Asymmetric Dearomative Fluorination of 2-Naphthols with a Dicarboxylate Phase-Transfer Catalyst

Article abstract of DOI:10.1002/anie.202005367

A linked dicarboxylate phase-transfer catalyst enables smooth asymmetric dearomative fluorination of 2-naphthols with Selectfluor under mild conditions to give the corresponding 1-fluoronaphthalenone derivatives in a highly enantioselective manner. This r

Full text of DOI:10.1002/anie.202005367

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Accepted Article
Title: Asymmetric Dearomative Fluorination of 2-Naphthols with
Dicarboxylate Phase-Transfer Catalyst
Authors: Hiromichi Egami, Taiki Rouno, Tomoki Niwa, Kousuke
Masuda, Kenji Yamashita, and Yoshitaka Hamashima
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10.1002/anie.202005367
Angewandte Chemie International Edition
COMMUNICATION
Asymmetric Dearomative Fluorination of 2-Naphthols with
Dicarboxylate Phase-Transfer Catalyst
Hiromichi Egami, Taiki Rouno, Tomoki Niwa, Kousuke Masuda, Kenji Yamashita, and Yoshitaka
Hamashima*
Abstract: A linked dicarboxylate phase-transfer catalyst enables
smooth asymmetric dearomative fluorination of 2-naphthols with
Selectfluor under mild conditions to give the corresponding 1-
fluoronaphthalenone derivatives in a highly enantioselective manner.
This reaction, which is compatible with various functional groups, is
the first example of catalytic asymmetric fluorination of 2-naphthols,
and is expected to be useful in the synthesis of bioactive molecules.
interaction between the carboxylate ion of the catalyst and the
N–H group of the substrate amide (vide infra). This
consideration prompted us to examine a phenolic hydroxyl group
as a hydrogen bond donor; since its acidity is much higher than
that of simple amides, we expected that it would interact more
effectively with the dicarboxylate phase-transfer catalyst. In this
report, we present the first example of catalytic asymmetric
dearomative fluorination of 2-naphthols using our dianionic
phase-transfer catalyst (Scheme 1c).
Organofluorine compounds have found widespread applications
in the pharmaceutical and agrochemical sciences,[1] and various
types of fluorinative transformations have been reported.[2]
However, dearomative fluorination of electron-rich aromatic
compounds has been less well studied.[3] Dearomatization is a
versatile strategy for the construction of three-dimensional
molecules, not only in biosynthesis, but also in synthetic organic
chemistry, and considerable attention has been directed to the
development of asymmetric dearomatization reactions.[4] In this
context, 2-naphthol derivatives are expected to be useful
substrates for dearomative fluorination, because the resulting
a. Chirality transfer fluorination by Yang and Wang
R1
R1
O
CuBr, LiOt-Bu
OH
R2
NFSI
t-BuOMe, 0 °C
F
Ar
= Ar
O O O O
S
S
Ph
N
F
Ph
NFSI
naphthalenone
framework
containing
a
transformable
b. 6-endo-Fluorocyclization of allylic amides
precatalyst (1)
conjugated enone unit is present in many naturally occurring
bioactive compounds.[5]
R3
O
Selectfluor (2)
Although Toste reported pioneering work on asymmetric
dearomative fluorination of phenol derivatives (followed by
dimerization via Diels-Alder reaction) using chiral phosphate
phase-transfer catalysis,[6] the reaction system was not
examined for 2-naphthols. In 2018, Yang and Wang reported
O
N
Na3PO4
R3
N
R1
H
R2
R1
toluene, rt
R2
F
Ph
Ph
up to 99% ee
copper-catalyzed
chirality
transfer-type
fluorinative
O
O
Cl
dearomatization of axially chiral 1-substituted 2-naphthols
(Scheme 1a).[7] However, while various types of enantioselective
dearomatization reactions of 2-naphthols[8] have been
investigated, catalytic asymmetric dearomative fluorination of 2-
naphthols has no precedent in the literature.
