Metal free electrophilic fluoro-cyclization of unsaturated N-hydroxy- and N-acetoxyamides with N-F reagents

Article abstract of DOI:10.1016/j.jfluchem.2015.04.011

Metal-free electrophilic fluoro-cyclizations of the respective unsaturated N-hydroxy- and N-acetoxy-amides under action of the 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2 2 2]octane bis(tetrafluoroborate) (F-TEDA-BF₄; trade name Selectfluor)

Full text of DOI:10.1016/j.jfluchem.2015.04.011

Accepted Manuscript
Title: Metal free electrophilic fluoro-cyclization of unsaturated
N-hydroxy- and N-acetoxyamides with N-F reagents
Author: Lyudmila F. Lourie Yurii A. Serguchev Anton V.
Bentya Maxim V. Ponomarenko Eduard B. Rusanov Michail
V. Vovk Andrey A. Fokin Nikolai V. Ignat’ev
PII:
S0022-1139(15)00117-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2015.04.011
FLUOR 8549
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
25-1-2015
9-4-2015
14-4-2015
Please cite this article as: L.F. Lourie, Y.A. Serguchev, A.V. Bentya, M.V. Ponomarenko,
E.B. Rusanov, M.V. Vovk, A.A. Fokin, N.V. Ignat’ev, Metal free electrophilic fluoro-
cyclizationofunsaturatedN-hydroxy-andN-acetoxyamideswithN-Freagents, Journal
of Fluorine Chemistry (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.04.011
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Highlights
1. Metal-free electrophilic fluoro-cyclizations of the unsaturated N-hydroxy- and N-
acetoxyamides leads to cyclic imidates
2. The stereoselectivity of fluoro-cyclization depends on the fluorinating reagent and
solvent
3. F-TEDA-FAP provides better stereoselectivity
1
Page 1 of 15

Graphical Abstract
Ph
Ph
F
Ph
H
F
F
N
Q
Q
O
O
O
R
O
n
O
Ph
+
n=2
n=1
RO N
RO N
RO N
Q = F-TEDA-BF4 or F-TEDA-FAP
R = H, C(O)CH3
2
Page 2 of 15

Graphical Abstract (synopsis)
Metal-free electrophilic fluoro-cyclizations unsaturated N-hydroxy- and N-acetoxyamides
under action of the 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoro-
borate) (F-TEDA-BF4) and F-TEDA-FAP (FAP = [(C2F5)3PF3]–) were studied in organic
solvents and ionic liquid 1-ethyl-3-methylimidazolium triflate.
3
Page 3 of 15

Metal free electrophilic fluoro-cyclization of unsaturated N-hydroxy- and N-
acetoxyamides with N-F reagents
Lyudmila F. Louriea, Yurii A. Sergucheva*, Anton V. Bentyaa, Maxim V. Ponomarenkoa,b,
Eduard B. Rusanova, Michail V. Vovka, Andrey A. Fokinc, Nikolai V. Ignat’evd*
aInstitute of Organic Chemistry, National Academy of Sciences of Ukraine,5 Murmanskaya Str.,02094
Kiev, Ukraine; serguch@gmail.com
bSchool of Engineering and Science, Jacobs University Bremen gGmbH, Campus Ring 1, 28759
Bremen, Germany
cDepartment of Organic Chemistry, Kiev Polytechnic Institute, pr. Pobedy 37,03056 Kiev, Ukraine
dMerck KGaA, PM-APR-FT, Frankfurter Str. 250, D-64271 Darmstadt, Germany;
nikolai.ignatiev@merckgroup.com; ignatiev@web.de
Dedicated to Professor Veronique Gouverneur of Oxford University, winner of the 2015 ACS
Award for Creative Work in Fluorine Chemistry
Keywords: Electrophilic fluoro-cyclization; Cyclic imidates; F-TEDA-FAP; Stereoselectivity
Abstract
Metal-free electrophilic fluoro-cyclizations of the respective unsaturated N-hydroxy-
and
N-acetoxy-amides
under
action
of
the
1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (F-TEDA-BF4; trade name SelectfluorTM)
and F-TEDA-FAP (FAP = [(C2F5)3PF3]–) were carried out in organic solvents and ionic liquid
1-ethyl-3-methylimidazolium triflate. The fluoro-cyclization of trans-N-acetoxy-4-phenylbut-3-
enamide (1), trans-N-hydroxy-4-phenylbut-3-enamide (2), N-hydroxy-4-phenylpent-4-
enamide (3) and N-acetoxy-4-phenylpent-4-enamide (4) results in the formation of cyclic
imidates. The influence of the nature of fluorinating reagent and solvent on the
stereoselectivity of fluoro-cyclization is discussed.
