Site-Specific Synthesis of β-Fluorinated γ-Butyrolactams via Decarboxylative Fluorination of β-Carboxyl-γ-Butyrolactams

Article abstract of DOI:10.1002/ejoc.201900685

Monofluorinated cyclic nitrogen-containing compounds are synthetically useful scaffolds in organic synthesis and medicinal applications. In this report, AgNO₃ mediated decarboxylative fluorination of β-carboxyl-γ-butyrolactams using Selectfluor as a fluorine source was described to achieve a site-specific synthesis of β-fluorinated γ-butyrolactams.

Full text of DOI:10.1002/ejoc.201900685

A Journal of
Accepted Article
Title: Site-specific Synthesis of β-Fluorinated γ-Butyrolactams via
Decarboxylative Fluorination of β-Carboxyl-γ-Butyrolactams
Authors: Supasorn Phae-nok, Manat Pohmakotr, Chutima Kuhakarn,
Vichai Reutrakul, and Darunee Soorukram
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900685
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900685
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201900685
FULL PAPER
Site-specific Synthesis of -Fluorinated -Butyrolactams via
Decarboxylative Fluorination of -Carboxyl--Butyrolactams
[
a]
[a]
[a]
[a]
Supasorn Phae-nok, Manat Pohmakotr, Chutima Kuhakarn, Vichai Reutrakul, and Darunee
[
a]
Soorukram*
Abstract: Monofluorinated cyclic nitrogen-containing compounds
fluorine atoms at specific position of cyclic nitrogen-containing
compounds can lead to the improved biological activities. A
recent example is PF-06650833, a chiral -fluorinated -
butyrolactam which exhibited potent and selective inhibitory
activity toward interleukin ‑ 1 receptor associated kinase 4
are synthetically useful scaffolds in organic synthesis and medicinal
applications. In this report, AgNO
3
mediated decarboxylative
®
fluorination of -carboxyl--butyrolactams using Selectfluor as a
fluorine source was described to achieve a site-specific synthesis of
[10a]

-fluorinated -butyrolactams.
(IRAK4) (Scheme 1a).
Therefore, the development of efficient
and site-specific stereoselective synthesis of chiral fluorinated -
butyrolactams is of considerable importance. Although synthetic
methods for the synthesis of -fluorinated carbonyl compounds
Introduction
[10]
are available,
those for selective synthesis of -fluorinated
[11]
carbonyl compounds are still limited (Scheme 1b).
There has been growing interest in organofluorine compounds in
various fields, including agrochemical, materials, and
pharmaceutical sciences. The presence of fluorine atoms or
fluorine-containing motifs in organic molecules was realized to
enhance physical, chemical, and biological properties of non-
Encouraged by our previous results on decarboxylative
fluorination of paraconic acids to access -fluorinated -
[13]
butyrolactones,
we envisioned that -fluorinated -
butyrolactams could be synthesized with a direct and site-
specific manner employing -carboxyl--butyrolactams 1 as
[
1]
fluorinated parent compounds.
As a result, there were
3
precursors. We report herein AgNO mediated decarboxylative
tremendous progresses in fluorination methods, including
electrophilic fluorination, using electrophilic fluorinating
®
fluorination of 1 employing Selectfluor as a fluorine source to
access a series of -fluorinated -butyrolactams 2 including
chiral derivatives that might be useful in organic synthesis and
drug discovery.
[2]
reagents, and nucleophilic fluorination, using fluoride ion
[
3]
[4]
sources. Recently, radical fluorination using the radical
reactivity of the traditionally nitrogen-based electrophilic
®
reagents such as Selectfluor , N-fluorobis(phenylsulfonyl)amine
(NFSI), and N-fluoropyridinium salts (NFPy’s) has also gained
much attentions. Among synthetic methodologies developed for
[
5]
radical fluorination toward fluorination of alkenes, fluorination
[
6]
3
[7]
of boronic acid derivatives, C(sp )–H fluorination, and C–C
[
8]
bond
activation,
decarboxylative
fluorination
(or
fluorodecarboxylation) of carboxylic acids has proved to be a
powerful and complementary approach for the formation of
3
[9]
C(sp )–F bonds.
The salient features of decarboxylative
fluorination include stability of the carboxylic acid precursors, the
ready availability of the fluorinating agents, and most importantly,
3
the site-specific formation of the C(sp )–F bond.
[
10][11]
Monofluorinated -butyrolactams (or pyrrolidin-2-ones)
bearing fluorine atom within functionalized structures are of
increasing demand in both academic researches and industrial
[
12]
sections, particularly in pharmaceutical industry.
This
attributed to the profound effects that the incorporation of
[
a]
S. Phae-nok, Prof. Dr. M. Pohmakotr, Assoc. Prof. Dr. C. Kuhakarn,
Prof. Dr. V. Reutrakul, Assoc. Prof. Dr. D. Soorukram
Department of Chemistry and Center of Excellence for Innovation in
Chemistry (PERCH-CIC), Faculty of Science, Mahidol University,
Rama VI Road, Bangkok 10400, Thailand
E-mail: darunee.soo@mahidol.ac.th
http://chemistry.sc.mahidol.ac.th/en/
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. a) Biologically active compounds containing -butyrolactam cores;
b) representative existing approaches and our method for the synthesis of β-
fluorinated -butyrolactams.
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European Journal of Organic Chemistry
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FULL PAPER
Results and Discussion
isolated in 48%, 6%, and 5% yields, respectively. The relative
stereochemistries of trans-2a and cis-2a were assigned on the
basis of the analysis of coupling constants between H-4 and H-5
Primarily, the racemic mixture of -carboxyl--butyrolactam 1a
[
15]
(rac-1a) was used as a model substrate to find an optimal
of 2a.
employing NaHCO
(Table 1, entries 10-12). The reaction did not proceed when
3
Attempts to use AgNO as a catalyst (20 mol%) or
reaction conditions and the results are summarized in Table 1.
Treatment of rac-1a (89:11, trans:cis)
3
(1 equiv.) as an additive gave inferior results
[
14a]
®
with Selectfluor (2
O (1:1 v/v)
®
equiv.) and AgNO (1 equiv.) in refluxing acetone/H
3
2
3
either AgNO or Selectfluor was excluded from the reaction;
for 12 h yielded a mixture of -fluorinated -butyrolactams 2a
and 3a as well as -butyrolactam 4a in a ratio of 5:1:1 ( H-NMR
analysis of the crude reaction mixture); 74% conversion based
on the recovery of rac-1a (Table 1, entry 1). Although 3a could
be removed from the obtained mixture, the separation of 2a and
rac-1a was recovered in quantitative yields (86–99% yields;
1
Table 1, entries 13 and 14). These results emphasized the
®
crucial roles of both Selectfluor or Ag(I) in the present reaction.
4
Lastly, other Ag(I) salts, including AgOAc and AgBF were also
evaluated but the results obtained were less satisfactory
(Table1, entries 15 and 16). After extensive investigation, the
4
a proved to be difficult. Next, various reaction parameters,
including solvents, reaction time, and the additive were
investigated with the goal to suppress the formation of 4a. After
optimum reaction conditions were chosen as follows: 1 (1
®
equiv.), AgNO
MeCN/H
On the basis of the precedent works
3
(1.5 equiv.), Selectfluor (1.5 equiv.) in refluxing
through screening, it was found that treatment of rac-1a with
2
O (1:4 v/v) for 6 h (Table 1, entry 9).
