Synthesis of New γ-Lactams with gem-Difluorinated Side Chains

Article abstract of DOI:10.1055/s-0039-1690715

A short and efficient approach has been designed for the synthesis of new γ-lactams that feature gem-difluorinated side-chains in position 4. The key steps involve 1,4-addition of nitroalkane anions on electrophilic gem-difluoroalkenes, followed by a cascade nitro reduction-heterocyclization. This flexible strategy also allows easy introduction of substituents in positions 3 or 5.

Full text of DOI:10.1055/s-0039-1690715

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
A. Soulieman et al.
Letter
Synlett
Synthesis of New -Lactams with gem-Difluorinated Side Chains
Ali Souliemana,b
Nicolas Gouaultb
Thierry Roisnelb
Frédéric Justaudb
Joël Boustieb
R1
F
F
F
F
6–8 steps
13 examples
3
R
R
4
5
O
O
R = aryl, alkyl groups
R1 = Me, Bn, allyl, propargyl
R2 = Me, Ph
N
R3
O
R2
gem-difluorinated
propargylic esters
gem-difluorinated
René Grée*b
Ali Hachem*a
γ - lactams
a Lebanese University, Faculty of Sciences (I) Laboratory for
Medicinal Chemistry and Natural Products, and PRASE-EDST,
Hadath, Lebanon
ahachem@ul.edu.lb
b Univ Rennes, CNRS (Institut for Chemical Sciences in
Rennes), UMR 6226, 35000 Rennes, France
rene.gree@univ-rennes1.fr
Received: 10.09.2019
Accepted after revision: 29.09.2019
Published online: 14.10.2019
On the other hand, it is known that the introduction of
fluorine to organic molecules strongly modifies their physi-
cal, chemical and biological properties, and this topic has
been covered in many reviews.3 However, to our knowledge,
only a few fluorinated -lactams have been described to
date.4 Thus, based on the previous experience gained in our
laboratories in the synthesis and uses of propargylic fluo-
rides, we have designed a strategy for the preparation of
novel -lactams with gem-fluorinated side chains (Scheme
1). This takes advantage of readily accessible and versatile
gem-difluoro propargylic derivatives.5 The target molecules
could be obtained by cyclization of amino ester intermedi-
ates with the desired fluorinated side chains. These deriva-
tives could be prepared by reduction of the corresponding
nitro compounds. These intermediates could, in turn, be ob-
tained by a Michael addition of the nitromethane anion on
electrophilic alkenes possessing the gem-difluoro chains.
The latter derivatives could be prepared by reduction of the
corresponding gem-difluoro propargylic esters.
DOI: 10.1055/s-0039-1690715; Art ID: st-2019-d0481-l
Abstract A short and efficient approach has been designed for the
synthesis of new -lactams that feature gem-difluorinated side-chains in
position 4. The key steps involve 1,4-addition of nitroalkane anions on
electrophilic gem-difluoroalkenes, followed by a cascade nitro reduc-
tion–heterocyclization. This flexible strategy also allows easy introduc-
tion of substituents in positions 3 or 5.
Key words fluorine, gamma lactams, gem-difluoropropargyl, hetero-
cycles, synthesis
The -lactam ring is part of the core structure of a large
number of natural and non-natural compounds covering a
broad spectrum of biological activities. This privileged scaf-
fold is widely present in important pharmaceuticals, such
as (R)-Rolipram, a selective phosphodiesterase-4 inhibitor
developed as a potential antidepressant drug, the antitus-
sive Cynometrine, and Brivaracetam, which exhibits anti-
convulsant properties (Figure 1).1 Furthermore, -lactams
also serve as versatile intermediates for the synthesis of
other medicinally relevant molecules and complex natural
products.2
The fluorinated alkynes 4a–h were prepared in three
steps, as indicated in Scheme 2 and Table 1.