1. Introduction
Organofluorine compounds are of interest for development of new agrochemicals and
pharmaceuticals. Introduction of fluorine or fluorinated moieties often positively influences the
properties of biologically active substances. By this reason, the development of convenient
protocols to prepare the fluorinated compounds is of great importance [1-5]. In particular, the
fluorinated heterocyclic building blocks are on demand.
Electrophilic halo-cyclization of unsaturated carboxylic acids and their derivatives with
chlorine, bromine, iodine or halo-reagents as electrophiles is a useful methodology for
preparation of a variety of functionalized lactons, lactams, oxazolines and cyclic amides,
which are valuable synthones for natural products syntheses [6-8]. The electrophilic
cyclization of unsaturated N-hydroxy- and N-oxyamides (hydroxamic acids and O-acyl
hydroxamates) displays a straightforward protocol for the preparation of various β-lactam
4
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antibiotic analogues and antibacterial remedies [9-15]. The important entity in the structure of
these compounds is the β-lactam moiety. Such kind of β-lactams were prepared by the
electrophilic cyclization of β,γ-unsaturated hydroxamic acids and O-acyl hydroxamates with
bromine [16-18] or N-bromosuccinimide [19, 20]. The cyclic imidates are formed as a major
product
in
the
reaction
of
γ-phenyl-β,γ-unsaturated
hydroxamates
with
bis(collidine)bromine(I) hexafluorophosphate [21]. However, the use of organoselenium
reagents instead of bromine for cyclization of β,γ-unsaturated hydroxamic acids resulted in
the formation of N-hydroxy γ-lactams or/and cyclic imidates depending on the substituents
attached to the double bond [22]. These results show that the course of cyclization is strongly
depended on the nature of electrophilic reagents and reaction conditions. To our best
knowledge, the metal-free electrophilic fluoro-cyclization of unsaturated hydroxyamides is not
described in the literature.
The fluoro-cyclization of N-arylpent-4-enamides to 5-fluoromethyl-substituted γ-
lactams in aqueous media under action of AgNO3 and 1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (F-TEDA-BF4, SelectfluorTM) was recently
reported [23]. Reaction proceeds presumably through the radical mechanism where F-TEDA-
BF4 serves as fluorine source to generate in situ the silver fluoride species acting as
fluorinating reagent [23]. Iron(II)-catalyzed fluoroamination of functionalized hydroxylamines
in the presence of Et3N-HF was also described [24]. This reaction proceeds stepwise and
includes the ring closure followed by addition of fluorine to intermediately generated cyclic
carbocations.
Herein we present the results on the metal-free electrophilic fluoro-cyclization of
unsaturated N-hydroxy- and N-acetoxyamides induced by F-TEDA-BF4 and a new
fluorinating reagent F-TEDA-FAP, where FAP is [(C2F5)3PF3]– [25]. The fluorination of trans-
N-acetoxy-4-phenylbut-3-enamide (1), trans-N-hydroxy-4-phenylbut-3-enamide (2), N-
hydroxy-4-phenylpent-4-enamide (3), N-acetoxy-4-phenylpent-4-enamide (4), N-acetoxy-
trans-2-methylcinnamamide (5) was carried out in organic solvents and ionic liquid 1-ethyl-3-
methylimidazolium triflate ([emim][CF3SO3]).
2. Results and discussion
The fluoro-cyclization of trans-N-acetoxy amide 1 and trans-N-hydroxy amide 2 with
F-TEDA-BF4 in water, organic solvents (nitromethane and acetonitrile), and ionic liquid
[emim][CF3SO3] resulted in the formation of corresponding fluorinated trans-(1a) and cis-(1b)
N-acetoxyimidates, and trans-(2a) and cis-(2b) N-hydroxyimidates in moderate yields
(Scheme 1 and Table 1). The reactions proceeded very slowly (within 6 to 10 days) at room
temperature. Our attempts to accelerate the reactions by heating have failed, presumably
due to the lability of the starting compounds.
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Ph
Ph
N-F reagent
(1.2 equiv)
H
CN
O
F
F
N
O
O
Ph
O
R
R
O
R
O
+
Ph
O
r.t., 6-10 days
N
2c
,
N
1
trans
, R=C(O)CH3
cis
3% in CH3NO2;
1a,2a
1b,2b
15% in H2O
2, R=H
Scheme 1. Formation of trans-(1a) and cis-(1b) N-acetoxyimidates, and trans-(2a) and cis-
(2b) N-hydroxyimidates.