®
[9b]
Selectfluor and AgNO
3
(1.5 equiv. each) in refluxing MeCN/H
2
O
and the above
(
2
1:4 v/v) for 6 h gave the best results; 82% conversion with
a:3a:4a in ratio of 15:2:1 (Table 1, entry 9). After
chromatographic separation, trans-2a, cis-2a, and 3a were
observation, a mechanistic pathway for the decarboxylative
a
fluorination of rac-1a is proposed (Scheme 2). The oxidation of
®
Ag(I) by Selectfluor generates an Ag(III)-F intermediate (A).
Table 1. Optimization of the reaction conditions for the decarboxylative fluorination of rac-1a.
®
[a]
[c]
Entry
Ag(I) source
equiv.)
Selectfluor
(equiv.)
Solvent (ratio, v/v)
Time (h)
% Conversion
(2a:3a:4a)
% Yield of 2a (trans:cis)
[b]
(
1
2
3
AgNO
AgNO
AgNO
AgNO
AgNO
AgNO
AgNO
AgNO
3
3
3
3
3
3
3
3
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
2
2
acetone/H
2
O (1:1)
12
12
12
12
12
12
6
74 (5:1:1)
N.D.
MeCN/H O (1:1)
2
82 (4:1:trace)
63 (4:1:0)
42 (6:1)
39 (6:1)
38 (4:1)
28 (4:1)
32 (5:1)
56 (4:1)
28 (5:1)
2
2
H O
[d]
[e]
4
2
CH
DCE/H
benzene/H
2
2
Cl
2
/H
O (1:1)
O (1:1)
2
O (1:1)
57 (1:0:trace)
32 (1:0:trace)
41 (1:0:0)
[d]
[e]
5
2
2
[d]
6
2
[e]
7
8
9
2
MeCN/H
MeCN/H
MeCN/H
MeCN/H
MeCN/H
MeCN/H
MeCN/H
MeCN/H
MeCN/H
MeCN/H
2
2
2
2
2
2
2
O (1:4)
O (1:4)
O (1:4)
O (1:4)
O (1:4)
O (1:4)
O (1:4)
O (1:4)
O (1:4)
O (1:4)
84 (3:1:trace)
53 (19:6:1)
82 (15:2:1)
40 (6:1:0)
1
6
[f]
AgNO
AgNO
AgNO
AgNO
3
3
3
3
(1.5)
(0.2)
(1.5)
(1.5)
1.5
1.5
1.5
1.5
1.5
-
6
48 (trans-2a), 6 (cis-2a)
10
6
N.D.
[
d]
1
1
6
53 (1:0:trace)
61 (1:0:trace)
50 (4:1)
51 (4:1)
[
d]
1
2
12
6
[g]
[g]
1
3
4
5
6
-


[h]
[h]
1
1
1
AgNO
3
(1.5)
2
2
2
6


AgOAc (1.5)
AgBF (1.5)
1.5
1.5
6
16 (11:1:0)
31 (3:1:0)
9 (N.D.)
4
6
21 (N.D.)
1
[
a] Based on the recovery of rac-1a. [b] The ratio of 2a, 3a, and 4a was determined by H NMR analysis of the crude mixture. [c] Trans:cis ratio of 2a was
1
2 3
determined by H NMR analysis after column chromatography (SiO ). [d] NaHCO (1 equiv.) was added. [e] Trace of the corresponding ,-unsaturated -
butyrolactam was observed. [f] Trans-3a was isolated in 5% yield. See the Experimental Section. [g] rac-1a was recovered (99% yield). [h] rac-1a was
recovered (86% yield). N.D. = not determined.
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European Journal of Organic Chemistry
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Intermediate A then undergoes a single electron-transfer (SET)
process with a carboxylate anion B derived from rac-1a to give
an Ag(II)-F intermediate (C) and the corresponding carboxyl
radical D. Radical D then undergoes decarboxylation to give
alkyl radical E. Subsequent abstraction of a fluorine atom from C
by E leads to -fluorinated -butyrolactams 2a as a mixture of
trans-2a (major) and cis-2a (minor). The -fluorinated -
butyrolactam 3a was proposed to arise from the competitive
[16]
oxidative debenzylation while 4 could be formed from trapping
hydrogen atom of and the oxidative debenzylation
a
E
processes. Notably, the formation of A derived from Ag(I) and
®
Selectfluor is crucial for this transformation since the reaction
®
did not proceed if either Selectfluor or Ag(I) was excluded from
the reaction (Table 1, entries 13 and 14).
Scheme 3. Synthesis of starting materials 1.
[16]
oxidative cleavage. In addition, the reaction of rac-1j (90:10,
trans:cis), bearing a p-Tol group at the  position of the lactam
1
ring, gave 2j (45% yield, trans-2j:cis-2j = 93:7, H-NMR analysis)
(Table 2, entry 10) along with a mixture of compounds derived
from competitive oxidation at a methyl group on the aromatic
ring being observed.
It is worth mentioning that compounds 1 with a N-H lactam
scaffold readily underwent the decarboxylative fluorination. Thus,
the reaction of rac-1k (99:1, trans:cis) gave a mixture of trans-2k
and cis-2k. Delightfully, the mixture of trans-2k and cis-2k were
Scheme 2. Proposed mechanism for the decarboxylative fluorination of rac-1a.
With the optimized reaction conditions in hand, we next
explored the generality and functional group compatibility of the
reaction. Substrates 1 were synthesized as shown in Scheme
2
readily separated by means of chromatographic methods (SiO )
to give trans-2k (37% yield) and cis-2k (25% yield) (Table 2,
entry 11). The reaction could also be applied with a chiral
substrate. Under standard reaction conditions, (2S,3S)-1k (dr =
[14]
3
.
The results of the decarboxylative fluorination of 1 are
summarized in Table 2. Under standard reaction conditions, the
decarboxylative fluorination of rac-1b-1j gave the corresponding
products 2b-2j in moderate to good yields (21-83% yields)
9
(
9:1) gave (4S,5R)-2k (42% yield) and (4R,5R)-2k (29% yield)
Table 2, entry 12). Similarly, chiral substrates 1l-1n also gave
the corresponding chiral -fluorinated -butyrolactams 2l-2n in
7-50% yields with moderate ratios of the two diastereomers
trans:cis = 4:1) (Table 2, entries 13–15). For the products 2l-2n,
each pair of the two diastereomers can be readily separated by
chromatographic methods (SiO ) to yield the respective chiral
fluorinated compounds each as a single isomer. Notably, chiral
-fluorinated -butyrolactams possessing a N-H lactam scaffold
(Table 2, entries 2-10). It was found that substituents on the
3
(
nitrogen atom and the aromatic ring located at the  position of
the lactam ring had significant effect on the reaction efficiency.
While the reaction of 1d suffers from a competing fluorination on
the phenyl ring, the reactions of 1c and 1e-1h bearing a benzyl,
an electron-withdrawing, and an alkyl substituent, respectively,
gave the corresponding products 2c and 2e-2h in moderate to
good yields. In addition, while rac-1i (97:3, trans:cis) possessing
2

might be useful for further transformation to fluorinated
pyrrolidine drugs and related fluorinated nitrogen-containing
derivatives which may be found useful in pharmaceutical
sciences.
