Regiocomplementary synthesis of fluorinated bridged biphenyls

Article abstract of DOI:10.1055/s-0032-1316559

Complementary synthesis of two kinds of fluorinated bridged biphenyls has been developed by the combination of oxidative carbon-carbon bond formation and deoxyfluorination. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316559

1978▌
LETTER
lRetteergiocomplementary Synthesis of Fluorinated Bridged Biphenyls
Fluorinated Bridged Biphenyls
Hiroyuki Nemoto, Keita Takubo, Kazuki Shimizu, Shuji Akai*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan
Fax +81(54)2645672; E-mail: akai@u-shizuoka-ken.ac.jp
Received: 02.05.2012; Accepted after revision: 24.05.2012
OH
Abstract: Complementary synthesis of two kinds of fluorinated
OH
bridged biphenyls has been developed by the combination of oxida-
tive carbon–carbon bond formation and deoxyfluorination.
OH
HO
OMe
OMe
HO
Key words: fluorine, deoxyfluorination, biaryls, umpolung, hyper-
valent iodine
HO
OH
H
MeO
O
NHMe
HO
metasequirine B
OMe
jerusalemine
The introduction of fluorine atom(s) to pharmaceuticals or
agrochemicals often causes many beneficial effects such
as the dramatic improvement of their metabolic stability,
biological activity, lipophilicity, and bioavailability com-
pared to the original molecules.1–3 The substitution of an
oxygen functional group with a fluorine atom, which is
considered to be a kind of bioisostere, has been widely
used in drug discovery processes because the van der
Waals radius of fluorine is closer to that of oxygen as is its
electronegativity.2a While a large number of methodolo-
gies for the substitution of aliphatic hydroxyl groups with
fluorine atoms have been reported,4,5 the similar substitu-
tion of aromatic hydroxyl groups with fluorine atoms is
under development.6 We recently reported a variety of ex-
amples of the novel direct conversion of one of the hy-
droxy groups of a catechol derivative into fluorine via an
ortho-quinone generated in situ by oxidation.7
HO
MeO
OMe
OMe
MeO
MeO
MeO
MeO
N
NHAc
Me
kreysigine
NSC 51046
Figure 1 Biologically active bridged biphenyls
Thus, the fluorination of the 3-hydroxyspirodienone 2
would provide a fluorinated intermediate 3, which led to
2-fluoro bridged biphenyl 4 via the 1,2-migration of the
phenyl moiety. On the other hand, the fluorination of
ortho-quinone 6, generated in situ by the oxidation of 5,
would selectively proceed at the C3 carbonyl group be-
cause the C2 carbonyl group of 6 was stabilized by the
phenyl substituent.17 The substrates 2 and 5 would be
available from the same catechol 1 by the oxidative car-
bon–carbon bond formation and the subsequent dienone–
phenol rearrangement,18 respectively. Our experiments
based on this strategy led to the following results.
A class of compounds possessing a highly oxygenated
bridged biphenyl motif, such as metasequirine B,8 jerusa-
lemine,9 kreysigine,10 and NSC 5104611 (Figure 1), and
their derivatives exhibit some important biological activi-
ties including an anticancer activity and muscle-relaxant
effect. The substitution of one of the oxygen functional
groups of these compounds with a fluorine atom may en-
hance their metabolic stability and lipophilicity and pro-
duce novel biological activities, potentially producing
new drug candidates.12 Indeed, some fluorine-containing
bridged biphenyls have been synthesized, although only
around a dozen such compounds have been already re-
ported.13–16
While the intramolecular oxidative carbon–carbon bond
formations of phenols and that of their ethers have been
intensively investigated,19 similar reactions of catechols
have been limited to a single example which used FeCl3 to
produce a bridged biphenyl.20 According to this proce-
dure, we first treated 1a [R1 = R2 = R3 = OMe, X =
C(CO2Me)2] with FeCl3 (3 equiv) in EtOH–H2O; howev-
er, it gave a complex mixture without including any cy-
clized products. After extensive experiments using a
variety of oxidants, the use of PhI(OAc)2 (1.05 equiv) in
the presence of an acid in 1,2-dimethoxyethane (DME)
was found to produce 2a [R1 = R2 = R3 = OMe, X =
C(CO2Me)2] (Scheme 2). Methanesulfonic acid (MsOH)
proved most efficient that produced 2a in 95% isolated
yield (Table 1, entry 4). Trifluoroacetic acid (TFA) and
trifluoromethanesulfonic acid (TfOH) were less effective
in producing 2a in 35% and 58% NMR yields, respective-
ly (Table 1, entries 3 and 5). Without any acid or with
AcOH (5 equiv), the reaction gave complex mixtures in-
We envisioned that our deoxyfluorination method cou-
pled with oxidative carbon–carbon bond formation would
provide the unprecedented regiocomplementary prepara-
tion of two types of fluorinated bridged biphenyls 4 and 7,
having various substitution patterns, from the same start-
ing catechol 1 (Scheme 1). This method would feature the
use of two specific substrates 2 and 6 for the fluorination.
