A novel approach to the synthesis of benzo[b]fluoren-11-ones

Article abstract of DOI:10.1016/j.tetlet.2007.01.112

A novel intramolecular palladium-mediated arylation approach to benzo[b]fluoren-11-ones has been investigated. This approach involves the novel oxidation of the key starting 2-(2′-bromobenzyl)naphthols to 2-(2′-bromobenzyl)-1,4-naphthoquinones, followed b

Full text of DOI:10.1016/j.tetlet.2007.01.112

Tetrahedron Letters 48 (2007) 2147–2149
A novel approach to the synthesis of benzo[b]fluoren-11-ones
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Ana Martınez, Jose C. Barcia, Amalia M. Estevez, Fernando Fernandez, Lucıa Gonzalez,
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Juan C. Estevez and Ramon J. Estevez
Departamento de Quı´mica Orga´nica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Received 1 September 2006; revised 6 December 2006; accepted 19 January 2007
Available online 25 January 2007
Abstract—A novel intramolecular palladium-mediated arylation approach to benzo[b]fluoren-11-ones has been investigated. This
approach involves the novel oxidation of the key starting 2-(20-bromobenzyl)naphthols to 2-(20-bromobenzyl)-1,4-naphthoqui-
nones, followed by protection of the quinone moiety of the latter compounds and the final Pd-promoted bi-arylic cyclization of
the resulting 2-(20-bromobenzyl)-1,4-dimethoxynaphthalenes.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Quinones are compounds of perennial chemical interest
on account of their widespread occurrence in nature and
their wide ranging biological activity and industrial
applications.1 In fact, quinonoid systems have been
extensively studied in the context of continued interest
in the search for new antibiotics. For instance,
benzo[b]fluorene based quinonoids kinobscurinone
(9a),2 kinafluorenone (9b),3 stealthin A (10a)4 (a potent
radical scavenger), stealthin B (10b)4 and stealthin C
(10c)5 are metabolites found in the extract of Streptomy-
ces murayamaensis and prekinamycin (9c) has attracted
considerable attention because it is present in the bio-
synthetic pathways leading to the kinamycin family of
antibiotics, some of which display antibacterial and anti-
tumoural activity.6
hydes,11 we present here preliminary results of a novel
synthesis of benzo[b]fluorenones 8 (Scheme 1). This
new route is based on a strategy involving approach b
that precludes the limitations outlined above.
The starting 2-(2-bromobenzyl)-1-naphthol 4a12 was
easily and efficiently obtained by aldol condensation of
1-tetralone13 with o-bromobenzaldehyde13 followed by
a spontaneous oxidation of the resulting 2-benzyl-
idene-1-tetralone 3a under the reaction conditions.14
Subsequent oxidation with Fremy’s salt15 allowed us
to carry out the first transformation of a 2-benzyl-1-
naphthol (4a) into 2-benzyl-1,4-naphthoquinone (5a), a
compound that has both the carbon skeleton and the
quinone moiety required for the preparation of the tar-
get compound 8a. Palladium-mediated bi-arylic cycliza-
tion of 5a failed, but this desired ring closure was
achieved after protection of the quinone system of 5a.
Thus reduction of 5a with sodium dithionite followed
by transformation of dinaphthol 6a, which was directly
converted into dimethoxynapahthalene 7a by treatment
with methyl iodide in a basic medium.16 Finally, a mix-
ture of 7a, palladium acetate, triphenylphosphine and
sodium bicarbonate in DMF was heated at 100 ꢁC for
seven hours,9 to give the target benzo[b]fluorenone
8a17 directly in 55% yield, probably by cyclization and
oxidation.18
The biological activities as well as the unique structure
of these compounds (9 and 10) prompted their synthesis
by a biomimetic approach involving benzo[b]fluorenone
8c,7 which includes a naphthoquinone subunit masked
as 1,4-dimethoxynaphthalene. Several approaches to
this common precursor 8c have been reported, most
involving Friedel–Crafts closure8 of acylbiphenyls
(approach a) or Pd-mediated9 or Ti-mediated10 closure
of diphenylketones (approach b). But both approaches
involve complex preparation of aromatic ketones and
the latter includes a low yielding bi-arylic cyclization. As
a continuation of our work on tetracyclic naphthoqui-
nones by condensation of 1-indanones with benzalde-
The potential of this new synthetic route was confirmed
by the successful preparation of benzo[b]fluorenone 8b
from 1-tetralone and 2-bromo-4,5-dimethoxybenzalde-
hyde,19 via compounds 3b, 4b, 5b, 6b and 7b.