The relative stereochemistries of 2 were established on the
basis of the NMR analysis (see the Experimental Section). In
addition, for the minor isomer (cis isomer) of 2a, 2i, 2j, and 2k as
well as (4R,5R)-2k-(4R,5R)-2m, the relative stereochemistry
[17]
a p-ClC
6
H
4
group, gave 2i (21% yield; trans-2i:cis-2i = 91:9 by
H-NMR analysis) (Table 2, entry 9), compounds 1, bearing p-
MeOC or 3,4,5-(MeO) group did not provide the
1
6
H
4
3 6 2
C H
expected products (not shown) but were found decomposed
under the reaction conditions. This possibly attributed to the
ease of the electron rich aromatic system to undergo competitive
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European Journal of Organic Chemistry
10.1002/ejoc.201900685
FULL PAPER
was also established on the basis of the high-field shift of the
fluorine signal, which is a result of an anisotropic effect of the
position of fluorine atom on the side chain of 5 and 6 was also
confirmed by using the magnitude of the coupling constants
between carbons and fluorine (See the Experimental Section).
The formation of 5 and 6 can be explained. A competitive
remote intramolecular hydrogen atom abstraction of the alkyl
radical E derived from (2S,3S)-1m via a six-membered-ring
transition state leads to the corresponding alkyl radical F which
[
18]
benzene ring. Finally, the stereochemistries of (4S,5R)-2n and
4R,5R)-2n were assigned on the basis of the coupling constant
(
between H-4 and H-5 of the lactam ring. It is worth to emphasize
that in all cases, the major diastereomer of 2 is the one in which
the fluorine atom located on the opposite side to the larger
substituent at the  position. This implied that fluorination took
place from the less sterically hindered face of the radical
intermediate E (Scheme 2).
after abstraction of
a fluorine atom gives the observed
compound 5 (Scheme 4). For the formation of difluorinated
derivative 6, it was proposed that, under the oxidation conditions
[
19]
Interestingly, when (2S,3S)-1m and (2R,3S)-1n were used
employed, the amidyl radical G was generated and undergoes
site-selective remote radical generation via 1,5-hydrogen atom
transfer (1,5-HAT) providing alkyl radical H. Upon trapping with a
3
as substrates, a competitive remote C(sp )H fluorination took
place, leading to fluorinated -butyrolactams 5 and 6, each as a
mixture of diastereomers (11-12% yields) (Table 2, entries 14
and 15). The structures of 5 and 6 were established on the basis
of 1D and 2D NMR spectroscopy and mass spectrometry. The
second fluorine atom, the difluorinated derivative
6 was
obtained. Further exploration of the observed site-selective
remote fluorination is under investigation.
Table 2. Decarboxylative fluorination of -carboxyl--butyrolactams 1.
[a]
[a]
Entry
1
1 (dr)
Product 2; Yield (dr)
rac-1a (89:11, trans:cis)
trans-2a; 48%
cis-2a; 6%
2
[b]
[b]
rac-1b (61:21:15:3)
rac-2b; 65% (52:22:16:10)
3
4
1c
2c; 60%
[c]
1d
2d; 29%
5
1e
2e; 33%
6
1f
2f; 83%
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European Journal of Organic Chemistry
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7
1
g
h
2g; 75%
2h; 68%
8
9
1
rac-1i (97:3, trans:cis)
rac-1j (90:10, trans:cis)
trans-2i and cis-2i; 21% (91:9)
trans-2j and cis-2j; 45% (93:7)
10
11
[d]
rac-1k (99:1, trans:cis)
trans-2k; 37%
cis-2k;25%
1
2
3
[d]
(
2S,3S)-1k (99:1)
(4S,5R)-2k; 42%
(4R,5R)-2k; 29%
1
[
d]
(
2S,3S)-1l (95:5)
(4S,5R)-2l; 40%
(4S,5R)-2m; 30%
(4R,5R)-2l; 10%
(4R,5R)-2m; 7%
14
[
d]
(
2S,3S)-1m (93:7)
5; 12% (1:1)
15
[d]
(
2R,3S)-1n (75:25)
(4S,5R)-2n; 38%
(4R,5R)-2n; 10%
6; 11% (1:1)
1
[
a] The diastereomeric ratio (dr) was determined by H NMR analysis. [b] A mixture of four diastereomers of rac-1b was used as a
substrate. [c] A mixture of products derived from the fluorination on the phenyl ring was observed. [d] The diastereomeric ratio (dr)
1
was determined by H NMR analysis. The stereochemistry was assigned based on the transition state proposed in the
[14]
literatures.
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European Journal of Organic Chemistry
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1
3
2 3 3
Hz, 1H, CH ) ppm. C NMR (100 MHz, CDCl +CD OD, major one
marked*):  174.0 (CO*), 173.6 (CO*), 138.6 (C*), 137.7 (C), 135.1 (C*
and C), 128.9 (2 × CH* and 2 × CH), 128.4 (3 × CH* and 3 × CH), 128.1
(
6
(
2 × CH* and 2 × CH), 127.5 (CH* and CH), 126.7 (2 × CH* and 2 × CH),
3.8 (CH*), 62.4 (CH), 45.6 (CH*), 44.3 (CH * and CH), 43.0 (CH ), 33.4
CH *), 31.9 (CH ) ppm. Due to low intensity, some proton and carbon
peaks of cis-1a could not be detected.
2
2
2
2
1
1
-Benzyl-4-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylic acid (rac-
b): Methylation of rac-1a (89:11, trans:cis) gave rac-1b as a mixture of
four diastereomers (AD) (73% yield, dr = 61:21:15:3) after column
chromatography (SiO , 50%EtOAc in hexanes with a small amount of
formic acid); viscous oil; IR (neat): max 3030, 1728, 1643 cm . H NMR
400 MHz, CDCl , integrated equally for all isomers):  7.35−6.85 (m, ArH
of all isomers), 5.08 (d, J = 14.7 Hz, 1H, CHH of C), 5.02 (d, J = 14.4 Hz,
2
−
1 1
(
3
1
1
H, CHH of A), 4.98 (d, J = 14.2 Hz, 1H, CHH of B), 4.80 (d, J = 5.2 Hz,
H, CH of C), 4.56 (d, J = 6.9 Hz, 1H, CH of A), 4.46 (d, J = 8.1 Hz, 1H,
CH of B), 4.34 (d, J = 3.8 Hz, 1H, CH of D), 3.39 (d, J = 14.6 Hz, 1H,
CHH of A), 3.14 (dd, J = 7.0, 9.2 Hz, 1H, CH of A), 3.10−2.93 (m, 3H, 3 ×
CH of A and C), 2.75 (m, 1H, CH of B), 2.66 (m, 1H, CH of B), 1.35 (d, J
3
= 7.0 Hz, 3H, CH
.2 Hz, 3H, CH of C) ppm. C NMR (100 MHz, CDCl
B), 175.9 (CO of A), 175.2 (CO of B), 174.7 (CO of A), 139.0 (C of C),
38.3 (C of B), 138.0 (C of A), 135.5 (C of B), 135.4 (C of A), 129.1 (2 ×
CH of A), 128.6 (4 × CH of A), 128.5 (2 × CH of A), 127.3 (2 × CH of A),
1.8 (CH of B), 61.1 (CH of A), 55.0 (CH of B), 51.8 (CH of C), 51.4 (CH
of A), 44.8 (CH of C), 44.6 (CH of B), 44.5 (CH of A), 40.8 (CH of B),
38.4 (CH of A), 38.2 (CH of C), 16.0 (CH of B), 12.0 (CH of C), 12.3
CH of A) ppm. Due to low intensity, some proton and carbon peaks of
minor isomers of 1b could not be detected. MS: m/z (%) relative intensity
3
of B), 1.15 (d, J = 7.4 Hz, 3H, CH
3
of A), 1.10 (d, J =
Scheme 4. Proposed mechanism for the observed remote C(sp )H
fluorination.
