Regioselective superacid-catalyzed electrocyclization of diphenylmethyl cations to fluorenes, phenanthrols and benzofurans

Article abstract of DOI:10.1055/s-2001-16083

Cationic electrocyclization of α-benzoyldiphenylmethanols in the presence of superacid provides fluorenes, phenanthrols and benzofurans in good to moderate yields. A single substitution leads to regioselective cationic electrocyclizations.

Full text of DOI:10.1055/s-2001-16083

PAPER
1487
Regioselective Superacid-Catalyzed Electrocyclization of Diphenylmethyl
Cations to Fluorenes, Phenanthrols and Benzofurans
R
egioselective Ele
a
ctrocycliza
o
tionof
D
iphe
h
nylmethyl
C
i
ations
r
to
F
luore
o
nes, Phenanthrols
a
nd Benzofurans oshida,a Tomohiko Ohwada*b
a
Faculty of Pharmaceutical Sciences, Nagoya City University, 3–1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
b
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7–3-1 Hongo, Bunkyo-ku, Tokyo 113–0033, Japan
Fax +81(3)58414730; E-mail: ohwada@mol.f.u-tokyo.ac.jp
Received 27 March 2001; revised 16 April 2001
gave 9-acetylfluorene (4b),6 whereas -methoxycarbon-
yldiphenylmethanol (2c) gave 9-methoxycarbonylfluo-
rene (4c) (Scheme 1).2,7,8
Abstract: Cationic electrocyclization of -benzoyldiphenylmetha-
nols in the presence of superacid provides fluorenes, phenanthrols
and benzofurans in good to moderate yields. A single substitution
leads to regioselective cationic electrocyclizations.
The chemical behavior of the monocations 1, generated
Key words: carbocations, electrocyclizations, regioselectivity, su- under neutral and strongly acidic conditions were also re-
ported from this laboratory,8,9 and were divergent from
peracid, diphenylmethyl cations
those described.2,6,10,11 -Benzoyldiphenylmethanol (2d,
R1 = R2 = H, Scheme 2), a precursor of the unsubstituted
cation 1d (Scheme 4), reacted in trifluoromethanesulfonic
acid (TFSA) at –48°C to afford the fluorene 4d, along
with the phenanthrene derivative 9-phenylphenanthr-10-
ol (5d) (Scheme 2). No benzofurans 3 were obtained in
TFSA. This superacid-catalyzed fluorene cyclization of
2d was also reported by Olah and Wu in the same acid,12
although the yields were a little divergent. The same au-
thors also reported the formation of 9-phenanthrol (79%
yield) by TFSA-catalyzed cyclization of benzoin.12
Diphenylmethyl cations 1 and related diarylmethyl cat-
ions substituted with electron-withdrawing groups consti-
tute a typical class of destabilized cations, i.e.
carbocations bearing electron-withdrawing groups direct-
ly attached to the carbenium ion center.1 The prototype
diphenylmethyl cations 1 (Scheme 1) bearing electron-
withdrawing substituents (RC=O) have been generated in
the presence of acids,2 or by flash-laser photolysis,3 and
characterized as discrete stable ions. The cations 1 under-
go three modes of electrocyclization reactions (see
Scheme 2): (1) cyclization to form benzofurans 3, (2) cy-
clization to give fluorenes 4, and (3) cyclization to give
phenanthrols 5. The first isolation of the relevant carboca-
tion, the di-p-anisyl(4-methoxybenzoyl)methyl cation
(1a), as a stable crystalline antimony pentafluoride salt,
was reported by Takeuchi et al., who showed that heating
the salt 1a in a neutral solvent (1,2-dichloroethane, 50°C,
8 h), gave the benzofuran 3a in 94% yield (Scheme 3).4,5
In contrast to this heteroatom cyclization process, the
acetyl, acid, ester and amide analogs underwent electrocy-
clic coupling of the two aromatic rings, leading to fluo-
rene derivatives. Thus, -acetyldiphenylmethanol (2b)
The monocations 1c and 1d could be generated as stable
entities at –50°C by the reaction of the -chloro ketones
6c and 6d with silver salts (Scheme 4).8a However, no flu-
orene, phenanthrol or benzofuran was formed under these
neutral conditions. When the stable cation was added to
TFSA at –48°C, fluorene and the phenanthrol were pro-
duced (Scheme 2). This led to the proposals that the fluo-
renes 4 and phenanthrols 5 do not arise directly from the
monocation 1, and that the real intermediate is the dication
7 (Scheme 1), formed by protonation of the -carbonyl
group by TFSA. The involvement of the dicationic inter-
mediate 7 was supported by kinetic studies of the acidity-
dependent reactions, and by theoretical evaluation of en-
CF3SO3H
H+
+
H+
O
R
O
R
OH
O
R
+
+
HO
R
- H2O
2b,c
1b,c
7b,c
4b,c
b: R = CH3
c: R = OCH3
Scheme 1
ergetics.9
Synthesis 2001, No. 10, 30 07 2001. Article Identifier:
In this context, -benzoyldiphenylmethanols 2d–k can
produce fluorene, phenanthrol and benzofuran by acid-
1437-210X,E;2001,0,10,1487,1494,ftx,en;F02901SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1488
N. Yoshida, T. Ohwada
PAPER
R1
R1
R1
O
O
OH
OH
CF3SO3H
CF3SO3H
HO
R2
R2
R1
R2
R2
4d-k
2d-k
5d-k
5'd-k
CF3CO2H
R1
d: R1 = H, R2 = H
e: R1 = CH3, R2 = H
f: R1 = F, R2 = H
g: R1 = penta-F, R2 = H
h: R1 = CF3, R2 = H
i: R1 = CH3O, R2 = H
j: R1 =H, R2 = CH3
O
O
k: R1 =H, R2 = F
R2
R1
R2
3i
3'i
Scheme 2
catalyzed electrocyclization through cationic intermedi- hydrins 9 of substituted benzophenones 8, followed by
ates (Scheme 2). The former two cyclizations represent an acidic hydrolysis of the intermediate imines (Scheme 5).13
acid-catalyzed electrocyclization wherein two aromatic
rings participate, and the latter cyclization represents a
The acid-catalyzed cyclizations of -benzoyldiphenyl-
methanols 2d–k were studied, and yields and reaction
conditions are summarized in the Table. In the case of the
parent -benzoyldiphenylmethanol (2d), superacid-cata-
heteroatom cyclization, all these being of synthetic inter-
est.2b There has been no systematic study of the ring-clos-
ing regiochemistry of cationic electrocyclization wherein
several modes of cyclization are possible. Herein we deal
with the substituent effects on the modes of the relevant
electrocyclization reactions in order to reveal the synthet-
ic potential of cationic electrocyclizations in which ben-
zene rings participate.