F
F
F
F
F
F
O
O
R
R
R
O
O
O
NH2
NO2
NH
O
Me
N
MeO
gem-difluorinated
HO
g-lactams
N
O
N
F
F
O
O
NH2
F
F
gem-difluorinated
propargylic esters
R
O
O
N
H
N
O
R
O
(R)-Rolipram
Antidepressant and
antiinflammatory
Cynometrine
Antitussive and
analgesic
Me
Brivaracetam
Antiepileptic
O
Scheme 1 Retrosynthetic analysis for the preparation of -lactams
with fluorinated side chains in position 4
Figure 1 Some biologically active -lactam containing molecules
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
A. Soulieman et al.
Letter
Synlett
The addition of methyl propiolate to a range of alde-
hydes (aromatic and alkyl) afforded propargylic alcohols
2a–h in fair to good yields. Subsequent oxidation with Jones
reagent gave the ketones 3a–h, also in excellent yields.
ing Lindlar catalyst to give the alkenes 5a–h in good to ex-
cellent yields. During these reductions, minor amounts of
the corresponding E-isomers were obtained in a few cases.
On these electrophilic alkenes, the Michael addition of
the nitromethane anion was performed in a classical way
by using potassium carbonate as the base and DMSO as sol-
vent, affording adducts 6a–h in good to excellent yields.
Reduction of the nitro group proved to be a little more
challenging. After optimization studies we found that the
combination of NiCl2·6H2O and NaBH4,6 gave the best re-
sults, affording the target molecules 7a–h in excellent
yields (Table 2), except for 7d, for which cleavage of the C–
Br bond occurred, affording 7a. On the other hand, hydroge-
nation in the presence of Pd(OH)2 gave only the -lactam 7a
for compounds 6c and 6d, bearing the halogen substituents
on the aromatic ring. Under these conditions and for these
two molecules, both the reduction of the nitro group and
dehalogenation occurred.
OH
n-BuLi (1–1.2 equiv)
TMSCl (2–2.5 equiv)
Jones reagent
acetone
O
O
R
+
O
R
H
THF, –90 °C
O
0 °C
1a–h
O
2a–h
O
F
F
R
R
DAST
60 °C
O
O
O
O
3a–h
4a–h
Scheme 2 Synthesis of alkynes 4a–h with the gem-difluoroalkylated
chains
Table 1 Synthesis of Alkynes 2a–h, 3a–h, and 4a–h with gem-Difluo-
roalkylated Chains
Table 2 Synthesis of -Lactams 5a–h, 6a–h, and 7a–h with the gem-
Difluoroalkylated Chains in Position 4
Entry
SM
R
Yield (%)
2
3
4
Entry
SM
R
Yield (%)
1
2
3
4
5
6
7
8
1a
Ph
2a (90)
2b (69)
2c (70)
2d (64)
2e (81)
2f (77)
2g (70)
2h (60)
3a (80)
3b (74)
3c (79)
3d (84)
3e (95)
3f (93)
3g (77)
3h (82)
4a (65)
4b (91)
4c (62)
4d (76)
4e (70)
4f (25)
4g (79)
4h (60)
5
6
7
1b
1c
1d
1e
1f
PhCH2CH2
4-ClC6H4
2-BrC6H4
4-FC6H4
4-MeOC6H4
4-F3CC6H4
n-C8H17
1
2
3
4
5
6
7
8
4a
Ph
5a (86)
5b (65)
5c (94)
5d (35)a
5e (75)
5f (79)
5g (80)
5h (71)
6a (90)
6b (80)
6c (88)
6d (79)
6e (87)
6f (86)
6g (85)
6h (70)
7a (80)
7b (77)
7c (84)
–
4b
4c
4d
4e
4f
PhCH2CH2
4-ClC6H4
2-BrC6H4
4-FC6H4
4-MeOC6H4
4-F3CC6H4
n-C8H17
7e (90)
7f (92)
7g (95)
7h (84)
1g
1h
4g
4h
a From 40% conversion.
Fluorination with diethylaminosulfur trifluoride (DAST)
then afforded the target intermediates 4a–h in satisfactory
yields, except for 4f, for which some decomposition occurred.
The conversion into the target -lactams was achieved
in three more straightforward steps (Scheme 3). First, the
semi-hydrogenation of the triple bond was performed us-
All compounds 2–7 have spectroscopic (1H, 19F and 13C
NMR) and mass spectrometric data consistent with their
structures (see the Supporting Information). In addition, X-
ray crystallographic analysis confirmed the structures of -
lactams 7a and 7e (Figure 2).7
F
F
O
O
F
CH3NO2
K2CO3
F
Lindlar Cat.