1
3
7
3
3
):  176.0 (CO of
1
Conclusions
6
2
2
2
In conclusion, the direct and site-specific synthesis of -
fluorinated -butyrolactams via AgNO mediated decarboxylative
3
fluorination of -carboxyl--butyrolactams using Selectfluor as a
fluorine source was described. The developed methods should
be found useful and applicable to the synthesis of -fluorinated
-butyrolactams and related fluorinated nitrogen-containing
compounds which are an important class of compounds toward
organic synthesis and pharmaceutical science.
3
3
(
3
®
+
3
(
09 [(M) , 34], 218 (100), 175 (37), 160 (51), 146 (37), 132 (34), 118
40), 106 (31), 91 (43), 77 (21). HRMS (ESI-TOF) m/z: [M − H] calcd. for
: 308.1287, found 308.1298.
19 3
C H18NO

1
1
-Benzyl-5-oxopyrrolidine-3-carboxylic acid (1c): H NMR (400 MHz,
CDCl +CD OD):  7.30−7.17 (m, 3H, ArH), 7.17−7.08 (m, 2H, ArH), 4.43
d, J = 14.8 Hz, 1H, CHH), 4.32 (d, J = 14.8 Hz, 1H, CHH), 3.50−3.33 (m,
3
3
(
2
(
1
3
H, CH
100 MHz, CDCl
(2 × CH), 127.9 (2 × CH), 127.7 (CH), 48.7 (CH ), 46.5 (CH ), 35.6 (CH),
2
), 3.17−3.03 (m, 1H, CH), 2.78−2.56 (m, 2H, CH
2
) ppm. C NMR
3
+CD OD):  174.6 (CO), 173.2 (CO), 135.5 (C), 128.6
3
Experimental Section
2
2
2
34.0 (CH ) ppm.
1
13
19
General: The H, C and F NMR were recorded on either Bruker
Ascend™400 (400 MHz) or JNM-ECZS (400 MHz) spectrometer in
1
5
-Oxo-1-phenylpyrrolidine-3-carboxylic acid (1d): H NMR (400 MHz,
+CD OD):  7.56−7.44 (m, 2H, ArH), 7.34−7.26 (m, 2H, ArH),
.15−7.08 (m, 1H, ArH), 4.08 (dd, J = 6.6, 9.8 Hz, 1H, CHH), 4.05−3.90
m, 1H, CHH), 3.36−3.23 (m, 1H, CH), 2.88 (dd, J = 7.6, 17.6 Hz, 1H,
CDCl
7
(
3
3
CDCl
The IR spectra were recorded on ALPHA FT-IR Spectrometer. The mass
spectra were recorded on Thermo Finnigan Polaris mass
3 3 3
or CDCl /CD OD using tetramethylsilane as an internal standard.
a
Q
13
CHH), 2.80 (dd, J = 9.6, 17.6 Hz, 1H, CHH) ppm. C NMR (100 MHz,
CDCl +CD OD):  174.3 (C), 172.4 (C), 138.2 (C), 128.8 (2 × CH), 125.2
CH), 120.5 (2 × CH), 50.7 (CH ), 35.6 (CH), 35.3 (CH ) ppm.
spectrometer. The high-resolution mass spectra were recorded on an
HR-TOF-MS Micromass model VQ-TOF2 mass spectrometer. Melting
points were recorded on a Büchi M-565 Melting Point Apparatus and
uncorrected. The specific optical rotation values were recorded on a
Jasco P-1020 polarimeter. Tetrahydrofuran (THF) was freshly distilled
under argon from sodium-benzophenone ketyl. Column chromatography
was performed by using Merck silica gel 60 (Art 7734). Other common
3
3
(
2
2
1-(4-Bromophenyl)-5-oxopyrrolidine-3-carboxylic acid (1e): white
solid; m.p. 164−166 °C (CH OH/hexanes). IR (neat):  3093, 1728,
3
max
−
1 1
1642 cm . H NMR (400 MHz, CDCl +CD OD):  7.42 (s, 4H, ArH), 4.05
3
3
(dd, J = 6.2, 9.8 Hz, 1H, CHH), 3.96 (dd, J = 8.8, 10.0 Hz, 1H, CHH),
1
3
solvents [dichloromethane (CH
2
Cl
2
), ethyl acetate (EtOAc) and hexanes]
3.33−3.23 (m, 1H, CH), 2.93−2.75 (m, 2H, CH ) ppm. C NMR (100
2
were distilled before use. Compounds rac-1arac-1j were synthesized
according to the literature procedures.
MHz, CDCl +CD OD):  174.2 (CO), 172.3 (CO), 137.5 (C), 131.8 (2 ×
3
3
[14]
2 2
CH), 121.6 (2 × CH), 117.9 (C), 50.4 (CH ), 35.4 (CH), 35.3 (CH ) ppm.
+
+
MS: m/z (%) relative intensity 285 [(M+H) , 21], 284 (M , 10), 186 (90),
184 (100), 172 (70), 77 (20). HRMS (ESI-TOF) m/z: [M − H] calcd. for
1
-Benzyl-5-oxo-2-phenylpyrrolidine-3-carboxylic acid (rac-1a): dr =
1
3 3
89:11 (trans:cis); H NMR (400 MHz, CDCl +CD OD, interpreted equally
11 9 3
C H BrNO : 281.9771, found 281.9775.
for both isomers, major one marked*):  7.38−7.25 (m, 7H, ArH* and
ArH), 7.25−7.16 (m, 7H, ArH* and ArH), 7.14−7.02 (m, 4H, ArH* and
ArH), 7.01−6.90 (m, 2H, ArH*), 5.06 (d, J = 14.8 Hz, 1H, CHH), 5.00 (d, J
1-(2-Chlorophenyl)-5-oxopyrrolidine-3-carboxylic acid (1f): white
solid; m.p. 166−168 °C (CH OH/hexanes). IR (neat):  3276, 1694,
3
max
−
1
1
=
1
14.8 Hz, 1H, CHH*), 4.68 (d, J = 9.0 Hz, 1H, CH), 4.63 (d, J = 5.4 Hz,
H, CH*), 3.48 (d, J = 14.8 Hz, 1H, CHH*), 3.42 (d, J = 14.8 Hz, 1H,
CHH), 3.56−3.47 (m, 1H, CH), 3.10 (dd, J = 10.7, 17.4 Hz, 1H, CH ),
.06−2.95 (m, 1H, CH*), 2.91−2.73 (m, 2H, CH *), 2.57 (dd, J = 9.2, 17.4
1657 cm
3 3
. H NMR (400 MHz, CDCl +CD OD):  7.44−7.38 (m, 1H,
ArH), 7.30−7.20 (m, 3H, ArH), 3.97−3.90 (m, 2H, CH ), 3.44−3.32 (m,
2
1
3
2
1H, CH), 2.92−2.72 (m, 2H, CH2) ppm.
C NMR (100 MHz,
3
2
CDCl +CD OD):  174.3 (CO), 173.3 (CO), 135.0 (C), 132.0 (C), 130.3
3
3
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201900685
FULL PAPER
(
(
(
CH), 129.5 (CH), 129.2 (CH), 127.8 (CH), 51.7 (CH
2
), 36.7 (CH), 33.8
mL). The aqueous phase was collected, acidified with 6N HCl (to pH 4-
+
CH
100), 90 (7). HRMS (ESI-TOF) m/z: [M − H] calcd. for C11
2
) ppm. MS: m/z (%) relative intensity 239 (M , 4), 204 (61), 127
5), and extracted with CH
was washed with water, brine, dried over anhydrous Na
concentrated to give (2S,3S)-1k: dr = 99:1; yellow solid; m.p. 160−162 °C
2
Cl
2
(3 × 30 mL). The combine organic phase
H
9
ClNO
3
:
2
SO , and
4
2
38.0276, found 238.0263.
