii) NaOMe, MeOH, rt, 24 h. (iii) NaBH4, i-PrOH, rt, 6 h.
o-nitrobenzaldehyde 8b—gave the expected tetra-
methoxylated nitrophenylnaphthoquinone 10d, which
has previously been used to obtain tetramethoxylated
indolonapthoquinone 12d.4k
Bruemmer, U. Sci. Pharm. 1998, 66, 279; (c) Lin, T.-S.;
Xu, A.-P.; Zhu, L.-Y.; Cosby, L.; Sartonelli, A. J. Med.
Chem. 1989, 32, 1467; (d) Kappe, T.; Wildpanner, H.
Monatsch. Chem. 1988, 119, 727; (e) Lin, T.-S.; Xu, A.-P.;
Zhu, L.-Y.; Divo, A.; Sartonelli, A. J. Med. Chem. 1981,
34, 1634; (f) Jacobsen, N.; Wengel, A. Pestic. Sci. 1986,
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Fry, M.; Latter, V. S.; McHardy, N. Eur. J. Med. Chem.
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Chem. 1981, 24, 295; (j) Ikushima, H.; Okamoto, M.;
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H. J. Antibiot. 1980, 33, 1107.
In conclusion, we have established an efficient method
for the preparation of o-acetylbenzoic acids, which are
convenient starting materials for unrestricted access to
isochroman-1,4-diones 4, benzylideneisochroman-1,4-
diones 5, 2-hydroxy-3-phenyl-1,4-naphthoquinones 7
and indolonaphthoquinones 12. Work is currently in
progress to synthesize a variety of indolonanaphtho-
quinones for chemical and biological studies. We are
also studying the application of this synthetic method-
ology to the preparation of natural compounds of
chemical and biological interest, including the synthesis
of compounds related to indolonaphthoquinones, such
us ellipticines, benzofuronaphthoquinones and ben-
zopironaphthoquinones, all of which have well-docu-
mented antibiotic and/or antitumoral activity.1
3. For industrial uses of naphthoquinones see: (a) For appli-
cations in color chemistry, see: Yoshida, K.; Yamanaka,
Y.; Euno, Y. Chem. Lett. 1994, 2051; Takagi, K.; Mat-
suoka, M.; Hamano, K.; Kitao, T. Dyes Pigments 1984,
5, 241. (b) For applications in hair dying, see: Kikuchi,
M.; Komatsu, K.; Nakano, M. Dyes Pigments 1990, 12,
107. (c) For applications as photostabilizers, see: Escolas-
tico, C.; Santa Maria, M. D.; Claramunt, R. M.; Jimero,
M. L.; Alkorta, I.; Foces-Foces, C.; Cano, F. H.;
Elguero, J. Tetrahedron 1994, 50, 12489.
Acknowledgements
4. (a) Cruces, J.; Estevez, J. C.; Castedo, L.; Estevez, R. J.
Tetrahedron Lett. 2001, 42, 4825; (b) De Frutos, O.;
Atienza, C.; Echavarren, A. M. Eur. J. Org. Chem. 2001,
163; (c) Qabaja, G.; Jones, G. B. J. Org. Chem. 2000, 65,
7187; (d) Martinez, E.; Martinez, L.; Treus, M.; Estevez,
J. C.; Estevez, R. J.; Castedo, L. Tetrahedron 2000, 56,
6023; (e) Qabaja, G.; Perchellet, E. M.; Perchellet, J.-P.e.;
Jones, G. B. Tetrahedron Lett. 2000, 41, 3007; (f) Mar-
tinez, A.; Estevez, J. C.; Estevez, R. J.; Castedo, L.
Tetrahedron Lett. 2000, 41, 2365; (g) Kobayashi, K.;
Taki, T.; Kawakita, M.; Uchida, M.; Morikawa, O.;
Konishi, H. Heterocycles 1999, 51, 349; (h) Martinez, E.;
Martinez, L.; Estevez, J. C.; Estevez, R. J.; Castedo, L.
We thank the Ministry of Education and Culture
(DGES) and the Xunta de Galicia for financial support,
as well as the latter organization for a grant to Jose´ C.
Barcia.