N+
CO2H HO2C
–
2BF4
N+
F
Ph
Ph
precatalyst (1)
Selectfluor (2)
c. This work: Asymmetric fluorinative dearomatization of 2-naphthol
We have been working on several types of
fluorofunctionalization of organic molecules,[9] and we recently
1, 2
Na2CO3
R2
R2
developed
a
dicarboxylate phase-transfer catalyst
1 for
OH
O
CH2Cl2, 0 °C
Selectfluor (2) to form a chiral fluorinating reagent in situ; this
proved to be highly effective for enantioselective 6-endo-
fluorocyclization and deprotonative fluorination of allylic amides
(Scheme 1b).[10] The high enantioselectivity observed in these
reactions can be rationalized as arising from hydrogen-bonding
R1
R1
F
Scheme 1. Prior reactions and the present enantioselective dearomative
fluorination of 2-naphthols.
In order to optimize the reaction conditions, 1-phenyl-2-
naphthol (3a) was chosen as a test substrate (Table 1). First, the
conditions established in the previous study [10a] were applied to
this substrate. To our delight, the desired dearomative
fluorination occurred preferentially to give the product 4a in 58%
yield with 71% ee (entry 1). To improve the reaction efficiency,
reaction parameters such as base, solvent, and temperature
were screened. Inorganic bases affected the chemical yield, but
[a]
Dr. H. Egami, T. Rouno, T. Niwa, K. Masuda, Dr. K. Yamashita,
Prof. Dr. Y. Hamashima
School of Pharmaceutical Sciences
University of Shizuoka
52-1 Yada, Suruga-ku, Shizuoka 422-8526 (Japan)
E-mail: hamashima@u-shizuoka-ken.ac.jp
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.202005367
Angewandte Chemie International Edition
COMMUNICATION
had little influence on the enantioselectivity (entries 1-4). Among
the solvents examined, chlorinated solvents gave higher
enantioselectivity (entries 3, 5-8). In CH2Cl2 at 0 °C, the
enantioselectivity was as high as 93% (entry 9). When
Selectfluor II was used in place of 2, the product 4a was formed
in high yield, albeit with somewhat lower enantioselectivity (entry
10). In contrast, N-fluorobenzenesulfonamide (NFSI) was totally
ineffective (entry 11). The following control experiments clearly
indicate the superiority of our dicarboxylate catalyst over other
Table 1. Optimization of the reaction conditions.[a]
pre-cat. (10 mol %)
2 (1.5 equiv)
base (1.5 equiv)
OH
O
solvent, 48 h
F
Ph
Ph
3a
4a
entry
base
solvent
pre-cat.
temp.
(°C)
yield
(%)[b]
ee
(%)
chiral anionic catalysts. Thus, when a phosphoric acid
precatalyst (TRIP) was tested, no reaction occurred at 0 °C.
Although the reaction proceeded smoothly at room temperature,
the enantioselectivity was only moderate (entry 12). The use of 5
1
Na3PO4
Na2HPO4
Na2CO3
K3CO3
toluene
toluene
toluene
toluene
benzene
ClC6H5
CHCl3
1
1
1
1
1
1
1
1
1
rt
rt
rt
rt
rt
rt
rt
rt
0
58
71
69
70
67
77
85
81
86
93
2
81
or
enantioselectivity (entries 13 and 14). In addition, simple
binaphthyl dicarboxylic acid was not effective for this
6
having
a
longer alkyl linker resulted in lower
3
quant.
54
7
4
fluorination reaction (entry 15). These results suggest the
importance of the presence of two carboxylate units at an
appropriate distance. Interestingly, 4a was formed even in the
absence of 1 (entry 16). This indicates that the phase-transfer
ability of 1 is high enough to overcome the background racemic
reaction. It is noteworthy that the undesired aromatic fluorinative
substitution reaction was not observed under the optimal
conditions. Considering that several fluorinated products are
formed in the homogenous reaction in MeCN, phase-transfer
catalysis appears to be essential for the clean synthesis of
fluorinated naphthalenone derivatives.