Table 1. Fluorocyclization of trans-N-acetoxy-(1) and trans-N-hydroxy-4-phenylbut-3-
enamide (2).
Trans/cis
N–F
reagent
Sub-
strate
Base or
salt
Yield
(a+b) %
Entry
Solvent
by
19FNMR
1
2
3
4
5
6
7
8
9
F-TEDA-BF4
F-TEDA-BF4
F-TEDA-BF4
F-TEDA-BF4
F-TEDA-FAP
F-TEDA-BF4
F-TEDA-BF4
F-TEDA-BF4
F-TEDA-BF4
1
1
1
1
1
1
2
2
2
–
–
–
CH3NO2
CH3CN
69
68
30
53
53
55
48
40
64
1.3
1.3
1.3
1.0
0.6
0.6
0.6
0.8
1.7
[emim][CF3SO3]
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
H2O
a
K2CO3
-
KFAPb
–
KFAPb
–
a 1 equiv., b 2 equiv.
The reaction of 1 and 2 with F-TEDA-BF4 likely occurs via addition of fluorine to double bond
resulting in the formation of carbo-cationic intermediate that undergoes 5-endo-cyclization
into trans-(1a) and cis-(1b) N-acetoxyimidates, and trans-(2a) and cis-(2b) N-
hydroxyimidates (Scheme 1). The reason for O-cyclization is presumably higher
nucleophilicity of carbonyl oxygen in comparison to amide’s nitrogen bearing hydroxy or
acetoxy group (Milliken charges: δO = -0.728, δN = -0.062 for compound 1 and δO = -0.748, δN
= -0.013 in the case of compound 2). Products of nucleophilic oxygen-attack, but not
nitrogen-attack, were described for the intramolecular halo-cyclization of unsaturated amides,
which had no electron-withdrawing group attached to the nitrogen [6].
The fluoro-cyclization of trans-N-acetoxy-4-phenylbut-3-enamide (1, R = C(O)CH3)
with F-TEDA-BF4 in organic solvents (nitromethane, acetonitrile), as well as in
[emim][CF3SO3], resulted in the formation of trans-isomer 1a as the main product. The
diastereomeric ratio of 1a/1b (1.3) doesn’t depend on the reaction media used (Table 1,
entries 1-3). The configuration of the products 1a,b was confirmed by X-ray analysis, where
in both trans- and cis-diastereomers syn-position of the acetoxy group to the ring oxygen was
proven (Fig. 1).
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1a
1b
Fig. 1. Molecular structures of trans-N-acetoxyimidate 1a and cis-N-acetoxyimidate 1b
(CCDC 1043973 and 1043974).
Attempt to prepare fluorinated lactam by means of fluoro-cyclization of 1 by adding of base,
which was usually used in halo-cyclizations of amides [6,16-18] to facilitate the N-cyclization,
failed. The fluoro-cyclization of 1 in presence of K2CO3 proceeded non-stereoselectively
giving fluoroimidates 1a and 1b, the products of O-cyclization, in molar ratio 1:1 (Table 1,
entry 4).
We also tested the fluoro-cyclization of 1 with the new N–F reagent F-TEDA-FAP
(FAP = tris(pentafluoroethyl)trifluorophosphate) that was recently synthesized through the
anion exchange between F-TEDA-BF4 and KFAP salt in acetonitrile [25]. F-TEDA-FAP
possess better solubility in organic solvents in comparison to F-TEDA-BF4. Surprisingly, the
fluoro-cyclization of 1 with F-TEDA-FAP changed the stereoselectivity relatively to that with
F-TEDA-BF4. Preferable formation of cis-fluoro-N-hydroxyimidate 1b was observed in this
case (Table 1, entry 5). Probably, FAP anion only weakly coordinates to the carbocationic
center that drives fast intramolecular O-cyclization towards the cis-isomer. We also found
similar stereoselectivity when the fluorocyclization of 1 was conducted with F-TEDA-BF4 and
KFAP salt in the ratio 1:2 (in situ generation of F-TEDA-FAP). This may have preparative
applications (Table 1, entries 5 and 6) for carbocationic stereo-selective cyclizations.
