Diastereoselective α-Fluorination of N- tert-Butanesulfinyl Imidates

Article abstract of DOI:10.1021/acs.joc.8b02375

A diastereoselective α-fluorination of N-tert-butanesulfinyl imidates was developed. Deprotonation of N-tert-butanesulfinyl imidates with lithium hexamethyldisilazide generates aza-enolates that can be intercepted, with excellent diastereocontrol, by the inexpensive electrophilic fluorinating agent NFSI. This protocol was applied to the preparation of synthetically useful trans-2-fluoro-cyclohexamine with high enantiomeric purity (99.5% ee).

Full text of DOI:10.1021/acs.joc.8b02375

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pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Diastereoselective α‑Fluorination of N-tert-Butanesulfinyl Imidates
Wei Huang,‡ Yun Yao,† Yan-Jun Xu,‡ and Chong-Dao Lu*,†,‡
†School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
‡Key Laboratory of Plant Resources and Chemistry of Arid Zones, Xinjiang Technical Institute of Physics and Chemistry, Chinese
Academy of Sciences, Urumqi 830011, China
S
* Supporting Information
ABSTRACT: A diastereoselective α-fluorination of N-tert-butane-
sulfinyl imidates was developed. Deprotonation of N-tert-butanesul-
finyl imidates with lithium hexamethyldisilazide generates aza-enolates
that can be intercepted, with excellent diastereocontrol, by the
inexpensive electrophilic fluorinating agent NFSI. This protocol was
applied to the preparation of synthetically useful trans-2-fluoro-
cyclohexamine with high enantiomeric purity (99.5% ee).
Scheme 1. Electrophilic α-Fluorination of N-tert-
Butanesulfinyl Imidates
rganofluorine compounds are important because of their
O
broad applications in pharmaceutical agents1 and
agrochemicals.2 Diastereoselective C−F bond formation is an
effective way to incorporate fluorine into organic compounds
with desired stereochemistry.3 For example, electrophilic
fluorination of enolates is broadly used to construct C−F
bonds.3 For this process, catalytic asymmetric protocols have
been developed when the substrate is carboxylic derivatives
that are easily enolized, such as β-keto acid derivatives or their
analogues,4 oxindoles,5 α-aryl acetic acid derivatives,6 and
benzofuran-2-(3H)-ones.7 Enolization of carboxylic acid
derivatives with a weakly acidic α-proton is usually carried
out using stoichiometric amounts of strong bases or Lewis
acids. Diastereoselectivity is controlled by using chiral
auxiliaries such as Evans’ oxazolidinones or trans-Fox
(fluorinated oxazolidine).8 Recent examples of electrophilic
fluorination of enolates include Zakarian’s TiCl4-promoted
diastereoselective electrophilic fluorination of chiral N-
acyloxazolidinones9 and Brigaud’s enantioselective fluorination
of trans-Fox-derived amide enolates.10
Another approach to achieving diastereoselective fluorina-
tion may be to use N-tert-butanesulfinyl (N-tBS) imidates,
which are chiral equivalents of carboxylic acid derivatives and
have been used to diastereoselectively construct C−C,11,12,13,14
C−N,15 C−O,16 and C−S17 bonds in the α-position via
reaction between the aza-enolates and suitable electrophiles
(Scheme 1a). Diastereoselective α-functionalization of N-tBS
imidates is synthetically attractive because their chiral starting
materials, (RS)- and (SS)-enantiomers of N-tert-butanesulfina-
mide,18 are readily available and because N-tBS imidates can be
conveniently converted to esters, amides, N-tBS imines, and
amines.10,12c,15−17
philic fluorination reagent N-fluorobenzenesulfonimide (NSFI,
Table 1). Deprotonation of 1a with lithium hexamethyldisila-
zide (LiHMDS) in THF at −78 °C and subsequent
introduction of NSFI led to complete consumption of 1a
within 1 h and gave α-fluorinated product 2a with 10:1 dr
(entry 1). Changing the reaction solvent to dichloromethane
or ether improved diastereoselectivity to 15:1 dr (entries 2−3).
When toluene was used as solvent, excellent diastereocontrol
was observed (>50:1 dr), and the desired fluorination product
2a was isolated in 84% yield (entry 4). We also examined the
reactions using NaHMDS or KHMDS as base. In these cases,
better diastereoselectivities were obtained when the solvent
was THF rather than toluene (entry 5 vs 6; entry 7 vs 8).
Using the optimized reaction conditions for the α-
fluorination of N-tBS imidates (LiHMDS, NSFI, toluene),
we evaluated the substrate scope (Table 2). Linear aliphatic-
substituted imidates 1b−d (entries 2−4) and their counter-
parts containing functionalities such as chlorine (1e, entry 5),
4-methoxybenzyloxy group (1f, entry 6), vinyl group (1g, ent-
Here we report electrophilic α-fluorination of N-tBS
imidates (Scheme 1b) and demonstrate its synthetic utility
by efficiently preparing enantioenriched trans-2-fluoro-cyclo-
hexamine.
Initially, we investigated the feasibility of α-fluorination
Received: September 13, 2018
using (RS)-N-tBS imidate 1a with the inexpensive9 electro-
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b02375
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The Journal of Organic Chemistry
Note
1g, and 1h, entries 7−8), and alkynyl group (1i, entry 9)
underwent α-fluorination to afford the corresponding products
2b−i in 70−86% yields with excellent dr (>20:1). Higher
yields (89−90%) were obtained for the imidates 1j and 1k
bearing a branched alkyl group at the α-position (entries 9−
10). In the cases of 1e and 1h, we hydrolyzed the initially
formed α-fluorinated imidates using aqueous H2SO4 in order
to remove uncharacterized byproducts that had the same Rf
value as the desired product (entries 4 and 7). The hydrolysis
products, α-fluorinated N-tert-butanesulfinyl caboxamides 2e
and 2h, were quite polar and were easily purified using column
chromatography.
A range of α-aryl- and α-heteroaryl-substituted imidates 2l−
w gave products in good yields with high dr (entries 11−22).
Steric hindrance from bulky ortho substitutions did not
compromise diastereoselectivity (entries 14 and 21). The
reaction proceeded well in the presence of electron-rich (entry
15) and electron-deficient (entry 19) substitutions on aromatic
rings. Yield and dr remained good when the fluorination of 1l
was scaled up to 1 g (entry 11).
Next, we tested the possibility of chlorinating N-tBS imidate.
Reacting aza-enolized imidate 1b with the chlorinating reagent
N-chlorosuccinimide (NCS) in dichloromethane in the
presence of boron trifluoride gave α-chlorinated imidate 3 in
80% yield with 15:1 dr (Scheme 2).19 Diastereoselectivity was
moderate or poor when the Lewis acid was removed or when
the base was changed from LHMDS to NaHMDS or KHMDS
(Scheme 2).
Table 1. Optimization of the Diastereoselectivity of α-
Fluorination
a
b
b
entry
1
2
3
4
5
6
7
8
base
solvent
dr (yield)
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
THF
CH2Cl2
Et2O
toluene
THF
toluene
THF
10:1
15:1
15:1
>50:1 (84%)
33:1
9:1
c
d
40:1
6:1
toluene
a
Reaction conditions: 1a (0.30 mmol), base (1.2 equiv), and NSFI
(1.2 equiv) in anhydrous solvent at −78 °C. Reactions were complete
b
1
at −78 °C in 1 h. Diastereoselective ratios were determined by H
c
NMR spectroscopy of the crude reaction mixture. Reaction went to
d
completion in 30 min. Isolated yield of single diastereomer after
silica gel chromatography.
Table 2. Substrate Scope of the α-Fluorination of N-tert-
a
Butanesulfinyl Imidates
Scheme 2. α-Chlorination of N-tert-Butanesulfinyl Imidate
b
c
entry
imidate (R)
1b (Me)
1c (nPr)
product yield (%)
dr
1
2
3
4
5
6
7
8
2b
2c
2d
2e
2f
84
86
81
d
>20:1
>20:1
>20:1
>20:1
>20:1
1d (BnCH2)
1e [Cl(CH2)3]
1f [PMBO(CH2)3]
1g (allyl)
1h (PhCCCH2)
1i (PhCCCH2)
1j (iPr)
71
74
e
e
2g
2h
2i
85 (81)
>20:1 (>20:1)
>20:1
d
70
75
90
>20:1
>20:1
9
2j
10
11
12
13
14
15
16
17
18
19
20
21
22
1k (cyclohexyl)
1l (Ph)
2k
2l
89
83 (84)
>20:1
>20:1 (>20:1)
>20:1
>20:1
>20:1
>20:1
10:1
12:1
>20:1
16:1
>20:1
>20:1
11:1
Acidic hydrolysis of α-fluorinated N-tBS imidate 2l using 4
M H2SO4 in MeOH provided the corresponding N-tBS
caboxamide 4 in nearly quantitative yield (Scheme 3). X-ray
crystal diffraction analysis of 4 allowed unambiguous assign-
ment of the absolute configuration of the fluorine-containing
stereogenic center, which also enabled the determination of the
(2S)-configuration of 2l and its α-fluorinated N-tBS imidate
analogues. NaBH4 reduction easily transformed 2l to N-tBS
amine 5.
To demonstrate the synthetic utility of this fluorination
protocol, trans-2-fluoro-cyclohexamine derivatives20 were
prepared from 2g (Scheme 3). Cyanide-promoted amidine
formation, followed by LiAlH4 reduction, gave N-tBS imine 6.
Subsequent nucleophilic addition of allylmagnesium bromide
in the presence of diethyl zinc provided the vicinal fluoroamine
7 in 80% yield with 10:1 dr. In contrast, 5:1 dr was observed in
absence of Et2Zn. Treatment of diene 7 with second-
generation Grubbs catalyst led to ring-closing metathesis,
yielding functionalized cyclohexene 8. Hydrogenation, acid-
promoted cleavage of the sulfinyl group, and protection of the
f
f
1m (4-MeC6H4)
1n (3-MeC6H4)
1o (2-MeC6H4)
1p (4-MeOC6H4)
1q (4-FC6H4)
1r (4-ClC6H4)
1s (4-BrC6H4)
1t (4-CF3C6H4)
1u (3,4-diClC6H3)
1v (2,4-diClC6H3)
1w (2-thienyl)
2m
2n
2o
2p
2q
2r
2s
2t
2u
2v
2w
82
73
75
73
80
81
82
84
79
68
81
a
Reaction conditions: 1 (0.30 mmol), LiHMDS (0.36 mmol), and
NFSI (0.36 mmol) in anhydrous toluene (4.0 mL) at −78 °C.