5
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
91
6
84
7
91
8[c]
9[d]
CH2Cl2
CH2Cl2
97
quant.
(97)[e]
10[f,g]
11[f,h]
12[c]
13[f]
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1
0
0
rt
0
0
0
0
95
83
-
1
trace
79
Table 2. Asymmetric fluorination of 1-substituted 2-naphthols.[a]
TRIP
–26
–61
24
–15
-
1 (10 mol %)
2 (1.5 equiv)
Na2CO3 (1.5 equiv)
5
6
7
-
89
14[f]
81
OH
O
CH2Cl2, 0 °C, 18 h
F
R
R
15[f]
78
3
4
entry
R
yield (%)[b]
ee (%)
16[f]
39
1
4-MeO-C6H4
4-F-C6H4
4-CHO-C6H4
3-CHO-C6H4
3,5-diCl-C6H3
2-naphthyl
3-thiophenyl
cyclohexyl
i-Pr
b
c
d
e
f
86
86
91
87
95
91
90
97
98
95
92
83
92
92
88
85
85
92
93
89
83
81
[a] The reactions were carried out with 1 (10 mol %), 2 (1.5 equiv), and base
(1.5 equiv) on a 0.1 mmol scale, unless otherwise mentioned. [b] Determined
by 1H NMR analysis using 1,1,2,2-tetrachloroethane as an internal standard.
[c] Run for 24 h. [d] Run for 18 h. [e] Isolated yield. [f] Run for 36 h. [g] Run
with Selectfluor II instead of 2. [h] Run with NSFI instead of 2.
2
3
4
Ph
Ph
5
O
O
n
CO2H HO2C
N+
N+
–
6
g
h
i
2BF4
Ph
Ph
F
7
1: n = 1, 5: n = 2, 6: n = 3
Selectfluor II
8
Ar
O
P
O
Ph
9
j
O
CO2H
CO2H
10
11[c]
allyl
k
l
OH
Me
Ar
Ph
TRIP: Ar = 2,4,6-tri(i-Pr)C6H2
7
[a] The reactions were carried out with 1 (10 mol %), 2 (1.5 equiv), and
Na2CO3 (1.5 equiv) on a 0.1 mmol scale, unless otherwise mentioned. [b]
Isolated yield. [c] Run for 48 h.
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10.1002/anie.202005367
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COMMUNICATION
(4n-4r). It is noteworthy that bromo and triflate groups tolerate
the reaction, and can therefore serve as useful handles for
further transformation (4o, 4r). Interestingly, the reaction of 3s
having a substituent at the 8-position proceeded in a highly
enantioselective manner, even though the chlorine atom is close
to the reaction site. A methyl group at the 4-position did not have
a significant impact. For example, 4t was obtained in 90% yield
with 87% ee, though the enantioselectivity was somewhat
reduced by a bulkier phenyl group at the 4-position (4u).
Unfortunately, the incorporation of a substituent at the 3-position
decreased the enantioselectivity (4v), suggesting that the
difference in steric demand between the C1 and C3 positions is
crucial for achieving high face selectivity at the naphthalene ring.
Having established the optimized reaction conditions, we
examined the fluorination reaction of various 1-substituted 2-
naphthols (Table 2). An electron-donating methoxy group slightly
reduced the enantioselectivity, although the reaction proceeded
regioselectively without concomitant formation of the aromatic
fluorination product (entry 1). It is noteworthy that aromatic
aldehyde, which is readily oxidizable, could tolerate this reaction
(entries 3 and 4), and the desired products were obtained in high
yield with 92% and 88% ee, respectively. The fluorination is also
applicable to heteroaromatic compounds. For example,
a
thiophene derivative was converted to the dearomatized product
without difficulty (entry 7), whereas the homogeneous reaction
afforded a complex mixture. In addition to aromatic substituents,
2-naphthols with an aliphatic substituent were examined. As
A tentative model of the reaction mechanism is shown in
Figure 1, although the details remain to be elucidated.
