Synthesis of Morita–Baylis–Hillman-fluorides using 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine

Article abstract of DOI:10.1016/j.tet.2021.132387

Morita–Baylis–Hillman (MBH)-fluorides are valuable platforms for asymmetric allylic substitution reactions. However, the preparation of MBH-fluorides requires the use of an explosive fluorinating reagent, namely (diethylamino)sulfur trifluoride (DAST). Th

Full text of DOI:10.1016/j.tet.2021.132387

Tetrahedron 97 (2021) 132387
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of MoritaeBayliseHillman-fluorides using 1,1,2,2-
tetrafluoroethyl-N,N-dimethylamine
,
Yuji Sumii a, Takato Nagasaka a, Ayaka Matsuno a b, Hidetoshi Hayashi b,
, d, e, *
Hideyuki Mimura c, Takumi Kagawa c, Norio Shibata a
a Department of Engineering, Nagoya Institute of Technology, Gokiso, Showa-Ku, Nagoya, 466-8555, Japan
b Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-Dori, Mizuho-Ku, Nagoya, 467-8603, Japan
c Tosoh Finechem Corporation, 4988 Kaiseicho, Shunan, Yamaguchi, 746-0006, Japan
d Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso, Showa-Ku, Nagoya, 466-8555, Japan
e Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University, 688 Yingbin Avenue, 321004, Jinhua, China
a r t i c l e i n f o
a b s t r a c t
Article history:
MoritaeBayliseHillman (MBH)-fluorides are valuable platforms for asymmetric allylic substitution re-
actions. However, the preparation of MBH-fluorides requires the use of an explosive fluorinating reagent,
namely (diethylamino)sulfur trifluoride (DAST). Thus, we herein report a safe, alternative method for the
preparation of MBH-fluorides via the deoxyfluorination of MBH-alcohols using 1,1,2,2-tetrafluoroethyl-
N,N-dimethylamine (TFEDMA). Accordingly, a variety of MBH-alcohols were smoothly converted to their
corresponding MBH-fluorides in moderate to good yields without the requirement for an activator. This
fluorination reaction was found to proceed via an SN1 process involving a stable allylic cation
intermediate.
Received 1 July 2021
Received in revised form
4 August 2021
Accepted 6 August 2021
Available online 10 August 2021
Keywords:
Fluorination
TFEDMA
DAST
© 2021 Elsevier Ltd. All rights reserved.
1. Introduction
presence of silicon-containing nucleophiles, the MBH-fluorides are
efficiently activated, and can be converted into their corresponding
MoritaeBayliseHillman (MBH) adducts are valuable multi-
functional synthetic building blocks for various complex molecules,
including heterocyclic compounds [1]. Significantly, under asym-
metric organocatalysis using chiral amines and phosphines, MBH
adducts react smoothly with various nucleophiles via SN2ʹ or dual
SN2ʹ pathways to enantioselectively provide allylic substitution
products bearing a stereogenic CeC, CeO, CeS, CeN, or CeP bond
[2]. Among the numerous synthetic transformations of MBH ad-
ducts reported to date, MBH-acetates and carbonates are critical in
the context of asymmetric allylic substitution (AAS) reactions. On
the other hand, MBH-halides such as bromides are known, but have
rarely been used in such applications, likely due to their inherent
instability [3]. However, in 2014, MBH-fluorides emerged as an
alternative platform for the AAS reaction [4a]. As shown in Fig. 1a,
MBH-fluorides possess an allylic carbon center bearing a fluorine
atom. In contrast to the other MBH-halides, the MBH-fluorides are
stable due to the presence of a strong Csp3-F bond. Notably, in the
allylic substitution products via a selective CeF bond activation
process induced by silicon [4]. Moreover, in the presence of cata-
lytic amounts of cinchona alkaloids, various AAS reactions between
the MBH-fluorides and silylated nucleophiles have been reported,
including trifluoromethylation [4a], alkynylation [4b], difluor-
omethylation [4c,d], and tetrazole-methylation reactions [4e],
among others [4feh]. In addition, CeH-containing substrates, such
as HCCl3, HC6F5, CHF(SO2Ph), are also directly applicable as nucle-
ophiles in the presence of trifluoromethyl trimethyl silane,
CF3SiMe3 (Fig. 1b) [4f].
The preparation of MBH-fluorides, however, is somewhat
tedious. As previously reported, they can be prepared from their
corresponding MBH-alcohols via
a deoxy-fluorination with
(diethylamino)sulfur trifluoride (DAST) in low to moderate yields
[4]. Although DAST has been widely used for various deoxyfluori-
nation reactions, DAST is unstable toward moisture and is highly
explosive under heating conditions (>90 ꢀC) (Fig. 1c) [5]. Without
an alternative method for their preparation, these issues could
restrict the use of the MBH-fluorides as platforms for AAS reactions.
Thus, we became interested in the use of 1,1,2,2-tetrafluoroethyl-
N,N-dimethylamine (TFEDMA) for the deoxyfluorination of MBH-
* Corresponding author. Department of Engineering, Nagoya Institute of Tech-
nology, Gokiso, Showa-Ku, Nagoya, 466-8555, Japan.
E-mail address: nozshiba@nitech.ac.jp (N. Shibata).
https://doi.org/10.1016/j.tet.2021.132387
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

Y. Sumii, T. Nagasaka, A. Matsuno et al.
Tetrahedron 97 (2021) 132387
Table 1
Optimization of the deoxyfluorination reaction of MBH-alcohol 1a using TFEDMAa.
entry
solvent
temp
time
2a yield (%)b
3a yield (%)b
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
rt
40 min
20 min
5 min
1 h
10 min
2 h
12 h
24 h
10 min
11 h
1 h
40 min
20 min
10 min
20 min
3 h
56
56
52
57
16
16
10
15
16 (16c)
13
11
e
40 ꢀC
60 ꢀC
0
0
ꢀC
ꢀC-rt
62 (59c)
51
ꢁ20 ꢀC
ꢁ40 ꢀC
48
trace
57
15
40
55
59
59
53
0
0
0
0
0
0
0
0
rt
ꢀCert
ꢀCert
ꢀCert
ꢀCert
ꢀCert
ꢀCert
ꢀCert
ꢀCert
9
ClCH2CH2Cl
MeCN
14
5
10
11
12d
13e
14f
15g
16h
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
16
15
15
15
14
e
Fig. 1. MBH-adducts. (a) Structures of the MBH-acetates, carbonates, halides, and
fluorides. (b) Examples of the asymmetric allylic substitution reactions of MBH-
fluorides. (c) Preparation of the MBH-fluorides using DAST. (d) Deoxyfluorination of
MBH-alcohols using TFEDMA (this work).
10
a
Reaction conditions: TFEDMA (1.5 equiv) was added to a solution of MBH-
alcohol (0.2 mmol, 1.0 equiv) in dry solvent (2.0 mL, 0.1 M) in a Teflon® bottle at
0 ꢀC, and the reaction mixture was stirred at the desired temperature (rt: 17e24 ꢀC).
alcohols to yield MBH-fluorides. TFEDMA is a commercially avail-
able, inexpensive, thermally stable fluorinating reagent, and was
developed by Petrov et al., in 2001 [6]. TFEDMA can be quantita-
tively prepared by mixing N,N-dimethylamine and tetrafluoro-
ethylene (TFE, a component of Teflon®), and so can be considered a
promising fluorinating reagent for industrial applications [7].