lyzed cyclization favored the formation of the fluorene 4d
(76%) over that of 9-phenylphenanthr-10-ol (5d) (9%).8
Therefore the ratio of the yields of fluorene/phenanthrol
(ratio 4:5 in the Table) was 8.4. This can be understood in
terms of feasibility of formation of 5-membered ring over
6-membered ring.14 A single substituent on the benzene
The -benzoyldiphenylmethanols 2d–k (except 2g, see ring can significantly modify the cyclization preference
experimental) can be readily prepared through the addi- (Table). Methyl substitution at one of the benzene rings of
tion of Grignard reagents to O-trimethylsilylated cyano- the diphenylmethanol moiety as in 2e affords a mixture of
fluorene 4e and phenanthrol 5e, the former being favored
H3CO
H3CO
O
O
50 ºC, 8 h
CH2ClCH2Cl
+
94 % (reference 4)
H3CO
OCH3
H3CO
OCH3
1a
3a
Scheme 3
AgBF4
AgBF4
or
CF3CO2Ag
or
O
O
O
O
CF3CO2Ag
+
+
Cl
Cl
OCH3
OCH3
CH2Cl2
CH2Cl2
6c
1c
6d
1d
Scheme 4
Synthesis 2001, No. 10, 1487–1494 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Regioselective Electrocyclization of Diphenylmethyl Cations to Fluorenes, Phenanthrols and Benzofurans
1489
R1
R1
R1
(1)R2
(2)
MgBr
OTMS
CN
O
TMSCN
ZnI2
O
HO
H3O+
8
9
2
R2
Scheme 5
over the latter. The ratio of the yields of fluorene/phenan- 4h was formed. When the acid catalyst is trifluoroacetic
throl (6.3) decreased as compared with that of 2d (8.4). acid (TFA), a much weaker acid than TFSA, no cyclized
Thus, the methyl substituenet changed the modes of the product was formed from 2h (Table). Instead, -ben-
cyclizations to some extent.
zoylphenyl(p-trifluoromethylphenyl)methyl trifluoroace-
tate was obtained in 27% yield, together with the recovery
(47%) of the starting alcohol 2h. The former product can
be formed by nucleophilic attack of trifluoroacetate anion
to the corresponding carbocation 1 (see Scheme 1). This
result is consistent with the previous proposals that the
fluorenes 4 and phenanthrols 5 do not arise from the
monocations 1, and that the cyclizations require superacid
catalysis.8,9
On the other hand, pentafluoro substitution as in 2g15 can
lead to exclusive formation of the phenanthrol derivative
5’g. This is a reasonable outcome because the fluorene cy-
clization was inhibited due to the perfluoro substitution.
However, substitution of a single fluorine atom on the
benzene ring as in 2f can change the cyclization prefer-
ence: 2f favored the formation of phenanthrol (5’f, 45%
yield) over fluorene (4f, 35% yield) (ratio 4/5 = 0.78).
Generally in the case of the phenanthrene cyclizations, Substitution of a methoxy group at the R1 position also has
two regio-isomers are possible, 5 and 5’ (Scheme 2). In a significant effect on the cyclizations. The substrate 2i
the cases of 2f and 2g, a single isomer of the phenanthrols exclusively affords the benzofuran derivative 3i
5’f and 5’g, respectively, was predominantly formed (Scheme 2). A single substitution of a methoxy group is
while the methyl analog 2e favored the phenanthrol struc- sufficent to activate the benzofuran cyclization (cf. 1a in
ture 5e. In the case of trifluoromethyl group as the R1 sub- Scheme 3). In the case of the benzofuran cyclization, two
stituent, the TFSA-catalyzed cyclization of 2h at –45°C regioisomers are also possible. In this case a single iso-
for 30 minutes gave the phenanthrol 5’h exclusively in mer, 3i rather than 3’i, was predominantly formed. The
44% yield. No isomer of the phenanthrol 5h or fluorene benzofuran cyclization of 2i can also be catalyzed by
Table Acid-Catalyzed Electrocyclizations of -Benzoyldiphenylmethanols
Substrate
R1
R2
Acid
Temp. (°C)a Time (h)
Yieldb
Ratio
3
4
5
4/5c
2dd
2e
2f
H
H
TFSA
TFSA
TFSA
TFSA
TFSA
TFA
–48
–48
–48
–48
–48
0
0.5
3.0
2.5
1.5
0.5
2.0
22.0
2.0
8.0
0.6
0
0
0
0
0
0
76
63
35
0
9
8.4
6.3
0.78
–
CH3
F
H
10 (5e)
H
45 (5’f)
2g
2h
2he
2i
penta-F
CF3
CF3
CH3O
CH3O
H
H
41 (5’g)
H
0
44 (5’h)
–
H
0
0
–
H
TFSA
TFA
40
47 (3i)
0
0
–
2i
H
0
52 (3i)
0
0
–
2j
CH3
F
TFSA
TFSA
–48
–48
0
0
69
83
14 (5’j)
4.9
–
2k
H
0
a
2°C.
b Isolated yields.
c Ratio of the yields of fluorene (4)/phenanthrol (5).
d Reference.8a
e
-Benzoylphenyl(p-trifluoromethylphenyl)methyl trifluoroacetate (27%) and recovery (47%).