SYNLETT 2012, 23, 1978–1984
Advanced online publication: 26.07.2012
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3
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2
1
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1
4
3
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0
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DOI: 10.1055/s-0032-1316559; Art ID: ST-2012-U0387-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Fluorinated Bridged Biphenyls
1979
O
OH
F
F
F
2
OH
O
R1
R1
OH
OH
R2
R3
R2
R1
R1
3
R2
R3
deoxyfluorination
R2
R3
rearrangement
R3
oxidation
X
X
X
X
1
2
3
4 (C-2 fluorination)
rearrangement
OH
O
OH
2
2
R1
R1
R1
OH
O
F
R2
R2
R3
R2
R3
3
3
deoxyfluorination
oxidation
R3
X
X
X
5
6
7 (C-3 fluorination)
Scheme 1 Outline of the preparation of two types of fluorinated bridged biphenyls 4 and 7
cluding ortho-quinone 8a, and no cyclization products Other ethereal solvents, such as THF, dioxane, and Et2O,
were obtained (Table 1, entries 1 and 2).
were also available for producing 2a, albeit in lower
yields (Table 1, entries 6–8). The dienone–phenol rear-
rangement of 2a took place to quantitatively give the
bridged biphenyl 5a by the treatment with MsOH (1
equiv) at 80 °C for 24 hours.
OH
O
PhI(OAc)2
R1
R1
(1.05 equiv)
acid
OH
O
R2
R3
R2
R3
(see Table 1)
We next applied these conditions to various catechols 1b–
f (Table 2). While the yields of the cyclization reaction (1
→ 2) were dependent on the electron density of the phenyl
moiety of the side chain (Table 2, entries 1–4), the
Thorpe–Ingold effect21 was only slightly observed (Table
2, entries 1 and 2 vs. entries 5 and 6). Although the mono-
methoxy derivative 1c gave a complex mixture under the
standard conditions, the slow addition of a solution of
PhI(OAc)2 in DME to a solution of 1c in DME over 30
minutes followed by the treatment with MsOH (20 equiv)
provided 2c in 43% yield (Table 2, entry 3). The rear-
rangement reactions of 2b–f smoothly occurred to give
5b–f in high yields (Table 2, entries 2–6). A similar cycli-
zation of 1g directly gave 5g, and the formation of 2g was
not observed at all (Table 2, entry 7).
solvent
X
X
1
8
O
OH
OH
R1
OH
R2
R3
R1
MsOH
R2
R3
DME
80 °C
X
X
2
5
Scheme 2 Oxidative cyclization of catechols 1 to give 2 and 5
Table 1 Some Typical Results of the Cyclization of 1a to 2aa
Entry
Solvent
Acid (equiv)
Temp Time Yieldof2a
(%)b
We then turned our attention to the fluorination of spiro-
dienone 2a. Although α,β-unsaturated carbonyl com-
pounds are known to be poorly reactive substrates for the
fluorination,22 2a reacted with Deoxofluor23 and provided
the desired ortho-fluorophenol 4a (40% NMR yield)
along with its regioisomer 9a (19% NMR yield) and a
difluoroketone 3a (14% NMR yield; Table 3, entry 1).24
The formation of 9a was unexpected, because 9a was pro-
duced by the migration of the phenyl group onto the more
electron-rich C2 position.25 Compound 3a was obtained
as a major product when DAST26 was used (Table 3, entry
2). While Xtalfluor-E27 exclusively caused the dienone–
phenol rearrangement of 2a to give 5a quantitatively (Ta-
ble 3, entry 3), the addition of Et3N·3HF27 effectively sup-
pressed the rearrangement and provided 4a and 9a in 41%
and 14% NMR yields, respectively (Table 3, entry 4). Al-
though a similar reaction was slow in chloroform, the ratio
of 4a to 9a was higher (Table 3, entry 5). The use of a
mixed solvent, i-Pr2O–CHCl3 (1:1), improved the yield of
4a significantly (63% NMR yield; Table 3, entry 6). The
(°C)
(h)
1
2
3
4
5
6
7
8
DME
DME
DME
DME
DME
THF
–
5
5
48
48
48
24
1
n.d.c
n.d.c
35
AcOH (5)
TFA (5)
MsOH (1)
TfOH (0.1)
MsOH (1)
MsOH (1)
MsOH (1)
5
5
87 (95)d
58
0
5
24
24
24
85
dioxane
Et2O
25
5
71
66
a Reaction conditions: PhI(OAc)2 (1.05 equiv) was added to a 0.1 M
solution of 1 in the presence of an acid, and the reaction mixture was
stirred at the given temperature.