However, the utility of TFEDMA for deoxyfluorination processes has
yet to be examined in detail [6,7].
Thus, to address the above issues, we herein report the efficient
and straightforward synthesis of MBH-fluorides from MBH-
alcohols using TFEDMA (Fig. 1d). For this purpose, a variety of
MBH-alcohols are converted into their corresponding MBH-
fluorides using a solution of TFEDMA in dichloromethane at tem-
peratures ranging from 0 ꢀC to rt (17e24 ꢀC) over a relatively short
reaction time (i.e., 30 min). The application of a chiral MBH-alcohol
to this system is also investigated to reveal the reaction pathway.
b
Yields were determined by 19F NMR spectroscopic analysis of the crude product
using trifluorotoluene as an internal standard.
c
Isolated yield.
TFEDMA (1.0 equiv).
TFEDMA (1.2 equiv).
TFEDMA (2.0 equiv).
The reaction was performed in a glass bottle.
Deoxo-Fluor® (1.5 equiv) was used instead of TFEDMA.
d
e
f
g
h
this test reaction, only 10 % of the desired 2a was obtained (entry
16). The starting materials almost disappeared in all the cases, and
additional byproducts were observed while we couldn't identify
them.
With the optimized conditions in hand, we examined the sub-
strate scope of the TFEDMA-mediated deoxyfluorination reaction
using a variety of MBH-alcohols (Table 2). It was found that sub-
strates bearing an electron-donating Me, OMe, or halogen substit-
uent on the benzene ring (1be1i) provided the corresponding
MBH-fluorides 2be2i in moderate to good yields (39e63 %
yields), while the sterically demanding o-Br-phenyl MBH-alcohol
1h was converted to 2h in a lower yield of 32 %. In addition, sub-
strates 1je1m, which bear electron-withdrawing groups (i.e., NO2,
CN, CO2Me, and CF3) were also readily converted into their corre-
sponding MBH-fluorides (2je2m) in good yields (40e58 %).
Furthermore, naphthalene-substituted MBH-alcohol (1n) gave the
desired product 2n in 50 % yield, and the reaction of ethyl and
sterically bulky tert-butyl esters (1oe1r) also proceeded to give the
corresponding MBH-fluorides (2oe2r) in good yield (44e62 %).
Subsequently, the conversion of MBH-alcohols bearing aliphatic
substituents (i.e., cyclohexyl-containing 1s and phenylethyl-
containing 1t) produced the desired MBH-fluorides in yields of
16 % (2s) and 45 % (2t). The indole-derived substrate 1u also gave
the desired product 2u in 31 %. Unfortunately, the isatin-derived
MBH adduct 1v having a tertiary alcohol was not converted ideally.
We next examined the deoxyfluorination of MBH-phosphonate
alcohol 4a and MBH-acrylonitrile alcohol 4b using TFEDMA under
the optimal conditions determined above. As indicated in Scheme 1,
the desired fluorides 5a (47 %) and 5b (32 %) were obtained as
inseparable mixtures with their regioisomers 6a (18 %, E/Z mixture)
and 6b (34 %).
2. Results and discussion
For optimization of the deoxyfluorination reaction of MBH-
alcohols
1 using TFEDMA, methyl 2-(hydroxy(phenyl)methyl)
acrylate (1a) was initially employed as a model substrate (Table 1).
More specifically, the deoxyfluorination of 1a was carried out using
1.5 equivalents of TFEDMA in CH2Cl2 (0.1 M) at rt. After a reaction
completed, the desired MBH-fluoride (2a) was obtained in 56 %
yield, along with the regioisomeric allylic fluoride 3a in 16 % yield
as an E/Z mixture (entry 1). Heating the reaction was not found to
have any beneficial effect on the yield (entries 2 and 3), and a
similar result was obtained when a temperature of 0 ꢀC was
employed (entry 4). However, a slightly increased yield of 62 %
(59 % isolated yield) was obtained when the TFEDMA reagent was
added at 0 ꢀC and the reaction was conducted at rt (entry 5).
Lowering the reaction temperature further (i.e., to ꢁ20 and ꢁ40 ꢀC)
reduced the yield further (entries 6 and 7), and neither solvent
screening (entries 8e11) nor variation in the amount of TFEDMA
employed (entries 12e14) improved the reaction outcome. Inter-
estingly, we also found that carrying out the reaction in a Teflon®
bottle was preferable; otherwise, the yield was slightly compro-
mised (entries 5 vs 15). Furthermore, for comparison, we attempted
the use of Deoxo-Fluor® for the transformation of 1a to 2a. Deoxo-
Fluor®, i.e., bis(2-methoxyethyl)aminosulfur trifluoride, was
developed as a thermally stable alternative to DAST [8]. However, in
2

Y. Sumii, T. Nagasaka, A. Matsuno et al.
Tetrahedron 97 (2021) 132387
Table 2
Substrate scope for the deoxyfluorination reaction of MBH-alcohols using TFEDMAa.
reaction conditions (Scheme 2b), and found that 1a was smoothly
transformed into the corresponding racemic MBH-fluoride 2a in
43 % yield (1 % ee).
The above result indicated that the deoxyfluorination of MBH-
alcohol 1 using TFEDMA proceeds via an SN1 process rather than
the previously reported SN2 process. We therefore considered that
during this reaction, MBH-alcohol 1 reacts with TFEDMA to give an
intermediate I with the loss of HF. This HF then activates inter-
mediate I via hydrogen bonding to provide a stable allyl cation
intermediate II with the elimination of difluoroacetamide 7 via an
SN1 process. Such activation of I by HF is key due to the fact that we
found that the reaction is slightly hampered by the use of standard
glassware instead of a Teflon® bottle (Table 1, entry 15) [9]. Finally,
fluoride attacks at the more stable benzylic cation (route a) rather
than terminal cation (route b) to give MBH-fluoride 2 as the major
product, along with the regioisomer 3. The difluoroacetamide 7,
presumably as a complex with HF was also released [10] (Fig. 2).
Scheme 1. Deoxyfluorination of MBH-phosphonate alcohol 4a and MBH-acrylonitrile
alcohol 4b using TFEDMA. aYields were determined by 19F NMR spectroscopic analyses
of the crude products using trifluorotoluene as an internal standard.
Previously, Petrov et al. reported that (S)-methyl mandelate can
be converted into the desired methyl (R)-2-fluoro-2-phenylacetate
in 65 % yield with inversion of stereochemistry via cyclic SN2 pro-
cess, while the enantiopurity of the fluoride is low (26 % ee)
(Scheme 2a) [6,7a]. We therefore examined the deoxyfluorination
reaction using chiral, non-racemic 1a (85 % ee) under the optimized
Scheme 2. Deoxyfluorination reaction of chiral alcohols using TFEDMA. aSee reference
Fig. 2. Proposed reaction mechanism for the deoxyfluorination of MBH-alcohols using
7a.
TFEDMA.