Dicarboxylate catalyst A generated in situ undergoes ion
exchange reaction with Selectfluor (2), which is almost insoluble
in CH2Cl2, allowing for the transfer of 2 from the solid phase to
shown in entries
8 and 9, cyclohexane- and isopropyl-
substituted compounds underwent the fluorination reaction with
high enantioselectivity. In addition, smaller substituents such as
a methyl and an allyl group were also available (entries 10 and
11). It is noteworthy that the dearomative fluorination proceeded
predominantly even in the presence of an alkene moiety (entry
10).
1
the liquid phase to give a chiral Selectfluor B.[11] Since H NMR
experiments suggested a hydrogen-bonding interaction between
2-naphthol and the carboxylate catalyst A,[10,12] we consider that
the phenolic substrate forms a ternary assembly C, which is
important not only for acceleration of the reaction, but also for
enantioface discrimination. The absolute configuration of the
products was deduced to be S on the basis of an X-ray analysis
of enantio-pure 4a (Figure 2).[13]
Table 3. Asymmetric fluorination of disubstituted 2-naphthols.[a]
1 (10 mol %)
5
4
6
2 (1.5 equiv)
3
2 (solid phase)
Na2CO3 (1.5 equiv)
R
R
7
OH
O
O
O
O
O
8
CH2Cl2, 0 °C, 18 h
F
Ph
Ph
–
–
–
–
2OC
2OC
CO2
CO2
N+
3
4
2Na+
Ph
2 NaBF4 Cl
O
Ph
Br
A
B
N+
F
O
O
O
O Ph
O
F
Ph
F
Ph
F
Ph
F Ph
–
–
3
2OC
CO2
4m: quant., 90% ee 4n: quant., 92% ee
4p: quant., 89% ee
4o: 90%, 88% ee
4
H
O
N+
Cl
R1
N+
F
O
MeO
O
TfO
O
C
F
Ph
F
Ph
F Ph
Cl
R2
4s: 70%, 84% ee
4q: 98%, 94% ee
4r: 89%, 78% ee
Ph
Br
Figure 1. Proposed mechanism.
O
O
O
F
Ph
F
Ph
F
Ph
4t: 90%, 87% ee
4v: quant., 38% ee
4u: 81%, 74% ee
[a] The reactions were carried out with 1 (10 mol %), 2 (1.5 equiv), and
Na2CO3 (1.5 equiv) on a 0.1 mmol scale, unless otherwise mentioned.
We next investigated multiply substituted 2-naphthol
derivatives. As shown in Table 3, the reaction showed broad
generality with respect to the substitution pattern on the
naphthalene ring. The 5-phenyl-substituted compound 3m
provided 4m in high yield with 90% ee. The reaction was
compatible with substitution at the 6- and 7-positions, affording
the desired products with good to excellent enantioselectivity
Figure 2. X-ray structure of 4a.
To confirm the utility of the reaction, we examined the
conversion of the fluorinated product 4a, as shown in Scheme 2.