b Yield was determined by 1H NMR analysis using 1,1,2,2-tetrachlo-
roethane as the internal standard.
c Not detected.
d Isolated yield.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1978–1984

1980
H. Nemoto et al.
LETTER
Table 2 Oxidative Cyclization of Various Catechols 1a–g to 2a–f and 5a–ga
Entry
1
R1
R2
R3
X
Isolated yield
Isolated yield
of 2 (%)
of 5 (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
OMe
H
OMe
OMe
H
OMe
OMe
OMe
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
CH2
2a 95
2b 77
2c 43b
2d 64c
2e 90
2f 86
2g –
5a 99
5b 96
5c 99
5d 95
5e 88d
5f 86d
5g 58e
H
H
–OCH2O–
OMe
OMe
OMe
OMe
H
OMe
OMe
OMe
CH2
1g
OMe
NTs
a Reaction conditions: PhI(OAc)2 (1.05 equiv) was added to the 0.1 M solution of 1 in the presence of MsOH (1.0 equiv) and stirred at 0 °C for
24 h.
b Slow addition of a solution of PhI(OAc)2 (1.05 equiv) in DME to a solution of 1c in DME over 30 min followed by the treatment with MsOH
(20 equiv) and stirred for 18 h.
c MsOH (3.0 equiv) was used.
d Overall yield from 1e or 1f.
e The reaction was conducted at 0.01 M using 50 equiv of MsOH and stirred at 0 °C for 1 h.
Table 3 Optimization of Conditions for the Fluorination of 2aa
O
F
F
F
F
OH
HO
O
+
OH
OH
OH
fluorination
MeO
MeO
MeO
3
2
MeO
MeO
MeO
MeO
reagent (6 equiv)
additive (6 equiv)
MeO
MeO
MeO
MeO
MeO
+
+
MeO
MeO
MeO
solvent
50 °C, 1.5 h
X
X
X
X
X
[X = C(CO2Me)2]
2a
4a
9a
3a
5a
Entry
Fluorination
reagent
Additive
Solvent
Yield of
Yield of
Yield of
Yield of
Yield of
4a (%)b
9a (%)b
3a (%)b
5a (%)b
2a (%)b
1
2
Deoxofluor
DAST
–
i-Pr2O
i-Pr2O
i-Pr2O
i-Pr2O
CHCl3
40 (30)c
21
19
15
–
14
47
–
–
–
–
–
–
–
–
–
18
–
–
–
–
–
3
Xtalfluor-E
Xtalfluor-E
Xtalfluor-E
Xtalfluor-E
Xtalfluor-E
Xtalfluor-E
Xtalfluor-E
Xtalfluor-E
Xtalfluor-E
Xtalfluor-M
Fluolead
–
–
99
–
4
Et3N·3HF
Et3N·3HF
Et3N·3HF
Et3N·5HF
Et3N·2HF
Et3N·HF
Et3N·HF
Et3N·HF
Et3N·3HF
Et3N·3HF
41
14
5
–
5
28
–
54
–
6
i-Pr2O–CHCl3 (1:1)
i-Pr2O–CHCl3 (1:1)
i-Pr2O–CHCl3 (1:1)
i-Pr2O–CHCl3 (1:1)
i-Pr2O–CHCl3 (2:1)
i-Pr2O–CHCl3 (1:2)
i-Pr2O
63
16
–
–
7
–
–
–
8
65
17
21
10
8
–
18
–
9
79
–
10
11
12
13
33
–
–
34
–
–
dec.
dec.
i-Pr2O
a Reaction conditions: The fluorination reagent was added to a solution of 2a and an additive in the given solvent, and the reaction mixture was
stirred at 50 °C for 1.5 h.
b The yield was determined by 1H NMR and 19F NMR analysis using 4-fluorotoluene as the internal standard; dec. = decomposed.
c Isolated yield in parentheses.