Synthesis 2001, No. 10, 1487–1494 ISSN 0039-7881 © Thieme Stuttgart · New York

1490
N. Yoshida, T. Ohwada
PAPER
-Benzoylphenyl(p-tolyl)methanol (2e)13
TFA. In TFA the cyclization reaction to benzofuran 3i
proceeded readily at 0°C for 2 hours. Thus, as judged
from the reaction conditions (long reaction time and high
temperature in TFSA), the superacid catalyst (TFSA) re-
tarded the benzofuran cyclization. This is consistent with
the previous assessment of the involvement of the mono-
cationic intermediate 1 of the benzofuran cyclization.4,9
To the Grignard reagent prepared from p-bromobenzene (4.207 g, 3
equiv) and Mg turnings (716 mg, 3.3 equiv) in anhyd Et2O (7 mL)
was added a solution of 9e (2.701 g, 9.16 mmol) in anhyd Et2O (4
mL) over 30 min and the reaction mixture was stirred at r.t. for 4 h.
Aq 10% H2SO4 (200 mL) was added, the mixture stirred at 40°C for
2 h and evaporated to give a residue consisting of a mixture of a ke-
tol and an imine. In order to complete hydrolysis of the imine, a so-
lution of the residue in EtOH (35 mL) was treated with 3 N aq HCl
(1 mL) at 50°C for 30 min. The residue, obtained after evaporation
of the solvent, was diluted with CHCl3, the organic layer was
washed with brine and dried (Na2SO4). The solvent was evaporated
to give a residue, which was flash-chromatographed (EtOAc–hex-
ane, 1:19) to give 1.655 g (61%) of ketol 2e as a pale yellow oil.
Substitution of the benzene ring of the benzoyl moiety,
i.e. influence of substituent R2, was also studied. The
methyl group at the R2 position as in 2j produced fluorene
4j (69% yield) and phenanthrol 5j (= 5’j, in this case)
(14% yield). The ratio of the yields of fluorene/phenan-
throl (4.9) decreased as compared with that in the case of
1H NMR (CDCl3): = 7.719 (2 H, dd, J = 8.43, 1.28 Hz), 7.463–
2d (8.4), suggesting encouragement of the phenanthrene 7.258 (9 H, m), 7.146 (2 H, d, J = 7.88 Hz), 4.936 (1 H, s), 2.344 (3
H, s).
cyclization by the CH3 group. On the other hand, fluorine
MS (EI+): m/z = 197 (M+ – COPh).
substitution at the R2 position in 2k suppressed the forma-
tion of phenanthrol, and the fluorene 4k was exclusively
formed (83%) (Table).
Acid-Catalyzed Reaction of -Benzoylphenyl(p-tolyl)methanol
(2e)
In summary, cationic electrocyclizations of the -ben-
zoyldiphenylmethanols in the presence of superacid pro-
vide fluorenes, phenanthrols and benzofurans in good to
moderate yields. Although substituent effects on the cat-
ionic electrocyclization reactions have been poorly stud-
ied, the present work reveals a trend that relatively
electron-rich benzene rings preferentially participate in
the relevant cationic electrocyclizations. This tendency is
crucial for the observed selectivities between fluorene/
phenanthrol cyclizations (except in the case of 2e), and
between cyclized isomers (i.e. benzofurans 3i and 3’i, and
phenanthrols 5 and 5’). The present substitution effects
therefore provide regioselective cationic electrocycliza-
tions with synthetic potential.
To pre-cooled TFSA (58 mL, 500 equiv) at –48°C (in a dry ice-
MeCN bath) was added a solution of 2e (400 mg, 1.32 mmol) in an-
hyd CH2Cl2 (3 mL) over 10 min. After stirring at –48°C for 3 h, the
mixture was poured into ice-water and extracted with CHCl3. The
organic layer was washed with brine and dried (Na2SO4). The sol-
vent was evaporated to give a residue which was flash-chromato-
graphed (CHCl3–hexane, 1:4 to 2:3) to give phenanthrol 5e (39.1
mg, 10%) as a colorless oil and fluorene 4e (237.2 mg, 63%) as a
colorless solid.
Fluorene 4e
Colorless needles; mp 118.0–119.6°C (recrystallized from CH2Cl2–
hexane).
1H NMR (CDCl3): = 7.800 (1 H, d, J = 7.70 Hz), 7.744 (2 H, dd,
J = 8.43, 1.10 Hz), 7.641 (1 H, s), 7.480 (1 H, dd, J = 7.52, 7.33 Hz),
7.402 (1 H, dd, J = 7.51, 7.33 Hz), 7.365–7.212 (7 H, m), 7.066 (1
H, dd, J = 7.70, 0.92 Hz), 5.538 (1 H, s), 2.441 (3 H, s).
The melting points were measured with a Yanaco Micro Melting
Point Apparatus (MP-500D) and are uncorrected. H NMR (400
MS (EI+): m/z = 284 (M+).
1
Anal. Calcd for C21H16O H2O: C, 86.78; H, 5.79. Found: C, 86.65;
H, 5.69.
MHz) spectra were measured on a JEOL Caliber-GX400 NMR
spectrometer with TMS as an internal reference in CDCl3 as the sol-
vent, unless otherwise specified. Chemical shifts are shown in ppm.
Coupling constants are given in Hertz. HRMS (EI+) spectra were re-
corded on a Jeol JMS-SX 102A instrument. IR spectra were record-
ed as KBr suspension on a Nicolet Avatar 360 FT-IR spectrometer.
Trifluoromethanesulfonic acid (TFSA) was purchased from Central
Glass Co. (Japan), and was used after distillation under reduced
pressure. The combustion analyses were carried out in the microan-
alytical laboratory of this faculty.
Phenanthrol 5e
1H NMR (CDCl3): = 8.703 (1 H, d, J = 7.52 Hz), 8.462 (1 H, s),
8.371 (1 H, dd, J = 8.61, 1.47 Hz), 7.783–7.182 (9 H, m), 5.389 (1
H, s), 2.568 (3 H, s).
MS (EI+): m/z = 284 (M+).
HRMS (EI+): m/z Calcd for C21H16O: 284.1202. Found: 284.1196.