3

Y. Sumii, T. Nagasaka, A. Matsuno et al.
Tetrahedron 97 (2021) 132387
3. Conclusion
anhydrous Na2SO4, and the filtrate was concentrated under
reduced pressure to give the crude product. Purification was by
column chromatography (hexane/EtOAc, hexane/Et2O or hexane/
DCM) to give the corresponding MBH-fluoride.
We herein report the development of a safe, alternative syn-
thetic route to MoritaeBayliseHillman (MBH)-fluorides from MBH-
alcohols
using
1,1,2,2-tetrafluoroethyl-N,N-dimethylamine
(TFEDMA) instead of the explosive (diethylamino)sulfur trifluoride
(DAST). Using this procedure, various MBH-alcohols were smoothly
converted into their corresponding MBH-fluorides in moderate to
good yields within 30 min. Since our described route avoids the
necessity to employ DAST, we expect that it will expand the utility
of MBH-fluorides as valuable platforms for various asymmetric
allylic substitution reactions. Moreover, due to the fact that MBH-
adducts are considered a new class of bioactive compounds [11],
and the fact that fluorine-containing compounds have shown sig-
nificant potential in the pharmaceutical [12a] and agrochemical
industries [12b], we expect that the MBH-fluorides will also be
valuable in the design of novel biologically active molecules. The
further application of the MBH-fluorides in this direction is
ongoing.
4.2.1. Methyl 2-(fluoro(phenyl)methyl)acrylate (2a)
Following the general deoxyfluorination procedure using allylic
alcohol 1a (38.4 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/Et2O
(20:1) to give the desired product 2a (21.8 mg, 59 %) as a colorless
oil and regioisomeric allylic fluoride 3a (6.2 mg, 16 %, E/Z mixture
(major:minor ¼ 6.5:1)) as a colorless oil. 2a: 1H NMR (300 MHz,
CDCl3)
d
: 7.44e7.32 (m, 5H), 6.47e6.45 (m, 1H), 6.29 (d, J ¼ 45.9 Hz,
1H), 6.03 (br s, 1H), 3.72 (s, 3H) ppm. 19F NMR (282 MHz, CDCl3)
d
: ꢁ171.27 (d, J ¼ 46.6 Hz,1F) ppm. MS (EI) m/z: [M]þ 193. Analytical
data are consistent with reported values.4a 3a: 1H NMR (300 MHz,
CDCl3)
d
: 8.08 (d, J ¼ 4.0 Hz, 0.87H), 7.51e7.50 (m, 1.74H), 7.46e7.42
(m, 2.61H), 7.35 (br s, 0.65H), 7.07 (d, J ¼ 3.7 Hz, 0.13H), 5.23 (d,
J ¼ 47.6 Hz, 1.74H), 5.16 (d, J ¼ 47.0 Hz, 0.28H), 3.88 (s, 2.6H), 3.71 (s,
0.4H) ppm. 19F NMR (282 MHz, CDCl3)
d
: ꢁ205.3 (td, J ¼ 47.4, 3.4 Hz,
4. Experimental section
2.6F), ꢁ211.6 (td, J ¼ 47.4, 3.4 Hz, 0.4F) ppm. 13C{1H} NMR (126 MHz,
CDCl3)
d
: 167.4, 147.7 (d, J ¼ 7.3 Hz), 139.6 (d, J ¼ 10.9 Hz), 134.1 (d,
4.1. General information
J ¼ 3.6 Hz), 130.2, 130.0 (d, J ¼ 3.6 Hz), 129.1, 128.9, 128.6 (d,
J ¼ 16.3 Hz), 128.4, 126.7 (d, J ¼ 14.5 Hz), 84.2 (d, J ¼ 169.9 Hz), 77.2
(d, J ¼ 161.7 Hz), 52.6, 52.0 ppm. MS (EI) m/z: [M]þ 193. Analytical
data of Z isomer of 3a are consistent with reported values [14].
Reactions were performed under anhydrous conditions with
flame dried glassware under a positive pressure of nitrogen. All
reaction mixtures were stirred magnetically. Room temperature
was in the range of 17e24 ꢀC. Solvents were transferred via syringes
and were introduced into the reaction vessels through rubber
septa. All reactions were monitored by thin layer chromatography
(TLC) carried out on 0.25 mm silica gel (60-F254) (Merck). The TLC
plates were visualized using 254 nm UV light or heating following
treatment with an aqueous solution of 7 % phosphomolybdic acid
or KMnO4. Column chromatography was carried out on a column
4.2.2. Methyl 2-(fluoro(p-tolyl)methyl)acrylate (2b)
Following the general deoxyfluorination procedure using allylic
alcohol 1b (41.2 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(20:1) to give the desired product 2b (21.9 mg, 53 %) as a colorless
oil. 1H NMR (300 MHz, CDCl3)
d
: 7.28 (d, J ¼ 9.1 Hz, 2H), 7.18 (d,
J ¼ 7.6 Hz, 2H), 6.45e6.44 (m, 1H), 6.25 (d, J ¼ 46.2 Hz, 1H), 6.03 (d,
packed with 60 N spherical neutral size 40e50 mm (Kanto Chemi-
J ¼ 1.0 Hz, 1H), 3.71 (s, 3H), 2.36 (s, 3H) ppm. 19F NMR (282 MHz,
cal) or 63e210
m
m (FUJIFILM Wako) silica-gel. NMR spectra were
CDCl3)
d
: ꢁ169.75 (d, J ¼ 44.8 Hz, 1F) ppm. MS (EI) m/z: [M]þ 208.
recorded on a Varian Mercury 300 spectrometer for the 1H NMR
(300 MHz) and 19F NMR (282 MHz) spectra, and a Bruker Avance
500 spectrometer for the 1H NMR (500 MHz) and 13C{1H} NMR
Analytical data are consistent with reported values [4a].
4.2.3. Methyl 2-(fluoro(m-tolyl)methyl)acrylate (2c)
(125 MHz) spectra. The chemical shifts (
d
) were measured in parts
Following the general deoxyfluorination procedure using allylic
alcohol 1c (41.2 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(45:1) to give the desired product 2c (26.2 mg, 63 %) as a colorless
per million with respect to the solvent (1H: CDCl3,
d
¼ 7.26 ppm; 13
C
{1H}: CDCl3,
d
¼ 77.16 ppm) or an internal standard (19F: C6F6,
d
¼ ꢁ162.2 ppm in CDCl3) and the coupling constants (J) are given
in hertz. The following abbreviations denote the corresponding
peak multiplicities: s, singlet; d, doublet; t, triplet; q, quadruplet;
dd, doublet of doublets; td, triplet of doublets; dt, doublet of trip-
lets; m, multiplet; br, broad. Mass spectra were recorded using a
JEOL JMS-Q1050GC (EI-MS) and a SHIMADZU LCMS-2020 (ESI-MS)
system. Fourier transform infrared (FT-IR) spectra were recorded on
a JASCO FT/IR-4100 spectrometer. High-resolution mass spec-
trometry (HR-MS) was performed on a Waters Synapt G2 HDMS
(ESI-MS). MBH-alcohols 2,4 were prepared according to reported
method [4a,4d,4g,13]. TFEDMA (86 % purity) was available from
Tosoh Finechem Corporation.
oil. 1H NMR (300 MHz, CDCl3)
d: 7.28e7.17 (m, 4H), 6.45 (s, 1H), 6.25
(d, J ¼ 45.9 Hz, 1H), 6.02 (s, 1H), 3.72 (s, 3H), 2.36 (s, 3H) ppm. 19
F
NMR (282 MHz, CDCl3)
d
: ꢁ170.86 (d, J ¼ 46.6 Hz, 1F) ppm. MS (EI)
m/z: [M]þ 208. Analytical data are consistent with reported values
[4a].
