Synthesis of hydroxy-7H-benzo[c]fluoren-7-ones

Article abstract of DOI:10.1055/s-2004-822890

An efficient synthesis of 2-, 3- and 4-hydroxy-7H-benzo[c]fluoren-7-ones, useful intermediates for the synthesis of photochromic naphthopyrans, is described. The synthetic approach involves the use of oxazolines as activating groups for aromatic nucleophilic substitution and starts with readily available dimethoxynaphthaldehydes.

Full text of DOI:10.1055/s-2004-822890

LETTER
1015
Synthesis of Hydroxy-7H-benzo[c]fluoren-7-ones
Synthesis of
H
a
ydroxy-
7
H
u
-benzo[
c
]flu
l
oren-7-
o
ones J. Coelho,* Maria A. Salvador, M. Manuel Oliveira, Luis M. Carvalho
Centro de Química – Vila Real, Universidade de Trás-os-Montes e Alto Douro, 5001-911 Vila Real, Portugal
Fax +351(259)350480; E-mail: Pcoelho@utad.pt
Received 18 December 2003
In order to prepare new photochromic naphthopyrans
fused to indene rings at other faces, it is necessary to pre-
pare 7H-benzo[c]fluoren-7-ones with the hydroxyl group
in other positions. The 6-hydroxy isomer has been re-
Abstract: An efficient synthesis of 2-, 3- and 4-hydroxy-7H-ben-
zo[c]fluoren-7-ones, useful intermediates for the synthesis of pho-
tochromic naphthopyrans, is described. The synthetic approach
involves the use of oxazolines as activating groups for aromatic
nucleophilic substitution and starts with readily available di- cently prepared through reaction of phenyl acetone with
methoxynaphthaldehydes.
dimethyl phthalate followed by acid promoted cycliza-
tion.5 The 1-, 2-, 3- and 4-hydroxyl isomers have not yet
Key words: phenols, fused-ring systems, nucleophilic aromatic
substitutions, hydroxy-7H-benzo[c]fluoren-7-ones
been prepared. Since the methods used to prepare the 5-
and 6-hydroxy derivatives cannot be applied to other
isomers, we decided to investigate a general route to
hydroxy-7H-benzo[c]fluoren-7-ones.
Naphthols are essential intermediates in the synthesis of
photochromic naphthopyrans.1 The one-pot reaction of
these compounds with diarylpropynols affords naphtho-
pyrans in fair to good yields (Scheme 1). The reaction is
quite general and a large variety of substituted or fused
naphthols as well as propynols can be used.2
In this paper we describe an efficient and general ap-
proach to 7H-benzo[c]fluorenones, bearing the hydroxyl
group in the 2-, 3- and 4-positions. The same approach has
already been applied to the synthesis of the 5-hydroxy
isomer.6
4,5-Dihydrooxazoles (oxazolines) are very useful auxilia-
ries for the introduction of various substituents in aroma-
tic nuclei. These versatile compounds, which are readily
available from aryl carboxylic acids, can be selectively
metalled in the ortho-position and then allowed to react
with different electrophiles to give ortho-substituted
oxazolines. Similarly, o-methoxy aryl carboxylic acids,
after conversion to the corresponding oxazolines, react
with nucleophiles displacing the methoxyl group leading
to ortho-substituted oxazolines. Hydrolysis of the latter
furnishes the ortho-substituted aryl carboxylic acids
(Scheme 3).7
Ar
Ar
OH
O
HO
Ar
Acid
+
∆
Ar
Scheme 1
In the last 5 years, indeno-fused naphthopyrans have been
intensively studied due to their improved properties when
compared to other substituted naphthopyrans.1 In particu-
lar naphtho[1,2-b]pyrans fused to indene rings in the f-
face have met considerable success.3 The synthesis of
such compounds (Scheme 2) requires the preparation of
5-hydroxy-7H-benzo[c]fluoren-7-one, a red naphthol ob-
tained in 5 steps from benzophenone and diethyl succinate
using standard methods.3a–g,4
N
O
OH
O
O
OH
N
O
E
E
n-BuLi
R1
E+
R2
O
2 Steps
O
OH
N
O
OH
OMe
O
O
OH
Nu
N
O
OMe
Nu
Nu
Indeno-fused naphthopyran
5-hydroxy-7H-benzo[c]fluoren-7-one
Scheme 2
Scheme 3
Due to their ready availability, the relative inertness to-
ward reaction at the oxazole ring, and the mild hydrolytic
conditions for ring opening, oxazolines have been used
SYNLETT 2004, No. 6, pp 1015–1018
Advanced online publication: 25.03.2004
DOI: 10.1055/s-2004-822890; Art ID: G35903ST
© Georg Thieme Verlag Stuttgart · New York
0
6.