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When 4a was treated with MeMgBr at –78 °C, tertiary alcohol 8
was obtained as a single diastereomer, the stereochemistry of
which was determined by NMR analysis after methyl ether
formation.[12] In addition, -bromination proceeded without
difficulty, offering an alternative route to 4v. Since the bromo
group within 4v can be in principle transformed by means of
cross-coupling reactions, this compound should be a convenient
platform for further derivatization. Furthermore, epoxidation
occurred smoothly to afford 9 in a diastereoselective manner
when H2O2 was used as an oxidant under basic conditions. The
stereochemistry of 9 was determined by X-ray analysis.[14] In
contrast, treatment with m-chloroperbenzoic acid (mCPBA)
predominantly provided Baeyer-Villiger product 10. When 10
was exposed to acidic conditions in MeOH, the ring-opening
product 11 was obtained in good yield. Interestingly, the 6-
membered hemiaminal 12 was formed in the reaction with n-
butylamine under aerobic conditions.[11,15]
Experimental Section
General procedure for the dearomative fluorination of 2-naphthols: To a
solution of 3a (22.0 mg, 0.1 mmol), 1 (9.7 mg, 10 mol %), and Na2CO3
(15.9 mg, 1.5 equiv) in CH2Cl2 (0.5 mL) was added Selectfluor (53.1 mg,
1.5 equiv) at 0 °C. The reaction mixture was stirred for 18 h at 0 °C, then
diluted with EtOAc, and filtered through a pad of Celite. The filtrate was
evaporated under reduced pressure, and the residue was purified by
column chromatography on silica gel (n-hexane / ethyl acetate = 5/1) to
provide 4a as a colorless solid (23.1 mg, 97%). The ee was determined
by chiral HPLC analysis to be 93%.
Acknowledgements
This work was supported by Grant-in-Aid for Scientific Research
(Nos. 18K06585, and 19H03353), and grants from Uehara
Memorial Foundation, Nagase Science and Technology
Foundation, and Basis for Supporting Innovative Drug
Discovering and Life Science Research (BINDS) from the Japan
Agency for Medical Research and Development (AMED). We
are grateful to Dr. Tomoyuki Kimura of Institute of Microbial
Chemistry for X-ray analysis.
MeMgBr
O
THF
OH
F Ph
F
Ph
8: 86%, 94% ee
4a: 93% ee
Br
Keywords: fluorination • dearomatization • asymmetric reaction
• phase-transfer catalyst • naphthol
Br2, Et3N
CH2Cl2
O
F
Ph
4v: 40%, 93% ee
[1]
a) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications, 2nd ed.; Wiley-VCH: Weinheim, 2013; b) I. Ojima,
Fluorine in Medicinal Chemistry and Chemical Biology; Wiley-Blackwell:
Oxford, 2009; c) V. Gouverneur, K. Müller, Fluorine in Pharmaceutical
and Medicinal Chemistry: From Biophysical Aspects to Clinical
Applications; Imperial College Press: London, 2012; d) K. Müller, C.
Faeh, F. Diederich, Science, 2007, 317, 1881-1886.
O
H2O2, NaOH
acetone/H2O
O
X ray structure of 9
MeO OMe
F
Ph
9: 77%, 94% ee
[2]
a) K. Mikami, Y. Itoh, M. Yamanaka, Chem. Rev. 2004, 104, 1-16; b) J.-
A. Ma, D. Cahard, Chem. Rev. 2008, 108, PR1-PR43; c) N. Shibata, S.
Mizuta, H. Kawai, Tetrahedron: Asymmetry 2008, 19, 2633-2644; d) T.
Liang, C. N. Neumann, T. Ritter, Angew. Chem. Int. Ed. 2013, 52,
8214-8264; e) J. R. Wolstenhulme, V. Gouverneur, Acc. Chem. Res.
2014, 47, 3560-3570; f) X. Yang, T. Wu, R. J. Phipps, F. D. Toste,
Chem. Rev. 2015, 115, 826-870; g) Y. Zhu, J. Han, J. Wang, N.
Shibata, M. Sodeoka, V. A. Soloshonok, J. A. S. Coelho, F. D. Toste,
Chem. Rev. 2018, 118, 3887-3964; h) I. Ojima, Frontiers of
Organofluorine Chemistry, World Scientific, Singapore, 2020.
H2SO4
MeOH
mCPBA
O
O
CH2Cl2
phosphate buffer
(pH = 6.86)
OMe
O
F
Ph
10: 73%, 93% ee
F
Ph
11: 72%, 94% ee
OH
n-Bu
n-BuNH2, air
MeCN
N
O
F
Ph
[3]
[4]
[5]
a) W. T. Pennington, G. Resnati, D. D. DesMarteau, J. Org. Chem.