*
Corresponding author. Tel.: +34 981 563100x14242; fax: +34 981
591014; e-mail: qorjec@usc.es
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.112

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A. Martı´nez et al. / Tetrahedron Letters 48 (2007) 2147–2149
Br
R
R
Br
R
R
Br
R
R
i
H
OH
O
O
O
3
2
1
4
OMe
OH
OH
O
Br
R
R
Br
R
R
Br
R
R
iii
iv
ii
7
OMe
OH
v
6
5
O
OH
D
O
B
OH
D
OR5
R4
R3
R2
A
B
C
A
C
X
R
Me
OH
O
NH2
OR
O
R1 OR5
O
9
8
10
Scheme 1. Compounds 1, 2, 3, 4, 5, 6, 7: (a) R = H; (b) R = OMe. Compound 8: (a) R1 = R2 = R3 = R4 = H, R5 = OMe; (b) R1 = R4 = H,
R2 = R3 = R5 = OMe; (c) R1 = R4 = R5 = OMe, R2 = Me, R3 = H; (d) R1 = R4 = R5 = OH, R2 = Me, R3 = H. Compound 9: (a) X = O, R = OH;
(b) X = O, R = OMe; (c) X = N2, R = OH. Compound 10: (a) R = CH2OH; (b) R = CHO; (c) R = Me. Reagents and conditions: (i) t-BuOK/t-
BuOH, reflux, 23 h (70–74% yield); (ii) (a) Fremy’s salt, KH2PO4, acetone/H2O, rt, 2.5 h (80–92% yield); (iii) Na2S2O4, H2O/dioxane, rt, 5 h; (iv)
K2CO3, MeI, t-BuOK/THF, DMF, rt, 15 h (75–89% yield, two steps); (v) Pd(OAc)2, PPh3, NaHCO3, DMF, 100 ꢁC, 7 h (50–55% yield).
7. Gore, M. P.; Gould, S. J.; Weller, D. D. J. Org. Chem.
1991, 56, 2289.
8. Hauser, F. M.; Zhou, M. J. Org. Chem. 1996, 61, 5722.
9. Qabaja, G.; Jones, G. B. J. Org. Chem. 2000, 65, 7187.
10. Koyama, H.; Kamikawa, T. J. Chem. Soc., Perkin Trans.
1 1998, 203.
11. (a) Cruces, J.; Estevez, J. C.; Castedo, L.; Estevez, R. J.
Tetrahedron Lett. 2001, 42, 4825; (b) Martinez, A.;
Estevez, J. C.; Estevez, R. J.; Castedo, L. Tetrahedron
Lett. 2000, 41, 2365.
In summary, we have developed a general synthesis of
benzo[b]fluorenones 8 that includes the novel oxidation
of 2-benzylnaphth-1-ols (4) to 2-benzyl-1,4-naphthoqui-
nones (5) and the novel cyclization of 2-benzyl-1,4-
dimethoxynaphthalenes (7). This route is shorter and
simpler than the previous ones, so may have great utility
for an efficient preparation of stealthins A, B and C
(10a–c) and their analogues. An additional milestone is
the synthesis of kynamycin antibiotics, since they are
benzo[b]fluorene derivatives 9c that have a saturated
and highly functionalized D ring. Work currently in pro-
gress in this area includes studies directed at improving
the efficiency of the cyclization of compounds 7.