Methanol
R
O
R
DMSO
O
4a–h
5a–h
F
F
F
F
O
NiCl2.6H2O
NaBH4
R
R
O
Figure 2 Structures of 7a and 7e by X-ray crystallographic analysis
O
NH
O2N
6a–h
7a–h
The next step was the extension of molecular diversity
around the -lactam scaffold. One obvious way was the in-
troduction of R1 substituents on the carbon vicinal to the
Scheme 3 Synthesis of -lactams 7a–h with the gem-difluoroalkylated
chains in position 4
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

C
A. Soulieman et al.
Letter
Synlett
lactam carbonyl. Thus, lactam 7e, selected as a model, was
first protected as its N-Boc derivative and then alkylation
reactions were performed to introduce various R1 groups at
the desired position (Scheme 4). These reactions (Table 3)
proved to be completely stereoselective, affording only the
trans isomers 9a–d.
methyl group at position 3 and the proton at position 4.
Similar results were obtained for compounds 9b–d and the
structure of 9b was confirmed by X-ray crystallographic
analysis (Figure 3).7
F
F
F
F
Boc2O
DMAP
O
O
CH3CN
86%
N
NH
F
F
Boc
7e
8e
F
F
R1
9a: R1 = Me
9b: R1 = Bn
9c: R1 = allyl
H
R1–I
LiHMDS/THF
–90 °C
3
4
O
(
)
H
Figure 3 Structure of 9b by X-ray crystallographic analysis
N
9d: R1 = propargyl
F
Boc
To expand the scope of this approach, a second option
was to introduce a CH2-R2 group on the carbon vicinal to
the nitrogen atom. By using the ,-unsaturated ester 5e as
a representative model, this could be achieved by the addi-
tion of nitroalkyl groups, instead of nitromethane. First the
reaction of 1-nitropropane on 5e gave a 1:1 mixture of ad-
ducts 10e and 11e, in 66% overall yield, as shown in Scheme
5. These compounds were separable by chromatography
and we could establish that, not surprisingly, there was a
slow equilibration between these two stereoisomers under
basic conditions. For both compounds, reduction of the ni-
tro group, under the same conditions as before, afforded the
-lactams 12e and 13e, respectively, stereoselectively in
good yields. Their stereochemistry was again established by
extensive NMR studies. In particular for 13e, strong NOESY
correlations were observed between the protons of the
methylene group at position 5 and the neighboring proton
Scheme 4 Introduction of R1 substituents in position 3
Table 3 Synthesis of -Lactams Substituted in Position 3
Entry
R1
Me
Yield (%)
1
2
3
4
9a (90)
9b (62)
9c (42)
9d (30)
Bn
allyl
propargyl
The stereochemistry of compound 9a was assigned
on the basis of extensive NMR experiments. In particular,
1H–19F HOESY experiments revealed strong correlations be-
tween the fluorine atoms and the proton at position 3. Fur-
thermore, NOE correlations were observed between the
base
R2
F
F
F
F
NO2
O
O
F
O
O
F
K2CO3
DMSO
+
O
O
NO2
NO2
F
F
R2
R2
(
)
F
(
)
10e: R2 = Me
14e: R2 = Ph
11e: R2 = Me
15e: R2 = Ph
R = Me
R = Ph
5e
NiCl2⋅6H2O
NaBH4
NiCl2⋅6H2O
NaBH4
F
F
F
F
4
5
4
5
O
+
O
H
H
NH
NH
F
F
R2
(
)
R2
(
)
12e: R2 =Me
16e: R2 = Ph
13e: R2 = Me
17e: R2 = Ph
Scheme 5 Synthesis of -lactams substituted in position 5
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

D
A. Soulieman et al.
Letter
Synlett
at position 4 of this heterocycle; no such correlations were
observed in the case of its diastereoisomer 12e.
orine Chemistry; Ojima, I.; McCarthy, J. R.; Welch, J. T., Ed.; ACS
Symposium Series 639: Washington DC, 1996. (g) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008,
37, 320. (h) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
(i) Fustero, S.; Sanz-Cervera, J. F.; Acena, J. L.; Sanchez-Rosello,
M. Synlett 2009, 525. (j) Hunter, L. Beilstein J. Org. Chem. 2010, 6,
38. (k) Qing, F.-L.; Zheng, F. Synlett 2011, 1052. (l) Gillis, E. P.;
Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med.
Chem. 2015, 58, 8315. (m) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.;
Zhu, W.; Aceňa, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Chem.
Rev. 2016, 116, 422. (n) Yerien, D. E.; Bonesi, S.; Postigo, A. Org.