Synlett 2012, 23, 1978–1984
© Georg Thieme Verlag Stuttgart · New York

LETTER
Fluorinated Bridged Biphenyls
1981
addition of Et3N·5HF completely inhibited the reaction strates 2b,c provided 4b,c in good yields accompanied by
(Table 3, entry 7), and the yield of 4a increased as the ratio 9b,c (Table 4, entries 2 and 3). Although the reactions of
of Et3N to HF increased (Table 3, entries 7–9). The 2d–f with Xtalfluor-E led to complex mixtures, those with
change in the i-Pr2O–CHCl3 ratio had little effect on im- Deoxofluor provided 4d–f in 23–52% yields (Table 4, en-
proving the yield of 4a (Table 3, entries 10 and 11). The tries 4–6). Compounds 4a–f and 9a–f were easily separat-
use of other fluorination reagents, such as Xtalfluor-M27 ed by silica gel column chromatography.
and Fluorlead,28 caused substrate decomposition. As a
consequence, the use of Xtalfluor-E and Et3N·HF in i-
Pr2O–CHCl3 (1:1; Table 3, entry 9) were the optimal con-
The fluorination of the bridged catechols 5a–g was con-
ducted according to our previous study7 (equation 2 in
Scheme 3). Thus, 5a–g was treated with PhI(OAc)2 (1.05
equiv) in the presence of MgO (2.3 equiv) in CHCl3 at 0
°C for five minutes, and Deoxofluor (6 equiv) was then
ditions, and 4a was isolated in 74% yield along with 9a
(18% yield; Table 4, entry 1).29,30
We next applied the optimal conditions to the spirodie- added. The reaction mixture was stirred at 40 °C for one
nones 2b–f (equation 1 in Scheme 3, Table 4). The sub- hour.
O
F
F
HO
OH
Xtalfluor-E
Et3N·HF
R1
OH
R1
R2
R3
R2
R1
R2
R3
(1)
+
R3
i-Pr2OH–CHCl3
(1:1)
50 °C, 1.5 h
X
X
X
9a–f
2a–f
4a–f
OH
OH
1) PhI(OAc)2
MgO, CHCl3
5 min
then Deoxofluor
40 °C, 1 h
R1
F
R1
OH
R2
R3
R2
R3
(2)
+
4a–g
X
2) NaBH4, EtOH
X
7a–g
5a–g
R1
R2
R3
X
for 2, 4, 5, 7, and 9:
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
CH2
OMe
H
OMe
OMe
H
OMe
OMe
OMe
a
b
c
H
H
-OCH2O-
d
e
OMe
OMe
OMe
H
OMe
OMe
OMe
OMe
CH2
NTs
f
g
OMe
Scheme 3 Deoxyfluorination of 2 and 5
Table 4 Isolated Yields of 4 and 9 from 2a and of 7 and 4 from 5b
Entry
Compd 2
Isolated yield Isolated yield
Entry
Compd 5
Isolated yield Isolated yield
of 4 (%)
of 9 (%)
of 7 (%)
of 4 (%)
1
2a
2b
2c
2d
2e
2f
4a 74
4b 54
4c 54
4d 26
4e 52
4f 23
9a 18
9b 28
9c 32
9d 15
9e 4
7
8
5a
5b
5c
5d
5e
5f
7a 43
7b 37d
7c 37
7d 41
7e 41
7f 44
7g 62
4a 23
4b 18d
4c 17
4d 25
4e 25
4f 32
4g 10
2
3
9
4c
5c
6c
10
11
12
13
9f 7
5g
a Reaction conditions: Xtalfluor-E (6.0 equiv) was added to a solution of 2 and Et3N·HF (6.0 equiv) in i-Pr2O–CHCl3 (1:1, 0.2 M), and the re-
action mixture was stirred at 50 °C for 1.5 h.
b Reaction conditions: PhI(OAc)2 (1.05 equiv) was added to a solution of 5 in CHCl3 (0.2 M) in the presence of MgO (2.3 equiv), and the re-
action mixture was stirred at 0 °C for 5 min. Deoxofluor (6.0 equiv) was added to the solution, and the reaction mixture was stirred at 40 °C for
1 h.
c The reaction was conducted using Deoxofluor in CHCl3 instead of using Xtalfluor-E/Et3N·HF in i-Pr2O–CHCl3.
d Compounds 7b and 4b were obtained as a mixture, and their yields were determined by 1H NMR analysis.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1978–1984

1982
H. Nemoto et al.
LETTER
Y.; García-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science
2009, 325, 1661.
(7) Nemoto, H.; Nishiyama, T.; Akai, S. Org. Lett. 2011, 13,
2714.
(8) Enoki, A.; Takahama, S.; Kitao, K. Mokuzai Gakkaishi
1977, 23, 579.