2
5
(
1
Et
650 cm
ArH), 3.21 (dd, J = 9.1, 9.1 Hz, 1H, CH), 2.75 (dd, J = 9.1, 17.4 Hz, 1H,
2
O/hexanes). [] −80.4 (c 1.5, CH
3
OH). IR (neat): max 3247, 1706,
D
5
(
6
-Oxo-1-propylpyrrolidine-3-carboxylic acid (1g): pale yellow oil; IR
−1
1
.
H NMR (400 MHz, CDCl
3
+CD OD):  7.26−7.08 (m, 5H,
3
−
1 1
neat): max 1720, 1631 cm . H NMR (400 MHz, CDCl
3
):  3.63 (dd, J =
.2, 10.2 Hz, 1H, CHH), 3.54 (dd, J = 8.2, 10.6 Hz, 1H, CHH), 3.29−3.10
13
CHH), 2.36 (dd, J = 9.1, 17.4 Hz, 1H, CHH), 1.79 (s, 3H, CH
NMR (100 MHz, CDCl +CD OD):  176.8 (CO), 172.3 (CO), 140.9 (C),
28.2 (2 × CH), 127.7 (CH), 125.7 (2 × CH), 63.6 (C), 52.6 (CH), 32.7
3
) ppm.
C
(m, 2H, CH
2
and 1H, CH), 2.80−2.63 (m, 2H, CH
2
), 1.56−1.42 (m, 2H,
) ppm. C NMR (100 MHz, CDCl ): 
), 44.3 (CH ), 35.9 (CH), 34.1 (CH ),
) ppm. MS: m/z (%) relative intensity 172 [(M+H) ,
1], 171 (M , 1), 142 (4). HRMS (ESI-TOF) m/z: [M − H] calcd. for
: 170.0823, found 170.0820.
1
3
3
3
CH
2
), 0.83 (t, J = 7.4 Hz, 3H, CH
3
3
1
(
2
[
1
2
6
75.8 (CO), 173.5 (CO), 49.2 (CH
2
2
2
+
+
CH
2
), 28.7 (CH
04 (68), 176 (26), 132 (100), 104 (21), 77 (12). HRMS (ESI-TOF) m/z:
: 218.0823, found 218.0822.
3
) ppm. MS: m/z (%) relative intensity 220 [(M + H) , 1],
0.3 (CH ), 11.1 (CH
2
3
+
M − H] calcd. for C12
H
12NO
3
8 3
C H12NO
(
1
(
(
−
(
3
2
2S,3S)-2-Ethyl-5-oxo-2-phenylpyrrolidine-3-carboxylic acid [(2S,3S)-
l]: According to the procedure described for (2S,3S)-1k, the reaction of
R,E)-2-methyl-N-(1-phenylpropylidene)propane-2-sulfinamide gave
2S,3S)-1l: dr = 95:5, white powder, m.p. 144−146 °C (EtOAc); []
1
-Butyl-5-oxopyrrolidine-3-carboxylic acid (1h): pale yellow oil; IR
−
1 1
(
6
neat): max 1722, 1633 cm . H NMR (400 MHz, CDCl
.0, 10.0 Hz, 1H, CHH), 3.60 (dd, J = 9.2, 9.6 Hz, 1H, CHH), 3.39−3.19
and 1H, CH), 2.84−2.69 (m, 2H, CH ), 1.57−1.44 (m, 2H,
), 1.38−1.24 (m, 2H, CH ), 0.91 (t, J = 7.4 Hz, 3H, CH
):  176.1 (CO), 173.3 (CO), 49.1 (CH
), 35.9 (CH), 34.1 (CH ), 29.1 (CH ), 19.9 (CH ), 13.7 (CH
MS: m/z (%) relative intensity 186 [(M+H) , 63], 182 (M , 2), 142 (100),
6 (82). HRMS (ESI-TOF) m/z: [M − H] calcd. for C : 184.0979,
found 184.0978.
3
):  3.68 (dd, J =
27
D
(m, 2H, CH
2
2
−1 1
3
10.2 (c 0.6, CH OH). IR (neat): max 3202, 1688, 1648 cm
.
H NMR
1
3
CH
2
2
3
) ppm.
), 42.5
) ppm.
C
400 MHz, CDCl
3
+CD OD):  7.72 (s, 1H, NH), 7.30−7.10 (m, 5H, ArH),
3
NMR (100 MHz, CDCl
CH
3
2
.21 (dd, J = 8.6, 8.6 Hz, 1H, CH), 2.70 (dd, J = 8.6, 17.6 Hz, 1H, CHH),
(
2
2
2
2
3
.45−2.30 (m, 2H, 2 × CHH), 2.00−1.85 (m, 1H, CHH), 0.65 (t, J = 7.4
+
+
13
3 3 3
Hz, 3H, CH ) ppm. C NMR (100 MHz, CDCl +CD OD):  178.0 (CO),
9
9 3
H14NO
1
(
74.2 (CO), 138.8 (C), 128.3 (2 × CH), 127.8 (CH), 126.1 (2 × CH), 68.1
C), 52.2 (CH), 33.7 (CH ), 32.8 (CH ), 8.5 (CH ) ppm. MS: m/z (%)
relative intensity 233 [(M) , 6], 204 (40), 178 (51), 149 (100), 95 (64), 81
2
2
3
+
1
1
-Benzyl-2-(4-chlorophenyl)-5-oxopyrrolidine-3-carboxylic acid (rac-
i): dr = 97:3 (trans:cis); white solid; m.p. 190−194 °C (CH Cl /hexanes).
NMR (400 MHz,
OD):  7.35−7.27 (m, 2H, ArH), 7.25−7.17 (m, 3H, ArH), 7.06
d, J = 8.4 Hz, 2H, ArH), 7.00−6.92 (m, 2H, ArH), 4.99 (d, J = 14.8 Hz,
+
(
71), 67 (44), 55 (57). HRMS (ESI-TOF) m/z: [M + Na] calcd. for
Na: 256.0944, found 256.0943.
2
2
−
1
1
13 3
C H15NO
IR (neat):
CDCl +CD
3 3
(
max 3061, 1726, 1649 cm
.
H
(
[
2S,3S)-2-Butyl-5-oxo-2-phenylpyrrolidine-3-carboxylic
acid
(2S,3S)-1m]: According to the procedure described for (2S,3S)-1k, the
1H, CHH), 4.59 (d, J = 5.9 Hz, 1H, CH), 3.46 (d, J = 14.8 Hz, 1H, CHH),
reaction of (R,E)-2-methyl-N-(1-phenylpentylidene)propane-2-sulfinamide
gave (2S,3S)-1m: dr = 93:7, yellow powder; m.p. 80−82 °C (EtOAc). []
−
(
1
3
3
.02−2.93 (m, 1H, CH), 2.90−2.76 (m, 2H, CH
+CD OD):  173.6 (CO), 173.5 (CO), 137.2 (C), 134.9 (C),
34.2 (C), 129.1 (2 × CH), 128.5 (2 × CH), 128.2 (2 × CH), 128.1 (2 ×
CH), 127.6 (CH), 63.2 (CH), 45.6 (CH), 44.3 (CH ), 33.4 (CH ) ppm. MS:
m/z (%) relative intensity 329 [(M) , 47], 238 (100), 146 (66), 118 (44),
04 (49), 91 (44), 77 (2). HRMS (ESI-TOF) m/z: [M − H] calcd. for
15ClNO : 328.0746, found 328.0748.