Reactions were complete within 1 h. Isolated yield after silica gel
chromatography. Diastereoselective ratios were determined by H
NMR spectroscopy of the crude reaction mixture. Refers to imidate
hydrolysis product (N-tBS amide). The reaction of ent-1g afforded
ent-2g. Reaction on 1 g scale.
b
c
1
d
e
f
B
DOI: 10.1021/acs.joc.8b02375
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Note
products was carried out by flash column chromatography using 200−
300 mesh silica gel. Visualization on analytical thin layer
chromatography (TLC) was achieved by the use of UV light (254
nm) and treatment with aqueous ceric ammonium molybdate
followed by heating. High-resolution mass spectra (HRMS) were
measured using electron spray ionization with a time-of-flight mass
analyzer (ESI-TOF). Proton and carbon magnetic resonance spectra
(1H NMR and 13C{1H} NMR) were recorded on a 400 MHz (1H
NMR at 400 MHz and 13C{1H} NMR at 100 MHz) spectrometer
with solvent resonance as the internal standard (1H NMR: CDCl3 at
Scheme 3. Transformation of α-Fluorinated N-tert-
Butanesulfinyl Imidates and Application to Synthesis of
Cyclic trans-β-Fluoroamine
1
7.26 ppm; 13C{1H} NMR: CDCl3 at 77.16 ppm). H NMR data are
reported as follows: chemical shifts, multiplicity (br s = broad singlet,
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet),
coupling constant(s) in Hz, integration.
Materials. Toluene and ether were distilled from sodium/
benzophenone. Dichloromethane was distilled from CaH2. (RS)-tert-
Butanesulfinamide with ee >99.0% was purchased from a commercial
source and used as received. The known compounds 1a−d, 1f−g, 1i−
j, and 1l−v were prepared according to the reported procedur-
e.11a,b,16,17 The new compounds 1e and 1h were prepared via
alkylation of α-trimethylsilyl N-tert-butanesulfinyl acetimidate and
subsequent desilylation according to the reported procedure.16 The
new compound 1k was prepared by olefination of cyclohexanone with
α-triethylsilyl N-tert-butanesulfinyl acetimidate and subsequent hydro-
genation. The new compound 1w was prepared by the reaction of N-
tert-butanesulfinamide with the corresponding orthoester.11a
Methyl (R)-N-(tert-Butylsulfinyl)-5-chloropentanimidate (1e).
The reported alkylation−desilylation procedure16 was followed
using α-trimethylsilyl acetimidate (500 mg, 2.0 mmol) and 1-
chloro-3-iodopropane (531.4 mg, 2.6 mmol, 1.3 equiv), which
provided 1e as a colorless oil (264.3 mg, 52%). Rf = 0.30 (petroleum
ether/ethyl acetate = 4/1); [α]2D5 = −86.0 (c 0.10, MeOH); 1H NMR
(400 MHz, CDCl3) δ 3.75 (s, 3H), 3.57−3.52 (m, 2H), 2.72−2.68
(m, 2H), 1.83−1.80 (m, 4H), 1.20 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 176.2, 56.0, 54.3, 44.4, 32.1, 31.9, 23.7, 22.0; HRMS
(ESI-TOF) m/z calcd for C10H21ClNO2S [M + H]+ 254.0976, found
254.0978.
Methyl N-((R)-tert-Butylsulfinyl)-5-phenylpent-4-enimidate (1h).
The reported alkylation−desilylation procedure16 was followed using
α-trimethylsilyl acetimidate (500 mg, 2.0 mmol) and (E)-(3-
iodoprop-1-en-1-yl)benzene (636.7 mg, 2.6 mmol, 1.3 equiv), which
provided 1h as a colorless oil (381.4 mg, 65%). Rf = 0.30 (petroleum
ether/ethyl acetate = 5/1); [α]2D5 = −84.8 (c 0.50, MeOH); 1H NMR
(400 MHz, CDCl3) δ 7.33−7.18 (m, 5H), 6.43 (d, J = 15.6 Hz, 1H),
6.21−6.14 (m, 1H), 3.77 (s, 3H), 2.86 (t, J = 8.0 Hz, 2H), 2.58−2.54
(m, 2H), 1.21 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.0,
137.4, 131.4, 128.6, 128.1, 127.3, 126.2, 55.9, 54.2, 32.6, 29.8, 22.0;
HRMS (ESI-TOF) m/z calcd for C16H24NO2S [M + H]+ 294.1522,
found 294.1525.
resulting primary amine with a Boc group provided 9 in 86%
yield. The optical rotation of 9 was consistent with the
reported data.21 The trans-2-fluoro-cyclohexamine showed
99.5% ee based on chiral HPLC. For this chromatography,
we had to replace the Boc protecting group with Cbz in order
to render the compound detectable by the UV−vis detector.
The observed stereochemistry of this fluorination can be
rationalized by hypothesizing the formation of a chair−
chairlike 8/4 bicyclic transition state TS-1 via sulfone-lithium
bonding (Scheme 4).22 Approach of NFSI from the Si-face of
Scheme 4. Rationalization of Stereochemistry
Procedure for the Preparation of 1k. To a stirred solution of α-
triethylsilyl N-tert-butanesulfinyl acetimidate (583.0 mg, 2.0 mmol,
1.0 equiv) in 5.0 mL THF was added LiHMDS (1.2 M in THF, 2.0
mL, 2.4 mmol, 1.2 equiv) at −78 °C. After the reaction mixture was
stirred for 30 min at −78 °C, the solution of cyclohexanone (255.2
mg, 2.6 mmol, 1.3 equiv) in 3.0 mL THF was added. The reaction
mixture was then stirred at −78 °C for 4 h. After quenching with
saturated aqueous ammonium chloride, the reaction mixture was
extracted with ethyl acetate for three times. The combined organic
layers were washed with brine and dried over anhydrous Na2SO4,
filtered, and concentrated under vacuum. The residue was purified by
flash column chromatography on silica gel to afford N-tert-
butanesulfinyl cyclohexylideneacetimidate (221.3 mg, 43%, unopti-
mized) as a colorless oil.
A round-bottom flask containing N-tert-butanesulfinyl cyclo-
hexylideneacetimidate (206.0 mg, 0.8 mmol) and 10 wt % of
Pd(OH)2/C (50 mg). MeOH (5.0 mL) was charged, and the flask
was evacuated and backfilled with H2. The reaction was stirred under
a balloon of H2 until TLC indicated complete consumption of the
starting material. Upon completion, the reaction was filtered through
Celite, rinsing with EtOAc, and concentrated in vacuo. The residue
the trans-(RS)-aza-enolate would give (RS, 2S)-fluorination
product. Approach of NFSI from the Re-face would be less
favored since the bulky tBu group of the trans-aza-enolate can
hinder the Re-face attack of NSFI (Scheme 4).
In summary, we have developed a process for diaster-
eoselective α-fluorination of N-tert-butanesulfinyl imidates. A
range of chiral α-fluorinated imidates can be accessed with
high diastereoselectivities. This protocol was used to construct
synthetically useful trans-2-fluoro-cyclohexamine derivatives
with high enantiopurity.
EXPERIMENTAL SECTION
■
General Experimental Details. All reactions were performed
under an argon atmosphere in flame-dried glassware with magnetic
stirring using standard Schlenk techniques. All solvents were purified
according to the standard procedures. Purification of the reaction
C
DOI: 10.1021/acs.joc.8b02375
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The Journal of Organic Chemistry
Note
was purified by flash column chromatography on silica gel to afford N-
tert-butanesulfinyl cyclohexylacetimidate as a colorless oil (203.4 mg,
98%).
34.6 (d, JC−F = 21.7 Hz), 22.2, 18.1, 13.7; HRMS (ESI-TOF) m/z
calcd for C10H21FNO2S [M + H]+ 238.1272, found 238.1274.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-fluoro-4-phenylbutanimi-
date (2d). According to the general procedure, the reaction using
imidate 1d (84.4 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 360 uL,
0.36 mmol), and fluorination reagent NFSI (113.5 mg, 0.36 mmol)
afforded 2d (72.8 mg, 81%) as a colorless oil. Rf = 0.21 (petroleum
ether/ethyl acetate = 8:1); [α]2D5 = −132.0 (c 0.10, MeOH); 1H NMR
(400 MHz, CDCl3) δ 7.31−7.27 (m, 2H), 7.22−7.18 (m, 3H), 5.74
(ddd, J = 48.4, 8.8, 3.6 Hz, 1H), 3.78 (s, 1H), 2.87−2.74 (m, 2H),
2.34−2.15 (m, 2H), 1.22 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3)
Methyl (R)-N-(tert-Butylsulfinyl)-2-cyclohexylacetimidate (1k). Rf
= 0.30 (petroleum ether/ethyl acetate = 5/1); [α]2D5 = −101.0 (c 0.10,
MeOH); 1H NMR (400 MHz, CDCl3) δ 3.73 (s, 3H), 2.62−2.46 (m,
2H), 1.87−1.59 (m, 6H), 1.26−1.22 (m, 2H), 1.18 (s, 9H), 1.13−
0.92 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.6, 55.8, 54.0,
40.0, 35.9, 33.1, 26.14, 26.11, 26.09, 22.0; HRMS (ESI-TOF) m/z
calcd for C13H26NO2S [M + H]+ 260.1679, found 260.1681.
Procedure for the Preparation of 1w. The mixture of N-tert-
butanesulfinamide (1.82 g, 15 mmol, 1.0 equiv), 2-(2,2,2-
trimethoxyethyl)thiophene (6.1 g, 30 mmol, 2.0 equiv), and p-
toluenesulfonic acid (25.8 mg, 0.01 equiv) was stirred at 105 °C for 3
h. Volatile materials were removed in vacuo, and the residue was
purified by flash column chromatography on silica gel to afford
(thiophen-2-yl)acetimidate as a colorless oil (2.8 g, 72%).