1992, 57, 1536-1539; b) A. Martin, M.-P. Jouannetaud, J.-C. Jacquesy,
Tetrahedron Lett. 1996, 37, 7735-7738; c) O. Karam, A. Martia, M.-P.
Jouannetaud, J.-C. Jacquesy, Tetrahedron Lett. 1999, 40, 4138-4186;
d) S. Stavber, M. Jereb, M. Zupan, Synlett 1999, 10, 1375-1378; e) G.
Stavber, M. Zupan, M. Jereb, S. Stavber, Org. Lett. 2004, 6, 4973-4976.
For recent reviews, see: a) W. Sun, G. Li, L. Hong, R. Wang, Org.
Biomol. Chem. 2016, 14, 2164-2176; b) W.-T. Wu, L. Zhang, S.-L. You,
Chem. Soc. Rev. 2016, 45, 1570-11580; c) L. Pantaine, X. Moreau, V.
Coefard, C. Greak, Tetrahedron Lett. 2016, 57, 2567-2574; d) B. K.
Liebov, W. D. Harman, Chem. Rev. 2017, 117, 13721-13755; e) A.
Claraz, G. Masson, Org. Biomol. Chem. 2018, 16, 5386-5402.
12: 62%, 93% ee
Scheme 2. Transformations of 4a.
In summary, we present the first successful methodology for
asymmetric dearomative fluorination of 2-naphthols, enabling
the construction of chiral fluorinated naphthalenone derivatives.
The reaction proceeds smoothly under dianionic phase-transfer
catalysis conditions, and various functional groups are well
tolerated. The utility of the products was demonstrated by the
derivatization of 4a. Considering the potentially high reactivity of
For selected reports, see: a) P. W. Jeffs, D. G. Lynn, J. Org. Chem.
1975, 40, 2958-2960; b) J. P. McCormick, T. Shinmyozu, J. P.
Pachlatko, T. R. Schafer, J. W. Gardner, R. D. Stipanovic, J. Org.
Chem. 1984, 49, 34-40; c) R. D. Stipanovic, J. P. McCormick, E. O.
Schlemper, B. C. Hamper, T. Shinmyozu, W. H. Pirkle, J. Org. Chem.
1986, 51, 2500-2504; d) M. Essenberg, P. B. Grover Jr., E. C. Cover,
Phytochemistry, 1990, 29, 3107-3113; e) H. J. Zeringue, Jr.,
the ketone group with heteroatom-based nucleophiles within
[1,16]
biomolecules,
we believe that the availability of chiral
fluorinated naphthalenones and their derivatives will facilitate
drug development. Further investigation of this reaction system
is ongoing in our laboratory.
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10.1002/anie.202005367
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COMMUNICATION
Phytochemistry 1990, 29, 1789-1791; f) K. Krohn, G. Zimmermann, J.
Org. Chem. 1998, 63, 4140-4142; g) X.-Z. Wang, B.-Y. Yang, G.-J. Lin,
Y.-Y. Xie, H.-L. Huang, Y.-J. Liu, DNA Cell Biol. 2012, 31, 1468-1474;
h) Y. Zhang, Y.-B. Liu, Y. Li, S.-G. Ma, L. Li, J. Qu, D. Zhang, X.-G.
Chen, J.-D. Jiang, S.-S. Yu, J. Nat. Prod. 2013, 76, 1058-1063; i) X.-Z.
Wang, H.-H. Yang, W. Li, B.-J. Han, Y.-J. Liu, New J. Chem. 2015, 40,
5255-5267; j) T. A. Wagner, J. Liu, L. S. Puckhaber, A. A. Bell, H.
Williams, R. D. Stipanovic, Phytochemistry 2015, 115, 59-69; k) Y.
Chen, H.-H. Yang, X.-Z. Wang, H.-C. Song, RSC Adv. 2016, 6, 72703-
72714; l) W.-J. Wei, P.-P. Zhou, C.-J. Lin, W.-F. Wang, Y. Li, K. Gao, J.