The diastereomeric ratio of the products 2a,b depends on the solvent used. N-
hydroxy amide 2 reacts with F-TEDA-BF4 in nitromethane leading to the preferable formation
of cis-fluoro-N-hydroxyimidate 2b (Table 1, entry 7). Almost the same result was obtained
when KFAP was added to the reaction mixture (Table 1, entry 8). Apparently, both [BF4]- and
FAP-anion interact with acidic proton of the N-O-H group ([BF4]- more efficiently). That
enlarges the electron density on carbonyl oxygen facilitating rush cyclisation after addition of
7
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fluorine to double bond. In both cases (Table 1, entry 7 and 8) the cis-isomer 2b is preferably
formed. However, the predominant formation of trans-fluoro-N-hydroxyimidate 2a was
observed when reaction was carried out in water (Table 1, entry 9) presumably due to the
strong solvation of the reaction center. It looks that reaction proceeds in this case stepwise:
addition of F and cyclization via intermediate formation of carbocation which has time (slow
kinetic) to assume energetically more favored configuration leading to the formation of trans-
isomer. In both reactions, in nitromethane as well as in water, the 2c was isolated as a by-
product. The formation of the unsaturated nitrile 2c was observed earlier in electrophilic
bromo-cyclization of -phenyl-,-unsaturated hydroxamates [21].
Computational simulation [26] shows that in the case of electrophilic fluoro-cyclization
of 2 the syn-conformation of the fluorinated products 2a,b is stabilized additionally by the
intramolecular OHO hydrogen bonding with energy gain of ca. 6.0 kcal∙mol–1 (Fig. 2). The
computational results are well in agreement with syn-conformation of the products 2a,b
determined by NMR spectra, where multiplicities and chemical shifts of the characteristic
signals are similar to the NMR spectra of the products 1a,b.
Fig. 2. The M06-2X/cc-pVDZ and MP2/cc-pVDZ relative energies (kcal∙mol–1) of syn- and
anti-2a.
The fluoro-cyclization of N-hydroxy amide 3, which contains a terminal double bond,
with F-TEDA-BF4 in nitromethane results in the formation of fluoromethyl-N-hydroxyimidate
3a and difluoromethyl-N-hydroxyimidate 3b in 53% and 5% isolated yields, correspondingly
(Scheme 2).
8
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Ph
Ph
Ph
+
N-F reagent
(1.2 equiv.)
H
H
H
F
N
N
F
N
OR
OR
OR
-H+
r.t., 6-10 days
O
O
O
B
A
3
, R=H
-H+
4, R=C(O)CH3
F-TEDA-BF4
F
F
F
Ph
+
Ph
O
Ph
H
N
F
OR
O
-H+
F
O
C
RO N
RO N
3a, R=H, 53%
4a, R=C(O)CH3, Table 2
3b, R=H, 5%
4b, R=C(O)CH3, Table 2
Scheme 2. Fluoro-cyclization of N-hydroxy-4-phenylpent-4-enamide (3) and N-acetoxy-4-
phenylpent-4-enamide (4).
This reaction likely occurs via intermediately formed carbocation A that undergoes cyclization
to fluoromethyl-N-hydroxyimidate 3a and besides is deprotonated to fluoroalkene B with the
base released from F-TEDA-BF4. The follow-up electrophilic fluorination of B leads to
difluoroimidate 3b through carbocation C stabilized by conjugation with Ph-group. Similar
mechanism was proposed for electrophilic fluorocyclization of unsaturated carboxylic acids
and alkenols with F-TEDA-BF4 [27, 28].
The fluorocyclization of N-acetoxy amide 4 with F-TEDA-BF4 in nitromethane
proceeds similarly to that for amide 3 and results in the formation of monofluorinated (4a)
and difluorinated (4b) imidates with the ratio of ca. 4.9 estimated by 19F-NMR data (Scheme
2, Table 2).
Table 2. Fluorocyclization of N-acetoxy-4-phenylpent-4-enamide (4).
Isolated yields, %
N–F
Reagent
Time,
days
Ratio
a/b
Entry
Solvent
CH3NO2
4a
4b
1
2
3
F-TEDA-BF4
F-TEDA-BF4
F-TEDA-FAP
6
10
6
49
10
19
–
4.9
1.3
–
[emim][CF3SO3] 24
CH3NO2 51
When changing nitrometane to [emim][CF3SO3] the amount of gem-difluorinated compound
4b increases (the ratio of 4a/4b is 1.3; Table 2, entry 2) due to additional stabilization of the
carbocation A through its coordination with CF3SO3-anion. The latter retards the cyclization
and facilitates the deprotonation to the carbocation B. (Table 2, entry 2). On the contrary,
weakly coordinating anion [(C2F5)3PF3] of F-TEDA-FAP does not contribute to the
9
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stabilization of A that results exclusively in fast intramolecular cyclization to 4a (Table 2,
entry 3).