Methyl (R)-N-(tert-Butylsulfinyl)-2-(thiophen-2-yl)acetimidate
δ 169.1 (d, JC−F = 20.5 Hz), 140.2, 128.7, 128.6, 126.4, 88.1 (d, JC−F
=
183.7 Hz), 57.0, 54.6, 34.4 (d, JC−F = 22.0 Hz), 31.0 (d, JC−F = 3.6
Hz), 22.1; HRMS (ESI-TOF) m/z calcd for C15H23FNO2S [M + H]+
300.1428, found 300.1430.
(S)-N-((R)-tert-Butylsulfinyl)-5-chloro-2-fluoropentanamide (2e).
According to the general procedure, the reaction using imidate 1e
(76.1 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 360 uL, 0.36
mmol), and fluorination reagent NFSI (113.5 mg, 0.36 mmol)
generated α-fluorinated imidate that was hydrolyzed using 4 M aq.
H2SO4 to afford 2e (54.9 mg, 71%) as a colorless gum. Rf = 0.20
(petroleum ether/ethyl acetate = 1:1); [α]2D5 = +29.0 (c 0.10,
MeOH); 1H NMR (400 MHz, CDCl3) δ 7.54 (br s, 1H), 5.02 (ddd, J
= 49.2, 7.2, 4.0 Hz, 1H), 3.57 (t, J = 6.4 Hz, 2H), 2.26−1.90 (m, 4H),
(1w). Rf = 0.24 (petroleum ether/ethyl acetate = 6/1); [α]D25
=
−127.4 (c 0.50, MeOH); 1H NMR (400 MHz, CDCl3) δ 7.18 (dd, J
= 5.2, 1.2 Hz, 1H), 6.98−6.92 (m, 2H), 4.34 (dd, J = 14.8, 0.8 Hz,
1H), 4.08 (dd, J = 14.8, 0.8 Hz, 1H), 3.77 (s, 3H), 1.20 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 172.0, 135.6, 127.3, 127.0,
125.1, 56.4, 54.6, 32.9, 22.1; HRMS (ESI-TOF) m/z calcd for
1.29 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.4 (d, JC−F
=
C11H18NO2S2 [M + H]+ 260.0773, found 260.0775.
21.4 Hz), 91.4 (d, JC−F = 185.8 Hz), 57.4, 44.0, 29.9 (d, JC−F = 20.1
Hz), 27.6 (d, JC−F = 2.8 Hz), 22.1; HRMS (ESI-TOF) m/z calcd for
C9H18ClFNO2S [M + H]+ 258.0725, found 258.0726.
General Procedure for Fluorination. To a stirred solution of N-
tert-butanesulfinyl imidate (0.30 mmol, 1.0 equiv) in 2.0 mL toluene
was added LHMDS (1.0 M in THF, 360 uL, 0.36 mmol, 1.2 equiv) at
−78 °C. After the reaction mixture was stirred at −78 °C for 30 min,
a solution of NFSI (113.5 mg, 0.36 mmol, 1.2 equiv) in 2.0 mL
toluene was added dropwise. After stirring for 1 h at −78 °C, the
reaction was quenched with saturated aq. NaHCO3. The solution was
warmed to room temperature and extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under vacuum. The residue was purified by
flash column chromatography on silica gel.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-fluoro-3-phenylpropanimi-
date (2a). According to the general procedure, the reaction using
imidate 1a (80.3 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 360 uL,
0.36 mmol), and fluorination reagent NFSI (113.5 mg, 0.36 mmol)
afforded 2a (71.0 mg, 83%) as a colorless oil. Rf = 0.23 (petroleum
ether/ethyl acetate = 8:1); [α]2D5 = −176.0 (c 0.20, MeOH); 1H NMR
(400 MHz, CDCl3) δ 7.33−7.24 (m, 5H), 6.00 (ddd, J = 48.0, 7.2, 6.0
Hz, 1H), 3.75 (s, 3H), 3.26−3.19 (m, 2H), 1.21 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3) δ 168.1 (d, JC−F = 20.2 Hz), 135.0 (d, JC−F
= 3.6 Hz), 129.6, 128.7, 127.3, 88.7 (d, JC−F = 186.3 Hz), 57.1, 54.6,
38.7 (d, JC−F = 22.3 Hz), 22.2; HRMS (ESI-TOF) m/z calcd for
C14H21FNO2S [M + H]+ 286.1276, found 286.1273.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-fluoro-5-((4-
methoxybenzyl)oxy)pentanimidate (2f). According to the general
procedure, the reaction using imidate 1f (106.6 mg, 0.30 mmol),
LiHMDS (1.0 M in THF, 360 uL, 0.36 mmol), and fluorination
reagent NFSI (113.5 mg, 0.36 mmol) afforded 2f (82.9 mg, 74%) as a
colorless oil; Rf = 0.20 (petroleum ether/ethyl acetate = 5:1); [α]D25
=
1
−94.8 (c 0.25, MeOH); H NMR (400 MHz, CDCl3) δ 7.26−7.24
(m, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.76 (ddd, J = 48.4, 8.4, 4.4 Hz,
1H), 4.43 (s 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.52−3.45 (m, 2H),
2.10−1.71 (m, 4H), 1.22 (s 9H); 13C{1H} NMR (100 MHz, CDCl3)
δ 169.4 (d, JC−F = 20.4 Hz), 159.3, 130.6, 129.4, 113.9, 88.4 (d, JC−F
=
183.3 Hz), 72.7, 69.1, 57.0, 55.4, 54.6, 29.6 (d, JC−F = 23.0 Hz), 25.1
(d, JC−F = 3.2 Hz), 22.1; HRMS (ESI-TOF) m/z calcd for
C18H29FNO4S [M + H]+ 374.1796, found 374.1799.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-fluoropent-4-enimidate
(2g). According to the general procedure, the reaction using imidate
1g (65.2 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 360 uL, 0.36
mmol), and fluorination reagent NFSI (113.5 mg, 0.36 mmol)
afforded 2g (60.0 mg, 85%) as a colorless oil; Rf = 0.22 (petroleum
ether/ethyl acetate = 5:1); [α]2D5 = −184.0 (c 0.20, MeOH); 1H NMR
(400 MHz, CDCl3) δ 5.89−5.74 (m, 2H), 5.21−5.14 (m, 2H), 3.78
(s, 3H), 2.78−2.58 (m, 2H), 1.21 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3) δ 168.3 (d, JC−F = 20.2 Hz), 130.9 (d, JC−F = 5.1 Hz), 119.6,
87.6 (d, JC−F = 185.2 Hz), 57.1, 54.5, 36.9 (d, JC−F = 22.4 Hz), 22.2;
HRMS (ESI-TOF) m/z calcd for C10H19FNO2S [M + H]+ 236.1115,
found 236.1117.
Methyl (R)-N-((S)-tert-Butylsulfinyl)-2-fluoropent-4-enimidate
(ent-2g). According to the general procedure, the reaction using
imidate ent-1g (80.3 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 360
uL, 0.36 mmol), and fluorination reagent NFSI (113.5 mg, 0.36
mmol) afforded ent-2g (57.2 mg, 81%) as a colorless oil; Rf = 0.22
(petroleum ether/ethyl acetate = 5:1); [α]2D5 = +185.0 (c 0.20,
MeOH). The NMR data of ent-2g are consistent with those of 2g.
HRMS (ESI-TOF) m/z calcd for C10H19FNO2S [M + H]+ 236.1115,
found 236.1116.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-fluoropropanimidate (2b).
According to the general procedure, the reaction using imidate 1b
(57.4 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 360 uL, 0.36
mmol), and fluorination reagent NFSI (113.5 mg, 0.36 mmol)
afforded 2b (52.7 mg, 84%) as a colorless oil. Rf = 0.20 (petroleum
ether/ethyl acetate = 8:1); [α]2D5 = −144.0 (c 0.10, MeOH); 1H NMR
(400 MHz, CDCl3) δ 5.85 (dq, J = 48.0, 6.8 Hz, 1H), 3.81 (s, 3H),
1.61 (dd, J = 24.0, 6.8 Hz, 3H), 1.23 (s, 9 H); 13C{1H} NMR (100
MHz, CDCl3) δ 170.0 (d, JC−F = 20.1 Hz), 85.2 (d, JC−F = 180.8 Hz),
57.0, 54.7, 22.1, 18.6(d, JC−F = 23.3 Hz); HRMS (ESI-TOF) m/z
calcd for C8H17FNO2S [M + H]+ 210.0959, found 210.0961.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-fluoropentanimidate (2c).
According to the general procedure, the reaction using imidate 1c
(65.8 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 360 uL, 0.36
mmol), and fluorination reagent NFSI (113.5 mg, 0.36 mmol)
afforded 2c (61.2 mg, 86%) as a colorless oil. Rf = 0.23 (petroleum
ether/ethyl acetate = 7:1); [α]2D5 = −152.0 (c 0.10, MeOH); 1H NMR
(400 MHz, CDCl3) δ 5.74 (ddd, J = 48.8, 8.8, 4.0 Hz, 1H), 3.80 (s,
3H), 2.01−1.75 (m, 2H), 1.58−1.43 (m, 2H), 1.23 (s, 9H), 0.97 (t, J
(S)-N-((R)-tert-Butylsulfinyl)-2-fluoro-5-phenylpent-4-enamide
(2h). According to the general procedure, the reaction using imidate
1h (88.0 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 360 uL, 0.36
mmol), and fluorination reagent NFSI (113.5 mg, 0.36 mmol)
generated α-fluorinated imidate that was hydrolyzed using 4 M aq.