O-Trimethylsilylcyanohydrin of 4-Fluorobenzophenone (9f)
To a solution of 8f (2.00 g, 10 mmol) and a catalytic amount of ZnI2
(154 mg, 0.48 mmol) in anhyd CH2Cl2 (32 mL) was added TMSCN
(4.048 g, 4 equiv) at 0°C over 60 min. The mixture was stirred at
50°C for 24 h. The residue, obtained after evaporation of the sol-
vent, was diluted with CHCl3, and the organic layer was washed
with brine and dried (Na2SO4). The solvent was evaporated to give
9f (2.706 g, 93%) as a colorless oil.
1H NMR (CDCl3): = 7.519–7.439 (4 H, m), 7.394–7.313 (3 H, m),
7.042 (2 H, t, J = 8.62 Hz), 0.137 (9 H, s).
MS (EI+): m/z = 299 (M+).
O-Trimethylsilylcyanohydrin of 4-Methylbenzophenone (9e)13
To a solution of 8e (2.00 g, 10.2 mmol) and a catalytic amount of
ZnI2 (163 mg, 0.51 mmol) in anhyd CH2Cl2 (40 mL) was added
TMSCN (4.26 g, 4 equiv) at 0°C under argon over 30 min. The mix-
ture was stirred at 50°C for 12 h. The residue, obtained after evap-
oration of the solvent, was diluted with CHCl3, and the organic layer
was washed with brine and dried (Na2SO4). The solvent was evap-
orated to give 9e (2.701 g, 76%) as a pale yellow oil.
1H NMR (CDCl3): = 7.488 (2 H, dd, J = 8.25, 1.46 Hz), 7.377–
7.323 (5 H, m), 7.153 (2 H, d, J = 8.07 Hz), 2.338 (3 H, s), 0.129 (9
H, s).
MS (EI+): m/z = 295 (M+).
-Benzoyl(4-fluorophenyl)phenylmethanol (2f)
To the Grignard reagent prepared from bromobenzene (4.564 g, 3
equiv) and Mg turnings (777 mg, 3.3 equiv) in anhyd Et2O (12 mL)
Synthesis 2001, No. 10, 1487–1494 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Regioselective Electrocyclization of Diphenylmethyl Cations to Fluorenes, Phenanthrols and Benzofurans
1491
was added a solution of 9f (2.706 g, 9.7 mmol) in anhyd Et2O (4
mL) over 20 min. The mixture was stirred at r.t. for 6 h and added
to aq 10% H2SO4 (200 mL) and stirred at r.t. for 18 h. The mixture
was extracted with CHCl3, and the organic layer was washed with
brine and dried (Na2SO4). The residue, obtained after evaporation of
the solvent, was dissolved in EtOH (35 mL), and the resultant solu-
tion was treated with 3 N aq HCl (3 mL) at 50°C for 5 h. The solvent
was evaporated to give a residue which was flash-chromatographed
(EtOAc–hexane, 1:9) to give 2f (1.791 g, 60%) as colorless needles;
mp 78.4–79.4°C (recrystallized from CH2Cl2–hexane).
Anal. Calcd for C15H11F3O2 0.8H2O: C, 62.31; H, 3.09. Found: C,
62.25; H, 3.11.
Acid-Catalyzed Reaction of -Benzoyl(pentafluoro-
phenyl)phenylmethanol (2g)
To pre-cooled TFSA (23.4 mL, 500 equiv) at –48°C (in a dry ice-
MeCN bath) was added 2g (200 mg, 0.53 mmol) over 5 min. After
stirring at –48°C for 1 h, the mixture was poured into ice-water (400
mL), extracted with CHCl3, the CHCl3 layer washed with brine and
dried (Na2SO4). The solvent was evaporated to give a residue which
was flash-chromatographed (CHCl3–hexane, 3:7) to give phenan-
throl 5’g (67 mg, 41%) as a solid.
1H NMR (CDCl3): = 7.695 (2 H, dd, J = 8.43, 1.28 Hz), 7.484–
7.278 (10 H, m), 7.023 (2H, t, J = 8.98 Hz), 4.976 (1 H, s).
MS (EI+): m/z = 201 (M+ – COPh).
Phenanthrol 5’g
Off-white powder; mp 140.0–144.2°C (recrystallized from hexane–
CH2Cl2).
Anal. Calcd for C20H15FO2: C, 78.42; H, 4.94. Found: C, 78.24; H,
4.96.
1H NMR (CDCl3): = 8.755 (1 H, d, J = 8.43 Hz), 8.703 (1 H, d,
J = 8.06 Hz), 8.309 (1 H, d, J = 7.88 Hz), 7.795 (1 H, t, J = 7.32 Hz),
7.716 (1 H, t, J = 7.52 Hz), 7.578 (1 H, t, J = 7.15 Hz), 7.522 (1 H, t,
J = 7.70 Hz), 5.233 (1 H, s).
MS (EI+): m/z = 360 (M+).
HRMS (EI+): m/z Calcd for C20H9F5O: 360.0554. Found: 360.0573.
Acid-Catalyzed Reaction of -Benzoyl(4-fluorophenyl)-
phenylmethanol (2f)
To pre-cooled TFSA (28.8 mL, 500 equiv) at –48°C (in a dry ice-
MeCN bath) was added a solution of 2f (200 mg, 0.65 mmol) over
10 min. After stirring at –48°C for 2.5 h, the mixture was poured
into ice-water (300 mL), extracted with CHCl3, and the organic lay-
er was washed with brine and dried (Na2SO4). The solvent was
evaporated to give a residue which was flash-chromatographed
(CHCl3–hexane, 3:7) to give phenanthrol 5’f (85 mg, 45%) as a pink
solid and fluorene 4f (65 mg, 34%) as a colorless solid.
O-Trimethylsilylcyanohydrin of 4-Trifluoromethylbenzo-
phenone (9h)
To a solution of 8h (3.00 g, 12 mmol) and a catalytic amount of ZnI2
(191 mg, 0.6 mmol) in CH2Cl2 (40 mL) was added TMSCN (2.38
g, 2 equiv) at 0°C over 30 min. The mixture was stirred at 40°C for
24 h. The residue, obtained after evaporation of the solvent, was di-
luted with CHCl3, and the organic layer was washed with brine and
dried (Na2SO4). The solvent was evaporated to give 9h in quantita-
tive yield as a yellow oil.