F
OH
OH
F
F-TEDA-BF4
(1.2 equiv.)
F
Ph
H
H
H2O
N
Ph
Ph
N
OAc
OAc
OAc
N
Ph
CH3NO2, r.t.,
10 days
O
O
OH
O
N
5
6
, 40%
AcO
D
Scheme 3. Fluorination of N-acetoxy-trans-2-methylcinnamamide (5).
Our attempts to build the fluorinated four-membered cycle through the reaction of N-acetoxy-
trans-2-methylcinnamamide (5) with F-TEDA-BF4 in nitromethane were unsuccessful. Only
the open-chain fluorinated compound 6 was isolated in 40% yield after quenching the
reaction mixture with water (Scheme 3). Presumably, intermediately formed labile four-
membered fluorinated oxetane D undergoes rapid hydrolysis to the N-acetoxy-3-phenyl-3-
hydroxy-2-fluoro-2-methylpropioamide 6.
3. Conclusion
The fluorocyclization of trans-N-acetoxy-4-phenylbut-3-enamide (1) and trans-N-
hydroxy-4-phenylbut-3-enamide (2) with N-F reagents (F-TEDA-BF4 and F-TEDA-FAP)
results in the formation of diastereomeric mixtures of fluorinated N-acetoxy- and N-hydroxy-
imidates. The use of F-TEDA-FAP instead F-TEDA-BF4 reverses the diastereoselectivity in
favour of the cis-fluoro-N-acetoxyimidate 1b formation. Syn-configurations of fluorinated N-
acetoxyimidates 1a and 1b were confirmed by X-ray analysis.
The fluorocyclization of the N-hydroxy-(3) and N-acetoxy-4-phenylpent-4-enamides
(4) with terminal double bond under action of F-TEDA-BF4 in nitromethane proceeds with the
formation of monofluorinated (3a,4a) and gem-difluorinated (3b,4b) imidates. The use of the
F-TEDA-FAP reagent instead of F-TEDA-BF4 in nitromethane results in the formation of the
monofluorinated product 4a exclusively.
4. Experimental section
Analytical Instruments.
The NMR spectra were recorded on spectrometers Varian VXR-300 [1H (300 MHz), 13C (75.5
19
MHz), F (282.2 MHz)], Varian UNITY plus 400 [1H (399.9 MHz), 13C (100.5 MHz), 19F (376
MHz)] and Bruker Avance DRX-500 [1H (500 MHz), 13C (125.7 MHz)] using CDCl3 as a
solvent and TMS or CCl3F as internal standards. Mass spectra were measured on a Thermo
Finnigan LCQ Advantage LC/mass detector instrument.
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Chemicals.
Unsaturated N-acetoxy- and N-hydroxy-amides 1, 2, 3, 4, and 5 were synthesized according
to known procedures [21,29].
Typical fluoro-cyclization protocol in nitromethane. The dry nitromethane (10 ml) and F-
TEDA-BF4 or F-TEDA-FAP (1.8mmol, 1.2 equiv) were placed into a three-necked flask
equipped with a reflux condenser. Argon gas was passed through the reaction mixture for 20
min. After addition of the corresponding substrate (1.5 mmol) the mixture was stirred at
ambient temperature until the reaction was completed (monitoring by TLC). Then, water (25
ml) was added to reaction mixture and the product was extracted with dichloromethane
(3×15 ml). Organic phase was washed two times with water, dried with MgSO4 and filtered.
After evaporation of the solvent the product was purified by column chromatography on silica
gel with eluent: n-hexane/ethyl acetate (3:2).
Products characterization:
(4R,5S,Z)-4-fluoro-5-phenyldihydrofuran-2(3H)-one O-acetyl oxime (1a)
White crystals, m.p. 134-135°C;1H NMR (500 MHz, CDCl3): δ 7.41 (m, 3H), 7.26 (m, 2H),
3
2
13
5.87 (d, JHF = 20.5 Hz), 5.21 (d, JHF = 52.5 Hz), 3.11 (m, 2H), 2.20 (s, 3H, CH3); C NMR
3
1
(126 MHz, CDCl3): δ 167.6, 162.3, 134.0 (d, J = 9.5 Hz), 128.8, 124.3, 93.9 (d, J = 187.0
Hz), 90.1 (d, 2J = 25.3 Hz), 32.3 (d, 2J = 23.9 Hz), 18.9; 19F NMR (376 MHz, CDCl3): δ –172.0
(m, J = 52.5, 29.3, 20.3 Hz); LC/MS: m/z 260 (M+Na)+, 238 (M+H)+, 196 (M+H-OAc)+; Anal.