Biomol. Chem. 2016, 14, 8398. (o) Meanwell, N. A. J. Med. Chem.
2018, 61, 2022; and references cited therein.
The same reactions were performed starting with 2-ni-
troethylbenzene, affording a 1:1 inseparable mixture of 14e
and 15e in 83% overall yield. After reduction of the nitro
groups, the desired -lactams 16e and 17e could be sepa-
rated by chromatography and their stereochemistries were
established by NMR analysis as described for 12e and 13e.
In conclusion, we have developed a flexible synthesis of
novel -lactams with gem-fluorinated side-chains at posi-
tion 4 of the heterocyclic ring.8 Furthermore, molecular di-
versity was increased by adding other substituents in posi-
tions 3 and 5 of the -lactam. Molecules of this type are of
interest in various areas of bioorganic or medicinal chemis-
try and further studies will be performed in the near future.
(4) (a) Okano, T.; Takakura, N.; Nakano, Y.; Okajima, A.; Eguchi, S.
Tetrahedron 1995, 51, 1903. (b) Fustero, S.; Fernandez, B.; Bello,
P.; del Pozo, C.; Arimitsu, S.; Hammond, G. B. A. Org. Lett. 2007,
9, 4251. (c) Mai, W.-P.; Wang, F.; Zhang, X.-F.; Wang, S.-M.;
Duan, Q.-P.; Lu, K. Org. Biomol. Chem. 2018, 16, 6491. (d) Phae-
Nok, S.; Pomakotr, M.; Kuhakarn, C.; Reutrakul, V.; Soorukram,
D. Eur. J. Org. Chem. 2019, 4710. (e) Sim, J. H.; Park, J. H.; Maity,
P.; Song, C. E. Org. Lett. 2019, 21, 6715.
Funding Information
This research has been supported in Lebanon by the Research Grant
program at the Lebanese University. In France it was supported by the
CNRS and the University of Rennes 1 (CNRS UMR 6226). We thank the
European FEDER funds for acquisition of the D8Venture X-ray diffrac-
tometer used for crystal structure determination. The authors would
like to acknowledge the National Council for Scientific Research of
Lebanon (CNRS-L)/Agence Universitaire de la Francophonie (AUF)/and
the Lebanese University (UL) for granting a doctoral fellowship to Ali
Soulieman.()
(5) Hachem, A.; Grée, D.; Chandrasekhar, S.; Grée, R. Synthesis 2017,
49, 2101; and references cited therein.
(6) (a) Camps, P.; Muñoz-Torrero, D.; Sánchez, L. Tetrahedron:
Asymmetry 2004, 15, 2039. (b) Hassanloie, N.; Zeynizadeh, B.;
Ashuri, S.; Hassanloie, F. Org. Chem.: Indian J. 2014, 10, 59.
(7) CCDC 1941252 (for compound 7a), CCDC 1941251 (for com-
pound 7e) and CCDC 1941250 (for compound 9b) contain the
supplementary crystallographic data for this paper. The data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/getstructures.
(8) Typical Procedures: Synthesis of Methyl 4,4-Difluoro-4-
phenylbut-2-ynoate (4a)
Acknowledgment
To propargylic ketone 3a (1 g, 5.31 mmol), one drop of 95%
ethanol and DAST (4.2 mL, 31.8 mmol, 6 equiv) were added. The
reaction mixture was stirred at 60 °C for 6 h. After returning to
room temperature and aqueous work-up, the reaction mixture
was extracted with DCM (3 × 40 mL). The organic layers were
separated, washed with H2O (3 × 20 mL), dried over Na2SO4, and
filtrated through silica. After purification by chromatography on
silica gel, the fluorinated compound 4a (0.73 g, 65%) was
obtained as a yellow oil; Rf = 0.4 (cyclohexane/EtOAc, 9:1). 1H
NMR (500 MHz, CDCl3):  = 7.71–7.59 (m, 2 H), 7.56–7.41 (m,
3 H), 3.84 (s, 3 H). 13C NMR (126 MHz, CDCl3):  = 152.4, 134.4
We are very grateful to the Centre Régional de Mesures Physiques de
l’Ouest, Rennes (CRMPO) team for the HRMS analyses and for some
NMR studies.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690715.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
2
5
(t, JC–F = 26.8 Hz), 131.4 (t, JC–F = 1.7 Hz), 128.8 (2C), 125.3 (t,
References and Notes
1
3
3JC–F = 4.9 Hz, 2C), 111.5 (t, JC–F = 235.1 Hz), 78.0 (t, JC–F
=
5.9 Hz), 77.4 (t, JC–F = 44.3 Hz), 53.4. 19F {H} NMR (471 MHz,
2
(1) For a recent comprehensive review, see: Caruano, J.; Muccioli, G.