4.2.4. Methyl 2-(fluoro(o-tolyl)methyl)acrylate (2d)
Following the general deoxyfluorination procedure using allylic
alcohol 1d (41.2 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(35:1) to give the desired product 2d (24.6 mg, 60 %) as a colorless
oil. 1H NMR (300 MHz, CDCl3)
d
: 7.33 (d, J ¼ 7.9 Hz, 1H), 7.29e7.18
4.2. General procedure for deoxyfluorination of the MBH-alcohols
using TFEDMA
(m, 3H), 6.55 (d, J ¼ 45.9 Hz, 2H), 6.49 (s,1H), 5.88 (d, J ¼ 0.9 Hz,1H),
3.75 (s, 3H), 2.40 (s, 3H) ppm. 19F NMR (282 MHz, CDCl3)
d: ꢁ173.22
(d, J ¼ 44.8 Hz, 1F) ppm. 13C{1H} NMR (126 MHz, CDCl3)
d: 165.6 (d,
TFEDMA (36.5
m
L, 0.3 mmol, 1.5 equiv) was added to a solution
J ¼ 4.5 Hz), 139.0 (d, J ¼ 22.7 Hz), 136.5 (d, J ¼ 4.5 Hz), 135.3 (d,
J ¼ 19.1 Hz), 130.8, 129.1 (d, J ¼ 2.7 Hz), 127.3 (d, J ¼ 8.2 Hz), 126.8 (d,
J ¼ 6.4 Hz), 126.2, 87.9 (d, J ¼ 171.7 Hz), 52.2, 19.1 ppm. MS (EI) m/z:
[M]þ 208. Analytical data are consistent with reported values [4a].
of the prepared MBH-alcohol (0.2 mmol, 1.0 equiv) in dry CH2Cl2
(2.0 mL) in a Teflon® bottle at 0 ꢀC, and the reaction mixture was
stirred at room temperature for 30 min. After this time, the mixture
was cooled to 0 ꢀC, saturated aqueous NaHCO3 was added to the
mixture, and the resulting mixture was extracted with CH2Cl2. The
combined organic layer was then washed with brine, dried over
4.2.5. Methyl 2-(fluoro(4-methoxyphenyl)methyl)acrylate (2e)
Following the general deoxyfluorination procedure using allylic
4

Y. Sumii, T. Nagasaka, A. Matsuno et al.
Tetrahedron 97 (2021) 132387
alcohol 1e (44.4 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(25:1) to give the desired product 2e (17.3 mg, 39 %) as a colorless
J ¼ 44.8 Hz, 1F) ppm. MS (EI) m/z: [M]þ 238. Analytical data are
consistent with reported values [4a].
oil. 1H NMR (300 MHz, CDCl3)
d
: 7.32 (dd, J ¼ 8.5,1.8 Hz, 2H), 6.90 (d,
4.2.11. Methyl 2-((4-cyanophenyl)fluoromethyl)acrylate (2k)
Following the general deoxyfluorination procedure using allylic
alcohol 1k (43.4 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(18:1) to give the desired product 2k (21.4 mg, 49 %) as a colorless
J ¼ 8.8 Hz, 2H), 6.43e6.43 (m, 1H), 6.22 (d, J ¼ 46.2 Hz, 1H), 6.05 (s,
1H), 3.81 (s, 3H), 3.70 (s, 3H) ppm. 19F NMR (282 MHz, CDCl3)
d
: ꢁ167.63 (d, J ¼ 46.0 Hz, 1F) ppm. MS (ESI) m/z: [M]þ 224.
Analytical data are consistent with reported values [4g].
oil. 1H NMR (300 MHz, CDCl3)
d
: 7.68 (d, J ¼ 7.9 Hz, 2H), 7.52 (d,
J ¼ 8.2 Hz, 2H), 6.50 (d, J ¼ 2.6 Hz, 1H), 6.31 (d, J ¼ 45.6 Hz, 1H), 6.07
4.2.6. Methyl 2-((4-bromophenyl)fluoromethyl)acrylate (2f)
(s, 1H), 3.73 (s, 3H) ppm. 19F NMR (282 MHz, CDCl3)
d: ꢁ175.98 (d,
Following the general deoxyfluorination procedure using allylic
alcohol 1f (54.2 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(20:1) to give the desired product 2f (30.0 mg, 55 %) as a colorless
J ¼ 44.8 Hz, 1F) ppm. MS (EI) m/z: [M]þ 218. Analytical data are
consistent with reported values [4g].
oil. 1H NMR (300 MHz, CDCl3)
d
: 7.51 (d, J ¼ 7.9 Hz, 2H), 7.27 (dd,
4.2.12. Methyl 4-(1-fluoro-2-(methoxycarbonyl)allyl)benzoate (2l)
Following the general deoxyfluorination procedure using allylic
alcohol 1l (50.1 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(15:1) to give the desired product 2l (29.0 mg, 58 %) as a colorless
J ¼ 7.6, 1.8 Hz, 2H), 6.46 (d, J ¼ 2.9 Hz, 1H), 6.23 (d, J ¼ 45.9 Hz, 1H),
6.04 (s, 1H), 3.72 (s, 3H) ppm. 19F NMR (282 MHz, CDCl3)
d
: ꢁ172.39
(d, J ¼ 44.8 Hz, 1F) ppm. MS (EI) m/z: [M]þ 272. Analytical data are
consistent with reported values [4a].
oil. 1H NMR (300 MHz, CDCl3)
d
: 8.04 (d, J ¼ 7.9 Hz, 2H), 7.46 (d,
J ¼ 7.9 Hz, 2H), 6.47 (d, J ¼ 2.4 Hz, 1H), 6.32 (d, J ¼ 45.9 Hz, 1H), 6.03
4.2.7. Methyl 2-((3-bromophenyl)fluoromethyl)acrylate (2g)
Following the general deoxyfluorination procedure using allylic
alcohol 1g (54.2 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(35:1) to give the desired product 2g (54.6 mg, 53 %) as a colorless
(s, 1H), 3.91 (s, 3H), 3.72 (s, 3H) ppm. 19F NMR (282 MHz, CDCl3)
d
: ꢁ174.43 (d, J ¼ 46.6 Hz, 1F) ppm. MS (EI) m/z: [M]þ 252.
