An efficient synthesis of dihydroxyfluorenones via in situ Pd(0)-catalyzed cross-coupling

Article abstract of DOI:10.1055/s-1998-2113

All six dimethoxyfluorenones 6a-f and dihydroxyfluorenones 7a-f, wherein substitution occurs at only one aromatic ring, were conveniently prepared by palladium(0)-catalyzed cross-coupling reactions of aryl bromides/triflates 2a-e with in situ generated ar

Full text of DOI:10.1055/s-1998-2113

SYNTHESIS
August 1998
1195
An Efficient Synthesis of Dihydroxyfluorenones via in Situ Pd(0)-Catalyzed Cross-
Coupling
Fred L. Ciske,*a Winton. D. Jones, Jr.b
a Pharmacia and Upjohn, 333 Portage Street, Kalamazoo, MI 49007, USA
Fax +1(616)8332516; E-mail: fred.l.ciske@am.pnu.com
b Hoechst Marion Roussel Inc., 2110 E. Galbraith Road, Cincinnati, OH 45215, USA
Received 21 November 1997; revised 8 January 1998
Abstract: All six dimethoxyfluorenones 6a–f and dihydroxyfluo-
renones 7a–f, wherein substitution occurs at only one aromatic
ring, were conveniently prepared by palladium(0)-catalyzed
cross-coupling reactions of aryl bromides/triflates 2a–e with in
situ generated arylboranes, derived from o-bromobenzamide 1a
and o-bromophenyloxazoline 1b.
Key words: dimethoxyfluorenone, dihydroxyfluorenone, in situ
Pd(0) cross-coupling, regioselectivity, regioisomers
Fluorenone derivatives are known to display a variety of
biological activities.1–3 Also, several methoxy and
hydroxyfluorenone derivatives are natural products whose
syntheses have recently been described.4–9 As part of our
investigation into the protein kinase inhibitory activity of
substituted fluorenones,10 we desired a convenient meth-
od for preparing all possible dihydroxy regioisomers in
which substitution occurs on only one aromatic ring of the
fluorenone nucleus.
Some syntheses of fluorenones employ fluorene,11 ben-
zophenone,12 or hexahydrofluorenone13a precursors. Un-
fortunately, these procedures either give isomeric
mixtures, are low yielding or offer limited access to cer-
tain isomers. Increased accessibility of substituted biphe-
nyls through numerous cross-coupling techniques makes
the intramolecular acylation reactions of biphenyl carbox-
ylic acids11 and biphenyl amides14 an attractive approach
to fluorenones. Of note are the recently reported in situ
Suzuki cross-coupling methods which obviate the need
for isolation of boronic acid intermediates.15 Furthermore,
the respective cyclization chemistries of biaryl-2-carbox-
ylic acids and biaryl-2-carboxamides, the classical and an-
ionic equivalent of the Friedel–Crafts reaction, are
complementary and enable the preparation of a complete
isomeric set. In an effort to obtain all possible dihydroxy-
fluorenone regioisomers 7a–f, we have employed and
here report a convenient synthetic approach utilizing, 1)
an efficient in situ generation and Pd(0)-catalyzed cross-
coupling of aryl boranes to prepare substituted biaryls; 2)
regiospecific remote aromatic metalation cyclization; and
3) a complementary Friedel–Crafts acylation cyclization.
Reagents and conditions: a) BuLi/THF, –70°C, then B(OMe)3, –70 to
0 °C, 1.5 h; b) 2 M Na2CO3/ (PPh3)4Pd/2a–e/DME/EtOH, reflux, 16
h (48–82%); c) LDA (2.5 equiv)/THF, –20°C to r.t., 16 h (76–91%);
d) HBr/AcOH, reflux, 16 h (62–92%)
Scheme 1
In order to obtain the sixth regioisomer 7f, we employed
the same in situ coupling procedure using 2a and oxazo-
line 1b as a masked carboxylic acid (Scheme 2). Acid hy-
drolysis of the ring-opened16 intermediate 4 gave biaryl-
2-benzoic acid 5 which underwent normal Friedel–Crafts
cyclization to regioselectively provide 2,3-dimethoxyflu-
oren-9-one (6f) in high yield.17 Fluorenone 6f cannot be
prepared by the anionic equivalent route since the more
acidic of two remote hydrogens is ortho to the methoxy
substituent (e.g. 3a regiospecifically gave 6a). Demethy-
lation of 6f provides 7f in high yield and completes the se-
ries of dihydroxyfluorenone regioisomers. Since the
viability of using substituted diethyl benzamides14 and
phenyloxazolines18 has been previously demonstrated, the
utility of this combined classical carbonium ion and car-
banion mediated approach is further significant consider-
ing that regiospecific control is possible on the other half
of the molecule (positions five through eight), thereby po-
tentially providing fluorenones of even greater structural
diversity.
