N-Fluoro-(3,5-di-tert-butyl-4-methoxy)benzenesulfonimide (NFBSI): A sterically demanding electrophilic fluorinating reagent for enantioselective fluorination

Article abstract of DOI:10.1016/j.jfluchem.2011.01.005

We disclose here a novel electrophilic fluorinating reagent, N-fluoro-(3,5-di-tert-butyl-4-methoxy)benzenesulfonimide (NFBSI) as a sterically demanding analogue of popular fluorinating reagent, N-fluorobenzenesulfonmide (NFSI). NFBSI improves the enantios

Full text of DOI:10.1016/j.jfluchem.2011.01.005

Journal of Fluorine Chemistry 132 (2011) 222–225
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Journal of Fluorine Chemistry
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Short communication
N-Fluoro-(3,5-di-tert-butyl-4-methoxy)benzenesulfonimide (NFBSI): A sterically
demanding electrophilic fluorinating reagent for enantioselective fluorination
Hiroyuki Yasui a, Takeshi Yamamoto a, Takehisa Ishimaru a, Takeo Fukuzumi a, Etsuko Tokunaga a,
Kakehi Akikazu b, Motoo Shiro c, Norio Shibata a,
*
a Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
b Department of Applied Chemistry, Shinshu University, 4-17-1, Wakasato, Nagano 380-8553, Japan
c Rigaku Corporation, 3-9-12 Matsubara-cho, Akishima, Tokyo 196-8666, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
We disclose here a novel electrophilic fluorinating reagent, N-fluoro-(3,5-di-tert-butyl-4-methoxy)-
benzenesulfonimide (NFBSI) as a sterically demanding analogue of popular fluorinating reagent, N-
fluorobenzenesulfonmide (NFSI). NFBSI improves the enantioselectivity of the products as much as 18%
for the cinchona alkaloid-catalyzed enantioselective fluorination of silylenol ether compared to the use
of NFSI.
Received 26 December 2010
Received in revised form 12 January 2011
Accepted 13 January 2011
Available online 20 January 2011
ß 2011 Elsevier B.V. All rights reserved.
Keywords:
Electrophilic fluorination
Fluorinating reagent
Catalytic
Enantioselective
Synthesis
Optically active organic molecules, having a C–F stereogenic
center, are important and versatile synthons for a number of
medicinally important products [1]. Many papers on the asym-
metric syntheses of optically active organo-fluorine compounds
have been reported based on a building block approach and a direct
method for the construction of the carbon–fluorine bond. Among
them, direct enantioselective electrophilic fluorination is going to
be quite practical and provides chiral fluoro-organic compounds
with a high level of enantioselectivities in the range of 90% ee [2]. In
2000, we reported the enantioselective fluorination of silylenol
also a recent topic in this field [7,8]. Research into the development
of effective chiral catalysts and ligands for enantioselective
fluorination reaction has thus been active. Commercially available
fluorinating reagents, Selectfluor1 [9] and NFSI [10] are two of the
most commonly used reagents for this process, in particular NFSI
since it is more effective in many cases. On the other hand, there
are few strategies for the development of an enantioselective
electrophilic fluorination reaction focusing on fluorinating
reagents. We therefore hypothesized that a sterically demanding
analogue of NFSI could improve the enantioselectivity of the
fluorination products more than with NFSI. In this paper, we report
the synthesis of a novel, sterically demanding electrophillic
fluorinating reagent, N-fluoro-(3,5-di-tert-butyl-4-methoxy)ben-
zenesulfonimide (NFBSI) and evaluate its effectiveness as an agent
for enantioselective fluorination of silylenol ether in the presence
of a catalytic amount of cinchona alkaloids. Our preliminary results
demonstrate that NFBSI has an advantage by improving the
enantioselectivity of the fluorination process compared to the
results obtained by the use of popular NFSI (Fig. 1).
ethers, b-keto esters and oxindoles using a stoichiometric amount
of cinchona alkaloids/Selectfluor1 combination [3a–d], and a
similar approach was also independently reported by Cahard and
co-workers [3e–f]. The catalytic version of this method was not
easy but several years later we finally achieved it by using N-
fluorobenzenesulfonmide (NFSI) and
a catalytic amount of
cinchona alkaloids in the presence of inorganic salts [4]. Around
the same period, metal salt-catalyzed enantioselective fluorination
of
b-keto esters and related compounds were successively
reported by several groups, including ours, since the first report
by Togni’s group in 2000 [5,6]. Furthermore the enantioselective
fluorination of aldehydes catalyzed by proline and its analogues is
NFBSI (1) was readily prepared according to the route outlined
in Scheme 1. Namely, sulfonyl chloride 3 [11], which was prepared
from 1,3-di-tert-butyl-2-methoxybenzene (2) with chlorosulfuric
acid (2.0 equiv.) in CHCl3 at À10 8C for 10 min [11], was treated
with ammonium chloride (3.0 equiv.) and 10 M NaOH at room
temperature for 4 h to afford aryl sulfonamide 4. The treatment of
sulfonamide 4 with 3 (3.0 equiv.) in the presence of sodium
* Corresponding author.
E-mail address: nozshiba@nitech.ac.jp (N. Shibata).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.01.005