G.; Robiette, R. Org. Biomol. Chem. 2016, 14, 10134.
CDCl3):  = –79.61 (s). HRMS (ESI): m/z [M + Na]+ calcd for
C
11H8O2F2Na: 233.03846; found: 233.0383 (1 ppm).
(2) (a) Xuan, J.; Studer, A. Chem. Soc. Rev. 2017, 46, 4329.
(b) Ordonez, M.; Cativiela, C.; Romero-Estudillo, I. Tetrahedron:
Asymmetry 2016, 27, 999. (c) Nay, B.; Riache, N.; Evanno, L. Nat.
Prod. Rep. 2009, 26, 1044. (d) Ramesh, P.; Suman, D.; Reddy, K. S.
N. Synthesis 2018, 50, 211.
(3) For selected reviews on this topic, see: (a) Müller, K.; Faeh, C.;
Diederich, F. Science 2007, 317, 1881. (b) O’Hagan, D. Chem. Soc.
Rev. 2008, 37, 308. (c) Hunter, L.; Kirsch, P.; Slawin, A. M. Z.;
O’Hagan, D. Angew. Chem. Int. Ed. 2009, 48, 5457. (d) Welch, J. T.
Tetrahedron 1987, 43, 3123. (e) Selective Fluorination in Organic
and Bioorganic Chemistry; Welch, J. T., Ed.; ACS Symposium
Series 456: Washington DC, 1991. (f) Biomedical Frontiers of Flu-
Synthesis of Methyl (Z)-4,4-Difluoro-4-phenylbut-2-enoate
(5a)
Methyl 4,4-difluoro-4-phenylbut-2-ynoate (4a; 0.5 g, 2.38
mmol) was stirred with Lindlar catalyst (10%) in MeOH (15 mL)
under hydrogen. The reaction was monitored by TLC and, on
completion, the reaction mixture was filtrated through Celite®
and the product was purified by chromatography to obtain the
methyl (Z)-4,4-difluoro-4-phenylbut-2-enoate (5a; 434 mg,
86%) as a colorless oil. Rf = 0.4 (cyclohexane/EtOAc, 8:2). 1H NMR
(500 MHz, CDCl3):  = 7.63–7.59 (m, 2 H), 7.46–7.41 (m, 3 H),
3
3
3
6.22 (dd, JH–F = 25.0, JH–H = 12.5 Hz, 1 H), 6.13 (dt, JH–H = 12.6,
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

E
A. Soulieman et al.
Letter
Synlett
4JH–F = 1.3 Hz, 1 H), 3.69 (s, 3 H). 13C NMR (126 MHz, CDCl3):  =
165.5, 135.9 (t, 2JC–F = 27.1 Hz), 134.7 (t, 2JC–F = 32.3 Hz), 130.4 (t,
5JC–F = 1.7 Hz), 128.6 (s, 2C), 125.5 (t, 3JC–F = 5.6 Hz, 2C), 124.9 (t,
3JC–F = 7.1 Hz), 118.6 (t, 1JC–F = 240.5 Hz), 52.1. 19F {H} NMR (471
MHz, CDCl3):  = –88.90 (s). HRMS (ESI): m/z [M + Na]+ calcd for
system, J = 250.8 Hz). HRMS (ESI): m/z [M + Na]+ calcd. for
C
12H13NO4F2Na: 296.07048; found: 296.0706 (0 ppm).
Synthesis of 4-(Difluoro(phenyl)methyl)pyrrolidin-2-one
(7a)
To a stirred solution of methyl 4,4-difluoro-3-(nitromethyl)-4-
phenylbutanoate (6a; 50 mg, 0.18 mmol) in MeOH (2 mL),
NiCl2·6H2O (85 mg, 0.36 mmol) was added at room tempera-
ture. After stirring for 5 min, NaBH4 (75 mg, 1.98 mmol) was
added in four portions. The reaction mixture was stirred for 30
min at room temperature, then a saturated solution of NH4Cl
was added and the reaction mixture was extracted with EtOAc
(3 × 5 mL). The combined organic layers were separated,
washed with H2O (3 × 5 mL), dried over Na2SO4, filtered and
concentrated under vacuum. 4-(Difluoro(phenyl)methyl)pyrro-
lidin-2-one 7a was precipitated and washed with Et2O to give a
white solid. Yield: 31 mg (80%); Rf = 0.2 (DCM/MeOH, 95:5); mp
C11H10O2F2Na: 235.05411; found: 235.0540 (0 ppm).