The subsequent reduction of the crude products by NaBH4
(5 equiv) afforded the desired ortho-fluorophenols 7a–g
as the major products along with their regioisomers 4a–g
(Table 4, entries 7–13).30
In summary, we have developed the complementary syn-
thesis of two kinds of fluorinated bridged biphenyls 4 and
7.31 The appropriate use of the 3-hydroxyspirodienones 2
and the biphenyls 5, as the substrates of the fluorination
reaction, both of which were available from the same
compounds 1, was the key for the selective preparation.
This is the first example of the concurrent formation of a
C–F bond and a new C–C bond by the combination of the
deoxyfluorination and the 1,2-phenyl migration (2 → 4).
Because fluorine is considered to be a bioisostere not only
of oxygen, but also of hydrogen,2 this method allows the
synthesis of the core structure of the deoxyfluorinated an-
alogues of multioxygenated bridged biphenyls, such as
metasequirine B,8 jerusalemine,9 and also of the fluorinat-
ed analogues of bridged biphenyls, such as NSC 51046.11
We are currently investigating the improvement of the re-
gioselectivity of the fluorination reactions, and the appli-
cation of this methodology to the synthesis of fluorinated
analogues of biologically important bridged biphenyls.
(9) Abu Zarga, M. H.; Sabri, S. S.; Al-Tel, T. H.; Atta-ur-
Rahman; Shah, Z.; Feroz, M. J. Nat. Prod. 1991, 54, 936.
(10) Badger, G. M.; Bradbury, R. B. J. Chem. Soc. 1960, 445.
(11) Brecht, R.; Haenel, F.; Seitz, G. Liebigs Ann./Recl. 1997,
2275; and references cited therein.
(12) (a) Ferrari, F.; Claudi, F. Pharmacol., Biochem. Behav.
1991, 38, 131. (b) Claudi, F.; Cardellini, M.; Cingolani, G.
M.; Piergentili, A.; Peruzzi, G.; Balduini, W. J. Med. Chem.
1990, 33, 2408. (c) Kirk, K. L.; Olubajo, O.; Buchhold, K.;
Lewandowski, G. A.; Gusovsky, F.; McCulloh, D.; Daly,
J. W.; Creveling, C. R. J. Med. Chem. 1986, 29, 1982.
(13) The fluorinated bridged biphenyls have been prepared based
on Ullmann couling reaction,14 ring contraction of
colchicine,15 and carbanion-induced reaction.16
(14) Ahmed, S. R.; Hall, D. M. J. Chem. Soc. 1960, 4165.
(15) Dilger, U.; Franz, B.; Roettele, H.; Schroeder, G.; Herges, R.
J. Prakt. Chem./Chem.-Ztg. 1998, 340, 468.
(16) (a) Ram, V. J.; Agarwal, N. Tetrahedron Lett. 2002, 43,
4769. (b) Ram, V. J.; Agarwal, N.; Saxena, A. S.; Sharon,
A.; Farhanollah; Maulik, P. R. J. Chem. Soc., Perkin Trans.
1 2002, 1426.
(17) In our previous study, the fluorination of ortho-quinones
mainly proceeded at the less stabilized carbonyl groups, see
ref. 7.
Acknowledgment
(18) The regioselectivity of the dienone–phenol rearrangement
was reported to be completely controlled by electronic
factors, see:Frimer, A. A.; Marks, V.; Sprecher, M.;
Gilinsky-Sharon, P. J. Org. Chem. 1994, 59, 1831.
(19) For examples, see: (a) Hackelöer, K.; Schnakenburg, G.;
Waldvogel, S. R. Org. Lett. 2011, 13, 916. (b) Zhai, L.;
Shukla, R.; Rathore, R. Org. Lett. 2009, 11, 3474.
(c) Hamamoto, H.; Anilkumar, G.; Tohma, H.; Kita, Y.
Chem.–Eur. J. 2002, 8, 5377. (d) Feldman, K. S.; Lawlor,
M. D. J. Am. Chem. Soc. 2000, 122, 7396. (e) Tanaka, M.;
Mukaiyama, C.; Mitsuhashi, H.; Maruno, M.; Wakamatsu,
T. J. Org. Chem. 1995, 60, 4339. (f) Schwartz, M. A.; Kim,
P. P. T. J. Org. Chem. 1988, 53, 2318.
This work was supported in part by Grants-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science and
Technology (MEXT), Japan. H.N. is a recipient of the JSPS Fellow-
ship for Young Scientists.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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(c) Matsumura, Y.; Mori, N.; Nakano, T.; Sasakura, H.;
Matsugi, T.; Hara, H.; Morizawa, Y. Tetrahedron Lett. 2004,
45, 1527.