12. All new compounds gave satisfactory analytical and
spectroscopic data. Selected physical and spectroscopic
data follow. Compound 4a. Mp 85–87 ꢁC (AcOEt/hex-
ane). 1H NMR (d, ppm, CDCl3): 4.22 (s, 2H, –CH2–), 5.26
(s, 1H, OH), 7.01–7.26 (m, 4H, 4 · Ar–H), 7.38–7.53 (m,
3H, 3 · Ar–H), 7.59 (d, 1H, J = 7.3 Hz, Ar–H), 7.75–7.84
(m, 1H, Ar–H), 8.08–8.16 (m, 1H, Ar–H). 13C NMR (d,
ppm, CDCl3): 36.3 (CH2), 118.5 (C), 120.7 (CH), 121.0
(CH), 124.6 (C), 124.7 (C), 125.4 (CH), 125.8 (CH), 127.7
(2 · CH), 128.1 (CH), 128.6 (CH), 130.3 (CH), 132.8
(CH), 133.7 (C), 138.6 (C), 148.8 (C). MS (m/z, %): 314
(M+, 16), 312 (M+, 15), 156 (100). Compound 4b. Mp
Acknowledgements
We thank the Xunta de Galicia for financial support.
We also thank the Xunta de Galicia for grants to Ana
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Martınez, Jose C. Barcia, Amalia Estevez and Fernando
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105–107 ꢁC (AcOEt/hexane). H NMR (d, ppm, CDCl3):
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Fernandez, and the University of Santiago de Compos-
3.60 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 4.13 (s, 2H, CH2),
5.59 (s, 1H, OH), 6.60 (s, 1H, Ar–H), 7.01 (s, 1H, Ar–H),
7.17 (d, 1H, J = 8.3 Hz, Ar–H), 7.35–7.46 (m, 3H, 3 · Ar–
H), 7.71–7.79 (m, 1H, Ar–H), 8.06–8.15 (m, 1H, Ar–H).
13C NMR (d, ppm, CDCl3): 35.7 (CH2), 55.8 (OCH3), 56.0
(OCH3), 113.0 (CH), 114.2 (C), 115.3 (CH), 119.1 (C),
120.4 (CH), 121.0 (CH), 124.6 (C), 125.3 (CH), 125.7
(CH), 127.5 (CH), 128.2 (CH), 130.7 (C), 133.5 (C), 148.1
(C), 148.5 (C), 148.7 (C). MS (m/z, %): 374 (M++2, 14),
372 (M+, 15), 218 (100). Compound 5a. Mp 121–123 ꢁC
(MeOH). 1H NMR (d, ppm, CDCl3): 4.06 (d, 2H,
J = 1.8 Hz, CH2), 6.41 (t, 1H, J = 1.8 Hz, Ar–H), 7.12–
7.22 (m, 1H, Ar–H), 7.27–7.34 (m, 2H, 2 · Ar–H), 7.57–
7.64 (m, 1H, Ar–H), 7.71–7.79 (m, 2H, 2 · Ar–H), 8.02–
8.08 (m, 1H, Ar–H), 8.12–8.17 (m, 1H, Ar–H). 13C NMR
(d, ppm): 35.8 (CH2), 125.0 (C), 126.1 (CH), 126.6 (CH),
127.8 (CH), 128.9 (CH), 131.8 (CH), 132.0 (C), 132.1 (C),
133.2 (CH), 133.7 (CH), 133.8 (CH), 135.5 (CH), 136.2
(C), 149.1 (C), 184.7 (C@O), 184.9 (C@O). MS (m/z, %):
328 (M++2, 14), 326 (M+, 15), 247 (100). Compound 5b.
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tela for a grant to Lucıa Gonzalez.