Analytical data are consistent with reported values [4g].
oil. 1H NMR (300 MHz, CDCl3)
d
: 7.53 (s, 1H), 7.48 (d, J ¼ 7.9 Hz, 1H),
4.2.13. Methyl 2-(fluoro(4-(trifluoromethyl)phenyl)methyl)acrylate
(2m)
7.34e7.32 (m, 1H), 7.27e7.22 (m, 1H), 6.48 (d, J ¼ 2.9 Hz, 1H), 6.23
(d, J ¼ 45.9 Hz, 1H), 6.05 (s, 1H), 3.73 (s, 4H) ppm. 19F NMR
Following the general deoxyfluorination procedure using allylic
alcohol 1m (52.0 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(30:1) to give the desired product 2m (26.9 mg, 51 %) as a colorless
(282 MHz, CDCl3)
d
: ꢁ172.73 (d, J ¼ 46.6 Hz, 1F) ppm. MS (EI) m/z:
[M]þ 272. Analytical data are consistent with reported values [4a].
oil. 1H NMR (300 MHz, CDCl3)
d
: 7.64 (d-like, J ¼ 7.9 Hz, 2H), 7.52 (d-
like, J ¼ 7.9 Hz, 2H), 6.49 (s,1H), 6.33 (d, J ¼ 45.9 Hz,1H), 6.06 (s,1H),
3.74 (s, 3H) ppm. 19F NMR (282 MHz, CDCl3)
4.2.8. Methyl 2-((2-bromophenyl)fluoromethyl)acrylate (2h)
Following the general deoxyfluorination procedure with allylic
alcohol 1h (54.2 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(30:1) to give the desired product 2h (54.6 mg, 32 %) as a colorless
d
: ꢁ63.23 (s,
3F), ꢁ174.79 (d, J ¼ 44.8 Hz, 1F) ppm. Analytical data are consistent
with reported values [4f].
oil. 1H NMR (300 MHz, CDCl3)
d
: 7.59 (d-like, J ¼ 7.9 Hz, 1H), 7.46
(dd, J ¼ 7.8, 1.6 Hz, 1H), 7.37 (t, J ¼ 7.5 Hz, 1H), 7.23 (t, J ¼ 7.8 Hz, 1H),
4.2.14. Methyl 2-(fluoro(naphthalen-2-yl)methyl)acrylate (2n)
Following the general deoxyfluorination procedure using allylic
alcohol 1n (48.5 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(30:1) to give the desired product 2n (24.2 mg, 50 %) as a colorless
6.67 (d, J ¼ 45.0 Hz, 1H), 6.52 (s, 1H), 5.78 (s, 1H), 3.78 (s, 3H) ppm.
19F NMR (282 MHz, CDCl3)
d
: ꢁ173.57 (d, J ¼ 44.8 Hz, 1F) ppm. MS
(EI) m/z: [MꢁBr]þ 193. Analytical data are consistent with reported
values [4a].
oil. 1H NMR (300 MHz, CDCl3)
d
: 7.88e7.85 (m, 4H), 7.53e7.48 (m,
3H), 6.47 (d, J ¼ 45.9 Hz, 2H), 6.51 (d, J ¼ 2.4 Hz, 1H), 6.10 (s, 1H),
4.2.9. Methyl 2-((4-chlorophenyl)fluoromethyl)acrylate (2i)
3.72 (s, 3H) ppm. 19F NMR (282 MHz, CDCl3)
d
: ꢁ171.15 (d,
Following the general deoxyfluorination procedure using allylic
alcohol 1i (45.3 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(20:1) to give the desired product 2i (27.0 mg, 59 %) as a colorless
J ¼ 44.8 Hz, 1F) ppm. MS (EI) m/z: [M]þ 244. Analytical data are
consistent with reported values [4a].
oil. 1H NMR (300 MHz, CDCl3)
d: 7.37e7.31 (m, 4H), 6.46 (d-like,
4.2.15. Ethyl 2-(fluoro(phenyl)methyl)acrylate (2o)
J ¼ 2.1 Hz, 1H), 6.24 (d, J ¼ 45.9 Hz, 1H), 6.04 (s, 1H), 3.72 (s, 3H)
Following the general deoxyfluorination procedure using allylic
alcohol 1o (41.2 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(30:1) to give the desired product 2o (22.6 mg, 54 %) as a colorless
ppm. 19F NMR (282 MHz, CDCl3)
d
: ꢁ171.96 (d, J ¼ 44.8 Hz, 1F) ppm.
MS (EI) m/z: [M]þ 228. Analytical data are consistent with reported
values [4a].
oil. 1H NMR (300 MHz, CDCl3)
d: 7.44e7.33 (m, 5H), 6.46 (d,
J ¼ 2.6 Hz, 1H), 6.29 (d, J ¼ 45.9 Hz, 1H), 6.02 (s, 1H), 4.22e4.11 (m,
4.2.10. Methyl 2-(fluoro(4-nitrophenyl)methyl)acrylate (2j)
2H), 1.23 (t, J ¼ 7.1 Hz, 3H) ppm. 19F NMR (282 MHz, CDCl3)
Following the general deoxyfluorination procedure using allylic
alcohol 1j (47.4 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(20:1) to give the desired product 2j (19.2 mg, 40 %) as a colorless
d
: ꢁ171.22 (d, J ¼ 46.6 Hz, 1F) ppm. MS (EI) m/z: [M]þ 208.
Analytical data are consistent with reported values [4d].
oil. 1H NMR (300 MHz, CDCl3)
d
: 8.23 (d, J ¼ 8.2 Hz, 2H), 7.58 (d,
J ¼ 8.2 Hz, 2H), 6.51 (d, J ¼ 2.6 Hz, 1H), 6.36 (d, J ¼ 45.6 Hz, 1H), 6.09
(s, 1H), 3.74 (s, 3H) ppm. 19F NMR (282 MHz, CDCl3)
: ꢁ176.11 (d,
4.2.16. Ethyl 2-((4-bromophenyl)fluoromethyl)acrylate (2p)
Following the general deoxyfluorination procedure with allylic
alcohol 1p (57.0 mg, 0.2 mmol), the obtained crude product was
d
5

Y. Sumii, T. Nagasaka, A. Matsuno et al.
Tetrahedron 97 (2021) 132387
purified by silica gel column chromatography with hexane/EtOAc
(30:1) to give the desired product 2p (35.6 mg, 62 %) as colorless oil.
J ¼ 7.4 Hz, 1H), 7.47e7.36 (m, 3H), 6.59 (s, 1H), 6.58 (d, J ¼ 45.6 Hz,
1H), 6.17 (s, 1H), 3.77 (s, 3H) ppm. 19F NMR (282 MHz, CDCl3)
1H NMR (300 MHz, CDCl3)
d
: 7.50 (d, J ¼ 8.2 Hz, 2H), 7.27 (d,
d
: ꢁ75.76 (s, 3F), ꢁ177.26 (d, J ¼ 46.6 Hz, 1F) ppm. MS (EI) m/z: [M]þ
J ¼ 6.5 Hz, 2H), 6.45 (d-like, J ¼ 1.5 Hz, 1H), 6.23 (d, J ¼ 45.9 Hz, 1H),
365. Analytical data are consistent with reported values [4g].
6.03 (s, 1H), 4.22e4.11 (m, 2H), 1.24 (t, J ¼ 7.1 Hz, 3H) ppm. 19F NMR
(282 MHz, CDCl3)
(126 MHz, CDCl3)
d
: ꢁ172.31 (d, J ¼ 44.8 Hz, 1F) ppm. 13C{1H} NMR
4.3. Deoxyfluorination of MBH-phosphonate alcohol (4a) using
TFEDMA
d
: 164.6 (d, J ¼ 6.4 Hz),139.3 (d, J ¼ 22.7 Hz), 136.7
(d, J ¼ 20.9 Hz),131.8,129.0 (d, J ¼ 5.4 Hz),125.9 (d, J ¼ 9.1 Hz),123.2
(d, J ¼ 3.6 Hz), 90.3 (d, J ¼ 175.3 Hz), 61.2, 14.2 ppm. MS (EI) m/z:
[M]þ 286. Analytical data are consistent with reported values [4d].