H2SO4 to afford 2h (62.4 mg, 70%) as a colorless gum; Rf = 0.25
(petroleum ether/ethyl acetate = 1:1); [α]2D5 = +27.0 (c 0.20,
= 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.6 (d, JC−F
20.3 Hz), 88.4 (d, JC−F = 183.5 Hz), 57.0, 54.5 (d, JC−F = 6.0 Hz),
=
D
DOI: 10.1021/acs.joc.8b02375
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
MeOH); 1H NMR (400 MHz, CDCl3) δ 7.46 (br s, 1H), 7.33−7.21
(m, 5H), 6.53 (d, J = 12.0 Hz, 1H), 6.19−6.11 (m, 1H), 5.14 (ddd, J
= 49.2, 5.2, 4.4 Hz), 2.97−2.72 (m, 2H), 1.17 (s 9H); 13C{1H} NMR
(100 MHz, CDCl3) δ 169.9 (d, JC−F = 21.5 Hz), 136.4, 135.3, 128.5,
127.8, 126.2, 121.0 (d, JC−F = 2.8 Hz), 91.3 (d, JC−F = 187.4 Hz),
57.3, 35.5 (d, JC−F = 19.7 Hz), 21.7; HRMS (ESI-TOF) m/z calcd for
C15H21FNO2S [M + H]+ 298.1272, found 298.1274.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-fluoro-5-phenylpent-4-yni-
midate (2i). According to the general procedure, the reaction using
imidate 1i (87.4 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 360 uL,
0.36 mmol), and fluorination reagent NFSI (113.5 mg, 0.36 mmol)
afforded 2i 69.6 mg, 75%) as a colorless oil; Rf = 0.25 (petroleum
ether/ethyl acetate = 8:1); [α]2D5 = −227.0 (c 0.25, MeOH); 1H NMR
(400 MHz, CDCl3) δ 7.41−7.26 (m, 5H), 6.05 (dt, J = 47.2, 6.4 Hz,
1H), 3.84 (s, 3H), 3.20−3.02 (m, 2H), 1.24 (s, 9H); 13C{1H} NMR
(100 MHz, CDCl3) δ 166.8 (d, JC−F = 19.9 Hz), 131.8, 128.3, 128.3,
123.0, 85.8 (d, JC−F = 188.0 Hz), 83.8, 82.1 (d, JC−F = 11.0 Hz), 57.3,
54.8, 24.0 (d, JC−F = 27.0 Hz), 22.2; HRMS (ESI-TOF) m/z calcd for
C16H21FNO2S [M + H]+ 310.1272, found 310.1274.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-fluoro-3-methylbutanimi-
date (2j). According to the general procedure, the reaction using
imidate 1j (65.6 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 360 uL,
0.36 mmol), and fluorination reagent NFSI (113.5 mg, 0.36 mmol)
afforded 2j (69.6 mg, 90%) as a colorless oil; Rf = 0.25 (petroleum
ether/ethyl acetate = 7:1); [α]2D5 = −163.8 (c 0.30, MeOH); 1H NMR
(400 MHz, CDCl3) δ 5.52 (dd, J = 48.0, 6.4 Hz, 1H), 3.79 (s, 3H),
2.39−2.21 (m, 1H), 1.23 (s, 9H), 1.01 (t, J = 6.8 Hz); 13C{1H} NMR
(100 MHz, CDCl3) δ 168.8 (d, JC−F = 20.6 Hz), 92.6 (d, JC−F = 185.2
Hz), 57.1, 54.4, 31.3 (d, JC−F = 21.0 Hz), 22.2, 18.1 (d, JC−F = 6.2
Hz), 17.2 (d, JC−F = 4.0 Hz); HRMS (ESI-TOF) m/z calcd for
C10H21FNO2S [M + H]+ 238.1272, found 238.1274.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-cyclohexyl-2-fluoroaceti-
midate (2k). According to the general procedure, the reaction using
imidate 1k (77.8 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 360 uL,
0.36 mmol), and fluorination reagent NFSI (113.5 mg, 0.36 mmol)
afforded 2k (74.1 mg, 89%) as a colorless oil; Rf = 0.30 (petroleum
ether/ethyl acetate = 6:1); [α]2D5 = −177.0 (c 0.40, MeOH); 1H NMR
(400 MHz, CDCl3) δ 5.54 (dd, J = 48.0, 6.4 Hz, 1H), 3.79 (s, 3H),
2.04−1.76 (m, 4H), 1.68−1.58 (m, 2H), 1.39−1.25 (m, 2H), 1.23 (s,
9H), 1.21−1.10 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.7
(d, JC−F = 20.6 Hz), 92.1 (d, JC−F = 184.0 Hz), 57.1, 54.4, 40.5 (d,
129.7, 127.9 (d, JC−F = 4.9 Hz), 88.1 (d, JC−F = 185.9 Hz), 57.2, 54.9,
22.2, 21.5; HRMS (ESI-TOF) m/z calcd for C14H21FNO2S [M + H]+
286.1272, found 286.1274.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-fluoro-2-(m-tolyl)-
acetimidate (2n). According to the general procedure, the reaction
using imidate 1n (80.2 mg, 0.30 mmol), LiHMDS (1.0 M in THF,
360 uL, 0.36 mmol), and fluorination reagent NFSI (113.5 mg, 0.36
mmol) afforded 2n (62.4 mg, 73%) as a colorless oil; Rf = 0.25
(petroleum ether/ethyl acetate = 8:1); [α]2D5 = −197.0 (c 0.10,
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.35−7.21 (m. 4H), 6.78
(d, J = 46.8 Hz, 1H), 3.86 (s, 3H), 2.38 (s, 3H), 1.19 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 167.8 (d, JC−F = 22.2 Hz),
138.8, 134.1 (d, JC−F = 20.6 Hz), 130.8 (d, JC−F = 2.5 Hz), 128.9,
128.3 (d, JC−F = 5.1 Hz), 124.9 (d, JC−F = 5.3 Hz), 88.1 (d, JC−F
=
185.9 Hz), 57.2, 54.9, 22.2, 21.6; HRMS (ESI-TOF) m/z calcd for
C14H21FNO2S [M + H]+ 286.1272, found 286.1275.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-fluoro-2-(o-tolyl)-
acetimidate (2o). According to the general procedure, the reaction
using imidate 1o (80.2 mg, 0.30 mmol), LiHMDS (1.0 M in THF,
360 uL, 0.36 mmol), and fluorination reagent NFSI (113.5 mg, 0.36
mmol) afforded 2o (64.1 mg, 75%) as a colorless oil; Rf = 0.26
(petroleum ether/ethyl acetate = 8:1); [α]2D5 = −156.0 (c 0.10,
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.37−7.29 (m, 2H), 7.24−
7.21 (m, 2H), 6.94 (d, J = 47.6 Hz, 1H), 3.92 (s, 3H), 2.49 (s, 3H),
1.16 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.5 (d, JC−F
=
21.8 Hz), 138.2 (d, JC−F = 3.4 Hz), 132.1 (d, JC−F = 18.6 Hz), 131.2
(d, JC−F = 2.1 Hz), 130.2 (d, JC−F = 3.6 Hz), 128.3 (d, JC−F = 5.0 Hz),
126.4 (d, JC−F = 2.1 Hz), 86.3 (d, JC−F = 185.0 Hz), 57.1, 54.9, 22.1,
19.2; HRMS (ESI-TOF) m/z calcd for C14H21FNO2S [M + H]+
286.1272, found 286.1274.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-fluoro-2-(4-
methoxyphenyl)acetimidate (2p). According to the general
procedure, the reaction using imidate 1p (85.0 mg, 0.30 mmol),
LiHMDS (1.0 M in THF, 360 uL, 0.36 mmol), and fluorination
reagent NFSI (113.5 mg, 0.36 mmol) afforded 2p (66.0 mg, 73%) as a
colorless oil; Rf = 0.22 (petroleum ether/ethyl acetate = 6:1); [α]D25
−212.0 (c 0.10, MeOH); H NMR (400 MHz, CDCl3) δ 7.49−7.47
(m, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 47.2 Hz, 1H), 3.86 (s,
3H), 3.82 (s, 3H), 1.17 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ
=
1
168.2 (d, JC−F = 22.9 Hz), 161.0 (d, JC−F = 2.8 Hz), 129.8 (d, JC−F
=
4.6 Hz), 126.1 (d, JC−F = 21.4 Hz), 114.4, 88.0 (d, JC−F = 182.0 Hz),
57.1, 55.4, 54.9, 22.2; HRMS (ESI-TOF) m/z calcd for
C14H21FNO3S [M + H]+ 302.1220, found 302.1224.
J
C−F = 20.6 Hz), 28.0 (d, JC−F = 5.5 Hz), 27.7 (d, JC−F = 3.2 Hz), 26.0,
25.9, 25.6, 22.2; HRMS (ESI-TOF) m/z calcd for C13H25FNO2S [M
+ H]+ 278.1585, found 278.1581.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-fluoro-2-(4-fluorophenyl)-
acetimidate (2q). According to the general procedure, the reaction
using imidate 1q (81.4 mg, 0.30 mmol), LiHMDS (1.0 M in THF,
360 uL, 0.36 mmol), and fluorination reagent NFSI (113.5 mg, 0.36
mmol) afforded 2q (69.4 mg, 80%) as a colorless oil; Rf = 0.20
(petroleum ether/ethyl acetate = 10:1); [α]2D5 = −191.6 (c 0.30,
MeOH); 1H NMR (400 MHz, CDCl3) δ 7.58−7.54 (m, 2H), 7.10 (t,
J = 8.4 Hz, 2H), 6.81 (d, J = 46.8 Hz, 1H), 3.85 (s, 3H), 1.20 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 167.2 (d, JC−F = 22.7 Hz), 163.7
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-fluoro-2-phenylacetimi-
date (2l). According to the general procedure, the reaction using
imidate 1l (65.6 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 360 uL,
0.36 mmol), and fluorination reagent NFSI (113.5 mg, 0.36 mmol)
afforded 2l (76.0 mg, 83%) as a colorless oil; Rf = 0.20 (petroleum
ether/ethyl acetate = 9:1); [α]2D5 = −219.0 (c 0.10, MeOH); 1H NMR
(400 MHz, CDCl3) δ 7.57−7.55 (m. 2H), 7.42−7.40 (m, 3H), 6.82
(d, J = 47.2 Hz, 1H), 3.85 (s, 3H), 1.19 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 167.7 (d, JC−F = 22.1 Hz), 134.2 (d, JC−F = 21.1 Hz),
130.0 (d, JC−F = 2.5 Hz), 129.0, 127.8 (d, JC−F = 5.3 Hz), 88.1 (d, JC−F
= 186.1 Hz), 57.2, 54.9, 22.2; HRMS (ESI-TOF) m/z calcd for
C13H19FNO2S [M + H]+ 272.1115, found 272.1117. A scale-up
preparation of 2l was carried out by using imidate 1l (1.0135 g, 4.00
mmol), LiHMDS (1.0 M in THF, 4.80 mL, 4.80 mmol), and
fluorination reagent NFSI (1.5136 g, 4.80 mmol), which afforded 2l
(0.9118 g, 84%) as a colorless oil.