Synthesis of Methyl 4,4-Difluoro-3-(nitromethyl)-4-phenyl-
butanoate (6a)
To methyl (Z)-4,4-difluoro-4-phenylbut-2-enoate (5a; 150 mg,
0.7 mmol) were added nitromethane (75 L, 1.4 mmol) and
potassium carbonate (289 mg, 2.1 mmol) in DMSO (3 mL). The
reaction mixture was stirred at room temperature and analyzed
by TLC. On completion, saturated NH4Cl (10 mL) was added and
the reaction mixture was extracted with EtOAc (3 × 20 mL). The
combined organic layers were separated, washed with H2O
(3 × 10 mL), dried over Na2SO4, filtered, and concentrated under
vacuum. After purification by chromatography on silica gel,
methyl 4,4-difluoro-3-(nitromethyl)-4-phenylbutanoate (6a;
174 mg, 90%) was obtained as a yellow oil; Rf =0.4 (cyclohex-
ane/EtOAc, 7:3). 1H NMR (300 MHz, CDCl3):  = 7.55–7.45 (m,
1
95 °C. H NMR (300 MHz, CDCl3):  = 7.45 (s, 5 H), 6.55 (s, 1 H,
2
3
2
NH), 3.2 (dd, JH–H = 9.9 Hz, JH–H = 7.0 Hz, 1 H), 3.40 (dd, JH–H
=
=
=
=
=
3
2
9.9 Hz, JH–H = 8.8 Hz, 1 H), 3.35–3.13 (m, 1 H), 2.51 (dd, JH–H
3
2
3
17.3 Hz, JH–H = 8.1 Hz, 1 H), 2.35 (dd, JH–H = 17.3 Hz, JH–H
2
3
5 H), 4.73 (dd, JH–H = 13.8 Hz, JH–H = 5.8 Hz, 1 H), 4.53 (dd,
9.6 Hz, 1 H). 13C NMR (75 MHz, CDCl3):  = 176.4, 135.4 (t, 2JC–F
2JH–H = 13.8 Hz, 3JH–H = 6.2 Hz, 1 H), 3.77–3.57 (m, 1 H), 3.62 (s, 3 H),
2.66 (dd, JH–H = 16.9 Hz, JH–H = 5.2 Hz, 1 H), 2.50 (dd, JH–H
26.4 Hz), 130.5 (t, JC–F = 1.7 Hz), 128.9 (2C), 125.2 (t, JC–F
5
3
2
3
2
1
2
=
6.3 Hz, 2C), 121.9 (t, JC–F = 244.7 Hz), 42.5 (t, JC–F = 28.4 Hz),
16.9 Hz, 3JH–H = 8.2 Hz, 1 H). 13C NMR (75 MHz, CDCl3):  = 170.8,
133.9 (t, 2JC–F = 25.8 Hz), 131.0, 129.0 (2C), 125.5 (t, 3JC–F = 6.4 Hz,
2C), 123.7 (dd, 1JC–F = 247.4 Hz), 73.4 (t, 3JC–F = 3.4 Hz), 52.3, 42.6
(t, 2JC–F = 27.1 Hz), 31.4 (dd, 3JC–F = 4.2, 3.0 Hz). 19F {H} NMR (282
MHz, CDCl3):  = –98.05 (AB system, J = 250.8 Hz), –104.55 (AB
42.0 (t, JC–F = 4.8 Hz), 30.8 (t, JC–F = 3.7 Hz). 19F NMR {H} (282
3
3
2
MHz, CDCl3):  = –103.04 (AB system, FA, JF–F = 248.2 Hz), –
2
104.48 (AB system, FB, JF–F = 248.2 Hz). HRMS (ESI): m/z [M +
Na]+ calcd for C11H11NOF2Na: 234.07009; found: 234.0699 (1
ppm).
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E