Following the general deoxyfluorination procedure using MBH-
phosphonate alcohol 4a (54.0 mg, 0.2 mmol), the obtained crude
product was purified by silica gel column chromatography with
hexane/EtOAc (1:2) to give the desired fluoride product (37.7 mg)
as inseparable mixture of regio-isomers (5a: 47 %, 6a:18 %). The
yield was determined by 19F NMR with trifluorotoluene as internal
4.2.17. tert-Butyl 2-(fluoro(phenyl)methyl)acrylate (2q)
Following the general deoxyfluorination procedure with allylic
alcohol 1q (46.9 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(55:1) to give the desired product 2q (21.0 mg, 44 %) as a colorless
standard. Pale yellow oil. 1H NMR (300 MHz, CDCl3)
d: 7.88 (dd,
J ¼ 23.2, 3.7 Hz, 0.1H), 7.59e7.30 (m, 5.2H), 6.33e6.28 (m, 0.7H),
6.16 (dq, J ¼ 45.0, 1.5 Hz, 0.7H), 6.09 (dd, J ¼ 46.2, 6.0 Hz, 0.7H),
5.21e5.04 (m, 0.6H), 4.18e4.12 (m, 0.4H), 4.02e3.88 (m, 2.9H),
3.82e3.74 (m, 0.7H), 1.35 (t, J ¼ 7.2 Hz, 0.5H), 1.24e1.20 (m, 2.4H),
oil. 1H NMR (300 MHz, CDCl3)
d: 7.37 (brd, 5H), 6.39e6.37 (m, 1H),
6.22 (dd, J ¼ 46.3, 1.0 Hz, 1H), 5.97e5.94 (m, 1H), 1.37 (s, 9H) ppm.
19F NMR (282 MHz, CDCl3)
d
: ꢁ170.30 (d, J ¼ 46.6 Hz, 1F) ppm. MS
(EI) m/z: [MꢁtBu þ H]þ 180. Analytical data are consistent with
1.14e1.10 (m, 3.1H) ppm. 19F NMR (282 MHz, CDCl3)
d
: ꢁ168.23 (dd,
reported values [4a].
J ¼ 45.7, 16.4 Hz, 0.72F), ꢁ203.18 (t, J ¼ 48.3 Hz, 0.1F), ꢁ207.91
to ꢁ207.53 (m, 0.18F) ppm. 13C{1H} NMR (126 MHz, CDCl3)
d: 151.6
(dd, J ¼ 10.9, 7.3 Hz),147.2 (dd, J ¼ 12.7, 6.4 Hz),139.7 (d, J ¼ 21.8 Hz),
138.3 (d, J ¼ 21.8 Hz),137.0 (dd, J ¼ 20.9, 2.7 Hz),134.9 (d, J ¼ 6.4 Hz),
134.0 (dd, J ¼ 21.3, 3.2 Hz), 130.9 (dd, J ¼ 10.4, 5.9 Hz), 130.1, 130.0,
129.8 (d, J ¼ 3.6 Hz), 129.6, 129.3, 129.2 (d, J ¼ 2.7 Hz), 128.9, 128.5,
128.3, 128.1, 127.3 (d, J ¼ 5.4 Hz), 125.9 (dd, J ¼ 178.9, 13.6 Hz), 124.7
(dd, J ¼ 183.0,14.1 Hz),124.0,123.9, 91.8 (dd, J ¼ 178.9,19.1 Hz), 85.0
(dd, J ¼ 173.5, 16.3 Hz), 77.3 (dd, J ¼ 166.2, 10.0 Hz), 62.4e62.2 (m),
16.4 (d, J ¼ 6.4 Hz), 16.3 (d, J ¼ 6.4 Hz), 16.1 (d, J ¼ 7.3 Hz) ppm. IR
(KBr): 3468, 2984, 1721, 1619, 1391, 1251, 1024, 970, 799, 734,
4.2.18. tert-Butyl 2-((4-bromophenyl)fluoromethyl)acrylate (2r)
Following the general deoxyfluorination procedure using allylic
alcohol 1r (62.6 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(55:1) to give the desired product 2r (30.4 mg, 48 %) as a colorless
oil. 1H NMR (300 MHz, CDCl3)
d
: 7.50 (d, J ¼ 7.9 Hz, 2H), 7.25 (d,
J ¼ 5.0 Hz, 2H), 6.38 (s, 1H), 6.17 (d, J ¼ 46.2 Hz, 1H), 5.95 (s, 1H), 1.39
(s, 9H) ppm. 19F NMR (282 MHz, CDCl3)
d: ꢁ171.36 (d, J ¼ 46.6 Hz,
1F) ppm. MS (EI) m/z: [Mꢁt-Bu þ H]þ 258. Analytical data are
699 cmꢁ1
.
consistent with reported values [4a].
4.2.19. Methyl 2-(cyclohexylfluoromethyl)acrylate (2s)
4.4. Deoxyfluorination of MBH-acrylonitrile alcohol (4b) using
Following the general deoxyfluorination procedure with allylic
alcohol 1s (39.6 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/DCM
(3:1) to give the desired product 2s (6.4 mg, 16 %) as a colorless oil.
TFEDMA
Following the general deoxyfluorination procedure using MBH-
acrylonitrile alcohol 4b (31.8 mg, 0.2 mmol), the obtained crude
product was purified by silica gel column chromatography with
hexane/EtOAc (6:1) to give the desired fluoride product (19.3 mg)
as inseparable mixture of regio-isomers (5b: 32 %, 6b: 34 %). The
yield was determined by 19F NMR with trifluorotoluene as internal
1H NMR (300 MHz, CDCl3)
d
: 6.38 (s, 1H), 5.86 (s, 1H), 5.12 (dd,
J ¼ 46.8, 3.8 Hz, 1H), 3.77 (s, 3H), 1.75e1.63 (m, 6H), 1.25e0.97 (m,
5H) ppm. 19F NMR (282 MHz, CDCl3)
d
: ꢁ192.34 (dd, J ¼ 46.6,
24.1 Hz, 1F) ppm. MS (EI) m/z: [MꢁC6H11
]
þ 118. Analytical data are
standard. Colorless oil. 1H NMR (300 MHz, CDCl3)
d: 7.83e7.81 (m,
consistent with reported values [4a].