0
5.
2
0
0
4

1016
P. J. Coelho et al.
LETTER
with success in the synthesis of various aromatic com- The naphthoic acids 2a–c were then converted to the
pounds as well as in the total synthesis of several natural oxazolines 3a–c in a three-step procedure: conversion to
products.8
the acid chloride, condensation with 2-methyl-2-amino-
propan-1-ol and then intramolecular cyclization with thio-
nyl chloride.8c,11 The oxazolines 3a–c were then treated at
room temperature for 24 hours with 6 equivalents of a
Et2O solution of PhMgBr affording after purification
(column chromatography) substituted oxazolines 4a–c.12
The removal of the dihydrooxazole activating group is
usually carried out under acidic conditions. For acid labile
compounds the CH3I methylation to form the oxazolinium
quaternary salt followed by basic hydrolysis constitutes
an excellent alternative and gave good results with oxazo-
lines 4a–c. After deprotection the corresponding
carboxylic acids were treated for 5 minutes with concen-
trated sulphuric acid affording the red methoxybenzo-
fluorenones 5a–c.13 Finally, heating a solution of
methoxybenzofluorenones in HBr/HOAc provided the
new hydroxy-7H-benzo[c]fluoren-7-ones (6a–c), in good
yield.14
Using the activating effect of the 4,5-dihydrooxazole
system for nucleophilic aromatic substitutions at the
ortho-position of 2-aryl-4,5-dihydrooxazoles as the key
step, we prepared three new hydroxy-7H-benzo[c]fluor-
enones in five steps from dimethoxy-2-naphthaldehydes
(Scheme 5). The latter can be very easily prepared, in ex-
cellent yields (70% overall), from commercially available
methoxy-a-tetralones (Scheme 4).9
OMe
O
O
O
H
ii
OH
i
iii
MeO
MeO
MeO
1a–c
Scheme 4 (i) NaH, HCO2Et, benzene; (ii) DDQ, dioxan; (iii)
K2CO3, MeI, MeCN.
In conclusion, we present herein a general approach for
the synthesis of hydroxy-7H-benzo[c]fluoren-7-ones
starting from readily available materials and involving the
use of oxazolines as auxiliaries for the functionalization of
naphthoic acids.
The oxidation of naphthaldehydes 1a–c was surprisingly
a difficult task using the classic oxidation methods
–
(MnO4 /OH–, Cr2O72–/H+) giving either very low yields or
promoting the complete degradation of the starting naph-
thaldehyde. The oxidation of these compounds was car-
ried out using the NaOCl2/resorcinol/CH3COOH system
in dioxane.10 Under these conditions the oxidation was
very fast and complete giving a very clean reaction mix-
ture from which the isolation of the carboxylic acids 2a–c
was a straightforward task.
Acknowledgment
The authors are grateful to FCT (Portugal’s Foundation for Science
and Technology) and FEDER for financial support through project
POCTI/QUI/38771/2001.
OMe
O
OMe
O
OMe
N
i
OH
ii
O
H
65–75%
42–91%
3a–c
MeO
MeO
MeO
30–39%
1a–c
2a–c
iii
Ph
N
O
iv
O
O
v
78–97%
63%
MeO
5a–c
MeO
6a
OH
4a–c
91%
v
v
93%
O
HO
O
HO
6b
6c
Scheme 5 (i) NaOCl2, resorcinol, HOAc, dioxane; (ii) 1) (COCl)2; 2) H2NC(Me)2CH2OH; 3) SOCl2; (iii) PhMgBr; (iv) 1) MeI; 2) NaOH
(aq), MeOH; 3) H2SO4; v) HBr, HOAc.