Thus, 2-bromo-N,N-diethylbenzamide (1a) (Scheme 1) un-
dergoes lithium-halogen exchange and boronation at the
2-position. Treatment of the boronate with dimethoxyaryl
bromides and aryl triflates 2a–e under modified in situ Su-
zuki conditions gave the biarylamides 3a–e. Intramolecular
cyclization occurs when 3a–e react with LDA in a remote
metalation process as described by Snieckus.14 The five
dimethoxyfluorenone regioisomers 6a–e thus formed are
easily demethylated with refluxing HBr/AcOH to give di-
hydroxyfluorenones 7a–e in good yield.

SYNTHESIS
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1196
N,N-Diethyl-3′,4′-dimethoxy-2-biphenylcarboxamide (3a); Typi-
cal Procedure:
To a solution of 2-bromo-N,N-diethylbenzamide (1a; 2.90 g,
11.3 mmol) in anhyd THF (50 mL) at –78°C was added BuLi (5 mL,
2.5 M in hexanes). After stirring for 30 min, B(OMe)3 (1.5 g, 14.7
mmol) was added and the mixture warmed to 0°C and stirred 1.5 h.
The solvent was evaporated under reduced pressure at r.t., then DME
(50 mL), EtOH (2 mL), 2 M aq Na2CO3 solution (11.3 mL),
(PPh3)4Pd (4 mol%, 390 mg) and 4-bromoveratrole (2a; 3.2 g, 14.7
mmol) were added. The mixture was heated at reflux for 16 h, then
cooled to r.t. and EtOAc (50 mL) added. After washing with brine, the
organic layer was seperated, dried (MgSO4), filtered and evaporated
under reduced pressure. The crude material was purified by chroma-
tography on silica gel (40% EtOAc in hexane) to give 3a (2.0 g, 6.4
mmol); yield: 57%; yellow oil. [LiCl (0.5 g) was also added during
the Pd coupling step of triflates 2b and 2e to obtain 3b and 3e].
HRMS (FAB, M+H): calc. 314.175619; found 314.174460.
IR (CHCl3): ν = 1624, 1520, 1252 cm–1.
1H NMR (CDCl3): δ = 0.74 (t, 3 H, J = 7.3 Hz), 0.95 (t, 3 H, J =
7.2 Hz), 2.69 (m, 1 H), 2.95 (m, 1 H), 3.12 (m, 1 H), 3.66 (m, 1 H),
3.89 (s, 3 H), 3.90 (s, 3 H), 6.88 (d, 1 H, J = 8.2 Hz), 7.02 (dd, 1 H, J
= 2.2, 8.2 Hz), 7.10 (d, 1 H, J = 2.2 Hz), 7.34–7.43 (m, 4 H).
13C NMR (CDCl3): δ = 12.26, 13.45, 38.40, 42.31, 55.91, 77.21,
110.96, 112.28, 121.03, 127.00, 127.22, 128.85, 129.24, 132.74,
136.32, 138.09, 148.55, 170.75.
Reagents and conditions: a) BuLi/THF, –70°C, then B(OMe)3, –70 to
0 °C, 1.5 h; b) 2 M Na2CO3/(PPh3)4Pd/2a/DME/EtOH, reflux, 16 h
(57%); c) 4.5 N HCl, 16 h, (70%); d) TFAA/CHCl3 (94%); e) HBr/
AcOH, reflux, 16 h (90%)
Scheme 2
Using the above procedure, the following compounds were prepared:
N,N-Diethyl-3′,5′-dimethoxy-2-biphenylcarboxamide (3b): from 1a
(2.00 g, 7.80 mmol) and 2b (4.20 g, 14.7 mmol); yield: 82%; pale yel-
low oil.
In summary, biaryl precursors to methoxyfluorenones
6a–f were made using a modified in situ Pd(0)-catalyzed
cross-coupling method. Dihydroxyfluorenone regioiso-
mers 7a–f were easily obtained in 30–69% overall yields.
IR (neat):ν = 1626, 1595, 1458, 1429, 1155 cm–1.