(dd, JC−F = 247.9, 2.1 Hz), 130.2 (d, JC−F = 3.1 Hz), 130.0 (dd, JC−F
=
8.7, 5.0 Hz), 116.1 (d, JC−F = 21.7 Hz), 87.4 (d, JC−F = 186.5 Hz),
57.4, 54.9, 22.2; HRMS (ESI-TOF) m/z calcd for C13H18F2NO2S [M
+ H]+ 290.1021, found 290.1023.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-(4-chlorophenyl)-2-fluo-
roacetimidate (2r). According to the general procedure, the reaction
using imidate 1r (86.3 mg, 0.30 mmol), LiHMDS (1.0 M in THF,
360 uL, 0.36 mmol), and fluorination reagent NFSI (113.5 mg, 0.36
mmol) afforded 2r (74.3 mg, 81%) as a colorless oil; Rf = 0.20
(petroleum ether/ethyl acetate = 10:1); [α]2D5 = −211.8 (c 0.30,
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-fluoro-2-(p-tolyl)-
acetimidate (2m). According to the general procedure, the reaction
using imidate 1m (80.2 mg, 0.30 mmol), LiHMDS (1.0 M in THF,
360 uL, 0.36 mmol), and fluorination reagent NFSI (113.5 mg, 0.36
mmol) afforded 2m (70.1 mg, 82%) as a colorless oil; Rf = 0.26
(petroleum ether/ethyl acetate = 8:1); [α]2D5 = −226.0 (c 0.10,
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.52−7.50 (m, 2H), 7.39
(d, J = 8.4 Hz, 2H), 6.82 (d, J = 46.4 Hz, 1H), 3.83 (s, 3H), 1.21 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.8 (d, JC−F = 22.3 Hz),
136.0 (d, JC−F = 2.8 Hz), 132.7 (d, JC−F = 21.3 Hz), 129.3, 129.1 (d,
JC−F = 5.5 Hz), 87.3 (d, JC−F = 186.8 Hz), 57.4, 55.0, 22.2; HRMS
(ESI-TOF) m/z calcd for C13H18FClNO2S [M + H]+ 306.0725,
found 306.0728.
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 6.8 Hz, 2H),
7.22 (d, J = 7.6 Hz, 2H), 6.76 (d, J = 46.8 Hz, 1H), 3.85 (s, 3H), 2.37
(s, 3H), 1.18 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.0 (d,
JC−F = 22.5 Hz), 140.1 (d, JC−F = 2.9 Hz), 131.2 (d, JC−F = 21.0 Hz),
E
DOI: 10.1021/acs.joc.8b02375
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Methyl (S)-2-(4-bromophenyl)-N-((R)-tert-Butylsulfinyl)-2-fluo-
roacetimidate (2s). According to the general procedure, the reaction
using imidate 1s (99.7 mg, 0.30 mmol), LiHMDS (1.0 M in THF,
360 uL, 0.36 mmol), and fluorination reagent NFSI (113.5 mg, 0.36
mmol) afforded 2s (86.1 mg, 82%) as a colorless oil; Rf = 0.20
(petroleum ether/ethyl acetate = 10:1); [α]2D5 = −205.5 (c 0.20,
DCM and NCS (80.1 mg, 0.6 mmol, 2.0 equiv) in 1.0 mL DCM were
sequentially added. After stirring for 1 h at −78 °C, the reaction was
quenched with 0.2 N aq. HCl and extracted with DCM. The organic
layer was washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated under vacuum. The residue was purified by flash
column chromatography on silica gel.
Methyl-N-((R)-tert-Butylsulfinyl)-2-chloropropanimidate (3). Col-
orless oil (54.2 mg, 80%); Rf = 0.20 (petroleum ether/ethyl acetate =
6:1); [α]2D5 = −238.0 (c 0.10, MeOH); 1H NMR (400 MHz, CDCl3)
δ 5.44 (q, J = 6.8 Hz, 1H), 3.81 (s, 3H), 1.68 (d, J = 6.8 Hz, 3H), 1.22
(s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 56.9, 55.0, 49.1, 22.1,
21.8; HRMS (ESI-TOF) m/z calcd for C8H17ClNO2S [M + H]+
226.0663, found 226.0667.
Procedure for Hydrolysis of 2l. To a stirred solution of 2l (54.3
mg, 0.20 mmol, 1.0 equiv) in 3.0 mL MeOH was added 4.0 M aq.
H2SO4 (1.0 mL) at rt. After the resultant solution was stirred for 1 h
at rt, the reaction was quenched with saturated aqueous NaHCO3 and
extracted with ethyl acetate for three times. The combined organic
extracts were washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The crude product was purified
by flash column chromatography on silica gel.
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.56−7.43 (m, 4H), 6.82
(d, J = 46.4 Hz, 1H), 3.83 (s, 3H), 1.21 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 166.7 (d, JC−F = 22.3 Hz), 133.3 (d, JC−F = 21.3 Hz),
132.2, 129.4 (d, JC−F = 5.3 Hz), 124.3 (d, JC−F = 3.1 Hz), 87.4 (d, JC−F
= 186.7 Hz), 57.4, 55.0, 22.2; HRMS (ESI-TOF) m/z calcd for
C13H18FBrNO2S [M + H]+ 350.0220, found 350.0221.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-fluoro-2-(4-
(trifluoromethyl)phenyl)acetimidate (2t). According to the general
procedure, the reaction using imidate 1t (96.4 mg, 0.30 mmol),
LiHMDS (1.0 M in THF, 360 uL, 0.36 mmol), and fluorination
reagent NFSI (113.5 mg, 0.36 mmol) afforded 2t (85.5 mg, 84%) as a
white solid; mp 37.5−38.9 °C; Rf = 0.30 (petroleum ether/ethyl
acetate = 6:1); [α]2D5 = −180.3 (c 0.30, MeOH); 1H NMR (400 MHz,
CDCl3) δ 7.72−7.66 (m, 4H), 6.96 (d, J = 46.4 Hz, 1H); 3.82 (s,
3H), 1,24 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.0 (d,
JC−F = 22.0 Hz), 138.2 (d, JC−F = 22.1 Hz), 132.3−131.3 (m), 127.8
(d, JC−F = 5.7 Hz), 125.9 (q, JC−F = 3.6 Hz), 123.9 (d, JC−F = 270.8
Hz), 87.1 (d, JC−F = 186.9 Hz), 57.6, 55.0, 22.3; HRMS (ESI-TOF)
m/z calcd for C14H18F4NO2S [M + H]+ 340.0989, found 340.0991.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-(3,4-dichlorophenyl)-2-flu-
oroacetimidate (2u). According to the general procedure, the
reaction using imidate 1u (96.7 mg, 0.30 mmol), LiHMDS (1.0 M
in THF, 360 uL, 0.36 mmol), and fluorination reagent NFSI (113.5
mg, 0.36 mmol) afforded 2u (80.6 mg, 79%) as a colorless oil; Rf =
0.20 (petroleum ether/ethyl acetate = 10:1); [α]2D5 = −188.2 (c 0.50,
MeOH); 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.50−7.41 (m,
2H), 6.86 (d, J = 46.4 Hz, 1H); 3.82 (s, 3H), 1,23 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3) δ 165.8 (d, JC−F = 22.0 Hz), 134.4 (d, JC−F
(S)-N-((R)-tert-Butylsulfinyl)-2-fluoro-2-phenylacetamide (4).
White solid (50.4 mg, 98%), mp 77.5−79.3 °C; Rf = 0.30 (petroleum
1
ether/ethyl acetate = 1:1); [α]2D5 = +123 (c 0.10, MeOH); H NMR
(400 MHz, CDCl3) δ 7.69 (br s, 1H), 7.42 (s, 5H), 5.85 (d, J = 48.4
Hz, 1H), 1.25 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.4 (d,
J
C−F = 24.6 Hz), 133.8 (d, JC−F = 19.5 Hz), 130.0 (d, JC−F = 2.2 Hz),
129.1, 126.4 (d, JC−F = 6.6 Hz), 91.8 (d, JC−F = 187.6 Hz), 57.7, 22.0;
HRMS (ESI-TOF) m/z calcd for C12H17FNO2S [M + H]+ 258.0959,
found 258.0961 (see Supporting Information).
Procedure for Reduction of 2l. To a stirred solution of 2l (54.3
mg, 0.20 mmol, 1.0 equiv) in 2.0 mL THF/H2O (9:1, v/v) was added
NaBH4 (30.3 mg, 0.80 mmol, 4 equiv) at rt. The resultant solution
was stirred for 2 h at rt before being quenched with saturated aqueous
ammonium chloride. The organic layer was separated, and the
aqueous layer extracted with ethyl acetate. The combined organic
extracts were washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The crude product was purified
by flash column chromatography on silica gel.
= 21.9 Hz), 134.2 (d, JC−F = 2.5 Hz), 133.3, 131.0, 129.4 (d, JC−F
=
6.0 Hz), 126.9 (d, JC−F = 5.6 Hz), 86.5 (d, JC−F = 187.5 Hz), 57.6,
55.0, 22.3; HRMS (ESI-TOF) m/z calcd for C13H17FCl2NO2S [M +
H]+ 340.0336, found 340.0340.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-(2,4-dichlorophenyl)-2-flu-
oroacetimidate (2v). According to the general procedure, the
reaction using imidate 1v (96.7 mg, 0.30 mmol), LiHMDS (1.0 M
in THF, 360 uL, 0.36 mmol), and fluorination reagent NFSI (113.5
mg, 0.36 mmol) afforded 2v (69.4 mg, 68%) as a colorless oil; Rf =
0.20 (petroleum ether/ethyl acetate = 10:1); [α]2D5 = −173.6 (c 0.50,
(R)-N-((S)-2-Fluoro-2-phenylethyl)-2-methylpropane-2-sulfina-
mide (5). Colorless oil (46.7 mg, 96%), Rf = 0.20 (petroleum ether/
ethyl acetate = 1:1); [α]2D5 = −19.0 (c 0.10, MeOH); H NMR (400
1
MHz, CDCl3) δ 7.40−7.32 (m, 5H), 5.63 (dt, J = 48.0, 5.6 Hz, 1H),
3.63−3.51 (m, 3H), 1.19 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3)
δ 137.3 (d, JC−F = 19.4 Hz), 128.9, 128.7, 125.7 (d, JC−F = 6.6 Hz),
94.0 (d, JC−F = 172.3 Hz), 56.3, 51.9 (d, JC−F = 25.1 Hz), 22.7; HRMS
(ESI-TOF) m/z calcd for C12H19FNOS [M + H]+ 244.1166, found
244.1167.