Calcd. for C12H12FNO3: C, 60.76; H, 5.10; N, 5.90. Found: C, 60.71; H, 5.02; N, 5.87.
X-ray Structure (see Supporting Information) determination for 1a.
Crystal data: C12H12FNO3, M 237.23, orthorhomic, space group P212121 ,а= 8.6617(9), b =
10.0279(11), c = 13.3467(16) Å, V = 1159.3(2)Å3, Z = 4, dc = 1.359 g·cm-3,  = 0.108 mm-1,
F(000) = 496, crystal size ca. 0.09  0.20  0.40 mm. All crystallographic measurements
were performed at room temperature on a Bruker Smart Apex II diffractometer operating in
the  and scans mode. The intensity data were collected within the range of 2.54 
26.32 using Mo-K radiation ( = 0.71078 Å). The intensities of 6481 reflections were
collected (2322 unique reflections, Rmerg = 0.039). The structure was solved by direct
methods and refined by the full-matrix least-squares technique in the anisotropic
approximation for non-hydrogen atoms using the Bruker SHELXTL program package [29]. All
hydrogen atoms were refined as ‘riding’ model. In the refinement 2322 reflections were used.
Convergence was obtained at R1 = 0.0771 and wR2 = 0.1131 for all reflection and R1 =
0.0454 and wR2 = 0.0983, GOF = 1.097 for 1631 observed reflections with I (I), 159
parameters; the largest and minimal peaks in the final difference map 0.16 and –0.18 e/Å3,
11
Page 11 of 15

weighting scheme is as follows:  = 1/[2(Fo2) + (0.0492P)2], where Р = (Fo2 + 2Fc2)/3), Full
crystallographic details have been deposited at Cambridge Crystallographic Data Centre
(CCDC). Any request to the CCDC for these materials should quote the full literature citation
and reference number CCDC 1043973.
(4S,5S,Z)-4-fluoro-5-phenyldihydrofuran-2(3H)-one O-acetyl oxime (1b)
3
White crystals, m.p. 104-105°C;1H NMR (500 MHz, CDCl3): δ 7.42 (m, 5H), 5.57 (dd, JHF
=
=
26.5 Hz, JHH‘ = 2.4 Hz, 1H), 5.33 (dm, 2JHF = 52.1 Hz, 1H), 3.28 (A-part, JAB = 18.0 Hz, 3JHF
22.1 Hz, 1H), 3.22 (B-part, JAB = 18.0 Hz, 3JHF = 37.9 Hz, JHH = 4.3 Hz, 1H), 2.17 (s, 3H); 13C
NMR (126 MHz, CDCl3): δ 168.3, 162.4, 131.7 (d,3J = 3.7 Hz), 129.4, 128.6, 127.3, 90.1 (d,
2
2
1J = 191.1 Hz), 89.0 (d, J = 20.4 Hz), 35.6 (d, J = 24.2 Hz), 19.4; 19F NMR (376 MHz,
CDCl3): δ –191.3 (m, J = 52.0, 37.7, 26.4, 22.5 Hz). LC/MS: m/z 260 (M+Na)+, 238 (M+H)+,
196 (M+H-OAc)+; Anal. Calcd. for C12H12FNO3: C, 60.76; H, 5.10; N, 5.90. Found: C, 60.73;
H, 5.06; N, 5.86.
X-ray Structure (see Supporting Information) determination for 1b.
Crystal data: C12H12FNO3, M 237.23, monoclinic, space group P21/c, а= 12.5764(12), b =
7.5009(8), c = 12.2587(13) Å, β = 95.357(6), V = 1151.4(2)Å3, Z = 4, dc = 1.369 g·cm-3,  =
0.109 mm-1, F(000) = 496, crystal size ca. 0.26  0.33  0.37 mm. All crystallographic
measurements were performed at room temperature on a Bruker Smart Apex II
diffractometer operating in the  and  scans mode. The intensity data were collected within
the range of 1.63  26.00 using Mo-K radiation ( = 0.71078 Å). The intensities of 8960
reflections were collected (2150 unique reflections, Rmerg = 0.0587). The structure was solved
by direct methods and refined by the full-matrix least-squares technique in the anisotropic
approximation for non-hydrogen atoms using the Bruker SHELXTL program package [29]. All
hydrogen atoms were refined isotropically. In the refinement 2150 reflections were used.