1H NMR (DMSO-d6):δ = 0.74 (t, 3 H, J = 7.2 Hz), 0.87 (t, 3 H, J =
7.3 Hz), 2.75 (m, 1 H), 2.90 (m, 1 H), 3.02 (m, 1 H), 3.57 (m, 1 H),
3.75 (s, 6 H), 6.50 (t, 1 H, J = 2.3 Hz), 6.57 (d, 2 H, J = 2.3 Hz), 7.29
(d, 1 H, J = 7.2 Hz), 7.39–7.51 (m, 3 H).
Melting points are uncorrected. 1H NMR spectra were obtained at 300
MHz unless otherwise indicated. All reagents were of commercial
quality and all reactions were carried out under an inert atmosphere.
2-Bromo-N,N-diethylbenzamide (1a) and 2-(2-bromophenyl)-4,4-
dimethyloxazoline (1b) were prepared according to literature proce-
dures.19a,b
13C NMR (DMSO-d6):δ = 11.88, 13.35, 37.71, 41.90, 55.16, 99.34,
106.62, 126.67, 127.59, 128.81, 129.09, 136.25, 137.52, 141.32,
160.22, 169.21.
MS (EI, 70 eV): m/z (%) = 313 (M+, 76), 241 (100), 214 (96).
3,5-Dimethoxyphenyl Trifluoromethanesulfonate (2b); Typical
Procedure:
N,N-Diethyl-2′,5′-dimethoxy-2-biphenylcarboxamide (3c): from 1a
(2.90 g, 11.3 mmol) and 2c (3.20 g, 14.7 mmol); yield: 57%; pale yel-
low oil.
To a solution of 3,5-dimethoxyphenol (10.0 g, 64.9 mmol) in CH2Cl2
(500 mL) at 0°C was added Et3N (25mL). Trifluoromethanesulfonic
anhydride (45.0 g, 160 mmol) was added dropwise with stirring. After
30 min, the mixture was allowed to reach r.t. and then poured into aq
NaHCO3 solution. The organic layer was seperated, dried (MgSO4),
filtered and concentrated under reduced pressure. The brown oil ob-
tained was purified by chromatography on silica gel (30% EtOAc in
hexane) and distilled using a Kugelrohr distillation apparatus to give
2b, identical in all respects to that reported in the literature;20 yield:
17.5 g (94%); yellow oil; bp 90–95°C / 0.1 Torr.
HRMS (FAB, M+H): m/z calc. 314.175619; found 314.175792.
IR (neat): ν = 1628, 1506, 1466, 1221 cm–1.
1H NMR (DMSO-d6):δ = 0.73 (t, 3 H, J = 7.3Hz), 0.82 (t, 3 H, J =
7.3 Hz), 2.70–3.13 (m, 3 H), 3.54 (m, 1 H), 3.64 (s, 3 H), 3.68 (s, 3
H), 6.72 (d, 1 H, J = 3.4 Hz), 6.88 (dd, 1 H, J = 3.4, 9.1 Hz), 6.98 (d,
1, J = 9.1 Hz), 7.28–7.43 (m, 4 H).
13C NMR (DMSO-d6):δ = 11.73, 13.51, 37.39, 41.58, 55.28, 55.75,
112.09, 113.51, 116.67, 126.07, 127.10, 127.83, 128.70, 130.75,
134.74, 137.12, 150.18, 152.51, 168.95.
Using the above procedure (without Kugelrohr distillation), the fol-
lowing compound was prepared:
N,N-Diethyl-2′,4′-dimethoxy-2-biphenylcarboxamide (3d): from 1a
(2.90 g, 11.3 mmol) and 2d (3.20 g, 14.7 mmol); yield: 65%; yellow
oil.
2,3-Dimethoxyphenyl Trifluoromethanesulfonate (2e): 2,3-Dimethoxy-
phenol (5.00 g, 32.4 mmol), CH2Cl2 (200 mL), Et3N (12 mL), trifluo-
romethanesulfonic anhydride (22.0 g, 78.0 mmol); yield: 72%; pale
yellow oil.
IR (neat): ν = 1628, 1514, 1462, 1288, 1209 cm–1.
1H NMR (DMSO-d6, 400 MHz):δ = 0.76 (t, 3 H, J = 7.0 Hz), 0.82 (t,
3 H, J = 7.0 Hz),2.68–3.20 (m, 3 H), 3.41–3.62 (m, 1 H), 3.68 (s, 3
H), 3.77 (s, 3 H), 6.51 (dd, 1 H, J = 2.4, 8.4 Hz), 6.61 (d, 1 H, J = 2.4
Hz), 7.03 (d, 1 H, J = 8.4 Hz), 7.25–7.40 (m, 4 H).