H. Yasui et al. / Journal of Fluorine Chemistry 132 (2011) 222–225
223
Fig. 1. Structures of electrophilic fluorinating reagents, Selectfluor1, NFSI and NFBSI (1).
Fig. 2. ORTEP X-ray crystallographic structure of NFBSI (1).
hydride (1.0 equiv.) in THF provided a symmetrical sulfonimide 5.
Finally, target fluorinating reagent, NFBSI (1) was obtained in a
pure state from 5 in 57% yield by passing 10% molecular fluorine
diluted with nitrogen in MeCN in the presence of spray-dried NaF
(10 equiv.) at À40 8C for 10 min followed by purification by silica-
gel column chromatography (Scheme 1).
asymmetric induction of NFBSI in the fluorine transfer reaction
with the same parameters when the best fluorinating reagent,
NFSI, was used. The cinchona alkaloid-catalyzed enantioselective
fluorination reaction [4] was selected as a model reaction. The
substrates for the reaction were carefully chosen to demonstrate
the efficiency of our novel reagent, since enantioselective synthesis
NFBSI (1) is a colourless crystalline solid, which is stable at room
temperature and can be kept in a refrigerator for several months.
Single-crystal X-ray crystallographic analysis of NFBSI (1) showed
that the central fluorine atom of NFBSI is covered by bulky
substituents (Fig. 2).
of
a
-fluoroketones still has a challenge [4] different from the case
-fluorinated -keto esters [6].
of enantioselective synthesis of
a
b
Selection of cinchona alkaloids for each reaction was based on our
previous observations for the same fluorination reaction [4] in
which the fluorination products had been isolated via column
chromatography on silica-gel and identified by comparison of their
MS- and NMR-spectral data as well as HPLC analysis with literature
With the target electrophilic fluorinating reagent NFBSI (1) in
hand, next it was of interest to compare the efficiency and
Scheme 1. Synthesis of fluorinating reagent, NFBSI (1).