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz, 1H),
7.43 (t, J = 1.6 Hz, 1H), 7.32 (dd, J = 8.4, 2.0 Hz, 1H), 7.05 (d, J =
45.2 Hz, 1H), 3.80 (s, 3H), 1.23 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3) δ 165.4 (d, JC−F = 22.2 Hz), 136.2 (d, JC−F = 2.7 Hz), 133.8
(d, JC−F = 4.6 Hz), 131.3 (d, JC−F = 21.8 Hz), 130.0 (d, JC−F = 8.4
Hz), 129.7, 127.7, 85.2 (d, JC−F = 184.1 Hz), 57.4, 55.0, 22.2; HRMS
(ESI-TOF) m/z calcd for C13H17FCl2NO2S [M + H]+ 340.0336,
found 340.0339.
Procedure for the Transformation of Imidate 2g to
Aldimine 6. To a solution of 2g (117.7 mg, 0.5 mmol, 1.0 equiv)
and morpholine (0.8 mL) in MeOH (0.2 mL) were added NaF (4.2
mg, 1.0 mmol, 0.20 equiv) and TMSCN (12.5 uL, 1.0 mmol, 0.20
equiv) sequentially. The reaction mixture was stirred at 50 °C
overnight and then cooled to rt. A 1.0 M solution of KOH was then
added, and the mixture was extracted three times with DCM. The
combined organic portions were dried over anhydrous Na2SO4,
filtered, and concentrated under vacuum. Column chromatography
purification on silica-gel column (50% ethyl acetate-petroleum ether)
afforded the desired amidine as a white solid. The amidine product
was then dissolved in 5.0 mL anhydrous THF in a round-bottomed
flask at 0 °C. LiAlH4 (22.8 mg, 0.60 mmol, 1.5 equiv) was slowly
added to the mixture. After complete consumption of starting
material, the reaction was quenched by addition of a saturated
aqueous solution of potassium sodium tartrate, and the resulting
mixture was diluted with ethyl acetate. The organic layer was
collected, and the aqueous layer was extracted with ethyl acetate. The
combined organic portions were dried over anhydrous Na2SO4,
filtered, and concentrated. The crude residue was purified by flash
column chromatography on silica gel.
Methyl (S)-N-((R)-tert-Butylsulfinyl)-2-fluoro-2-(thiophen-2-yl)-
acetimidate (2w). According to the general procedure, the reaction
of imidate 1w (77.8 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 360
uL, 0.36 mmol), and fluorination reagent NFSI (113.5 mg, 0.36
mmol) afforded 2w as a colorless oil (67.4 mg, 81%); Rf = 0.28
(petroleum ether/ethyl acetate = 7:1); [α]2D5 = −233.1 (c 0.63,
1
MeOH); H NMR (400 MHz, C6D6) δ 7.64 (d, J = 47.2 Hz, 1H),
7.31−7.29 (m, 1H), 6.82−6.81 (m, 1H), 6.58−6.56 (m, 1H), 3.28 (s,
3H), 1.04 (s, 9H); 13C{1H} NMR (100 MHz, C6D6) δ 165.8 (d, JC−F
= 23.3 Hz),136.1 (d, JC−F = 24.2 Hz), 130.3 (d, JC−F = 5.3 Hz), 128.2
(d, JC−F = 2.8 Hz), 127.1 (d, JC−F = 1.7 Hz), 83.4 (d, JC−F = 186.0
Hz), 57.0, 54.1, 22.1; HRMS (ESI-TOF) m/z calcd C11H17FNO2S2
[M + H]+ 278.0679, found 278.0682.
Procedure for the Preparation of 3. To a stirred solution of N-
tert-butanesulfinylimidate 1b (57.4 mg, 0.30 mmol, 1.0 equiv) in 2.0
mL DCM was added LHMDS (1.0 M in THF, 360 uL, 0.36 mmol,
1.2 equiv) at −78 °C. After the reaction mixture was stirred for 30
min at −78 °C, BF3·Et2O (85.1 mg, 0.6 mmol, 2.0 equiv) in 1.0 mL
F
DOI: 10.1021/acs.joc.8b02375
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(R)-N-((S)-2-Fluoropent-4-en-1-ylidene)-2-methylpropane-2-sul-
finamide (6). Colorless oil (69.1 mg, 67.3% for two steps); Rf = 0.25
(petroleum ether/ethyl acetate = 8:1); [α]2D5 = −245.0 (c 0.10,
Procedure for the Preparation of 10. To a solution of
compound 9 (21.7 mg, 0.10 mmol, 1.0 equiv) in DCM (1 mL) was
added CF3COOH (0.15 mL, 20.0 equiv). The resulting reaction
mixture was stirred at 0 °C for 1 h and then concentrated to dryness.
A solution of CbzCl (25.6 mg, 0.15 mmol, 1.5 equiv), DMAP (12.2
mg, 1.0 mmol, 1.0 equiv), and NEt3 (27 uL, 0.20 mmol, 2.0 equiv) in
DCM (1 mL) was added to the residue obtained above, and the
mixture was stirred at 0 °C for 2 h. Concentration of the reaction
mixture under vacuum and purification of the resultant residue by
flash column chromatography on silica gel afforded 10 as a white solid
(16.3 mg, 65% for two steps).
1
MeOH); H NMR (400 MHz, CDCl3) δ 8.11 (dd, J = 9.6, 3.2 Hz,
1H), 5.89−5.79 (m, 1H), 5.33−5.18 (m, 3H), 2.73−2.55 (m, 2H),
1.20 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.5 (d, JC−F
=
30.4 Hz), 131.1 (d, JC−F = 4.9 Hz), 119.6, 92.2 (d, JC−F = 175.5 Hz),
57.3, 37.5 (d, JC−F = 21.4 Hz), 22.5; HRMS (ESI-TOF) m/z calcd for
C9H17FNOS [M + H]+ 206.1009, found 206.1011.
Procedure for Addition of Grignard Reagent to Imine 6. To
a stirred solution of 6 (61.6 mg, 0.30 mmol, 1.0 equiv) in 3.0 mL
DCM at −48 °C were added allylmagnesium bromide (0.45 mL, 1.0
M in Et2O, 0.45 mmol, 1.5 equiv) and Et2Zn (60.0 uL, 1.0 M in THF,
0.2 equiv) sequentially. After stirring at −48 °C for 5 h and then rt
overnight, the reaction was quenched by aqueous ammonium
chloride. The organic layer was separated, and the aqueous layer
was extracted with DCM. The combined organic extracts were
washed with brine, dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The diastereoselectivity (10:1 dr) of the
Benzyl ((1S,2S)-2-Fluorocyclohexyl)carbamate (10). Mp 95.8−
97.6 °C; Rf = 0.30 (petroleum ether/ethyl acetate = 8:1); [α]D25
=
1
+24.0 (c 0.10, MeOH); H NMR (400 MHz, CDCl3) δ 7.55−7.16
(m, 5H), 5.12−5.08 (m, 2H), 4.80 (br s, 1H), 4.23 (dddd, J = 48.0,
12.0, 8.0, 4.0 Hz, 1H), 3.71−3.61 (m, 1H), 2.13−2.05 (m, 2H),
1.79−1.75 (m, 1H), 1.66−1.50 (m, 2H), 1.38−1.17 (m, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 156.1, 136.6, 128.6, 128.6,
128.2, 93.5 (d, JC−F = 177.0 Hz), 66.9, 54.4 (d, JC−F = 17.0 Hz), 31.3,
31.2 (d, JC−F = 5.0 Hz), 23.9, 23.4 (d, JC−F = 10.0 Hz). HRMS (ESI-
TOF) m/z calcd for C14H18FNaNO2 [M + H]+ 274.1214, found
274.1215.
1
reaction was determined by H NMR analysis of the crude product.
The crude product was purified by flash column chromatography on
silica gel.
(R)-N-((4S,5S)-5-Fluoroocta-1,7-dien-4-yl)-2-methylpropane-2-
sulfinamide (7). Colorless oil (59.4 mg, 80%); Rf = 0.25 (petroleum
ether/ethyl acetate = 3:1); [α]2D5 = −45.0 (c 0.10, MeOH); 1H NMR
(400 MHz, CDCl3) δ 5.90−5.72 (m, 2H), 5.25−5.09 (m, 4H), 4.66−
4.50 (m, 1H), 3.50−3.29 (m, 2H), 2.67−2.30 (m, 4H), 1.25 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 133.7, 132.7 (d, JC−F = 7.4 Hz),
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b02375.
■
S
119.4, 118.7, 93.4 (d, JC−F = 174.7 Hz), 58.0 (d, JC−F = 19.1 Hz),
56.7, 38.2 (d, JC−F = 2.8 Hz), 36.2 (d, JC−F = 21.8 Hz), 22.9; HRMS
(ESI-TOF) m/z calcd for C12H23FNOS [M + H]+ 248.1479, found
248.1481.
Procedure for RCM Reaction of 7. To a stirred solution of 7
(49.5 mg, 0.20 mmol, 1.0 equiv) in 3.0 mL DCM was added Grubbs
second-generation catalyst (40 mg, 0.04 mmol, 0.2 equiv) at rt. After
complete consumption of starting material, the reaction was quenched
by addition of a saturated aqueous solution of ammonium chloride.
The organic layer was separated, and the aqueous layer extracted with
DCM. The combined organic extracts were washed with brine, dried
over anhydrous Na2SO4, and concentrated under reduced pressure.