IR (neat): ν = 1424, 1252, 1215, 1142 cm–1.
1H NMR (CDCl3, 400 MHz): δ = 3.89 (s, 3 H), 3.95 (s, 3 H), 6.83 (dd,
1 H, J = 1.5, 8.4 Hz), 6.92 (dd,1 H, J = 1.5, 8.5 Hz), 7.05 (dd, 3 H,
J = 8.4, 8.5 Hz).
13C NMR (DMSO-d6): δ = 11.92, 13.49, 37.35, 41.49, 55.22, 55.32,
98.30, 104.36, 120.65, 126.08, 126.64, 127.78, 131.06, 131.30,
134.83, 137.31, 157.11, 160.21, 169.11.
13C NMR (CDCl3): δ = 56.20, 61.26, 112.28, 113.95, 117.12, 120.30,
123.56, 141.58, 142.84, 154.04.
MS (EI, 70eV): m/z (%) = 286 (M+, 71), 153 (100), 125 (62).
MS (CI, 120 eV): m/z (%) = 314 (M+H, 100), 241 (18).

SYNTHESIS
August 1998
1197
N,N-Diethyl-2′,3′-dimethoxy-2-biphenylcarboxamide (3e): from 1a
(2.00 g, 7.80 mmol) and 2e (4.20 g, 14.7 mmol); yield: 48%; yellow oil.
IR (neat): ν = 1630, 1580, 1474, 1425, 1265 cm–1.
1HNMR (CDCl3, 400 MHz): δ = 3.89 (s, 3 H), 4.11 (s, 3 H), 6.93 (d,
1 H, J = 8.0 Hz), 7.16 (d, 1 H, J = 8.0 Hz), 7.19–7.25 (m, 1 H), 7.42–
7.47 (m, 2 H), 7.62 (d, 1 H, J = 7.4 Hz).
1H NMR (CDCl3): δ = 0.82 (t, 3 H, J = 7.4Hz), 0.95 (t, 3 H, J = 7.4
Hz), 2.75–3.38 (m, 3 H), 3.73 (s, 3 H), 3.64–3.83 (m, 1 H), 3.89 (s, 3
H), 6.90 (dd, 2 H, J = 1.0, 8.5 Hz), 7.02 (q, 1 H, J = 8.5 Hz), 7.34–
7.44 (m, 4 H).
13C NMR (DMSO-d6): δ = 56.25, 61.28, 116.40, 117.86, 120.24,
123.57, 124.23, 128.16, 133.73, 134.95, 136.04, 143.59, 148.28,
153.75, 190.62.
13C NMR (CDCl3):δ = 11.82, 13.71, 37.99, 42.37, 55.81, 60.96,
112.00, 123.24, 123.36, 126.24, 127.28, 127.95, 130.64, 133.97,
135.25, 137.17, 146.42, 152.67, 170.20.
1,4-Dimethoxyfluoren-9-one (6c): from 3c (1.60 g, 5.1 mmol) and
LDA (12.8 mmol); yield: 89%; mp 164–166°C (MeOH) (Lit.13b,24
mp 165–166°C).
MS (EI, 70 eV): m/z (%) = 313 (M+, 26), 282 (100), 241 (54).
IR (KBr): ν = 1699 cm–1.
1HNMR (CDCl3, 400 MHz): δ = 3.89 (s, 3 H), 3.91 (s, 3 H), 6.74 (d,
1 H, J = 9.1 Hz), 6.97 (d, 1 H, J = 9.1 Hz), 7.21 (t, 1 H, J = 7.6 Hz),
7.40 (t, 1 H, J = 7.6 Hz), 7.60 (d, 1 H, J = 7.6 Hz), 7.80 (d, 1 H, J =
7.6 Hz).
N-(2-Hydroxy-1,1-dimethyl)-3′,4′-dimethoxy-2-biphenylcarboxam-
ide (4): from 2-(2-bromophenyl)-4,4-dimethyloxazoline (1b; 3.20 g,
12.7 mmol) in THF (100 mL) and 4-bromoveratrole (2a; 4.10 g,
19.0 mmol) in DME (100 mL) and EtOH (4 mL). Purified by chroma-
tography on silica gel (80% EtOAc in hexane); yield: 57%; white sol-
id; mp 93–95°C.