1H NMR (CDCl3): = 7.628 (4 H, s), 7.490 (2 H, d, J = 6.60 Hz),
7.375 (3 H, d, J = 7.52 Hz), 0.156 (9 H, s).
MS (EI+): m/z = 349 (M+).
Fluorene 5’f
Colorless solid; mp 149.1–150.0°C (recrystallized from hexane).
1H NMR (CDCl3): = 7.789 (2 H, d, J = 7.70 Hz), 7.760 (2 H, dd,
J = 8.43, 1.28 Hz), 7.534–7.269 (8 H, m), 6.907 (1 H, ddd, J = 9.16,
8.43, 2.38 Hz), 5.589 (1 H, s).
HRMS (EI+): m/z Calcd for C20H13FO: 288.0947. Found: 288.0950.
Anal. Calcd for C20H13FO H2O: C, 78.42; H, 4.92. Found: C, 78.46;
H, 4.93.
-Benzoylphenyl(4-trifluoromethylphenyl)methanol (2h)
To the Grignard reagent prepared from bromobenzene (4.706 g, 3
equiv) and Mg turnings (801 mg, 3.3 equiv) in anhyd Et2O (14 mL)
was added a solution of 9h (3.491 g, 10 mmol) in anhyd Et2O (4
mL) over 30 min. The mixture was stirred at r.t. for 4 h. The mixture
was added to 10% aq H2SO4 (200 mL), and stirred at r.t. for 11 h.
The mixture was extracted with CHCl3, and the organic layer was
washed with brine, and dried (Na2SO4). The residue, obtained after
evaporation of the solvent was dissolved in EtOH (35 mL), and the
resultant solution was treated with 3 N aq HCl (8 mL) at 40°C for 3
h. The solvent was evaporated to give a residue, which was diluted
with CHCl3. The organic layer was washed with brine and dried
(Na2SO4). The residue, obtained after evaporation of the solvent,
was flash-chromatographed (EtOAc–hexane, 1:9) to give 2h
(3.0824 g, 86%) as a yellow oil which solidified; colorless solid; mp
64.9–69.0°C (recrystallized from hexane).
Phenanthrol 5’f
Pink plates; mp 159.3–164.0°C (recrystallized from CHCl3–hex-
ane).
1H NMR (CDCl3): = 8.721 (1 H, dd, J = 8.25, 0.73 Hz), 8.682 (1
H, dd, J = 8.07, 0.72 Hz), 8.386 (1 H, dd, J = 7.52, 1.47 Hz), 7.753–
7.285 (9 H, m), 5.359 (1 H, s).
MS (EI+): m/z = 288 (M+).
Anal. Calcd for C20H13FO: C, 83.32; H, 4.54. Found: C, 83.03; H,
4.59.
-Benzoyl(pentafluorophenyl)phenylmethanol (2g)15
To a solution of pentafluorobenzene (2.0 g, 11.9 mmol) in Et2O (6
mL) was added a solution of BuLi in hexane (7.8 mL, 1.52 mmol/
mL, 1 equiv) at –55°C over 20 min under argon. The mixture was
stirred at –55°C for 2 h, and then cooled to –78°C. To the resultant
solution was added a solution of benzil (2.5 g, 1 equiv) in THF (3
mL) over 10 min and the mixture was stirred for 2 h at –78°C. The
cooling bath was removed to warm the mixture to r.t. The mixture
was stirred for 1 h, poured into 3 N aq HCl (200 mL), and extracted
with CHCl3. The organic layer was washed with brine and dried
(Na2SO4). The solvent was evaporated to give a residue which was
flash-chromatographed (EtOAc–hexane, 1:99) to give 2g (2.2 g,
49%) as a colorless powder; mp 106.9–108.2°C (recrystallized
from hexane).
1H NMR (CDCl3): = 7.702 (2 H, d, J =7.70 Hz), 7.585 (4 H, dd,
J = 12.28, 8.80 Hz), 7.483 (1 H, t, J = 7.33 Hz,), 7.375 (5 H, s), 7.372
(2 H, t, J = 7.88 Hz), 4.970 (1 H, s).
MS (EI+): m/z = 175 (M+ – COPh).
Anal. Calcd for C21H15F3O2: C, 70.78; H, 4.24. Found: C, 70.58; H,
4.53.
TFSA-Catalyzed Reaction of -Benzoylphenyl(4-trifluoro-
methylphenyl)methanol (2h)
To pre-cooled TFSA (27.8 mL, 500 equiv) at –48°C (in a dry ice-
MeCN bath) was added 2h (200 mg, 0.56 mmol) over 10 min. After
stirring at –48°C for 30 min, the mixture was poured into ice-water
1H NMR (CDCl3): 7.828 (2 H, d, J = 7.70 Hz), 7.643–7.331 (8 H,
m), 5.300 (1 H, s).
MS (EI+): m/z = 273 (M+ – COPh).
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N. Yoshida, T. Ohwada
PAPER
(300 mL), extracted with CHCl3, and the organic layer was washed
with brine and dried (Na2SO4). The solvent was evaporated to give
a residue, which was flash-chromatographed (CHCl3–hexane, 3:7)
to give phenanthrol 5’h (83.3 mg, 44%) as a solid.
1H NMR (CDCl3): = 7.714 (2 H, dd, J = 8.43, 1.28 Hz), 7.448–
7.228 (10 H, m), 6.865 (2 H, dd, J = 6.78, 2.20 Hz), 4.985 (1 H, s),
3.804 (3 H, s).
MS (EI+): m/z = 253 (M+ – COPh).
Phenanthrol 5’h
Pale yellow powder; mp 170.0–171.1°C (recrystallized from hex-
ane).
1H NMR (CDCl3): = 8.728 (2 H, d, J = 8.25 Hz), 8.691 (1 H, d,
J = 8.25 Hz), 8.395 (2 H, t, J = 7.88 Hz), 7.902 (2 H, d, J = 7.88 Hz),
7.762–7.291 (9 H, m), 5.28 (1 H, s).