224
H. Yasui et al. / Journal of Fluorine Chemistry 132 (2011) 222–225
while NFSI gave 7a in 52% ee. The enantioselectivity for the
fluorination of less bulky silylenol ether 6b was also improved
from 40% ee to 58% ee by the use of NFBSI instead of NFSI, although
the chemical yield decreased (Scheme 2b). The use of NFBSI instead
of NFSI thus resulted in as much as an 18% increase in
enantioselectivity, but the chemical yield of the fluorinated
products was sacrificed. The increase in enantioselectivity and
the decrease in chemical yield are surely due to the steric origin of
NFBSI. As mentioned in our previous papers and others [3,4], the
active fluorinating reagent should be an in situ generated common
N-fluorinated ammonium of cinchona alkaloid I and II rather than
NFSI and NFBSI themselves via transfer-fluorination reaction.
However, the anionic parts of I and II are different. Steric bulk
effect originated from an anion of (3,5-di-tert-butyl-4-methox-
y)benzenesulfonimide in II presumably helped to enhance the
enantiomeric excess of the products 7, while the reactivity was
sacrificed instead (Fig. 3; Scheme 2).
In conclusion, we have developed
a novel electrophilic
fluorinating reagent, NFBSI as a sterically demanding analogue
of popular fluorinating reagent NFSI, and investigated its utility for
cinchona alkaloid-catalyzed enantioselective fluorination of sily-
lenol ethers [13–16]. The enantioselectivities of their fluorinated
compounds were improved as much as 18% by using NFBSI (1)
compared to the use of NFSI; however, the reactivity of the reagent
decreased due to steric hindrance. Improvement of enantiomeric
excess without any sacrifice in isolated yield of the products
controlled by fluorinating reagents is the next challenge. We are
now working in this direction.
Acknowledgement
Scheme 2. Cinchona alkaloid-catalyzed enantioselective fluorination of silylenol
ethers 6a,b with NFSI or NFBSI (1).
This work was supported in part by KAKENHI (21390030,
22106515).
values [4,12]. We first attempted the enantioselective fluorination
of silylenol ether of 2-benzyl-1-indanone 6a in the presence of a
catalytic amount of quinine-1-naphtoate with an excess amount of
K2CO3 with NFBSI or NFSI in MeCN (Scheme 2a). NFBSI provided an
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1.0 ml/min, 254 nm) tR (major-(R)-isomer) = 9.7 min, tR (minor-(S)-iso-
mer) = 12.6 min (70% ee). The absolute configuration of 7a has already been
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[16] Synthesis of 7b: Reaction of 6b (21.9 mg, 0.10 mmol), 1 (72.2 mg, 0.120 mmol),
(DHQ)2PYR (8.8 mg, 0.010 mmol) and K2CO3 (83.2 mg, 0.600 mmol) in MeCN at
0 8C and purification by silica gel column chromatography (hexane/AcOEt = 90/
10) gave 7b (6.8 mg, 41%, 58% ee).; 1H NMR (200 MHz, CDCl3) d 1.63 (d,
J = 22.8 Hz, 3H), 3.29 (dd, J = 12.2, 17.4 Hz, 1H), 3.41 (dd, J = 22.8, 17.4 Hz, 1H),
7.38–7.45 (m, 2H), 7.65 (td, J = 7.5, 1.2 Hz, 1H), 7.8 (dd, J = 7.9, 0.6 Hz, 1H); 19F
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(M+); HPLC: (CHIRALCEL OB-H, hexane/iPrOH = 80/20, 1.0 ml/min, 254 nm) tR
(major-(R)-isomer) = 8.5 min, tR (minor-(S)-isomer) = 27.4 min (58% ee). The ab-
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[13] Synthesis of 1: To a stirred solution of 5 (701 mg, 1.21 mmol) in MeCN (25 mL) in
the presence of sodium fluoride (508 mg, 12.1 mmol) was introduced 10% F2 gas
in N2 at –40 8C for 10 min. Insoluble materials were removed by filtration, and
concentrated in vacuo. The crude residue was purified by silica gel column
chromatography (hexane/AcOEt = 98/2) and gave 1 (414 mg, 57%) as a colourless
crystalline solid. M.p. = 135–136 8C; 1H NMR (200 MHz, CDCl3) d 1.45 (s, 36H),
3.75 (s, 6H), 7.09 (s, 4H); 19F NMR (188 MHz, CDCl3) d À38.6 (s); IR (KBr): 2971,
1396, 1182 cmÀ1; EIMS m/z (rel intensity): 600 (M+, 5.0), 582 (14), 283 (28), 91
(47), 57 (100).