MS (CI, 120 eV): m/z (%) = 241 (M+H, 100).
13C NMR (CDCl3): δ = 55.92, 56.13, 114.02, 120.15, 120.97, 123.54,
124.22, 128.13, 132.21, 133.89, 134.00, 142.41, 149.52, 152.37,
192.00.
IR (KBr):ν = 3412, 3248, 1633 cm–1.
1HNMR (DMSO-d6): δ = 1.11 (s, 3 H), 3.28 (d, 2 H, J = 6.1 Hz), 3.33
(s, 2 H), 3.76 (s, 3 H), 3.77 (s, 3 H), 4.76 (t, 1 H, J = 6.1 Hz), 6.91–
7.01 (m, 3 H), 7.30–7.47 (m, 5 H).
2,4-Dimethoxyfluoren-9-one (6d): from 3d (1.2 g, 3.8 mmol) and
LDA (10 mmol); yield: 76%; mp 144–146°C (MeOH) (Lit.13a,b mp
116°C).
13C NMR (DMSO-d6): δ = 23.14, 54.78, 55.37, 55.58, 67.68, 111.58,
112.55, 120.77, 126.53, 127.70, 128.92, 129.61, 132.88, 137.84,
138.81, 148.24, 169.17.
IR (KBr): ν = 1713 cm–1.
1HNMR (CDCl3, 400 MHz): δ = 3.83 (s, 3 H), 3.90 (s, 3 H), 6.53 (d,
1 H, J = 2.0 Hz), 6.81 (d, 1 H, J = 2.0 Hz), 7.11 (t, 1 H, J = 7.4 Hz),
7.37 (t, 1 H, J = 7.4 Hz), 7.54 (d, 1 H, J = 7.4 Hz), 7.63 (d, 1 H, J =
7.4 Hz).
MS (CI, 120 eV): m/z (%) = 330 (M+H, 100), 241 (65).
3′,4′-Dimethoxy-2-biphenylcarboxylic Acid (5):
The amide 4 (2.00 g, 6.08 mmol) was added to 4.5 N HCl and the mix-
ture heated at reflux for 16 h. After cooling to r.t., the solid precipitate
was filtered and washed with H2O (100 mL) to give 5; yield: 1.10 g
(70%); mp 161–163°C (EtOH) (Lit.21 mp 162–165°C).
IR (KBr): ν = 3323, 1726, 1520, 1254 cm–1.
13C NMR (DMSO-d6): δ = 55.85, 55.95, 101.27, 104.96, 122.81,
123.01, 123.75, 127.17, 132.73, 135.39, 135.70, 143.63, 156.08,
162.15, 193.04.
MS (EI, 70 eV): m/z (%) = 240 (M+, 100).
1HNMR (CDCl3, 400 MHz): δ = 3.86 (s, 3 H), 3.91 (s, 3 H), 6.87–6.90
(m, 3 H), 7.37–7.43 (m, 2 H), 7.55 (m, 1 H), 7.91 (dd, 1 H, J = 1.1,
7.9 Hz), 8.36–12.20 (br, 1 H).
3,4-Dimethoxyfluoren-9-one (6e): from 3e (1.0 g, 3.2 mmol) and
LDA (7.9 mmol); yield: 78%; mp 141–143°C (MeOH) (Lit.22 mp
142.5 °C).
13C NMR (CDCl3): δ = 55.82, 55.85, 110.86, 112.00, 120.81, 126.94,
129.42, 130.49, 131.10, 131.95, 133.57, 142.81, 148.47, 148.54,
173.58.
IR (KBr): ν = 1701 cm–1.
1HNMR (CDCl3, 400 MHz): δ = 3.94 (s, 3 H), 3.96 (s, 3 H), 6.74 (d,
1 H, J = 8.1 Hz), 7.27 (t, 1 H, J = 7.2 Hz), 7.42 (d, 1 H, J = 8.1 Hz),
7.47 (t, 1 H, J = 7.2 Hz), 7.63 (d, 1 H, J = 7.2 Hz), 7.84 (d, 1 H, J =
7.2 Hz).
MS (CI, 120 eV): m/z (%) = 259 (M+H, 30), 258 (43), 241 (100).
13C NMR (CDCl3): δ = 56.14, 60.37, 111.19, 121.36, 123.77, 123.91,
128.01, 128.71, 134.48, 135.13, 136.30, 142.42, 144.75, 159.06,
192.36.