Synlett 2004, No. 6, 1015–1018 © Thieme Stuttgart · New York

LETTER
Synthesis of Hydroxy-7H-benzo[c]fluoren-7-ones
H). MS (EI): m/z (%) = 232 (100), 215 (30), 159 (31).
1017
References
1,7-Dimethoxy-2-naphthoic acid (2c): 75% yield, mp 114–
116 °C. IR (KBr): 3100–2500, 1687, 1257 cm–1. 1H NMR
(CDCl3): d = 7.88 (dd, J = 8.5 and 2.5 Hz, 1 H), 7.74 (d,
J = 7.0 Hz, 1 H), 7.59 (d, J = 7.0 Hz, 1 H), 7.35 (s, 1 H), 7.24
(d, J = 8.5 Hz, 1 H), 4.08 (s, 3 H), 3.92 (s, 3 H). MS (EI):
m/z (%) = 232 (100), 217 (49), 173 (50).
(1) Van Gemert, B. In Organic Photochromic and
Thermochromic Compounds, Vol. 1; Crano, J. C.;
Guglielmetti, R. J., Eds.; Plenum Press: New York, 1999,
Chap. 3, 111–140.
(2) (a) Iwai, I.; Ide, J. Chem. Pharm. Bull. 1963, 11, 1042.
(b) Coelho, P. J.; Carvalho, L. M.; Rodrigues, S.; Oliveira-
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2002, 58, 925. (c) Coelho, P. J.; Carvalho, L. M.; Abrantes,
S.; Oliveira, M. M.; Oliveira-Campos, A. M. F.; Samat, A.;
Guglielmetti, R. Tetrahedron 2002, 58, 9505. (d)Moustrou,
C.; Rebière, N.; Samat, A.; Guglielmetti, R.; Yassar, R.;
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(e) Oliveira, M. M.; Carvalho, L. M.; Moustrou, C.; Samat,
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Acta 2001, 84, 1163. (f) Queiroz, M. R. P.; Dubest, R.;
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Thomas, D. A.; Partington, S. M.; Hursthouse, M. B.;
Gelbrich, T. Eur. J. Org. Chem. 2003, 1220.
(3) (a) van Gemert, B. U.S. Patent 5645767, 1997. (b) Jibing,
L.; van Gemert, B. U.S. Patent 5869658, 1999. (c) Melzig,
M.; Mann, C.; Weigand, U. U.S. Patent 6146554, 2000.
(d) Nelson, C. M.; Chopra, A.; Petrovskaia, O. G.; Knowles,
D. B.; van Gemert, B.; Kumar, A. U.S. Patent 6296785,
2001. (e) Mann, C.; Weigand, U.; Melzig, M. U.S. Patent
6225466, 2001. (f) Mann, C.; Weigand, U.; Melzig, M. U.S.
Patent 6331625, 2001. (g) Mann, C.; Melzig, M.; Weigand,
U. U.S. Patent 6373615, 2002. (h) Petrosvskaia, O. G.;
Kumar, A. U.S. Patent 0071247A1, 2003.
(4) Baddar, F. G.; El-Newaihy, M. F.; Ayoub, M. S. J. Chem.
Soc. C 1971, 3332.
(5) Mann, C.; Melzig, M.; Weigand, U. U.S. Patent 6315918,
2001.
(6) Coelho, P. J.; Salvador, M. A.; Oliveira, M. M.; Carvalho, L.
M. Tetrahedron 2004, 60, 2593.
(7) Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837.
(8) (a) Meyers, A. I.; Gabel, R.; Mihelich, E. D. J. Org. Chem.
1978, 43, 1372. (b) Meyers, A. I.; Avila, W. B. J. Org.