(23) (a) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.;
Cheng, H. J. Org. Chem. 1999, 64, 7048. (b) Lal, G. S.; Pez,
G. P.; Pesaresi, R. J.; Prozonic, F. M. Chem. Commun. 1999,
215.
(5) (a) Singh, R. P.; Shreeve, J. M. Synthesis 2002, 2561.
(b) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
(6) For recent successful examples, see: (a) Tang, P.; Wang,
W.; Ritter, T. J. Am. Chem. Soc. 2011, 133, 11482. (b) Tang,
P.; Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2010, 132,
12150. (c) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhamg,
(24) The presence of the 3-hydroxyl moiety of 2a was found to be
essential for the fluorination by the fact that a similar
fluorination of the acetyl derivative 10 of 2a did not proceed
at all (Scheme 4).
Synlett 2012, 23, 1978–1984
© Georg Thieme Verlag Stuttgart · New York

LETTER
Fluorinated Bridged Biphenyls
1983
organic layer was washed with brine, dried (Na2SO4),
O
filtered, and concentrated in vacuo. The purification of the
residue by flash column chromatography (silica gel,
hexanes–EtOAc = 1:1) afforded 5a (100 mg, quant.) as a
colorless solid; mp 162.5–164.0 °C. IR (CHCl3): 3595,
3554, 1732 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.727 (1
H, d, J = 14.0 Hz), 2.731 (1 H, d, J = 14.0 Hz), 3.09 (1 H, d,
J = 14.0 Hz), 3.10 (1 H, d, J = 14.0 Hz), 3.54 (3 H, s), 3.74
(3 H, s), 3.75 (3 H, s), 3.85 (3 H, s), 3.90 (3 H, s), 5.94 (1 H,
br s), 6.21 (1 H, br s), 6.62 (1 H, s), 6.83 (1 H, s), 7.08 (1 H,
s). 13C NMR (125 MHz, CDCl3): δ = 36.2, 37.1, 52.8, 52.9,
56.0, 60.8, 61.2, 64.5, 109.5, 116.5, 116.8, 125.7, 128.0,
128.2, 131.6, 141.3, 142.4, 143.0, 150.3, 151.9, 171.2,
171.3. HRMS: m/z calcd for C22H24NaO9 [M + Na]+:
455.1313; found: 455.1339.
OAc
3
Deoxofluor
(6 equiv)
MeO
MeO
recovered starting material
CHCl3
50 °C, 3 h
CO2Me
MeO
CO2Me
10
Scheme 4
(25) Only one example has been reported of the migration of a
phenyl group onto the more electron-rich carbon,
see:Guinaudeau, H.; Elango, V.; Shamma, M.; Fajardo, V.
J. Chem. Soc., Chem. Commun. 1982, 1122.
(26) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
(27) (a) L’Heureux, A.; Bealieu, F.; Bennett, C.; Bill, D. R.;
Clayton, S.; LaFlamme, F.; Mirmehrabi, M.; Tadayon, S.;
Tovell, D.; Couturier, M. J. Org. Chem. 2010, 75, 3401.
(b) Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.;
Couturier, M.; LaFlamme, F.; L’Heureux, A. Org. Lett.
2009, 11, 5050.
(28) Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. J. Am. Chem.
Soc. 2010, 132, 18199.
(29) For detailed discussion on a plausible reaction mechanism
for the fluorination of 3-hydroxydienones 2 producing 4, 9,
and 3, see Supporting Information.
(30) Similar fluorination reactions using three equivalents of the
same fluorination reagents proceeded very slowly and
provided the products in lower yields (<30%).
(31) 3,3-Bis(methoxycarbonyl)-6,7,8-trimethoxy-1,2,3,4-
tetrahydroxy-naphthalene-1-spiro-1′-[3′-hydrooxy-
cyclohexa-2′,5′-dien-4′-one] (2a) – Typical Procedure for
the Cyclization of 1 to 2
Typical Procedure for the Fluorination of 2
Under a nitrogen atmosphere, Xtalfluor-E (95 mg, 0.41
mmol) was added to a solution of 2a (30 mg, 0.069 mmol)
and Et3N·HF (0.41 mmol), in situ prepared from Et3N·3HF
(22 μL, 0.14 mmol) and Et3N (38 μL, 0.28 mmol), in i-Pr2O–
CHCl3 (1:1, 0.35 mL) at 0 °C. The reaction mixture was
stirred for 1.5 h at 50 °C before being quenched with ice
water. CH2Cl2 was added, the layers were separated, and the
aqueous layer was extracted three times with CH2Cl2. The
combined organic layer was washed with brine, dried
(Na2SO4), filtered, and concentrated in vacuo. The
purification of the residue by flash column chromatography
(silica gel, hexanes–EtOAc = 3:1) afforded 4a (22 mg, 74%
yield) and 9a (6.0 mg, 18% yield).