Agric. Food Chem. 2017, 65, 5985-5993.
T. Ide, Y. Kawato, Y. Hamashima, Chem. Commun. 2015, 51, 16675-
16678; c) T. Ide, S. Masuda, Y. Kawato, H. Egami, Y. Hamashima, Org.
Lett. 2017, 19, 4452-4455; d) H. Egami, S. Masuda, Y. Kawato, Y.
Hamashima, Org. Lett. 2018, 20, 1367-1370; e) H. Egami, Y. Ito, T. Ide,
S. Masuda, Y. Hamashima, Synthesis 2018, 50, 2948-2953; f) T.
Rouno, T. Niwa, K. Nishibashi, N. Yamamoto, H. Egami, Y. Hamashima,
Molecules 2019, 24, 3464.
[10] a) H. Egami, T. Niwa, H. Sato, R. Hotta, T. Rouno, Y. Kawato, Y.
Hamashima, J. Am. Chem. Soc. 2018, 140, 2785-2788; b) T. Niwa, K.
Ujiie, H. Sato, H. Egami, Y. Hamashima, Chem. Pharm. Bull. 2018, 66,
920-922.
[6]
[7]
R. J. Phipps, F. D. Toste, J. Am. Chem. Soc. 2013, 135, 1268-1271.
P. Wang, J. Wang, L. Wang, D. Li, K. Wang, Y. Liu, H. Zhu, X. Liu, D.
Yang, R. Wang, Adv. Synth. Catal. 2018, 360, 401-405.
[11] a) V. Rauniyar, A. D. Lackner, G. L. Hamilton, F. D. Toste, Science
2011, 334, 1681-1684; b) J. Wu, Y.-M. Wang, A. Drljevic, V. Rauniyar,
R. J. Phipps, F. D. Toste, Proc. Natl. Acad. Sci. 2013, 110, 13729-
13733.
[8]
For selected papers, see: a) S. Dong, J. Zhu, J. A. Porco, Jr., J. Am.
Chem. Soc. 2007, 130, 2738-2739; b) S. Quideau, G. Lyvinec, M.
Marguerit, K. Bathany, A. Ozanne-Beaudenon, T. Buffeteau, D.
Cavagnat, A. Chénedé, Angew. Chem. Int. Ed. 2009, 48, 4605-4609; c)
T. Oguma, T. Katsuki, J. Am. Chem. Soc. 2012, 134, 20017-20020; d)
C.-X. Zhuo, S.-L. You, Angew. Chem. Int. Ed. 2013, 52, 10056-10059;
e) C. Bosset, R. Coffinier, P. A. Peixoto, M. E. Assal, K. Miqueu, J.-M.
Sotiropoulos, L. Pouységu, S. Quideau, Angew. Chem. Int. Ed. 2014,
53, 9860-9864; f) M. Uyanik, N. Sasakura, R. Kaneko, K. Ohori, K.
Ishihara, Chem. Lett. 2015, 44, 179-181; g) J. Nan, J. Liu, H. Zheng, Z.
Zuo, L. Hou, H. Hu, Y. Wang, X. Luan, Angew. Chem. Int. Ed. 2015, 54,
2356-2360; h) D. Yang, L. Wang, F. Han, D. Li, D. Zhao, R. Wang,
Angew. Chem. Int. Ed. 2015, 54, 2185-2189; i) S.-G. Wang, X.-J. Liu,
Q.-C. Zhao, C. Zheng, S.-B. Wang, S.-L. You, Angew. Chem. Int. Ed.
2015, 54, 14929-14932; j) J. Zheng, S.-B. Wang, C. Zheng, S.-L. You, J.
Am. Chem. Soc. 2015, 137, 4880-4883; k) Q. Yin, S.-G. Wang, X.-W.