Chem. 1981, 46, 3881. (c) Gant, T. G.; Meyers, A. I. J. Am.
Chem. Soc. 1992, 114, 1010.
(11) Data for oxazolines: 3a: 42% yield. IR (neat): 2965, 1643,
1376 cm–1. 1H NMR (CDCl3): d = 7.99 (d, J = 8.8 Hz, 1 H),
7.80 (m, 2 H), 7.41 (t, J = 7.8 Hz, 1 H), 6.86 (d, J = 7.5 Hz,
1 H), 4.16 (s, 2 H), 3.97 (s, 6 H), 1.43 (s, 6 H).
3b: 91% yield. IR (neat): 2958, 1637, 1621, 1359 cm–1. 1H
NMR (CDCl3): d = 8.14 (d, J = 9.1 Hz, 1 H), 7.80 (d, J = 8.7
Hz, 1 H), 7.46 (d, J = 8.7 Hz, 1 H), 7.16 (dd, J = 2.5 and 9.0
Hz, 1 H), 7.10 (d, J = 2.5 Hz, 1 H), 4.14 (s, 2 H), 3.97 (s, 3
H), 3.91 (s, 3 H), 1.41 (s, 6 H).
3c: 65% yield. IR (neat): 2965, 1631,1625, 1224 cm–1. 1H
NMR (CDCl3): d = 7.71 (d, J = 9.0 Hz, 1 H), 7.67 (d, J = 8.6
Hz, 1 H), 7.52 (m, 2 H), 7.19 (d, J = 9.0 Hz, 1 H), 4.16 (s, 2
H), 3.98 (s, 3 H), 3.93 (s, 3 H), 1.43 (s, 6 H).
(12) Data for oxazolines 4a: 30% yield. 1H NMR (CDCl3): d =
8.33 (d, J = 8.7 Hz, 1 H), 7.77 (d, J = 8.7 Hz, 1 H), 7.48–
7.34 (m, 5 H), 7.30 (d, J = 7.5 Hz, 1 H), 7.23 (t, J = 8.5 Hz,
1 H), 6.86 (d, J = 7.5 Hz, 1 H), 4.03 (s, 3 H), 3.72 (s, 2 H),
1.21 (s, 6 H).
4b: 36% yield. 1H NMR (CDCl3): d = 7.75 (m, 2 H), 7.54 (d,
J = 9.0 Hz, 1 H), 7.45–7.32 (m, 5 H), 7.17 (d, J = 2.5 Hz, 1
H), 7.04 (dd, J = 2.5 and 9.5 Hz, 1 H), 3.92 (s, 3 H), 3.69 (s,
2 H), 1.19 (s, 6 H).
4c: 39% yield. 1H NMR (CDCl3): d = 7.79 (m, 2 H), 7.63 (d,
J = 8.5 Hz, 1 H), 7.45–7.35 (m, 5 H), 7.17 (d, J = 2.5 and 9.1
Hz, 1 H), 6.94 (d, J = 2.5 Hz, 1 H), 3.71 (s, 2 H), 3.68 (s, 3
H), 1.19 (s, 6 H).
(13) Procedure for the Synthesis of 5a–c: A solution of
oxazoline 4a–c (0.69 g, 2.08 mmol) in MeI (10 mL) was
stirred at r.t. overnight and the excess of MeI removed under
reduced pressure. To the crude MeI salt, were added MeOH
(12 mL) and NaOH 20% (12 mL) and the mixture heated to
reflux for 12 h. The solution was extracted with Et2O and the
organic layer discarded. The aqueous layer was acidified
with HCl (aq), extracted with Et2O, dried (Na2SO4) and
concentrated to give the corresponding methoxy-1-phenyl-
2-naphthoic acid. Without further purification, H2SO4 (5
mL) was added. After stirring for 5 min at r.t. the resulting
dark colored solution was poured into ice (50 g) and then
extracted with Et2O (3 × 50 mL). The organic layer was
dried (Na2SO4) and the solvent was evaporated under
reduced pressure to give pure ketone 5a–c as red solids.