1.1H), 7.48e7.42 (m, 3.0H), 7.42e7.38 (m, 0.9H), 7.26 (d, J ¼ 4.0 Hz,
0.55H), 6.16 (dd, J ¼ 2.0, 1.1 Hz, 0.45H), 6.13 (t, J ¼ 1.7 Hz, 0.45H),
4.2.20. Methyl 3-fluoro-2-methylene-5-phenylpentanoate (2t)
Following the general deoxyfluorination procedure using allylic
alcohol 1t (44.1 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(45:1) to give the desired product 2t (20.2 mg, 45 %) as a colorless
5.93 (d, J ¼ 45.8 Hz, 0.45H), 5.07 (dd, J ¼ 47.0, 0.9 Hz, 1.1H) ppm. 19
F
NMR (282 MHz, CDCl3)
d
: ꢁ172.0 (d, J ¼ 44.8 Hz, 0.45F), ꢁ209.4 (t,
J ¼ 46.6 Hz, 0.55F) ppm. 13C{1H} NMR (126 MHz, CDCl3)
d: 147.3 (d,
J ¼ 8.2 Hz), 135.1 (d, J ¼ 20.9 Hz), 132.5, 131.7 (d, J ¼ 7.3 Hz), 131.5,
130.0, 129.4, 129.2, 129.1, 126.6 (d, J ¼ 6.4 Hz), 123.1 (d, J ¼ 27.2 Hz),
116.8 (d, J ¼ 2.7 Hz), 115.8 (d, J ¼ 4.5 Hz), 106.2 (d, J ¼ 18.2 Hz), 91.6
(d, J ¼ 181.6 Hz), 83.2 (d, J ¼ 177.1 Hz) ppm. IR (KBr): 3446, 3063,
oil. 1H NMR (300 MHz, CDCl3)
d: 7.36e7.31 (m, 2H), 7.26e7.24 (m,
3H), 6.40 (s, 1H), 6.01 (s, 1H), 5.37 (dd, J ¼ 47.2, 7.8 Hz, 1H), 3.80 (s,
3H), 2.95e2.73 (m, 2H), 2.33e1.93 (m, 2H) ppm. 19F NMR (282 MHz,
2219, 1626, 1452, 1368, 1294, 1170, 996, 933, 693 cmꢁ1
.
CDCl3)
d
: ꢁ186.38 to ꢁ186.73 (m, 1F) ppm. MS (EI) m/z: [MꢁHF]þ
202, [MꢁHFeCO2H]þ 143. Analytical data are consistent with re-
ported values [4g].
4.5. Deoxyfluorination of the MBH-alcohols using DAST
DAST (39.3 L, 0.3 mmol, 1.5 equiv) was added to a solution of
4.2.21. Methyl 2-(fluoro(1-((trifluoromethyl)sulfonyl)-1H-indol-3-
yl)methyl)acrylate (2u)
m
desired the MBH-alcohol (0.2 mmol, 1.0 equiv) in dry CH2Cl2
(2.0 mL) in a Teflon® bottle at ꢁ78 ꢀC, and the reaction mixture was
stirred at ꢁ78 ꢀC for 20e50 min. After this time, a saturated
aqueous solution of NaHCO3 was added, and the mixture was
extracted with CH2Cl2. The combined organic layer was then
washed with brine, dried over anhydrous Na2SO4, filtered, and the
Following the general deoxyfluorination procedure using allylic
alcohol 1u (72.7 mg, 0.2 mmol), the obtained crude product was
purified by silica gel column chromatography with hexane/EtOAc
(25:1) to give the desired product 2u (22.8 mg, 31 %) as a white
solid. 1H NMR (300 MHz, CDCl3)
d
: 7.91 (d, J ¼ 7.9 Hz, 1H), 7.70 (d,
6

Y. Sumii, T. Nagasaka, A. Matsuno et al.
Tetrahedron 97 (2021) 132387
filtrate was concentrated to give the corresponding crude product.
The yield was determined by 19F NMR analysis of the crude product
using trifluorotoluene as an internal standard.
Acknowledgement
This work was supported by JSPS KAKENHI grant 21H01933
(KIBAN B).
4.6. Deoxyfluorination of the MBH-alcohols using DeoxoFluor
References
DeoxoFluor (52.7 mL, 0.3 mmol, 1.5 equiv) was added to a solu-
tion of the desired MBH-alcohol (0.2 mmol, 1.0 equiv) in dry CH2Cl2
(2.0 mL) in a Teflon® bottle at 0 ꢀC, and the resulting mixture was
stirred at room temperature for 3 h. After subsequent cooling to
[1] (a) W.-Y. Huang, S. Anwar, K. Chen, Chem. Rec. 17 (2017) 363;
(b) N.-J. Zhong, Y.-Z. Wang, L. Cheng, D. Wang, L. Liu, Org. Biomol. Chem. 16
(2018) 5214;
(c) H. Guo, Y.C. Fan, Z. Sun, Y. Wu, O. Kwon, Chem. Rev. 118 (2018) 10049;
(d) Z.-C. Chen, Z. Chen, W. Du, Y.-C. Chen, Chem. Rec. 20 (2020) 541.
[2] (a) G. Masson, C. Housseman, J. Zhu, Angew. Chem. Int. Ed. 46 (2007) 4614;
(b) T.-Y. Liu, M. Xie, Y.-C. Chen, Chem. Soc. Rev. 41 (2012) 4101;
(c) R. Rios, Catal. Sci. Technol. 2 (2012) 267;
0
ꢀC, a saturated aqueous solution of NaHCO3 was added, and the
mixture was extracted with CH2Cl2. The combined organic layer
was then washed with brine, dried over anhydrous Na2SO4, and the
filtrate was concentrated under reduced pressure to give the cor-
responding crude product. The yield was determined by 19F NMR
spectroscopy of the crude product using trifluorotoluene as an in-
ternal standard.
(d) Y. Wei, M. Shi, Chem. Rev. 113 (2013) 6659.
[3] While MBH-Bromides Are Reported, MBH-Chlorides and Iodides Are Not
Found in Our SciFinder® Searching. Examples of MBH-bromides, see. (a)
J.W. Lim, K.H. Kim, S.H. Kim, J.N. Kim, Tetrahedron 70 (2014) 6831;
(b) N. Baioui, A. Abidi, F. Rezgui, Helv. Chim. Acta 99 (2016) 704;
(c) R.J. Reddy, Md. Waheed, J.J. Kumar, RSC Adv. 8 (2018) 40446;
(d) D. Yadav, S.K. Sharma, R.S. Menon, Org. Biomol. Chem. 17 (2019) 4073.
[4] MBH-fluorides. (a) T. Nishimine, K. Fukushi, N. Shibata, H. Taira, E. Tokunaga,
A. Yamano, M. Shiro, N. Shibata, Angew. Chem. Int. Ed. 53 (2014) 517;
(b) S. Okusu, H. Okazaki, E. Tokunaga, V.A. Soloshonok, N. Shibata, Angew.