The crude product was purified by flash column chromatography on
silica gel.
1H and 13C{1H} NMR spectra of all new compounds,
chiral HPLC analysis of compounds 10, and X-ray
crystal structure of compound 4 (CCDC 1859860)
(PDF)
Crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: clu@ms.xjb.ac.cn.
ORCID
■
Chong-Dao Lu: 0000-0001-8968-0134
(R)-N-((1S,6S)-6-Fluorocyclohex-3-en-1-yl)-2-methylpropane-2-
sulfinamide (8). Colorless gum (40.0 mg, 91%); Rf = 0.23 (petroleum
ether/ethyl acetate = 1:1); [α]2D5 = −45.0 (c 0.10, MeOH); 1H NMR
(400 MHz, CDCl3) δ 5.61−5.54 (m, 2H), 4.70−4.52 (m, 1H), 3.68−
3.59 (m, 1H), 3.27 (d, J = 6.0 Hz, 1H), 2.67−2.20 (m, 4H), 1.20 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3) δ 124.2 (d, JC−F = 1.7 Hz),
123.4 (d, JC−F = 6.8 Hz), 90.5 (d, JC−F = 175.5 Hz), 56.2, 54.5 (d, JC−F
= 20.7 Hz), 31.3 (d, JC−F = 4.3 Hz), 30.2 (d, JC−F = 21.2 Hz), 22.6;
HRMS (ESI-TOF) m/z calcd for C10H19FNOS [M + H]+ 220.1166,
found 220.1167.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21871292, 21572262, and U1403301)
and the Recruitment Program of Global Experts (Xinjiang
Program).
Procedure for the Preparation of 9. Treatment of diene 8
(21.9 mg, 0.10 mmol, 1.0 equiv) in EtOH with 10% Pd(OH)2/C (5.0
mg) under a H2 atmosphere for 12 h. Upon completion, the reaction
was filtered through Celite, rinsing with EtOAc, and concentrated in
vacuo. The crude material was purified by column chromatography to
afford the hydrogenation product as an off-white solid. The product
was then dissolved in 1.0 mL methanol, followed by the addition of 4
N HCl/MeOH (0.1 mL). The reaction mixture was stirred at rt for 30
min and then concentrated to dryness. A solution of (Boc)2O (24.0
mg, 0.11 mmol, 1.1 equiv) and NEt3 (30 uL, 0.22 mmol, 2.2 equiv) in
THF (1.0 mL) was added to the residue obtained above, and the
resulting mixture was stirred at rt for 6 h. Concentration of the
reaction mixture under vacuum and purification of the resultant
residue by flash column chromatography on silica gel afforded 9 as a
white solid (18.8 mg, 86% for three steps). The NMR spectra and
specific rotation of 9 are in agreement with that of the known
REFERENCES
■
(1) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Fluorine in Medicinal Chemistry. Chem. Soc. Rev. 2008, 37, 320−330.
́
́
(b) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; del Pozo, C.;
̃
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in
Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to
the Market in the Last Decade (2001−2011). Chem. Rev. 2014, 114,
2432−2506. (c) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.;
Acena, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation of
̃
Fluorine Containing Pharmaceuticals, Compounds Currently in Phase
II−III Clinical Trials of Major Pharmaceutical Companies: New
Structural Trends and Therapeutic Areas. Chem. Rev. 2016, 116, 422−
518.
(2) (a) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.;
Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry. J.
Med. Chem. 2015, 58, 8315−8359. (b) Fujiwara, T.; O’Hagan, D.
Successful Fluorine-Containing Herbicide Agrochemicals. J. Fluorine
compound (1S, 2S)-9: [α]2D2 = +29.5 (c 0.40, CHCl3); lit. [α]2D2
=
+27.5 (c 1.01, CHCl3).21
G
DOI: 10.1021/acs.joc.8b02375
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Chem. 2014, 167, 16−29. (c) Jeschke, P. Latest generation of halogen-
containing pesticides. Pest Manage. Sci. 2017, 73, 1053−1056.
anose. J. Org. Chem. 1997, 62, 7546−7547. (c) Davis, F. A.; Kasu, P.
V. N. Asymmetric Synthesis of α-Fluoro Ketones Using α-Fluoro
Oxazolidinone Carboximides. Tetrahedron Lett. 1998, 39, 6135−6138.
(d) Edmonds, M. K.; Graichen, F. H. M.; Gardiner, J.; Abell, A. D.
Enantioselective Synthesis of α-Fluorinated β2-Amino Acids. Org. Lett.
2008, 10, 885−887. (e) Nakayama, K.; Browne, D. L.; Baxendale, I.
R.; Ley, S. V. Studies of a Diastereoselective Electrophilic Fluorination
Reaction Employing a Cryo-Flow Reactor. Synlett 2013, 24, 1298−
1302. For enolate intermediates derived from chiral enamides, see:
(f) Xu, Y.-S.; Tang, Y.; Feng, H.-J.; Liu, J.-T.; Hsung, R. P. A Highly
Regio-and Stereoselective Synthesis of α-Fluorinated Imides via
Fluorination of Chiral Enamides. Org. Lett. 2015, 17, 572−575.
(9) Alvarado, J.; Herrmann, A. T.; Zakarian, A. Stereoselective α-
Fluorination of N-Acyloxazolidinones at Room Temperature within 1
h. J. Org. Chem. 2014, 79, 6206−6220.
(3) For reviews, see: (a) Liang, T.; Neumann, C. N.; Ritter, T.
Introduction of Fluorine and Fluorine-Containing Functional Groups.
Angew. Chem., Int. Ed. 2013, 52, 8214−8264. (b) Yang, X.; Wu, T.;
Phipps, R. J.; Toste, F. D. Advances in Catalytic Enantioselective
Fluorination, Mono-, Di-, and Trifluoromethylation, and Trifluor-
omethylthiolation Reactions. Chem. Rev. 2015, 115, 826−870.
(c) Champagne, P. A.; Desroches, J.; Hamel, J.-D.; Vandamme, M.;
Paquin, J.-F. Monofluorination of Organic Compounds: 10 Years of
Innovation. Chem. Rev. 2015, 115, 9073−9174. (d) Zhu, Y.; Han, J.;
Wang, J.; Shibata, N.; Sodeoka, M.; Soloshonok, V. A.; Coelho, J. A.
S.; Toste, F. D. Modern Approaches for Asymmetric Construction of
Carbon−Fluorine Quaternary Stereogenic Centers: Synthetic Chal-
lenges and Pharmaceutical Needs. Chem. Rev. 2018, 118, 3887−3964.
(4) For catalytic α-fluorination of β-keto acid derivatives and their
analogues, see: (a) Hintermann, L.; Togni, A. Catalytic Enantiose-
lective Fluorination of β-Ketoesters. Angew. Chem., Int. Ed. 2000, 39,
4359−4362. (b) Hamashima, Y.; Yagi, K.; Takano, H.; Tamas, L.;
(10) Lubin, H.; Dupuis, C.; Pytkowicz, J.; Brigaud, T. Crystal-
lization-Induced Dynamic Resolution of Fox Chiral Auxiliary and
Applications to the Diastereoselective Electrophilic Fluorination of
Amide Enolates. J. Org. Chem. 2013, 78, 3487−3492.
́
Sodeoka, M. An Efficient Enantioselective Fluorination of Various β-
(11) For alkylation reactions of N-tBS imidates or amidines, see:
(a) Kochi, T.; Ellman, J. A. Asymmetric α-Alkylation of N’-tert-
Butanesulfinyl Amidines. Application to the Total Synthesis of
(6R,7S)-7-Amino-7,8-dihydro-α-bisabolene. J. Am. Chem. Soc. 2004,
126, 15652−15653. (b) Colpaert, F.; Mangelinckx, S.; Verniest, G.;
De Kimpe, N. Asymmetric Synthesis of α-Alkylated N-Sulfinyl
Imidates as New Chiral Building Blocks. J. Org. Chem. 2009, 74,
3792−3797. (c) Colpaert, F.; Mangelinckx, S.; De Kimpe, N.
Asymmetric Synthesis of Chiral N-Sulfinyl 3-Alkyl- and 3-Arylpiper-
idines by α-Alkylation of N-Sulfinyl Imidates with 1-Chloro-3-
iodopropane. J. Org. Chem. 2011, 76, 234−244.
(12) For aldol reactions of N-tBS imidates, see: (a) Bartrum, H. E.;
Viceriat, A.; Carret, S.; Poisson, J.-F. Sulfinylimidates as Chiral Amide
Equivalents for Irreversible, Asymmetric Aldol Reactions. Org. Lett.
2014, 16, 1972−1975. (b) Li, C.-T.; Liu, H.; Xu, Y.-J.; Lu, C.-D. Aldol
Reaction of N-tert-Butanesulfinyl Imidates under Basic Conditions for
Diastereoselective Synthesis of anti-Aldols. J. Org. Chem. 2017, 82,
11253−11261. (c) Huang, W.; Liu, H.; Lu, C.-D.; Xu, Y.-J.
Diastereoselective Synthesis of 2-Methoxyimidoyloxiranes via Di-
methyl Phosphite-mediated Coupling of α-Keto N-sulfinyl imidates
with Aldehydes. Chem. Commun. 2016, 52, 13592−13595. (d) Huang,
W.; Liu, H.; Xu, Y.-J.; Lu, C.-D. Reaction of Silyllithium, α-Keto N-
tert-Butanesulfinyl Imidates and Aldehydes for Asymmetric Synthesis
of α-Substituted β-(Silyloxy)-α-hydroxy Acid Derivatives. J. Org.
Chem. 2017, 82, 10748−10755.
(13) For Mannich reactions of N-tBS imidates, see: (a) Colpaert, F.;
Mangelinckx, S.; De Kimpe, N. Asymmetric Synthesis of New Chiral
β-Amino Acid Derivatives by Mannich-type Reactions of Chiral N-
Sulfinyl Imidates with N-Tosyl Aldimines. Org. Lett. 2010, 12, 1904−
1907. (b) Colpaert, F.; Mangelinckx, S.; De Brabandere, S.; De
Kimpe, N. Asymmetric Synthesis of α-Chloro-β-amino-N-sulfinyl
Imidates as Chiral Building Blocks. J. Org. Chem. 2011, 76, 2204−
2213. (c) Semina, E.; Colpaert, F.; Van Hecke, K.; De Kimpe, N.;
Mangelinckx, S. Asymmetric Synthesis of δ-Chloro-β-Amino-N-
Sulfinyl Imidates as Versatile Chiral Building Blocks for the Synthesis
of 2,3-Disubstituted Piperidines. Eur. J. Org. Chem. 2015, 2015,
4847−4859.