1,3-Dimethoxyfluoren-9-one (6b); Typical Procedure:
To a stirred solution of LDA (13.5 mmol) in THF (50mL) was added
3b (1.70 g, 5.42 mmol) in THF (20 mL) at –20°C. The resulting so-
lution was allowed to warm to r.t. and stirred 16 h. Satd aq NH4Cl so-
lution (30 mL) was added and the organic layer seperated. The aq
NH4Cl layer was extracted with THF (70 mL) and the combined or-
ganic layers were dried (MgSO4). After filtration and evaporation of
the solvent under reduced pressure, the crude product was purified by
chromatography on silica gel (40% EtOAc in hexane) to give 6b
(1.18 g, 4.91 mmol); yield: 91%; mp 143–144°C (MeOH) (Lit.22 mp
143–144oC).
MS (CI, 120 eV): m/z (%) = 241 (M+H, 90), 258 (M+NH4).
2,3-Dimethoxyfluoren-9-one (6f): 3′,4′-Dimethoxy-2-biphenylcar-
boxylic acid (5; 1.3 g, 5.0 mmol) was dissolved in CHCl3 (25 mL) and
trifluoroacetic anhydride (TFAA, 5 mL, 35 mmol) added at r.t. After
30 min, the mixture was poured onto ice (30 g) and made basic with
K2CO3. The mixture was extracted with CH2Cl2 (2 × 20 mL) and the
combined organic layers were dried (MgSO4), filtered and evaporated
under reduced pressure. The crude product was purified by chroma-
tography on silica gel (40% EtOAc in hexane) to give 6f (1.13 g,
4.7 mmol); yield: 94%; mp 162–164°C (MeOH) (Lit.12 mp 164 °C).
IR (KBr): ν = 1705 cm–1.
IR (KBr): ν = 1690 cm–1.
1HNMR (CDCl3, 400 Mhz): δ = 3.80 (s, 3 H), 3.87 (s, 3 H), 6.14 (d,
1 H, J = 2.0 Hz), 6.53 (d,1H, J = 1.9 Hz), 7.17–7.24 (m, 1 H), 7.31–
7.36 (m, 2 H), 7.52 (d,1 H, J = 7.2 Hz).
1HNMR (CDCl3, 400 MHz): δ = 3.91 (s, 3 H), 4.00 (s, 3 H), 6.98 (s,
1 H,), 7.17 (s,1 H), 7.18 (t, 1 H, J = 7.4 Hz), 7.33 (d, 1 H, J = 7.4 Hz),
7.39 (t, 1 H, J = 7.4 Hz), 7.53 (d, 1 H, J = 7.4 Hz).
13C NMR (DMSO-d6): δ = 55.72, 56.11, 98.41, 100.62, 112.61,
120.82, 122.63, 129.53, 133.69, 134.83, 141.81, 147.68, 159.67,
167.32, 188.99.
13C NMR (CDCl3): δ = 56.22, 56.33, 103.39, 107.11, 119.07, 123.72,
126.84, 128.15, 134.18, 134.72, 139.45, 143.92, 149.71, 154.55,
193.12.
MS (CI, 120 eV): m/z (%) = 241 (M+H, 100).
Using the above procedure, the following compounds were prepared:
1,2-Dimethoxyfluoren-9-one (6a): from 3a (1.79 g, 5.7 mmol) and
LDA (13.7 mmol); yield: 84%; mp 113–115°C (MeOH) (Lit.23 mp
113–114 °C).
MS (EI, 70 eV): m/z (%) = 240 (M+, 100).
1,2-Dihydroxyfluoren-9-one (7a); Typical Procedure:
1,2-Dimethoxyfluoren-9-one (6a; 1.05 g, 4.3 mmol) was added to
48% aq HBr (20 mL) and glacial AcOH (6 mL) and the mixture was
HRMS (FAB, M+H): m/z calc.241.086469; found 241.086954.
IR (KBr): ν = 1709 cm–1.

SYNTHESIS
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stirred at reflux 16 h. After cooling to r.t., the dark mixture was
poured into H2O (75 mL) and filtered through a sintered glass funnel.
The solids were washed with H2O (3 × 50 mL) and then with CH2Cl2
(50 mL). The solids were dissolved into EtOAc (100 mL) on a steam
bath and the mixture filtered through Celite. The Celite was washed
with hot EtOAc (100mL) and the combined organic washings were
dried (MgSO4). Filtration and evaporation of solvent under reduced
pressure gave 7a; yield: 0.57 g (62%); mp 187–189°C (EtOH) (Lit.25
mp 188–189 °C).