References and notes
1. (a) Thomson, R. H. Naturally Occurring Quinones, 4th ed.;
Chapman and Hall: London, New York, 1997; (b)
Spyroudis, S. Molecules 2000, 5, 1291.
2. Gould, S. J.; Melville, C. R. Bioorg. Med. Chem. Lett.
1995, 5, 51.
3. Cone, M. C.; Melville, C. R.; Gore, M. P.; Gould, S. J. J.
Org. Chem. 1993, 58, 1058.
4. Shin-ya, K.; Furihata, K.; Teshima, Y.; Hayakawa, Y.;
Seto, H. Tetrahedron Lett. 1992, 33, 7025.
5. Gould, S. J.; Melville, C. R.; Cone, M. C.; Chen, J.;
Carney, J. R. J. Org. Chem. 1997, 62, 320.
6. (a) Gould, S. J. Chem. Rev. 1997, 97, 2499; (b) Marco-
Contelles, J.; Molina, M. T. Curr. Org. Chem. 2003, 7,
1433.

A. Martı´nez et al. / Tetrahedron Letters 48 (2007) 2147–2149
2149
Mp 151–153 ꢁC (MeOH). 1H NMR (d, ppm, CDCl3): 3.86
(s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.97 (d, 2H,
J = 1.6 Hz, CH2), 6.44 (t, 1H, J = 1.6 Hz, Ar–H), 6.80
(s, 1H, Ar–H), 7.06 (s, 1H, Ar–H), 7.67–7.78 (m, 2H,
2 · Ar–H), 7.99–8.16 (m, 2H, 2 · Ar–H). 13C NMR (d,
ppm, CDCl3): 35.4 (CH2), 56.0 (OCH3), 56.1 (OCH3),
114.0 (CH), 115.0 (C), 115.7 (CH), 126.1 (CH), 126.6
(CH), 127.8 (C), 132.0 (C), 132.1 (C), 133.6 (CH), 133.7
(CH), 135.3 (CH), 148.6 (C), 148.7 (C), 149.3 (C), 184.9
(C@O), 185.0 (C@O). MS (m/z, %): 388 (M++2, 5), 386
(M+, 6), 307 (100). Compound 7a. Mp 77–79 ꢁC (Et2O).
1H NMR (d, ppm, CDCl3): 3.81 (s, 3H, OCH3), 3.82 (s,
3H, OCH3), 4.28 (s, 2H, CH2), 6.48 (s, 1H, Ar–H), 6.96–
7.15 (m, 3H, 3 · Ar–H), 7.38–7.60 (m, 3H, 3 · Ar–H), 8.05
(d, 1H, J = 8.4 Hz, Ar–H), 8.22 (d, 1H, J = 7.9 Hz, Ar–
H). 13C NMR (d, ppm, CDCl3): 35.9 (CH2), 55.4 (OCH3),
61.9 (OCH3), 105.7 (CH), 121.8 (CH), 122.3 (CH), 124.8
(C), 125.0 (CH), 125.7 (C), 126.5 (CH), 127.0 (C), 127.4
(CH), 127.7 (CH), 128.5 (C), 130.5 (CH), 132.5 (CH),
140.2 (C), 147.3 (C–OCH3), 151.8 (C–OCH3). MS (m/z,
%): 358 (M+, 97), 356 (M+, 100). Compound 7b. Mp 83–
85 ꢁC (Et2O). 1H NMR (d, ppm, CDCl3): 3.67 (s, 3H,
OCH3), 3.86 (s, 6H, 2 · OCH3), 3.89 (s, 3H, OCH3), 4.24
(s, 2H, CH2), 6.51 (s, 1H, Ar–H), 6.64 (s, 1H, Ar–H), 7.07
(s, 1H, Ar–H), 7.40–7.58 (m, 2H, 2 · Ar–H), 8.07 (d, 1H,
J = 8.0 Hz, Ar–H), 8.21 (d, 1H, J = 7.8 Hz, Ar–H). 13C
NMR (d, ppm, CDCl3): 35.2 (CH2), 55.6 (OCH3), 55.9
(OCH3), 56.1 (OCH3), 62.0 (OCH3), 105.4 (CH), 113.4
(CH), 114.5 (C), 115.3 (CH), 121.8 (CH), 122.3 (CH),