MS (EI+): m/z = 338 (M+).
HRMS (EI+): m/z Calcd for C21H13F3O: 338.0907. Found:
TFSA-Catalyzed Reaction of -Benzoyl(4-methoxyphenyl)-
phenylmethanol (2i)
To pre-cooled TFSA (27.6 mL, 500 equiv) at –48°C (in a dry ice-
MeCN bath) was added a solution of 2i (200 mg, 0.63 mmol) in
CH2Cl2 (3 mL) over 10 min. After stirring at 24°C even for 10 h, the
reaction was very slow. After gentle heating at 40°C for 22 h, the
mixture was poured into ice-water. It was extracted with CHCl3, and
the organic layer was washed with brine and dried (Na2SO4). The
organic solvent was evaporated to give a residue which was flash-
chromatographed (CHCl3–hexane, 1:4 to 2:3) to give benzofuran 3i
(88 mg, 46%) as a colorless solid.
338.0916.
TFA-Catalyzed Reaction of -Benzoylphenyl(4-trifluoro-
methylphenyl)methanol (2h)
Benzofuran 3i
To pre-cooled TFA (10.7 mL, 500 equiv) at –15°C (in a dry ice-
CCl4 bath) was added 2h (100 mg, 0.28 mmol) over 10 min. After
stirring at –15°C for 1 h and then at 0°C for 2 h, the mixture was
poured into ice-water (300 mL). The mixture was extracted with
CHCl3, and the organic layer was washed with brine and dried
(Na2SO4). The solvent was evaporated to give a residue which was
flash-chromatographed (CHCl3–hexane, 1:9) to give -benzoylphe-
nyl(4-trifluoromethylphenyl)methyl trifluoroacetate (33.6 mg,
27%) as a colorless oil and the starting material 2h (46.5 mg, 47%
recovery).
Colorless powder; mp 126.0–126.9°C (recrystallized from hexane).
1H NMR (CDCl3): = 7.619 (2 H, dd, J = 6.72, 1.65 Hz), 7.513–
7.239 (9 H, m), 7.099 (1 H, d, J = 2.20 Hz), 6.876 (1 H, dd, J = 8.62,
2.20 Hz), 3.890 (3 H, s).
MS (EI+): m/z 300 (M+).
Anal. Calcd for C21H16O2: C, 83.98; H, 5.37. Found: C, 83.79; H,
5.54.
TFA-Catalyzed Reaction of -Benzoyl(4-methoxyphenyl)-
phenylmethanol (2i)
-Benzoylphenyl(4-trifluoromethylphenyl)methyl Trifluoro-
methylacetate
To pre-cooled TFA (9 mL, 500 equiv) at –15°C (in a dry ice-CCl4
bath) was added a solution of 2i (75.0 mg, 0.24 mmol) in CH2Cl2 (3
mL) over 10 min. After stirring at 0°C for 2 h, the mixture was
poured into ice-water. It was extracted with CHCl3, and the organic
layer was washed with brine and dried (Na2SO4). The organic sol-
vent was evaporated to give a residue, which was flash-chromato-
graphed (CHCl3–hexane, 1:4) to give benzofuran 3i (37.0 mg, 52%)
as a colorless solid. This product was identical with that obtained
above.
1H NMR (CDCl3): = 7.738 (2 H, d, J = 7.70 Hz), 7.683 (2 H, d,
J = 8.43 Hz), 7.637 (2 H, d, J = 7.70 Hz), 7.565 (2 H, d, J = 6.96 Hz),
7.515–7.399 (4 H, m), 7.345 (2 H, t, J = 7.70 Hz).
MS (EI+): m/z = 339 (M+ – CF3CO2), 105 (PhCO).
IR (KBr suspension): = 1794 (C=O of CF3CO2), 1695 cm–1 (C=O
of benzoyl).
O-Trimethylsilylcyanohydrin of 4-Methoxybenzophenone (9i)
To a solution containing 8i (2.00 g, 9.4 mmol) and a catalytic
amount of ZnI2 (150 mg, 0.47 mmol) in anhyd CH2Cl2 (31 mL) was
added TMSCN (3.73 g, 4 equiv) at 0°C over 15 min. The mixture
was stirred at 40°C for 12 h. The residue, obtained after evaporation
of the solvent, was diluted with CHCl3. The organic layer was
washed with brine, dried (Na2SO4) and the solvent was evaporated
to give 9i (2.790 g, 95%) as a yellow oil.
1H NMR (CDCl3): = 7.483 (2 H, ddd, J = 8.06. 2.10, 1.65 Hz),
7.391 (2 H, dd, J = 8.98, 2.20 Hz), 7.355–7.329 (3 H, m), 6.866 (2
H, dd, J = 8.17, 2.20 Hz), 0.129 (9 H, s).
O-Trimethylsilylcyanohydrin of Benzophenone 9j (= 9k)
To a solution of benzophenone (8j = 8k; 2.00 g, 11 mmol) and a cat-
alytic amount of ZnI2 (175 mg, 0.55 mmol, 0.05 equiv) in anhyd
CH2Cl2 (37 mL) was added TMSCN (4.36 g, 4 equiv) at 0°C over
0.5 h and the mixture was stirred at 40°C for 17 h. The residue, ob-
tained after evaporation of the solvent, was diluted with CHCl3, and
the organic layer was washed with brine and dried (Na2SO4). The
solvent was evaporated to give 9j (= 9k) (3.02 g, 97%) as a colorless
oil.
1H NMR (CDCl3): = 7.497 (4 H, ddd, J = 6.87, 2.20, 1.65 Hz),
7.376–7.294 (6 H, m), 0.135 (9 H, s).
MS (EI+): m/z = 281 (M+).
MS (EI+): m/z = 311 (M+).
-Benzoyl(4-methoxyphenyl)phenylmethanol (2i)
IR (KBr suspension): = 2326 cm–1 (CN).