Chem. Int. Ed. 55 (2016) 6744;
4.7. Preparation of chiral MBH-alcohol 1a
DMAP (0.156 mmol, 10 mol%) was added to a to a solution of
MBH-alcohol 1a (300 mg, 1.56 mmol, 1.0 equiv) and (Boc)2O
(0.37 mL, 1.63 mmol, 1.05 equiv) in dry CH2Cl2 (7.8 mL) at rt, and the
resulting mixture was stirred at rt for 10 h. After this time, the re-
action mixture was concentrated under reduced pressure to give
the crude product, which was purified by column chromatography
(hexane/CH2Cl2 ¼ 2:1) to give O-Boc MBH-alcohol (325 mg, 71 %
yield). The O-Boc-MBH-alcohol (282 mg, 0.965 mmol, 1.0 equiv)
was then dissolved in N,N-dimethylacetamide (9.7 mL), and CaF2
(c) Y. Sumii, T. Nagasaka, J. Wang, H. Uno, N. Shibata, J. Org. Chem. 85 (2020)
15699;
(d) Y. Zi, M. Lange, I. Vilotijevic, Chem. Commun. 56 (2020) 5689;
(e) T. Nishimine, H. Taira, S. Mori, O. Matsubara, E. Tokunaga, H. Akiyama,
V.A. Soloshonok, N. Shibata, Chem. Commun. 53 (2017) 1128;
(f) T. Nishimine, H. Taira, E. Tokunaga, M. Shiro, N. Shibata, Angew. Chem. Int.
Ed. 55 (2016) 359;
(g) Y. Zi, M. Lange, C. Schultz, I. Vilotijevic, Angew. Chem. Int. Ed. 58 (2019)
10727;
(h) M. Lange, Y. Zi, I. Vilotijevic, J. Org. Chem. 85 (2020) 1259.
[5] (a) W.J. Middleton, J. Org. Chem. 40 (1975) 574;
(377 mg, 4.83 mmol, 5.0 equiv), H2O (35 mL, 1.93 mmol, 2.0 equiv),
and (DHQD)2AQN (82.7 mg, 0.0965 mmol, 10 mol%) were added to
the mixture at 0 ꢀC. After stirring the resulting mixture at 0 ꢀC for
72 h, H2O was added, and extractions were carried out using hex-
ane and EtOAc. The combined organic layer was then washed with
brine, dried over anhydrous Na2SO4, and the filtrate was concen-
trated to give the crude product. Purification was by column
chromatography (hexane/EtOAc ¼ 3:1) to give the chiral MBH-
alcohol (85 % ee, 152 mg, 82 % yield). The enantiomeric excess
was determined by HPLC analysis (column: CHIRALPAK IH, n-hex-
(b) J. Cochran, Chem. Eng. News 57 (1979) 74;
(c) W.J. Middleton, Chem. Eng. News 57 (1979) 43;
(d) P.A. Messina, K.C. Mange, W.J. Middleton, J. Fluor. Chem. 42 (1989) 137.
[6] (a) V.A. Petrov, S. Swearingen, W. Hong, W.C. Petersen, J. Fluor. Chem. 109
(2001) 25;
(b) V. Petrov, J. Hu, T. Umemoto, in: Fluoroolefin-Amine Adduct Deoxo-
fluorination. Fluorination. Synthetic Organofluorine Chemistry, Springer,
Singapore, 2018;
(c) C.P. Junk, V.A. Petrov, 1,1,2,2-Tetrafluorethyl-N,N-Dimethylamine” in E-
EROS Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons, Ltd.,
2014, pp. 1e2.
[7] (a) C.P. Junk, V.A. Petrov, US 20090030246 A1 (2009);
(b) S. Bresciani, A.M.Z. Slawin, D. O'Hagan, J. Fluor. Chem. 130 (2009) 537;
(c) L.M. Grieco, G.A. Halliday, C.P. Junk, S.R. Lustig, W.J. Marshall, V.A. Petrov,
J. Fluor. Chem. 132 (2011) 1198;
ane/isopropanol ¼ 90:10, flow rate: 0.8 mL/min,
l
¼ 220 nm), t
(major) ¼ 25.6 min, t (minor) ¼ 18.6 min). All other analytical data
were consistent with that of the racemic 1a [4a].
(d) K. Araki, T. Katagiri, M. Inoue, J. Fluor. Chem. 157 (2014) 41.
[8] (a) G.S. Lal, G.P. Pez, R.J. Pesaresi, F.M. Prozonic, Chem. Commun. (1999) 215;
(b) G. S. Lal, G. P. Pez, U.S. Patent 6,080,886, 2000;. (c) G.S. Lal, G.P. Pez,
R.J. Pesaresi, F.M. Prozonic, H. Cheng, J. Org. Chem. 64 (1999) 7048;
(d) R.P. Singh, J.M. Shreeve, Synthesis 17 (2002) 2561.
[9] Y. Liang, A. Taya, Z. Zhao, N. Saito, N. Shibata, Beilstein J. Org. Chem. 16 (2020)
3052.
4.8. Deoxyfluorination of chiral MBH-alcohol 1a using TFEDMA
Following the general deoxyfluorination procedure using chiral
allylic alcohol 1a (85 % ee, 38.4 mg, 0.2 mmol), the obtained crude
product was purified by silica gel column chromatography with
hexane/Et2O (20:1) to give the desired product 2a (20.1 mg, 52 %,
1 % ee) as a colorless oil. The enantiomeric excess was determined
by HPLC analysis (column: CHIRALPAK IH, n-hexane/
[10] (a) M. Tsuda, H. Touhara, K. Nakanishi, N. Watanabe, Bull. Chem. Soc. Jpn. 49
(1976) 2391;
(b) B.P. Patel, R.H. Crabtree, J. Am. Chem. Soc. 118 (1996) 13105;
(c) D.-H. Lee, H.J. Kwon, B.P. Patel, L.M. Liable-Sands, A.L. Rheingold,
R.H. Crabtree, Organometallics 18 (1999) 1615;
(d) O.E. Okoromoba, J. Han, G.B. Hammond, B. Xu, J. Am. Chem. Soc. 136 (2014)
14381.
[11] (a) C.G. LimaeJunior, M.L.A.A. Vasconcellos, Bioorg. Med. Chem. 20 (2012)
3954;
isopropanol ¼ 99:1, flow rate: 0.5 mL/min,
l
¼ 220 nm), t
(major) ¼ 19.6 min, t (minor) ¼ 21.1 min). All other analytical data
were consistent with that of the racemic 2a [4a].
(b) H. Elleuch, W. Mihoubi, M. Mihoubi, E. Ketata, A. Gargouri, F. Rezgui,
Bioorg. Chem. 78 (2018) 24.
[12] (a) M. Inoue, Y. Sumii, N. Shibata, ACS Omega 5 (2020) 10633;
(b) Y. Ogawa, E. Tokunaga, O. Kobayashi, K. Hirai, N. Shibata, iScience 23
(2020) 101467.
[13] (a) H. Park, C.-W. Cho, M.J. Krische, J. Org. Chem. 71 (2006) 7892;
(b) V. Singha, G.P. Yadav, P.R. Maulik, S. Batra, Tetrahedron 64 (2008) 2979.
[14] C.H. Lim, S.H. Kim, H.J. Lee, H.J. Kim, J.N. Kim, Bull. Kor. Chem. Soc. 34 (2013)
993.
Declaration of competing interest
The authors declare the following financial interests/personal
relationships which may be considered as potential competing
interests: Norio Shibata reports financial support was provided by
Japan Society for the Promotion of Science.
7