125.0 (CH), 125.7 (C), 126.6 (CH), 127.6 (C), 128.5 (C),
132.2 (C), 147.1 (C–OCH3), 148.0 (C–OCH3), 148.4 (C–
OCH3), 151.9 (C–OCH3). MS (m/z, %): 419 (MH+, 26),
417 (MH+, 34), 201 (100). Compound 8b. Mp 215–217 ꢁC
Ar–H), 8.27 (d, 1H, J = 8.2 Hz, Ar–H). 13C NMR (d,
ppm, CDCl3): 56.2 (OCH3), 56.3 (OCH3), 61.3 (OCH3),
63.1 (OCH3), 106.0 (CH), 106.4 (CH), 120.2 (C), 122.2
(CH), 125.6 (CH), 126.7 (CH), 127.3 (C), 129.4 (C), 129.5
(CH), 131.0 (C), 133.5 (C), 137.6 (C), 145.7 (C–OCH3),
149.9 (C–OCH3), 153.2 (C–OCH3), 154.7 (C–OCH3), 189.5
(C@O). MS (m/z, %): 350 (M+, 92), 150 (100).
13. Commercial 1-tetralone and o-bromobenzaldehyde were
used (Supplier: Aldrichꢂ).
14. Batt, D. G.; Maynard, G. D.; Petraitis, J. J.; Shaw, J. E.;
Galbraith, W.; Harris, R. R. J. Med. Chem. 1990, 33, 360.
15. Majetich, G.; Liu, S.; Fang, J.; Siesel, D.; Zhang, Y. J.
Org. Chem. 1997, 62, 6928.
16. Kozikowski, P.; Xia, Y. J. Org. Chem. 1987, 52, 1375.
17. Experimental procedure for the preparation of 8a:
Pd(OAc)2 (44 mg, 0.20 mmol), PPh3 (104 mg, 0.40 mmol)
and NaHCO3 (48 mg, 0.40 mmol) were added to a
deoxygenated solution of 7a in dry DMF and the mixture
was heated at 100 ꢁ C under argon for 7 h. The reaction
mixture was then filtered over Celite and the solution was
evaporated to dryness under vacuum. The solid residue
was dissolved in AcOEt, and the solution was washed
(saturated aqueous solution of NaCl) and dried (anhy-
drous NaSO4). After the solvent was removed under
vacuum in a rotary evaporator, the solid residue was
subjected to column chromatography (eluant 3:7 AcOEt/
hexane) and 26.48 mg of compound 8a were isolated as a
yellow solid. Mp 215–217 ꢁC (CHCl3).
18. Compound 8a should result from benzylic oxidation of
compound 7a under the work-up conditions. For a related
oxidation, see: Owton, W. M.; Brunavs, M.; Miles, M. V.;
Dobson, D. R.; Steggles, D.; David, J. J. Chem. Soc.,
Perkin Trans. 1 1995, 931.
19. 2-Bromo-4,5-dimethoxybenzaldehyde was obtained by
bromination of 3,4-dimethoxybenzaldehyde, according
to: Charlton, J. L.; Alauddin, M. M. J. Org. Chem.
1986, 51, 3490.
1
(CHCl3). H NMR (d, ppm, CDCl3): 3.97 (s, 3H, OCH3),
4.02 (s, 3H, OCH3), 4.07 (s, 3H, OCH3), 4.28 (s, 3H,
OCH3), 7.26 (s, 1H, Ar–H), 7.45–7.54 (m, 2H, 2 · Ar–H),
7.61 (t, 1H, J = 8.2 Hz, Ar–H), 8.00 (d, 1H, J = 8.2 Hz,