(t, 1 H, J = 7.2 Hz), 7.40–7.53 (m, 3 H), 9.04–10.79 (br, 2 H).
13C NMR (DMSO-d6): δ = 108.70, 111.23, 119.56, 122.90, 125.15,
127.84, 134.31, 134.49, 137.65, 143.88, 146.11, 152.22, 192.14.
We gratefully acknowledge Prof. V. Snieckus (University of Waterloo)
for helpful discussions and Dr. D. Friedrich (Hoechst Marion Rous-
sel) for NMR spectral work.
HRMS (FAB, M+H): m/z calc. 213.055169; found 213.054350.
IR (KBr): ν = 1686 cm–1.
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(4) Sargent, M. V. J. Chem. Soc., Perkin Trans.1 1987, 2553.
(5) Wang, W.; Snieckus, V. J. Org. Chem. 1992, 57, 424.
(6) Jones, W. D.; Ciske, F. L. J. Org. Chem. 1996, 61, 3921.
(7) Gould, S. J.; Chen, J.; Cone, M. C.; Gore, M. P.; Melville, C. R.;
Tamayo, N. J. Org. Chem. 1996, 61, 5720.
(8) Hauser, F. M.; Zhou, M. J. Org. Chem. 1996, 61, 5722.
(9) Mohri, S.-i.; Stefinovic, M.; Snieckus, V. J. Org. Chem. 1997,
62, 7072.
(10) Jones, W. D.; Ciske, F. L. Unpublished results.
(11) Reiveschl, G.; Ray, F. E. Chem. Rev. 1938, 23, 287.
(12) Pol, V. A.; Wagh, S. M.; Barve, V. P.; Kulkarni, A. B. Indian J.
Chem. 1969, 7, 557.
1HNMR (DMSO-d6, 400 MHz): δ = 6.92 (d, 1 H, J = 7.8 Hz), 7.04 (d,
1 H, J = 7.8 Hz), 7.25 (t, 1 H, J = 7.7 Hz), 7.45–7.55 (m, 2 H), 7.59
(d, 1 H, J = 7.6 Hz), 9.49–10.37 (br, 2 H).
13C NMR (DMSO-d6): δ = 112.45, 118.69, 119.73, 119.86, 123.17,
127.54, 134.15, 134.35, 134.42, 144.00, 146.17, 191.83.
Using the above procedure, the following compounds were prepared:
1,3-Dihydroxyfluoren-9-one (7b): from 6b (1.10 g, 4.6 mmol); yield:
92%; mp 204–207 °C (EtOAc/hexane).
HRMS (FAB, M+H): m/z calc. 213.055169; found 213.054405.
IR (KBr): ν = 1661 cm–1.
1HNMR (DMSO-d6, 400 MHz): δ = 6.18 (d, 1 H, J = 1.8 Hz), 6.67 (d,
1 H, J = 1.8 Hz), 7.33 (t, 1 H, J = 7.4 Hz), 7.45–7.55 (m, 2 H), 7.65
(d, 1 H, J = 7.4 Hz), 9.36–11.33 (br, 2 H).
13C NMR (DMSO-d6): δ = 101.91, 102.98, 110.61, 120.41, 122.35,
129.11, 133.34, 135.37, 141.96, 147.09, 158.95, 165.71, 189.33.
(13) a) Ramana, M. M. V.; Potnis, P. V. Synthesis 1993, 575.
b) Observed NOE’s for structural confirmation.
1,4-Dihydroxyfluoren-9-one (7c): from 6c (1.10 g, 4.6 mmol); yield:
85%; mp >250 °C (EtOAc/hexane) (Lit.24 mp 263–264 °C).
HRMS (FAB, M+H): m/z calc. 213.055169; found 213.054611.
IR (KBr): ν = 1684 cm–1.
1HNMR (DMSO-d6, 400 MHz): δ = 6.68 (d, 1 H, J = 8.8 Hz), 6.96 (d,
1 H, J = 8.8 Hz), 7.24 (t, 1 H, J = 6.8 Hz), 7.46–7.54 (m, 2 H), 7.81
(d, 1 H, J = 6.9 Hz), 9.77 (br, 1 H), 9.83 (s, 1 H).
13C NMR (DMSO-d6): δ = 117.88, 120.38, 123.03, 123.69, 126.58,
126.68, 127.63, 133.50, 134.31, 142.80, 146.29, 149.99, 191.76.