Convergence was obtained at R1 = 0.0977 and wR2 = 0.2253 for all reflection and R1 =
0.0687 and wR2 = 0.2093, GOF = 1.04 for 1556 observed reflections with I (I), 202
parameters; the largest and minimal peaks in the final difference map 0.16 and –0.18 e/Å3,
weighting scheme is as follows:  = 1/[2(Fo2) + (0.015P)2], where Р = (Fo2 + 2Fc2)/3), Full
crystallographic details have been deposited at Cambridge Crystallographic Data Centre
(CCDC). Any request to the CCDC for these materials should quote the full literature citation
and reference number CCDC 1043974.
(4R,5S,Z)-4-fluoro-5-phenyldihydrofuran-2(3H)-one oxime (2a)
Colorless oil;1H NMR (400 MHz, C6D6): δ6.57–7.25 (bs, 1H), 6.97 (m, 3H), 6.80 (m, 2H), 5.21
(d, 3JHF = 21.1 Hz, 1H), 4.32 (dm, 2JHF = 53.5 Hz, 1H), 2.13 (A-part, JAB = 18.6 Hz, 3JHF = 23.1
Hz, 1H), 1.94 (B-part, JAB = 18.6 Hz, 3JHF = 34.0 Hz, 3JHH = 5.1 Hz, 1H); 13C NMR (126 MHz,
12
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CDCl3): δ 173.4 (C=N), 134.7 (d, J = 9.3 Hz), 128.8, 128.6, 124.4, 93.5 (d, J = 185.6 Hz),
19
85.2 (d, J = 26.2 Hz), 33.7 (d, J = 23.9 Hz); F NMR (188 MHz, CDCl3): δ –172.0 (m, J =
53.0 Hz); LC/MS: m/z 196 (M+H)+; Anal. Calcd. for C10H10FNO2: C, 61.53; H, 5.16; N, 7.18.
Found: C, 61.49; H, 5.12; N, 7.13.
(4S,5S,Z)-4-fluoro-5-phenyldihydrofuran-2(3H)-one oxime (2b)
White crystals, m.p. 61-62 °C; 1H NMR (400 MHz, C6D6): δ 6.90–7.20 (bs, 1H), 7.09 (m, 5H),
4.61 (d, 3JHF = 26.6 Hz, 1H), 4.30 (d, 2JHF = 53.0 Hz, 1H), 2.34 ( A-part, JAB = 18.6 Hz, 3JHF
=
19.4 Hz, 1H), 2.00 (B-part m, JAB = 18.6 Hz,3JHF = 40.0 Hz, 1H); 13C NMR (126 MHz, CDCl3):
δ 173.3 (C=N), 131.8 (d, J = 4.2 Hz), 128.6, 128.1, 126.2, 89.6 (d, J = 188.1 Hz), 83.8 (d, J =
20.9 Hz), 36.8 (d, J = 25.2 Hz); 19F NMR (188 MHz, CDCl3): δ –190.5 (m, J = 53.0 Hz);
LC/MS: m/z 196 (M+H)+; Anal. Calcd. for C10H10FNO2: C, 61.53; H, 5.16; N, 7.18. Found: C,
61.47; H, 5.12; N, 7.14.
The spectral data of the product 1c are identical to described previously [21].
5-(fluoromethyl)-5-phenyldihydrofuran-2(3H)-one oxime (3a)
Colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.20–8.20 (bs, 1H), 7.57–7.24 (m, 5H), 4.60 (A-
2
2
part,dd, JHF = 48.0 Hz, 2JAB = 10.3 Hz, 1H), 4.51 (B-part,dd, JHF = 48.0 Hz, 2JAB = 10.3 Hz,
1H), 2.81 (m, J = 15.0, 6.1 Hz, 1H), 2.72 (m, 1H), 2.58 (m, J = 15.0, 7.1 Hz, 1H), 2.36 (m,
13
3
1H); C NMR (126 MHz, CDCl3): δ 158.4, 138.1 (d, J = 5.0 Hz), 128.3, 128.1, 124.8, 90.5
2
1
3
(d, J = 18.4 Hz), 86.0 (d, J = 184.4 Hz), 30.8 (d, J = 2.7 Hz), 25.7; 19F NMR (376 MHz
CDCl3): δ–222.1 (t, J = 47.6 Hz); LC/MS: m/z 210 (M+H)+, 191 (M+H-F)+; Anal. Calcd. for
C11H12FNO2: C, 63.15; H, 5.78; N, 6.69. Found: C, 63.08; H, 5.75; N, 6.61.