2
) ppm. C NMR (100
26
D
MHz, CDCl
1
3
3
−1
1
34.7 (c 0.5, CHCl
400 MHz, CDCl ):  7.26−7.14 (m, 5H, ArH), 3.24 (dd, J = 8.6, 8.6 Hz,
H, CH), 2.70 (dd, J = 8.6, 17.2 Hz, 1H, CHH), 2.45−2.30 (m, 2H, 2 ×
), 1.04−0.90 (m,
) ppm. C NMR (100 MHz, CDCl ): 
77.4 (CO), 173.9 (CO), 139.1 (C), 128.4 (2 × CH), 127.8 (CH), 126.0 (2
CH), 67.5 (C), 51.9 (CH), 40.8 (CH ), 32.6 (CH ), 26.2 (CH ), 22.7
CH ), 13.8 (CH ) ppm. MS: m/z (%) relative intensity 204 (100), 132
81), 115 (4). HRMS (ESI-TOF) m/z: [M + H] calcd. for C15
62.1438, found 262.1439.
3
). IR (neat): max 3217, 1705, 1643 cm . H NMR
3
2
2
1
+
CHH), 1.92−1.80 (m, 1H, CHH), 1.30−1.15 (m, 2H, CH
2
1
×
(
(
2
2
1
C
13
H, CH
2
), 0.79 (t, 7.2 Hz, 3H, CH
3
3
18
H
3
1-Benzyl-5-oxo-2-(p-tolyl)pyrrolidine-3-carboxylic acid (rac-1j): dr =
2
2
2
1
3 3
90:10 (trans:cis); H NMR (400 MHz, CDCl +CD OD):  7.27−7.18 (m,
2
3
+
H20NO :
3
2H, ArH), 7.17−7.12 (m, 2H, ArH), 7.04−6.95 (m, 5H, ArH), 4.99 (d, J =
14.7 Hz, 1H, CHH), 4.58 (d, J = 5.6 Hz, 1H, CH), 3.44 (d, J = 14.7 Hz,
1
CH
H, CHH), 3.05−2.97 (m, 1H, CH), 2.90−2.75 (m, 2H, CH
2
), 2.32 (s, 3H,
(
2R,3S)-2-Butyl-5-oxopyrrolidine-3-carboxylic acid [(2R,3S)-1n]:
According to the procedure described for (2S,3S)-1k, the reaction of
R,E)-2-methyl-N-pentylidenepropane-2-sulfinamide gave (2R,3S)-1n: dr
1
3
3
) ppm. C NMR (100 MHz, CDCl
3
3
+CD OD):  174.1 (C), 173.5 (C),
1
×
3
38.3 (C), 135.7 (C), 135.3 (C), 129.7 (2 × CH), 128.4 (2 × CH), 128.2 (2
CH), 127.5 (CH), 126.8 (2 × CH), 63.6 (CH), 45.7 (CH), 44.2 (CH ),
3.6 (CH ), 20.9 (CH ) ppm.
(
2
26
=
1
75:25, sticky oil; [] +16.2 (c 0.9, CHCl
649 cm . H NMR (400 MHz, CDCl
3
3
). IR (neat): max 3221, 1718,
, interpret equally for both isomers,
major one marked*):  7.60 (s, 1H, NH), 7.54 (s, 1H, NH*), 3.90−3.77 (m,
H, CH and CH*), 3.37 (dt, J = 8.2, 8.3 Hz, 1H, CH), 2.90−2.80 (m, 1H,
CH*), 2.80−2.60 (m, 2H, CHH and CHH*), 2.60−2.54 (m, 1H, CHH*),
.48−2.36 (m, 1H, CHH), 1.70−1.58 (m, 1H, CHH*), 1.56−1.44 (m, 2H,
CHH* and CHH), 1.44−1.36 (m, 1H, CHH), 1.36−1.20 (m, 8H, CH * and
) ppm. C NMR (100 MHz,
, major one marked*):  178.2 (CO), 177.4 (CO*), 176.5 (CO*),
75.0 (CO), 58.0 (CH*), 56.1 (CH), 44.7 (CH*), 43.4 (CH), 36.0 (CH *),
*), 22.4 (CH
*) ppm. MS: m/z (%) relative intensity 185
D
2
3
−1 1
(
[
(
2S,3S)-2-Methyl-5-oxo-2-phenylpyrrolidine-3-carboxylic
(2S,3S)-1k]: A solution of diethyl succinate (0.87 g, 5 mmol) in dry THF
5 mL) was added dropwise to a solution of LDA (2.2 equiv.) at −78 C.
acid
2
°
2
After stirring for
phenylethylidene)propane-2-sulfinamide (5.5 mmol, 1.1 equiv.) in dry
THF (5 mL) was added dropwise at −78 C. The reaction was allowed to
stir at room temperature for 6 h then the obtained dark purple solution
was quenched with 2N HCl (30 mL) at −78 C and allowed to stir for 4 h
at room temperature. The resulting mixture was extracted with EtOAc (3
1
h,
a
solution of (R,E)-2-methyl-N-(1-
2
1
3
°
CH
CDCl
1
3
2 3 3
), 0.90−0.77 (m, 6H, CH * and CH
3
°
2
3.5 (CH
2
*), 32.7 (CH
2
), 31.2 (CH
2
), 28.3 (CH
2
), 27.8 (CH
2
2
and CH
2
*), 13.9 (CH
3
and CH
3
×
30 mL). The combined organic phase was washed with saturated
NaHCO and brine, dried over anhydrous Na SO , and concentrated to
provide a crude mixture. Filtration through a short column (SiO , 60%
EtOAc/hexanes) gave mixture of ester products which was
+
[
(M + H) , 1], 128 (13), 115 (32), 70 (15), 56 (100), 55 (7). HRMS (ESI-
3
2
4
TOF) m/z: [M − H] calcd. for C : 184.0979, found 184.0978.
9 3
H14NO
2
a
General procedure for the synthesis of -fluorinated--
butyrolactams 2: Compound 1 (0.5 mmol), AgNO (1.5 equiv.) and
Selectfluor (1.5 equiv.) were dissolved in a mixture of acetonitrile and
water (0.05 M, 1:4 %v/v). The resulting solution was stirred at reflux for 6
o
subsequently subjected to hydrolysis using conc. HCl (10 mL) at 80 C
for 6 h. After cooling to room temperature, the reaction mixture was
diluted with water (50 mL) and extracted with CH
3
®
2
Cl
2
(3 × 30 mL). The
(3 × 20
combined organic layer was extracted with saturated NaHCO
3
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201900685
FULL PAPER
h then it was cooled to room temperature and extracted with EtOAc (3 
58.0 Hz, 1H, CHF of c,c-2b), 4.65 (dd, J = 4.2, 53.7 Hz, 1H, CHF of c,t-
2b), 4.50 (d, J = 22.5 Hz, 1H, CH of t,c-2b), 4.44 (dd, J = 6.0, 14.3, 1H,
CH of t,t-2b), 4.37 (dd, J = 3.5, 23.1 Hz, 1H, CH of c,c-2b), 3.59 (d, J =
15.0 Hz, 1H, CHH of t,c-2b), 3.48 (d, J = 14.4 Hz, 1H, CHH of t,t-2b),
2
0 mL). The combined organic layer was washed with water, a saturated
aqueous NaHCO (30 mL), brine, and dried with anhydrous Na SO
Purification by column chromatography (SiO ) gave compound 2.