Dimethyl 10-Fluoro-5,7-dihydro-9-hydroxy-1,2,3-
trimethoxy-6H-dibenzo[a,c]cycloheptene-6,6-
dicarboxylate (4a)
Colorless solid; mp 146.0–147.0 °C. IR (CHCl3): 3578,
1734, 1254 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.72 (1
H, d, J = 14.5 Hz), 2.76 (1 H, d, J = 14.5 Hz), 3.13 (2 × 1 H,
d, J = 14.5 Hz), 3.60 (3 H, s), 3.76 (6 H, s), 3.87 (3 H, s), 3.90
(3 H, s), 5.39 (1 H, br), 6.63 (1 H, s), 6.93 (1 H, d, J = 9.0
Hz), 7.26 (1 H, d, J = 11.5 Hz). 13C NMR (125 MHz,
CDCl3): δ = 36.2, 37.0, 52.8, 52.9, 56.0, 60.8, 61.1, 64.4,
109.4, 117.1 (d, J = 18.0 Hz), 118.3, 124.8, 128.5 (d, J = 7.0
Hz), 131.4, 132.3 (d, J = 3.5 Hz), 141.6, 142.2 (d, J = 14.5
Under a nitrogen atmosphere, PhI(OAc)2 (78 mg, 0.24
mmol) was added to a solution of 1a (100 mg, 0.23 mmol)
and MsOH (15 μL, 0.23 mmol) in DME (2.3 mL) at 0 °C.
The reaction mixture was stirred for 24 h at 5°C before being
quenched with a sat. aq Na2S2O3 solution and H2O. EtOAc
was added, the layers were separated, and the aqueous layer
was extracted three times with EtOAc. The combined
organic layer was washed with brine, dried (Na2SO4),
filtered, and concentrated in vacuo. The purification of the
residue by flash column chromatography (silica gel,
hexanes–EtOAc = 2:1) afforded 2a (95 mg, 95% yield) as a
colorless solid; mp 159.0–162.0 °C. IR (CHCl3): 3447,
1734, 1647, 1238 cm–1. 1H NMR (500 MHz, CDCl3): δ =
2.36 (1 H, d, J = 15.0 Hz), 2.49 (1 H, d, J = 15.0 Hz), 3.13 (1
H, d, J = 16.5 Hz), 3.37 (1 H, d, J = 16.5 Hz), 3.60 (3 H, s),
3.75 (6 H, s), 3.77 (3 H, s), 3.85 (3 H, s), 5.94 (1 H, d, J = 3.0
Hz), 6.26 (1 H, s), 6.38 (1 H, d, J = 10.0 Hz), 6.51 (1 H, s),
6.89 (1 H, dd, J = 3.0, 10.0 Hz). 13C NMR (125 MHz,
CDCl3): δ = 35.0, 40.5, 42.7, 51.6, 52.9, 55.7, 60.5, 61.0,
107.3, 118.8, 122.9, 123.5, 129.0, 140.7, 146.0, 152.7,
153.2, 158.8, 171.1, 171.3, 181.5. HRMS: m/z calcd for
C22H25O9 [M + H]+: 433.1493; found: 433.1503.
Hz), 150.0 (d, J = 238 Hz), 150.6, 152.4, 170.8, 171.0. 19
F
NMR (470 MHz, CDCl3): δ = –146.5 (1 F, dd, J = 9.0, 11.5
Hz). HRMS: m/z calcd for C22H23FNaO8 [M + Na]+:
457.1269; found: 457.1289.