Liang, D.-W. Gao, J. Zheng, S.-L. You, Chem. Sci. 2015, 6, 4179-4183;
l) D. Shen, Q. Chen, P. Yan, X. Zeng, G. Zhong, Angew. Chem. Int. Ed.
2017, 56, 3242-3246; m) T. Dohi H. Sasa, K. Miyazaki, M. Fujitake, N.
Takenaga, Y. Kita, J. Org. Chem. 2017, 82, 11954-11960; n) M. Uyanik,
N. Sasakura, M. Mizuno, K. Ishihara, ACS Catal. 2017, 7, 872-876; o) Y.
Zhang, Y. Liao, X. Liu, X. Xu, L. Lin, X. Feng, Chem. Sci. 2017, 8,
6645-6649; p) Y.-F. Wang, J.-J. Shao, B. Wang, M.-M. Chu, S.-S. Qi,
X.-H. Du, D.-Q. Xu, Adv. Synth. Catal. 2018, 360, 2285-2290.
[12] See the supporting information.
[13] CCDC 1981709 contains the supplementary crystallographic data for
this paper.
[14] CCDC 1994834 contains the supplementary crystallographic data for
this paper.
[15] The details of the mechanism are not clear, but we assume that an
enamine intermediate, which is formed after addition of n-butylamine
and condensation between the resulting aldehyde and excess amine,
undergoes auto-oxidation resulting in C–C bond cleavage.
[16] a) A. Denis, F. Bretin, C. Fromentin, A. Bonnet, G. Piltan, A. Bonnefoy,
C. Agouridas, Bioorg. Med. Chem. Lett. 2000, 10, 2019-2022; b) X. Xu,
T. Henninger, D. Abbanat, K. Bush, B. Foleno, J. Hilliard, M. Macielag,
Bioorg. Med. Chem. Lett. 2005, 15, 883-887; c) T. Sugimoto, Y.
Shimazaki, A. Manaka, T. Tanikawa, K. Suzuki, K. Nanaumi, Y. Kaneda,
Y. Yamasaki, H. Sugiyama, Bioorg. Med. Chem. Lett. 2012, 22, 5739-
5743; d) Y.-H. Hsu, D. Bucher, J. Cao, S. Li, S.-W. Yang, G. Kokotos, V.
L. Woods Jr., J. A. McCammon, E. A. Dennis, J. Am. Chem. Soc. 2013,
135, 1330-1337; e) G. G. Zhanel, E. Hartel, H. Adam, S. Zelenitsky, M.
A. Zhanel, A. Golden, F. Schweizer, B. Gorityala, P. R. S. Lagacé-
Wiens, A. J. Walkty, A. S. Gin, D. J. Hoban, J. P. Lynch III, J. A.
Karlowsky, Drugs 2016, 76, 1737-1757.
[9]
a) H. Egami, J. Asada, K. Sato, D. Hashizume, Y. Kawato, Y.
Hamashima, J. Am. Chem. Soc. 2015, 137, 10132-10135; b) H. Egami,
This article is protected by copyright. All rights reserved.

10.1002/anie.202005367
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Our dianionic phase-transfer catalyst
enables fluorinative dearomatization
of 2-naphthols with Selectfluor to
afford the fluorinated naphthalenone
derivatives in good yield with high
enantioselectivity. Various functional
groups are tolerated under the
reaction conditions.
Hiromichi Egami, Taiki Rouno, Tomoki
Niwa, Kousuke Masuda, Kenji
Yamashita, and Yoshitaka Hamashima*
precatalyst
Selectfluor
Na2CO3
R2
R2
OH
O
CH2Cl2, 0 °C
R1
Page No. – Page No.
R1
F
up to 94% ee
Ph
O
Ph
Asymmetric Dearomative Fluorination
of 2-Naphthols with Dianionic Phase-
Transfer Catalyst
O
Cl
N+
N+
CO2H HO2C
–
2BF4
F
Ph
Ph
precatalyst
Selectfluor
This article is protected by copyright. All rights reserved.