3
2
4
.
2
2
=
1
.87−2.65 (m, 4H, 4 × CH of t,c-2b, t,t-2b, c,t-2b, and c,c-2b), 1.28 (d, J
7.6 Hz, 3H, CH of c,c-2b), 1.24 (dd, J = 1.6, 7.5 Hz, 3H, CH of t,c-2b),
.22 (dd, J = 2.9, 8.7 Hz, 3H, CH of t,t-2b) 1.18 (dd, J = 1.6, 7.2 Hz, 3H,
CH of c,t-2b), ppm. Due to low intensity, some proton peaks of minor
isomers could not be detected by H NMR spectroscopy. C NMR (100
1
1
-Benzyl-4-fluoro-5-phenylpyrrolidin-2-one (2a): The reaction of rac-
a (dr = 89:11) (147.7 mg, 0.5 mmol) with AgNO (127.4 mg, 0.75 mmol)
3
3
3
®
3
and Selectfluor (265.7 mg, 0.75 mmol) gave trans-2a (64.4 mg, 48%
yield), cis-2a (8.2 mg, 6% yield), and trans-3a (4.5 mg, 5% yield) after
column chromatography (SiO
3
1
13
2
, 30% EtOAc/hexanes).
3
MHz, CDCl
.0 Hz, C of t,c-2b), 129.3 (CH of t,c-2b), 128.7 (3 × CH of t,c-2b), 128.6
2 × CH of t,c-2b), 128.0 (CH of t,c-2b), 127.6 (2 × CH of t,c-2b), 126.3
3
):  174.5 (CO of t,c-2b), 135.5 (C of t,c-2b), 135.2 (d, JCF =
9
trans-2a: white solid; m.p. 67−69 °C (Et
2
O/hexanes). IR (neat): max 1678
):  7.38−7.28 (m, 3H, ArH), 7.28−7.17
m, 3H, ArH), 7.11−7.00 (m, 4H, ArH), 5.18 (d, J = 15.0 Hz, 1H, CHH),
.86 (dd, J = 5.5, 53.0 Hz, 1H, CHF), 4.55 (d, J = 23.6 Hz, 1H, CH), 3.53
d, J = 15.0 Hz, 1H, CHH), 2.87 (ddd, J = 5.5, 18.4, 35.2 Hz, 1H, CHH),
−1
1
(
(
cm
(
4
(
. H NMR (400 MHz, CDCl
3
1
1
CH of t,c-2b), 99.6 (d, JCF = 188.6 Hz, CHF of c,c-2b), 95.4 (d, JCF
=
1
188.5 Hz, CHF of c,t-2b), 94.7 (d, JCF = 188.0 Hz, CHF of t,c-2b), 93.0
1
2
(
d, JCF = 189.5 Hz, CHF of t,t-2b), 66.3 (d, JCF = 25.1 Hz, CH of c,t-2b),
2
2
1
3
66.1 (d, JCF = 26.0 Hz, CH of t,c-2b), 65.9 (d, JCF = 19.9 Hz, CH of c,c-
2

1
9
3
.67 (dd, J = 18.4, 26.4 Hz, 1H, CHH) ppm. C NMR (100 MHz, CDCl
3
):
CF = 9.6 Hz, C), 135.4 (C), 129.4 (2 × CH),
28.8 (CH), 128.7 (2 × CH), 128.0 (2 × CH), 127.7 (CH), 126.4 (2 × CH),
2
3
2b), 62.3 (d, JCF = 21.1 Hz, CH of t,t-2b), 44.5 (CH
2 2
of t,c-2b and CH of
171.8 (CO), 135.5 (d,
J
2
c,c-2b), 44.3 (CH
CH of c,c-2b), 42.5 (d, JCF = 21.4 Hz, CH of t,t-2b), 39.5 (d, JCF = 22.0
Hz, CH of c,t-2b), 39.2 (d, JCF = 21.8 Hz, CH of t,c-2b), 14.1 (d, JCF
2
of t,t-2b), 44.2 (CH of c,t-2b), 43.7 (d, JCF = 19.2 Hz,
2
2
2
1
2
2.2 (d, JCF = 184.1 Hz, CHF), 68.0 (d, JCF = 25.9 Hz, CH), 44.2 (CH
7.1 (d, JCF = 23.0 Hz, CH ) ppm. F NMR (376 MHz, CDCl ):  −167.1
2
),
2
3
2
19
=
=
2
3
3
3
4
1
.6 Hz, CH
0.4 Hz, CH
3
of c,c-2b), 13.0 (d, JCF = 4.8 Hz, CH
of t,c-2b), 7.8 (d, JCF = 11.7 Hz, CH
3
of t,t-2b), 8.0 (d, JCF
to −167.7 (m, 1F, CHF) ppm. MS: m/z (%) relative intensity 270 [(M +
H) , 45], 269 [(M) , 1], 249 (40), 132 (90), 117 (100), 91 (37), 77 (9).
3
+
+
3
3
of c,t-2b) ppm. Due to
+
low intensity, some proton peaks of minor isomers could not be detected
by C NMR spectroscopy. F NMR (376 MHz, CDCl
−
−
HRMS (ESI-TOF) m/z: [M + H] calcd. for C17
70.1286.
H17FNO: 270.1289, found
1
3
19
):  −175.5 to
176.0 (m, 1F, CHF of c,c-2b), −184.4 to −184.9 (m, 1F, CHF of t,t-2b),
185.6 to −186.1 (m, 1F, CHF of t,c-2b), −186.8 to −187.3 (m, 1F, CHF
2
3
−
1
1
cis-2a: pale yellow oil; IR (neat): max 1681 cm
CDCl ):  7.39−7.31 (m, 3H, ArH), 7.23−7.15 (m, 3H, ArH), 7.15−7.09 (m,
H, ArH), 6.96−6.88 (m, 2H, ArH), 5.14−4.98 (m, 1H, CHF), 5.12 (d, J =
4.6 Hz, 1H, CHH), 4.46 (dd, J = 5.0, 21.0 Hz, 1H, CH), 3.49 (d, J = 14.6
. H NMR (400 MHz,
+
3
of c,t-2b) ppm. MS: m/z (%) relative intensity 284 [(M + H) , 7], 131 (100),
+
2
1
91 (21), 77 (7). HRMS (ESI-TOF) m/z: [M + H] calcd. for C18H19FNO:
284.1445, found 284.1447.
1
3
Hz, 1H, CHH), 2.84−2.66 (m, 2H, CH
2
3
) ppm. C NMR (100 MHz, CDCl
3
):
CF = 10.0 Hz, C), 129.1 (2 × CH),
28.9 (CH), 128.7 (2 × CH), 128.6 (2 × CH), 128.5 (2 × CH), 127.8 (CH),
6.9 (d, JCF = 185.6 Hz, CHF), 65.6 (d, JCF = 20.2 Hz, CH), 44.2 (CH
8.4 (d, JCF = 24.9 Hz, CH ) ppm. F NMR (376 MHz, CDCl ):  −184.7
1-Benzyl-4-fluoropyrrolidin-2-one (2c): The reaction of 1c (219.2 mg, 1

1
8
3
172.3 (CO), 135.6 (C), 132.4 (d, J
®
mmol) with AgNO
3
(254.3 mg, 1.5 mmol) and Selectfluor (531.4 mg, 1.5
1
2
mmol) gave 2c (116.7 mg, 60% yield) after column chromatography
2
),
−
1
2
19
(
SiO
2
, 50% EtOAc/hexanes); pale-yellow oil; IR (neat): max 1685 cm
.