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J. C. Barcia et al. / Tetrahedron Letters 43 (2002) 5141–5144
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1
form/methanol). H NMR (250, ppm, CDCl3): 7.52–7.63
(m, 2H, ꢀCH, Ar-H), 7.70–7.78 (m, 1H, Ar-H), 7.89–7.96
(m, 2H, 2×Ar-H), 8.04–8.13 (m, 2H, 2×Ar-H), 8.26–8.37
(m, 2H, 2×Ar-H). MS (m/z, %): 296 (M++1, 48), 104
(100). Compound 9b. Mp 286–287°C (chloroform/
methanol). 1H NMR (500, ppm, DMSO): 4.00 (s, 6H,
2×-OCH3), 7.35, 7.59 and 7.60 (ss, 3H, ꢀCH and 2×Ar-
H), 7.66–7.70 (m, 1H, Ar-H), 7.84–7.87 (m, 1H, Ar-H),
8.06–8.08 (m, 1H, Ar-H), 8.11–8.13 (m, 1H, Ar-H). MS
(m/z, %): 356 (M++1, 100). Compound 9c. Mp 229–
230°C (chloroform/methanol). 1H NMR (250, ppm,
CDCl3): 4.01 (s, 3H, -OCH3), 4.05 (s, 3H, -OCH3), 7.63,
7.68 and 7.70 (ss, 3H, ꢀCH and 2×Ar-H), 7.87–7.97 (m,
2H, 2×Ar–H), 8.27–8.36 (m, 2H, 2×Ar–H). MS (m/z, %):
356 (M++1, 12), 149 (100). Compound 9d. Mp 291–292°C
(chloroform/methanol). 1H NMR (500, ppm, DMSO):
3.94 (s, 6H, 2×-OCH3), 4.00 (s, 6H, 2×-OCH3), 7.42, 7.60,
7.68 and 7.73 (ss, 5H, ꢀCH and 4×Ar-H). MS (m/z, %):
416 (M++1, 100). Compound 10c. Mp 251–252°C
(methanol). 1H NMR (250, ppm, DMSO): 3.84 (s, 3H,
-OCH3), 3.92 (s, 3H, -OCH3), 7.10 (s, 1H, Ar-H), 7.73 (s,
1H, Ar-H), 7.84–7.93 (m, 2H, 2×Ar-H), 7.96–8.03 (m,
1H, Ar-H), 8.06–8.12 (m, 1H, Ar-H). MS (m/z, %): 356
(M++1, 27), 149 (100). Compound 12c. Mp 275–277°C
(methanol). 1H NMR (250, ppm, DMSO): 3.66 (s, 3H,
-OCH3), 3.75 (s, 3H, -OCH3), 6.63 (s, 1H, Ar-H), 6.81 (s,
1H, Ar-H), 7.60–7.75 (m, 2H, 2×Ar-H), 7.92–8.02 (m,
2H, 2×Ar-H). MS (m/z, %): 307 (M+, 64), 66 (100).
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17. General procedure. A solution of 1.2 mmol of 1, 6 mmol
of BVE, 0.09 mmol of Pd(OAc)2 (7.5 mol%), 0.18 mmol
of Ph3P (Pd/ligand ratio 1:2) and 1.44 mmol of Et3N in
2.5 mL of dry degassified acetonitrile was heated at
100°C in a screw-capped Pyrex tube for the stated time.
The solution was cooled, filtered through Celite and
washed with water (25 mL). The solvents were evapo-
rated and a sample was examined by 1H NMR spec-
troscopy. The crude material was dissolved in a 1:1
mixture of 10% aq. HCl and THF (40 mL) and the
solution stirred for 1 h at rt. The THF was removed
under vacuum and the residue was extracted with
CH2Cl2. The extracts were washed with water until pH 7
was reached and dried with anhydrous Na2SO4, and the
solvents were removed. The stated yield of the reaction is
the yield after purification by flash chromatography on
silica gel.
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15. All new compounds gave satisfactory analytical and spec-
troscopic data. Selected physical and spectroscopic data
follow. Compound 3a (oil). 1H NMR (250, ppm, CDCl3):
2.83 (s, 3H, -COCH3); 3.89 (s, 3H, -OCH3); 7.38–7.61
(m, 3H, 3×Ar-H); 7.84 (dd, J=1 Hz and J=7 Hz, 1H,
Ar-H). MS (m/z, %): 262 (M+,70); 231 (100). Compound
1
3d. Mp 119–120°C (ethyl acetate). H NMR (250, ppm,
CDCl3): 2.42 (s, 3H, -COCH3), 3.81 (s, 3H, -OCH3), 3.86
(s, 3H, -OCH3), 3.87 (s, 3H, -OCH3), 6.79 (s, 1H, Ar-H),
7.28 (s, 1H, Ar-H). MS (m/z, %): 238 (M+, 21), 223 (100).
Compound 5a. Mp 168–169°C (chloroform/methanol).
1H NMR (250, ppm, CDCl3): 7.17 (s, 1H, -CH), 7.40–
7.45 (m, 3H, 3×Ar-H), 7.85–7.99 (m, 4H, 4×Ar-H), 8.22–
8.32 (m, 2H, 2×Ar-H). MS (m/z, %): 250 (M+, 51), 104
(100). Compound 5b. Mp 250–251°C (chloroform/
methanol). 1H NMR (250, ppm, CDCl3): 4.04 (s, 3H,
-OCH3), 4.05 (s, 3H, -OCH3), 7.16 (s, 1H, -CH), 7.39–
7.46 (m, 3H, 3×Ar-H), 7.61 (s, 1H, Ar-H), 7.65 (s, 1H,
Ar-H), 7.96–7.99 (m, 2H, 2×Ar-H). MS (m/z, %): 310
(M+, 83), 282 (100). Compound 7a. Mp 139–141°C
1
(methanol). H NMR (250, ppm, CDCl3): 7.40–7.54 (m,