5a: 97% yield, mp 192–193 °C. IR (KBr): 1706, 1263 cm–1.
1H NMR (CDCl3): d = 8.27 (d, J = 8.5 Hz, 1 H), 8.02 (d,
J = 8.5 Hz, 1 H), 8.00 (d, J = 7.5 Hz, 1 H), 7.72 (d, J = 8.5
Hz, 1 H), 7.67 (d, J = 7.5 Hz, 1 H), 7.54–748 (m, 2 H), 7.28
(t, J = 7.5 Hz, 1 H), 6.91 (d, J = 7.5 Hz, 1 H), 4.02 (s, 3 H).
MS (EI): m/z (%) = 260 (100), 245 (20), 217 (53), 189 (50).
5b: 86% yield, mp 146–147 °C. IR (KBr): 1708, 1272 cm–1.
1H NMR (CDCl3): d = 8.36 (d, J = 9.0 Hz, 1 H), 7.93 (d,
J = 7.5 Hz, 1 H), 7.68–7.59 (m, 2 H), 7.47 (m, 1 H), 7.22 (m,
2 H), 7.11 (d, J = 2.5 Hz, 1 H), 3.92 (s, 3 H). MS (EI): m/z
(%) = 260 (100), 217 (45), 189 (50).
(9) Gallagher, P. T.; Hicks, T. A.; Lightfoot, A. P.; Owton, W.
M. Tetrahedron Lett. 1994, 35, 289.
(10) Procedure for the Synthesis of 2a–c: A solution of sodium
chlorite (3.12 g, 80% purity, 27.6 mmol) in 7 mL of H2O was
added rapidly to a warm solution of dimethoxynaphth-
aldehyde 1a–c (4.10 g, 19.0 mmol), resorcinol (2.83 g, 21.6
mmol), t-butanol (18.5 mL), HOAc (a few drops) and p-
dioxane (16 mL). The reaction mixture was heated 10 min at
85 °C then cooled and concentrated under reduced pressure.
CH2Cl2 (20 mL) were added and the organic phase extracted
with aq NaOH (2%). The aqueous phase was separated,
acidified with HCl and extracted 3 times with CH2Cl2. The
organic phases were combined, washed with H2O, sat. NaCl,
dried (Na2SO4) and then the solvent was evaporated under
reduced pressure to give pure dimethoxynaphthoic acids
2a–c.
1,5-Dimethoxy-2-naphthoic acid (2a): 65% yield, mp 128–
130 °C. IR (KBr): 3100–2600, 1697, 1255 cm–1. 1H NMR
(CDCl3): d = 8.14 (d, J = 8.7 Hz, 1 H), 8.05 (d, J = 9.0 Hz, 1
H), 7.74 (d, J = 8.7 Hz, 1 H), 7.53 (t, J = 8.5 Hz, 1 H), 6.97
(d, J = 8.5 Hz, 1 H), 4.15 (s, 3 H), 4.03 (s, 3 H). MS (EI):
m/z (%) = 232 (100), 217 (20), 187 (30), 115 (40).
1,6-Dimethoxy-2-naphthoic acid (2b): 70% yield, mp 146–
147 °C. IR (KBr): 3100–2400, 1697, 1238 cm–1. 1H NMR
(CDCl3): d = 8.09 (m, 2 H), 7.62 (d, J = 8.7 Hz, 1 H), 7.28
(d, J = 8.5 Hz, 1 H), 7.20 (s, 1 H), 4.16 (s, 3 H), 3.98 (s, 3
5c: 78% yield, mp 126–128 °C. IR (KBr): 1725, 1274 cm–1.
1H NMR (CDCl3): d = 7.92 (d, J = 7.5 Hz, 1 H), 7.78 (d,
J = 9.0 Hz, 1 H), 7.72–7.67 (m, 2 H), 7.63 (d, J = 8.0 Hz, 1
H), 7.54–7.50 (m, 2 H), 7.31–7.24 (m, 2 H), 4.02 (s, 3 H).