Dimethyl 10-Fluoro-5,7-dihydro-11-hydroxy-1,2,3-
trimethoxy-6H-dibenzo[a,c]cycloheptene-6,6-
dicarboxylate (9a)
Colorless solid; mp 104.0–109.0 °C. IR (CHCl3): 3327,
1732, 1240 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.71 (1
H, d, J = 14.0 Hz), 2.73 (1 H, d, J = 14.0 Hz), 3.13 (1 H, d,
J = 14.0 Hz), 3.20 (1 H, d, J = 14.0 Hz), 3.70 (3 H, s), 3.76
(3 H, s), 3.77 (3 H, s), 3.90 (3 H, s), 3.93 (3 H, s), 6.70 (1 H,
s), 6.81 (1 H, dd, J = 5.0, 8.0 Hz), 6.99 (1 H, s), 7.01 (1 H, d,
J = 8.0, 10.0 Hz). 13C NMR (125 MHz, CDCl3): δ = 36.8,
36.9, 52.88, 52.92, 56.1, 61.3, 62.2, 64.2, 110.9, 115.1 (d,
J = 18.0 Hz), 121.3 (d, J = 2.0 Hz), 122.1 (d, J = 7.0 Hz),
126.4, 131.9 (d, J = 3.5 Hz), 132.4, 141.4, 141.5 (d, J = 12.0
Dimethyl 5,7-Dihydro-9,10-dihydroxy-1,2,3-trimethoxy-
6H-dibenzo[a,c]cycloheptene-6,6-dicarboxylate (5a) –
Typical Procedure for the Dienone–Phenol
Hz), 149.4, 152.9 (d, J = 241 Hz), 153.1, 170.6, 170.8. 19
F
NMR (470 MHz, CDCl3): δ = –138.9 (1 F, dd, J = 5.0, 10.0
Hz). HRMS: m/z calcd for C22H23FNaO8 [M + Na]+:
457.1269, found: 457.1271.
Rearrangement of 2 to 5
Under a nitrogen atmosphere, MsOH (15 μL, 0.23 mmol)
was added to a solution of 2a (100 mg, 0.23 mmol) in DME
(2.3 mL). The reaction mixture was stirred at 80 °C until 2a
was completely consumed (monitored by TLC analysis).
After cooling, the reaction was quenched with H2O. EtOAc
was added, the layers were separated, and the aqueous layer
was extracted three times with EtOAc. The combined
Typical Procedure for the Fluorination of 5
Under a nitrogen atmosphere, PhI(OAc)2 (78 mg, 0.24
mmol) was added to a mixture of 5a (100 mg, 0.23 mmol)
and MgO (21 mg, 0.53 mmol) in CHCl3 (1.2 mL) at 0 °C,
and the reaction mixture was stirred at the same temperature
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1978–1984

1984
H. Nemoto et al.
LETTER
Dimethyl 9-Fluoro-5,7-dihydro-10-hydroxy-1,2,3-tri-
methoxy-6H-dibenzo[a,c]cycloheptene-6,6-
dicarboxylate (7a)
for 5 min. Deoxofluor (0.25 mL, 1.4 mmol) was added, and
the reaction mixture was stirred for 1 h at 40 °C before being
quenched with ice water. CH2Cl2 was added, the layers were
separated, and the aqueous layer was extracted three times
with CH2Cl2. The combined organic layer was dried
(Na2SO4), filtered, and concentrated in vacuo. The residue
was dissolved in EtOH (1.2 mL), and NaBH4 (44 mg, 1.2
mmol) was added to the solution at 0 °C. The reaction
mixture was stirred overnight at r.t. before being quenched
with 1 M HCl. EtOAc was added, the layers were separated,
and the aqueous layer was extracted three times with EtOAc.
The combined organic layer was washed with brine, dried
(Na2SO4), filtered, and concentrated in vacuo. Purification
of the residue by flash column chromatography (silica gel,
hexanes–EtOAc–Et3N = 33:66:1) afforded 4a (24 mg, 23%
yield) and 7a (43 mg, 43% yield).
Colorless solid; mp 188.5–189.5 °C. IR (CHCl3): 3580,
1732, 1238 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.68 (1
H, d, J = 14.0 Hz), 2.73 (1 H, d, J = 14.0 Hz), 3.13 (1 H, d,
J = 13.0 Hz), 3.15 (1 H, d, J = 13.0 Hz), 3.61 (3 H, s), 3.76
(6 H, s), 3.88 (3 H, s), 3.90 (3 H, s), 5.26 (1 H, br), 6.64 (1
H, s), 7.03 (1 H, d, J = 11.0 Hz), 7.17 (1 H, d, J = 9.0 Hz).
13C NMR (125 MHz, CDCl3): δ = 36.0, 37.0, 52.8, 52.9,
56.0, 60.9, 61.1, 64.3, 109.4, 116.7 (d, J = 18.0 Hz), 119.0,
124.9, 128.3 (d, J = 6.0 Hz), 131.3, 132.5 (d, J = 3.5 Hz),
141.6, 142.1 (d, J = 13.0 Hz), 149.6 (d, J = 237 Hz), 150.7,
152.5, 170.9, 171.0. 19F NMR (470 MHz, CDCl3): δ =
–145.4 to –145.2 (1 F, m). HRMS: m/z calcd for
C22H23FNaO8 [M + Na]+: 457.1269; found: 457.1292.
Synlett 2012, 23, 1978–1984
© Georg Thieme Verlag Stuttgart · New York

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