(14) For 1,4-addition involving N-tBS imidates, see: (a) Wang, J. F.;
Zhou, Y.; Zhang, L.; Li, Z.; Chen, X. J.; Liu, H. Asymmetric Michael
Addition of N-tert-Butanesulfinyl Imidate with α,β-Unsaturated
Diesters: Scope and Application to the Synthesis of Indanone
Derivatives. Org. Lett. 2013, 15, 1508−1511. (b) Wang, H.-J.; Tang,
P.; Zhou, Q.-L.; Zhang, D.; Chen, Z.-T.; Huang, H.-X.; Qin, Y. One-
Pot Synthesis of Multisubstituted Butyrolactonimidates: Total
Synthesis of (−)-Nephrosteranic Acid. J. Org. Chem. 2015, 80,
2494−2502. (c) Huang, H.-X.; Wang, H.-J.; Tan, L.; Wang, S.-Q.;
Tang, P.; Song, H.; Liu, X.-Y.; Qin, Y. Asymmetric Michael Addition
Induced by (R)-tert-Butanesulfinamide and Syntheses of Chiral
Pyrazolidinone Derivatives. J. Org. Chem. 2016, 81, 10506−10516.
Ketoesters Catalyzed by Chiral Palladium Complexes. J. Am. Chem.
Soc. 2002, 124, 14530−14531. (c) Wang, X.; Lan, Q.; Shirakawa, S.;
Maruoka, K. Chiral Bifunctional Phase Transfer Catalysts for
Asymmetric Fluorination of β-Keto Esters. Chem. Commun. 2010,
46, 321−323.
(5) For catalytic α-fluorination of oxindoles, see: (a) Hamashima, Y.;
Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M. Catalytic
Enantioselective Fluorination of Oxindoles. J. Am. Chem. Soc. 2005,
127, 10164−10165. (b) Ishimaru, T.; Shibata, N.; Horikawa, T.;
Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M. Cinchona Alkaloid
Catalyzed Enantioselective Fluorination of Allyl Silanes, Silyl Enol
Ethers, and Oxindoles. Angew. Chem., Int. Ed. 2008, 47, 4157−4161.
(c) Li, J.; Cai, Y.; Chen, W.; Liu, X.; Lin, L.; Feng, X. Highly
Enantioselective Fluorination of Unprotected 3-Substituted Oxin-
doles: One-Step Synthesis of BMS 204352 (MaxiPost). J. Org. Chem.
2012, 77, 9148−9155. (d) Gu, X.; Zhang, Y.; Xu, Z. J.; Che, C. M.
Iron(III)-Salan Complexes Catalysed Highly Enantioselective Fluori-
nation and Hydroxylation of β-Keto Esters and N-Boc Oxindoles.
Chem. Commun. 2014, 50, 7870−7873.
(6) For catalytic α-fluorination of α-aryl acetic acid derivatives, see:
(a) Suzuki, T.; Hamashima, Y.; Sodeoka, M. Asymmetric Fluorination
of α-Aryl Acetic Acid Derivatives with the Catalytic System NiCl2−
Binap/R3SiOTf/2,6-Lutidine. Angew. Chem., Int. Ed. 2007, 46, 5435−
5439. (b) Ishimaru, T.; Shibata, N.; Reddy, D. S.; Horikawa, T.;
Nakamura, S.; Toru, T. DBFOX-Ph/Metal Complexes: Evaluation as
Catalysts for Enantioselective Fluorination of 3-(2-Arylacetyl-2-
thiazolidinones. Beilstein J. Org. Chem. 2008, 4, 16. (c) Reddy, D.
S.; Shibata, N.; Horikawa, T.; Suzuki, S.; Nakamura, S.; Toru, T.;
Shiro, M. A DBFOX-Ph-Based Combinatorial Catalyst for Enantio-
selective Fluorination of Aryl Acetyl and 3-Butenoyl Thiazolidinones.
Chem. - Asian J. 2009, 4, 1411−1415.
(7) For catalytic α-fluorination of acid chlorides, see: (a) Paull, D.
H.; Scerba, M. T.; Alden-Danforth, E.; Widger, L. R.; Lectka, T.
Catalytic, Asymmetric α-Fluorination of Acid Chlorides: Dual Metal-
Ketene Enolate Activation. J. Am. Chem. Soc. 2008, 130, 17260−
17261. (b) Erb, J.; Paull, D. H.; Belding, L.; Dudding, T.; Lectka, T.
From Bifunctional to Trifunctional (Tricomponent Nucleophile−
Transition Metal−Lewis Acid) Catalysis: The Catalytic, Enantiose-
lective α-Fluorination of Acid Chlorides. J. Am. Chem. Soc. 2011, 133,
7536−7546. For catalytic α-fluorination of benzofuran-2-(3H)-ones,
see: (c) Zhu, C.-L.; Fu, X.-Y.; Wei, A.-J.; Cahard, D.; Ma, J.-A. P-Spiro
Phosphonium Salts Catalyzed Asymmetric Fluorination of 3-
Substituted Benzofuran-2-(3H)-ones. J. Fluorine Chem. 2013, 150,
60−66.
(8) (a) Davis, F. A.; Han, W. Diastereoselective Fluorination of
Chiral Imide Enolates using N-Fluoro-o-benzenedisulfonimide
(NFOBS). Tetrahedron Lett. 1992, 33, 1153−1156. (b) Davis, F.
A.; Kasu, P. V. N.; Sundarababu, G.; Qi, H. Nonracemic α-Fluoro
Aldehydes: Asymmetric Synthesis of 4-Deoxy-4-fluoro-D-arabinopyr-
H
DOI: 10.1021/acs.joc.8b02375
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Note
(15) For α-amination of N-tBS imidates, see: Ma, P.-J.; Liu, H.; Lu,
C.-D.; Xu, Y.-J. Diastereoselective Electrophilic α-Hydroxyamination
of N-tert-Butanesulfinyl Imidates. Org. Lett. 2017, 19, 670−673.
(16) For α-hydroxylation of N-tBS imidates/amidines, see: Ma, P.-J.;
Liu, H.; Xu, Y.-J.; Aisa, H. A.; Lu, C.-D. Diastereoselective α-
Hydroxylation of N-tert-Butanesulfinyl Imidates and N′-tert-Butane-
sulfinyl Amidines with Molecular Oxygen. Org. Lett. 2018, 20, 1236−
1239.
(17) For α-hydroxylation of N-tBS imidates, see: Niu, S.-T.; Liu, H.;
Xu, Y.-J.; Lu, C.-D. Diastereoselective α-Sulfenylation of N-tert-
Butanesulfinyl Imidates. J. Org. Chem. 2018, 83, 10580−10588.
(18) For reviews of tert-butanesulfonamide, see: (a) Ellman, J. A.;
Owens, T. D.; Tang, T. P. N-tert-Butanesulfinyl Imines: Versatile
Intermediates for the Asymmetric Synthesis of Amines. Acc. Chem.
Res. 2002, 35, 984−995. (b) Ferreira, F.; Botuha, C.; Chemla, F.;
Perez-Luna, A. tert-Butanesulfinimines: Structure, Synthesis and
Synthetic Applications. Chem. Soc. Rev. 2009, 38, 1162−1186.
(c) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Synthesis and
Applications of tert-Butanesulfinamide. Chem. Rev. 2010, 110, 3600−
3740.
(19) The absolute configuration of chlorinated stereogenic center
was not assigned.
(20) For selected examples of enantioselective synthesis of β-
fluoroamines (1,2-fluoroamines), see: (a) Schulte, M. L.; Lindsley, C.
W. Highly Diastereoselective and General Synthesis of Primary β-
Fluoroamines. Org. Lett. 2011, 13, 5684−5687. (b) Appayee, C.;
Brenner-Moyer, S. E. Organocatalytic Enantioselective Olefin Amino-
fluorination. Org. Lett. 2010, 12, 3356−3359. (c) Kong, W.; Feige, P.;
de Haro, T.; Nevado, C. Regio- and Enantioselective Amino-
fluorination of Alkenes. Angew. Chem., Int. Ed. 2013, 52, 2469−
2473. (d) Vara, B. A.; Johnston, J. N. Enantioselective Synthesis of β-
Fluoro Amines via β-Amino α-Fluoro Nitroalkanes and a Traceless
Activating Group Strategy. J. Am. Chem. Soc. 2016, 138, 13794−
13797. (e) Trost, B. M.; Saget, T.; Lerchen, A.; Hung, C. I. Catalytic
Asymmetric Mannich Reactions with Fluorinated Aromatic Ketones:
Efficient Access to Chiral β-Fluoroamines. Angew. Chem., Int. Ed.
2016, 55, 781−784. (f) Mennie, K. M.; Banik, S. M.; Reichert, E. C.;
Jacobsen, E. N. Catalytic Diastereo- and Enantioselective Fluoroami-
nation of Alkenes. J. Am. Chem. Soc. 2018, 140, 4797−4802.
(21) Kalow, J.; Schmitt, D. E.; Doyle, A. G. Synthesis of β-
Fluoroamines by Lewis Base Catalyzed Hydrofluorination of
Aziridines. J. Org. Chem. 2012, 77, 4177−4183.
(22) For reactions involving a chelated, chairlike 6/4 bicyclic
transition state, see: (a) Kochi, T.; Tang, T. P.; Ellman, J. A.
Development and Application of a New General Method for the
Asymmetric Synthesis of syn- and anti-1,3-Amino Alcohols. J. Am.
Chem. Soc. 2003, 125, 11276−11282. For discussion of a closed
chair−chairlike eight-membered transition state for α-fluorination
using NSFI, see: (b) Beeson, T. D.; Macmillan, D. W. C.
Enantioselective Organocatalytic α-Fluorination of Aldehydes. J. Am.
Chem. Soc. 2005, 127, 8826−8828.
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