To the Grignard reagent prepared from bromobenzene (4.22 g, 3
equiv) and Mg turnings (718 mg, 3.3 equiv) in anhyd Et2O (7 mL)
was added a solution of 9i (2.79 g, 9 mmol) in anhyd Et2O (4 mL)
over 30 min. The mixture was stirred at r.t. for 4 h and added to 10%
aq H2SO4 (200 mL) and stirred at r.t. for 18 h. The mixture was ex-
tracted with CHCl3, and the organic layer was washed with brine,
and dried (Na2SO4). The residue obtained after evaporation of the
solvent was dissolved in EtOH (35 mL), and the resultant solution
was treated with 3 N aq HCl (5 mL) at 50°C for 12 h. The solvent
was evaporated to give a residue, which was diluted with CHCl3 and
the organic layer was washed with brine, and dried (Na2SO4). The
residue, obtained after evaporation of the solvent, was flash-chro-
matographed (EtOAc–hexane, 1:9) to give 2i (550 mg, 19%) as a
yellow oil.
-(p-Methylbenzoyl)diphenylmethanol (2j)
To the Grignard reagent prepared from p-bromotoluene (5.634 g, 3
equiv) and Mg turnings (880 mg, 3.3 equiv) in anhyd Et2O (8 mL)
was added a solution of 9j (3.226 g, 11.5 mmol) in anhyd Et2O (4
mL) over 15 min. The mixture was stirred at r.t. for 4 h and added
to aq 10% H2SO4 (200 mL) and stirred at 40°C for 13 h. It was then
extracted with CHCl3, the organic layer washed with brine, and
dried (Na2SO4). The residue, obtained after evaporation of the or-
ganic solvent was dissolved in EtOH (35 mL), and the resultant so-
lution was treated with 3 N aq HCl (8 mL) at 40°C for 2.5 h. The
solvent was evaporated to give a residue, which was diluted with
CHCl3, and the organic layer was washed with brine, and dried
(Na2SO4). The residue, obtained after evaporation of the solvent,
Synthesis 2001, No. 10, 1487–1494 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Regioselective Electrocyclization of Diphenylmethyl Cations to Fluorenes, Phenanthrols and Benzofurans
1493
was flash-chromatographed (EtOAc–hexane, 1:19) to give 2j
(2.5146 g, 75%) as a yellow oil which solidified; colorless solid; mp
64.5–65.5°C (recrystallizaed from hexane).
1H NMR (CDCl3): = 7.635 (2 H, d, J = 8.06 Hz), 7.424–7.324 (10
H, m), 7.079 (2 H, d, J = 7.88 Hz), 5.188 (1 H, s), 3.799 (3 H, s).
stirring at –48°C for 50 min, the mixture was poured into ice-water
(300 mL) and extracted with CHCl3. The organic layer was washed
with brine and dried (Na2SO4). The solvent was evaporated to give
a residue which was flash-chromatographed (CHCl3–hexane, 7:15
to 1:1 to 3:2) to give fluorene 4k (313.7 mg, 83%) as a solid.
MS (EI+): m/z = 183 (M+ – COPhCH3).
Fluorene 4k
Colorless needles; mp 126.0–126.7°C (recrystallized from hexane).
Anal. Calcd for C21H18O2: C, 83.42; H, 6.00. Found: C, 83.50; H,
6.11.
1H NMR (CDCl3): = 7.860 (2 H, d, J = 7.70 Hz), 7.667 (2 H, dd,
J = 9.62, 6.78 Hz), 7.467–7.283 (6 H, m), 6.979 (2 H, t, J = 8.61 Hz),
5.509 (1 H, s).
Acid-Catalyzed Reaction of -(4-Methylbenzoyl)diphenyl-
methanol (2j)
MS (EI+): m/z = 288 (M+).
To pre-cooled TFSA (58.5 mL, 500 equiv) at –48°C (in a dry ice-
MeCN bath) was added 2j (400 mg, 1.33 mmol) over 10 min. After
stirring at –48°C for 1 h, the mixture was poured into ice-water (300
mL) and extracted with CHCl3. The organic layer was washed with
brine and dried (Na2SO4). The solvent was evaporated to give a res-
idue which was flash-chromatographed (CHCl3–hexane, 1:4 to 1:1)
to give phenanthrol 5j (51.6 mg, 14%) as a colorless oil (solidfied)
and fluorene 4j (260.5 mg, 69%) as a yellow solid.
Anal. Calcd for C20H13FO: C, 83.32; H, 4.54. Found: C, 83.04; H,
4.65.
Acknowledgement
Part of the work was financially supported by Takeda Science
Foundation (Osaka, Japan).
Phenanthrol 5j
Colorless powder; mp 93.5–94.3°C (recrystallized from hexane).
References
1H NMR (CDCl3): = 8.667 (1 H, d, J = 8.25 Hz), 8.506 (1 H, s),
8.274 (2 H, d, J = 8.25 Hz), 7.623 (2 H, d, J = 7.15 Hz), 7.559–7.364
(7 H, m), 5.425 (1 H, s), 2.659 (3 H, s).
MS (EI+): m/z = 284 (M+).
HRMS (EI+): m/z Calcd for C21H16O: 284.1202. Found: 284.1194.
(1) (a) Creary, X. Chem. Rev. 1991, 91, 1625. (b) Creary, X.;
Hopkinson, A. C.; Lee-Ruff, E. Advances in Carbocation
Chemistry, Vol. 1; Creary, X., Ed.; JAI Press: Greenwich,
CT, 1989, 45. (c) Gassman, P. G.; Tidwell, T. T. Acc. Chem.
Res. 1983, 16, 279. (d) Tidwell, T. T. Angew. Chem., Int.
Ed. Engl. 1984, 23, 20.
(2) (a) Dao, L. H.; Maleki, M.; Hopkinson, A. C.; Lee-Ruff, E.
J. Am. Chem. Soc. 1986, 108, 5237. (b) Hopkinson, A. C.;
Lee-Ruff, E.; Maleki, M. Synthesis 1986, 366.
(3) Johnston, L. J.; Kwong, P.; Shelemay, A.; Lee-Ruff, E. J.