(14) Fu, J.-m.; Zhao, B.-p.; Sharp, M. J.; Snieckus, V. J. Org. Chem.
1991, 56, 1683.
(15) a) Maddaford, S. P.; Keay, B. A. J. Org. Chem. 1994, 59, 6501.
b) Giroux, A.; Han, Y.; Prasit, P. Tetrahedron Lett. 1997, 38,
3841.
(16) A similar ring-opened product was previously reported. See
Altman, J.; Bohnke, H.; Steigel, A.; Wulff, G. J Organomet.
Chem. 1986, 309, 241.
(17) 2% isolated yield of 1,2-dimethoxyfluoren-9-one.
(18) Chew, W.; Hynes, R. C.; Harpp, D. N. J. Org. Chem. 1993, 58,
4398.
2,4-Dihydroxyfluoren-9-one (7d): from 6d (0.44 g, 1.8 mmol); yield:
79%; mp >250 °C (EtOAc/hexane).
HRMS (FAB, M+H): m/z calc. 213.055169; found 213.054584.
IR (KBr): ν = 1697 cm–1.
1HNMR (DMSO-d6, 400 MHz): δ = 6.49 (d, 1 H, J = 2.0 Hz), 6.52 (d,
1 H, J = 2.0 Hz), 7.14 (t, 1 H, J = 7.4 Hz), 7.43–7.51 (m, 2 H), 7.61
(d, 1 H, J = 7.4 Hz), 9.92 (s, 1 H), 10.33 (s, 1 H).
13C NMR (DMSO-d6): δ = 103.34, 108.85, 119.82, 122.28, 123.55,
126.28, 132.74, 135.30, 136.25, 144.73, 154.41, 159.83, 193.59.
3,4-Dihydroxyfluoren-9-one (7e): from 6e (0.42 g, 1.7 mmol); yield:
83%; mp 240–242 °C (dec.) (EtOAc/hexane) [Lit.25 mp 240 °C
(dec.)].
(19) a) McCabe, E. T.; Barthel, W. F.; Gertler, S. I.; Hall, S. A.
J. Org. Chem. 1954, 19, 493.
HRMS (FAB, M+H): m/z calc. 213.055169; found 213.054277.
IR (KBr): ν = 1682 cm–1.
b) Meyers, A. I.; Temple, D. L.; Haidukewych, D.; Mihelich, E.
D. J. Org. Chem. 1974, 39, 2787.
1HNMR (DMSO-d6, 400 MHz): δ = 6.70 (d, 1 H, J = 7.7 Hz), 7.03 (d,
1 H, J = 7.7 Hz), 7.26 (t, 1 H, J = 7.2 Hz), 7.48–7.54 (m, 2 H), 7.80
(d, 1 H, J = 7.2 Hz), 9.24–11.22 (br, 2 H).
(20) Subramanian, L. R.; Hanack, M.; Chang, L. W. K.; Imhoff, M.
A.; Schleyer, P. v. R.; Effenberger, F.; Kurtz, W.; Stang, P. J.;
Dueber, T. E. J. Org. Chem. 1976, 41, 4099.
(21) Jeffs, P. W.; Archie, W. C.; Hawks, R. L.; Farrier, D. S. J. Amer.
Chem. Soc. 1971, 93, 3752.
(22) Sato, M.; Uchida, A.; Tsunetsugu, J.; Ebine, S. Tetrahedron
Lett. 1977, 2151.
(23) Nakano, J.; Katagiri, N.; Kato, T. Chem Pharm. Bull. 1982, 30,
2590.
13C NMR (DMSO-d6): δ = 114.35, 117.19, 123.09, 123.62, 125.86,
127.87, 129.17, 134.25, 134.51, 142.09, 142.95, 153.35, 191.84.
2,3-Dihydroxyfluoren-9-one (7f): from 6f (0.50 g, 2.1 mmol); yield:
90%; mp 239–241°C (EtOAc/hexane) (Lit.24 mp 237–238°C ).
HRMS (FAB, M+H): m/z calc. 213.055169; found 213.054440.
IR (KBr): ν = 1695 cm–1.
(24) Koelsch, C. F.; Flesch, R. N. J. Org. Chem. 1955, 20, 1270.
(25) Horner, L.; Baston, D. W. J. Liebigs Ann. Chem. 1973, 910.
1HNMR (DMSO-d6, 400 MHz): δ = 6.97 (s, 1 H), 7.09 (s, 1 H), 7.21