MS (EI): m/z (%) = 260 (100), 217 (60), 189 (45).
(14) Procedure for the Synthesis of 6a–c: A mixture of ketone
5a–c (0.34 g, 1.31 mmol), HOAc (2.5 mL) and HBr 47% (5
mL) was heated under reflux for 5 h. After cooling the
Synlett 2004, No. 6, 1015–1018 © Thieme Stuttgart · New York

1018
P. J. Coelho et al.
LETTER
reaction mixture was poured into 100 mL of H2O and
extracted with Et2O (3 × 50 mL). The combined organic
layers were extracted 3 times with NaOH (5%, 20 mL) and
the organic phase discarded. The aqueous phase was
acidified with HCl 10%, and extracted with Et2O (3 × 50
mL). The combined organic layers were dried (Na2SO4) and
the solvent evaporated under reduced pressure giving the
pure hydroxybenzofluorenones 6a–c.
4-Hydroxy-7H-benzo[c]fluoren-7-one (6a): 63% yield, mp
258–260 °C. IR (KBr): 3280, 1691 cm–1. 1H NMR (acetone-
d6): d = 9.39 (s, 1 H), 8.34 (d, J = 8.5 Hz, 1 H), 8.23 (d,
J = 7.5 Hz, 1 H), 8.17 (d, J = 8.5 Hz, 1 H), 7.68 (d, J = 8.5
Hz, 1 H), 7.66–7.62 (m, 2 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.40
(t, J = 7.5 Hz, 1 H), 7.11 (d, J = 7.5 Hz, 1 H). 13C NMR
(CDCl3/CD3OD): d = 195.4, 153.9, 145.2, 142.3, 134.5,
134.2, 131.7, 129.8, 129.5, 128.3, 128.2, 124.1, 123.7,
123.3, 118.1, 115.8, 110.4. MS (EI): m/z (%) = 246 (100),
218 (22), 189 (70). HRMS: Calcd for C17H10O2: 246.0681;
found: 246.0673.
3-Hydroxy-7H-benzo[c]fluoren-7-one (6b): 93% yield, mp
264–265 °C. IR (KBr): 3230, 1685 cm–1. 1H NMR (acetone-
d6): d = 9.21 (s, 1 H), 8.61 (d, J = 9.0 Hz, 1 H), 8.23 (d,
J = 7.5 Hz, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.62 (m, 3 H),
7.40 (t, J = 7.5 Hz, 1 H), 7.37 (dd, J = 2.5 and 9.1 Hz, 1 H),
7.34 (d, J = 2.5 Hz, 1 H). 13C NMR (CDCl3/CD3OD): d =
194.9, 157.2, 144.7, 143.3, 140.3, 134.8, 134.2, 129.0,
128.5, 127.6, 126.5, 123.6, 123.4, 123.1, 120.3, 120.1,
110.7. MS (EI): m/z (%) = 246 (100), 218 (15), 189 (45).
HRMS: Calcd for C17H10O2: 246.0681; found: 246.0676.
2-Hydroxy-7H-benzo[c]fluoren-7-one (6c): 91% yield, mp
263–265 °C. IR (KBr): 3276, 1685 cm–1. 1H NMR (acetone-
d6): d = 8.11 (d, J = 8.0 Hz, 1 H), 7.99 (d, J = 2.2 Hz, 1 H),
7.93 (d, J = 8.5 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.63 (m,
2 H), 7.52 (t, J = 8.0 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 1 H), 7.32
(dd, J = 2.3 and 8.9 Hz, 1 H). 13C NMR (CDCl3/CD3OD): d
= 195.3, 156.5, 145.4, 141.5, 134.5, 134.3, 133.2, 131.9,
131.0, 130.1, 129.7, 128.1, 123.8, 122.8, 120.8, 116.9,
106.4. MS (EI): m/z (%) = 246 (100), 217 (5), 189 (40).
HRMS: Calcd for C17H10O2: 246.0681, found: 246.0678.
Synlett 2004, No. 6, 1015–1018 © Thieme Stuttgart · New York