The difluorinated lactone 3b was not separated from the reaction mixture in pure form and
the formation of this compound was proved based upon the characteristic signals in NMR
1
2
spectra. H NMR (299.9 MHz, CDCl3): δ5.79 (t, JHF = 55.9 Hz, 1H); 19F NMR (188 MHz,
2
2
CDCl3): δ–129.4 (A-part, JAB = 283.0 Hz, JFH = 56.5 Hz, 1F, ABX), –130.9 (B-part, JFF
283.0 Hz, 2JFH = 56.5 Hz, 1F, ABX).
=
5-(fluoromethyl)-5-phenyldihydrofuran-2(3H)-one O-acetyl oxime (4a)
2
Colorless oil; 1H NMR (500 MHz, CDCl3): δ 7.46–7.29 (m, 5H), 4.54 (A-part,dd, JHF = 48.0
2
2
2
Hz, JAB = 10.4 Hz, 1H), 4.47 (B-part,dd, JHF = 48.0 Hz, JAB = 10.4 Hz, 1H), 3.08 (m, 1H),
13
2.90–2.72 (m, 2H), 2.40 (m, 1H), 2.13 (s, 3H); C NMR (126 MHz, CDCl3): δ 174.3, 168.2,
138. (d, 3J = 5.5 Hz), 128.7, 128.7, 125.1, 91.2 (d, 2J = 18.2 Hz), 87.1 (d, 1J = 184.8 Hz), 30.5
(d, J = 2.3 Hz), 26.3 (d, J = 2.1 Hz), 19.3; 19F NMR (376 MHz, CDCl3): δ –222.1 (t, J = 47.5
Hz); LC/MS: m/z 252 (M+H)+; Anal. Calcd. for C13H14FNO3: C, 62.14; H, 5.62; N, 5.57.
Found: C, 62.09; H, 5.58; N, 5.50.
13
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5-(difluoromethyl)-5-phenyldihydrofuran-2(3H)-one O-acetyl oxime (4b)
2
Colorless oil; 1H NMR (500 MHz, CDCl3): δ 7.57–7.34 (m, 5H), 5.80 (t, J = 55.5 Hz, 1H),
3.08 (m, 1H), 2.95–2.85 (m, 1H), 2.77 (m, 1H), 2.46 (m, 1H), 2.16 (s, 1H); 13C NMR (126
3
1
MHz, CDCl3): δ173.8, 136.1 (t, J = 3.6 Hz), 129.2, 128.7, 125.9, 115.0 (d, J = 249.4 Hz),
2
19
89.6 (t, J = 21.4 Hz), 28.3, 26.0, 19.3; F NMR (376 MHz, CDCl3): δ –129.8 (A-part, JAB
=
2
2
2
283.8 Hz, JFH = 55.0 Hz, 1F, ABX), –130.9 (B-part, JFF = 283.8 Hz, JFH = 55.0 Hz, 1F,
ABX); LC/MS: m/z 270 (M+H)+; Anal. Calcd. for C13H13F2NO3: C, 57.99; H, 4.87; N, 5.20.
Found: C, 57.92; H, 4.83; N, 5.15.
N-acetoxy-2-fluoro-3-hydroxy-2-methyl-3-phenylpropanamide (6)
White crystals, m.p. 89-90°C;1H NMR (500 MHz, CD3CN):δ 10.28 (bs, 1H), 7.54–7.13 (m,
3
3
13
5H), 4.87 (d, J = 24.8 Hz, 1H), 4.11 (bs, 1H), 2.17 (s, 3H), 1.28 (d, J = 22.6 Hz, 3H); C
NMR (126 MHz, CD3CN): δ 169.8 (d, 2J = 23.1 Hz), 169.5, 139.4, 129.2, 129.0, 100.2 (d, 1J =
192.1 Hz), 76.7 (d, 2J = 18.9 Hz), 21.6 (d, 2J = 22.6 Hz), 18.3; 19F NMR (188 MHz, CDCl3): δ
–178.6 (quin, J = 23.2 Hz); LC/MS: m/z 278 (M+Na)+, 238 (M-OH)+, 196 (M-OAc)+; Anal.
Calcd. for C12H14FNO4: C, 56.47; H, 5.53; N, 5.49. Found: C, 56.38; H, 5.50; N, 5.48.
Acknowledgement
Financial support from company Merck KGaA (Darmstadt, Germany) is gratefully
acknowledged.
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