Am. Chem. Soc. 1993, 115, 1664.
Fluorene 4j
Colorless needles; mp 126.9–128.5°C (recrystallized from hexane).
1H NMR (CDCl3): = 7.842 (2 H, d, J = 7.52 Hz), 7.659 (2 H, d,
J = 8.25 Hz), 7.427 (2 H, t, J = 7.52 Hz), 7.390 (2 H, d, J = 7.33 Hz),
7.265 (2 H, t, J = 7.51 Hz), 7.165 (2 H, d, J = 8.07 Hz), 5.599 (1 H,
s), 2.364 (3 H, s).
(4) Takeuchi, K.; Kitagawa, T.; Okamato, K. J. Chem. Soc.,
Chem. Commun. 1983, 7.
MS (EI+): m/z 284 (M+).
(5) Photochemical cyclizations of methoxy-substituted benzoin
esters (e.g., 4'-methoxybenzoin acetate) to give benzofurans
(2-phenyl-6-methoxybenzofuran) was reported by Sheehan,
J. C.; Wilson, R. M.; Oxford, A. W. J. Am. Chem. Soc. 1971,
93, 7222.
Anal. Calcd for C21H16O 0.48H2O: C, 86.07; H, 5.83. Found: C,
86.07; H, 5.54.
-(4-Fluorobenzoyl)diphenylmethanol (2k)
(6) It was reported that -acetyldiphenylmethanol (2b, R = CH3)
and -benzoyldiphenylmethanol (2d, R1 = R2 = H) cyclized
in H2SO4–CHCl3 by an electrocyclization mechanism
between the benzene ring and the carbonyl group, resulting
in the formation of the corresponding benzofurans,2,10
although the formation of the fluorene derivative 4d from 2d
has also been reported under similar conditions.11
(7) (a) Vorlander, D.; Pritzsche, A. Ber. Dtsch. Chem. Ges.
1913, 46, 1793. (b) Britzrzycki, A.; Herbst, C. Ber. Dtsch.
Chem. Ges. 1903, 36, 145. (c) Dobeneck, H. V.; Kiefer, R.
Liebigs Ann. Chem. 1965, 684, 115. (d) Arnold, R. T.;
Parham, W. E.; Dodson, R. M. J. Am. Chem. Soc. 1949, 71,
2439. (e) Hopkinson, A. C.; Khazanie, P. G.; Dao, L. H. J.
Chem. Soc., Perkin Trans. 2 1979, 1395. (f) Delacre, M.
Bull. Soc. Chim. Fr. 1918, 23, 229.
To the Grignard reagent prepared from 1-bromo-4-fluorobenzene
(5.765 g, 3 equiv) and Mg turnings (880 mg, 3.3 equiv) in anhyd
Et2O (8 mL) was added a solution of 9j (= 9k) (3.020 g, 10. 8 mmol)
in anhyd Et2O (5 mL) over 5 min. The mixture was stirred at r.t. for
5 h, then added to aq 10% H2SO4 (200 mL), and stirred at 40°C for
24 h. The mixture was extracted with CHCl3, the organic layer was
washed with brine and dried (Na2SO4). The residue, obtained after
evaporation of the solvent was dissolved in EtOH (35 mL), and the
solution was treated with 3 N aq HCl (8 mL) at 40°C for 9 h. The
solvent was evaporated to give a residue, which was diluted with
CHCl3. The organic layer was washed with brine and dried
(Na2SO4). The residue, obtained after evaporation of the solvent,
was flash-chromatographed (EtOAc–hexane, 1:39) to give 2k
(1.698 g, 65%) as a yellow solid; colorless powder; mp 82.9–
83.1°C (recrystallized from hexane–CH2Cl2).
(8) (a) Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1988, 110,
1862. (b) Ohwada, T.; Shudo, K. J. Org. Chem. 1989, 54,
5227.
1H NMR (CDCl3): = 7.707 (2 H, d, J = 7.70 Hz), 7.557–7.438 (6
H, m), 7.311 (2 H, t, J = 7.70 Hz), 4.776 (1 H, s).
(9) Ohwada, T.; Suzuki, T.; Shudo, K. J. Am. Chem. Soc. 1998,
120, 4629.
(10) Hopkinson, A. C.; Dao, L. H.; Duperrouzel, P.; Maleki, M.;
Lee-Ruff, E. J. Chem. Soc., Chem. Commun. 1983, 727.
(11) Maleki, M.; Hopkinson, A. C.; Lee-Ruff, E. Tetrahedron
Lett. 1983, 24, 4911.
Anal. Calcd for C20H15FO2: C, 70.42; H, 4.94. Found: C, 70.19; H,
4.97.
Acid-Catalyzed Reaction of -(4-Fluorobenzoyl)diphenyl-
methanol (2k)
To pre-cooled TFSA (57.8 mL, 500 equiv) at –48°C (in a dry ice-
MeCN bath) was added 2k (400 mg, 1.3 mmol) over 6 min. After
Synthesis 2001, No. 10, 1487–1494 ISSN 0039-7881 © Thieme Stuttgart · New York

1494
N. Yoshida, T. Ohwada
PAPER
(13) (a) Krepski, L. R.; Heilmann, S. M.; Rasmussen, J. K.
Tetrahedron Lett. 1983, 24, 4075. (b) Gassman, P. G.;
Talley, J. J. Tetrahedron Lett. 1978, 3773.
(14) Johnson, C. D. Acc. Chem. Res. 1993, 26, 476.
(15) Chambers, R. D.; Clark, M. J. Chem. Soc., Perkin Trans. 1
1972, 2469.
(12) (a) Olah, G. A.; Wu, A.-H. J. Org. Chem. 1991, 56, 2531 .
(b) For a review of superelectrophiles, see: Olah, G. A.
Angew. Chem., Int. Ed. Engl. 1993, 32, 767. (c) See also:
Olah, G. A.; Klumpp, D. A.; Nlyer, G.; Wang, Q. Synthesis
1996, 321.
Synthesis 2001, No. 10, 1487–1494 ISSN 0039-7881 © Thieme Stuttgart · New York