2
3
1
H NMR (400 MHz, CDCl
3
):  7.32−7.10 (m, 5H, ArH), 5.28−5.03 (m, 1H,
), 3.48 (ddd, J = 4.7, 12.2, 32.2
Hz, 1H, CHH), 3.40 (dd, J = 12.2, 26.6 Hz, 1H, CHH), 2.79−2.58 (m, 2H,
to −185.2 (m, 1F, CHF) ppm. MS: m/z (%) relative intensity 249 (33), 178
6), 160 (8), 132 (29), 117 (32), 106 (100), 91 (35), 77 (24). HRMS (ESI-
CHF), 4.44 (ABq, J = 14.9 Hz, 2H, CH
2
(
+
TOF) m/z: [M + H] calcd. for C17H17FNO: 270.1289, found 270.1298.
1
3
CH
×
2 3
) ppm. C NMR (100 MHz, CDCl ):  171.3 (CO), 135.6 (C), 128.8 (2
1
trans-3a: yellow solid; m.p. 97−108 °C (Et
2
O/hexanes). IR (neat): max
):  7.38−7.30 (m, 2H, ArH),
.30−7.25 (m, 1H, ArH), 7.25−7.17 (m, 2H, ArH), 6.82 (s, 1H, NH), 4.96
CH), 128.0 (2 × CH), 127.8 (CH), 85.9 (d, JCF = 177.7 Hz, CHF), 53.5
−
1 1
2
2
3
7
207, 1710 cm . H NMR (400 MHz, CDCl
3
(
d, JCF = 25.2 Hz, CH
2
), 46.2 (CH
F NMR (376 MHz, CDCl ):  −172.8 to −173.4 (m, 1F, CHF) ppm. MS:
m/z (%) relative intensity 194 [(M + H) , 100], 146 (27), 118 (22), 104
2 2
), 38.8 (d, JCF = 23.7 Hz, CH ) ppm.
1
9
3
+
(
dd, J = 5.8, 53.6 Hz, 1H, CHF), 4.85 (d, J = 23.6 Hz, 1H, CH), 2.71 (ddd,
+
J = 5.8, 18.2, 32.5 Hz, 1H, CHH), 2.49 (ddd, J = 1.3, 18.2, 26.2 Hz, 1H,
CHH) ppm. C NMR (100 MHz, CDCl
(
14), 91 (45). HRMS (ESI-TOF) m/z: [M + Na] calcd. for C11H12FNONa:
1
3
3
3
):  175.0 (CO), 137.8 (d,
J
J
CF
=
=
216.0795, found 216.0793.
1
8.6 Hz, C), 129.2 (2 × CH), 128.6 (CH), 125.6 (2 × CH), 94.8 (d,
CF
2
2
1
1
1
-Phenyl-4-fluoropyrrolidin-2-one (2d): The reaction of 1d (205.2 mg,
184.7 Hz, CHF), 64.7 (d,
J
CF = 25.7 Hz, CH), 36.7 (d,
JCF = 23.2 Hz,
®
1
9
.0 mmol) with AgNO
.5 mmol) gave 2d (51.6 mg, 29% yield) after column chromatography
50% EtOAc/hexanes); yellow solid; m.p. 66−70 °C
3
(254.2 mg, 1.5 mmol) and Selectfluor (531.4 mg,
CH
2
) ppm. F NMR (376 MHz, CDCl ):  −167.6 to −168.1 (m, 1F, CHF)
3
+
ppm. MS: m/z (%) relative intensity 179 [(M) , 83], 149 (44), 121 (49),
+
(
(
SiO
Et O/hexanes). IR (neat): max 1696 cm . H NMR (400 MHz, CDCl
.65−7.60 (m, 2H, ArH), 7.45−7.38 (m, 2H, ArH), 7.25−7.18 (m, 1H, ArH),
2
,
104 (100), 91 (51), 81 (82), 77 (39). HRMS (ESI-TOF) m/z: [M + Na]
−1 1
3
): 
calcd. for C10 10FNONa: 202.0639, found 202.0638.
H
2
7
1-Benzyl-4-fluoro-3-methyl-5-phenylpyrrolidin-2-one (rac-2b): The
5.39 (dt, J = 4.8, 53.3 Hz, 1H, CHF), 4.20 (ddd, J = 4.6, 12.1, 32.4 Hz,
reaction of rac-1b (dr = 61:21:15:3) (309.4 mg, 1 mmol) with AgNO
3
1H, CHH), 4.07 (dd, J = 12.1, 25.2 Hz, 1H, CHH), 3.07−2.82 (m, 2H,
®
1
3
(
254.3 mg, 1.5 mmol) and Selectfluor (531.4 mg, 1.5 mmol) gave rac-2b
2 3
CH ) ppm. C NMR (100 MHz, CDCl ):  170.5 (CO), 138.5 (C), 129.0 (2
1
as four diastereomers [3,4-trans-4,5-cis (t,c); 3,4-trans-4,5-trans (t,t); 3,4-
cis-4,5-trans (c,t); and 3,4-cis-4,5-cis (c,c)]. Purification by column
chromatography (SiO
×
CH), 125.1 (CH), 120.1 (2 × CH), 85.3 (d, JCF = 177.7 Hz, CHF), 55.4
2
2
19
(
(
d,
J
CF = 25.2 Hz, CH
2 2
), 40.1 (d, JCF = 23.6 Hz, CH ) ppm. F NMR
2
, 20% EtOAc/hexanes) gave a mixture of t,c-2b, t,t-
376 MHz, CDCl
3
):  −172.8 to −173.5 (m, 1F, CHF) ppm. MS: m/z (%)
1
9
+
2b, c,t-2b, and c,c-2b (52:22:16:10, determined by F-NMR analysis)
relative intensity 179 [(M) , 71], 130 (11), 106 (100), 77 (28). HRMS (ESI-
TOF) m/z: [M + Na] calcd. for C10
−
1
+
(
183.4 mg, 65% yield) as a viscous oil; IR (neat): max 1695, 1418 cm .
H
H10FNONa: 202.0644, found 202.0638.
1
3
NMR (400 MHz, CDCl , integrated equally for all isomers): 
1-(4-Bromophenyl)-4-fluoropyrrolidin-2-one (2e): The reaction of 1e
7.36−7.25 (m, 2H, ArH of t,c-2b), 7.25−7.17 (m, 3H, ArH of t,c-2b),
7.12−7.02 (m, 5H, ArH of t,c-2b), 5.19 (d, J = 15.0 Hz, 1H, CHH of t,c-
2b), 5.14 (d, J = 14.4 Hz, 1H, CHH of t,t-2b), 5.13 (d, J = 16.4 Hz, 1H,
(
142.1 mg, 0.5 mmol) with AgNO (127.8 mg, 0.75 mmol) and
Selectfluor (265.9 mg, 0.75 mmol) gave 2e (42.1 mg, 33% yield) after
column chromatography (SiO , 50% EtOAc/hexanes); brown semi-solid;
H NMR (400 MHz, CDCl ):  7.48−7.40 (m,
H, ArH), 5.30 (dt, J = 5.1, 54.0 Hz, 1H, CHF), 4.07 (ddd, J = 4.6, 11.8,
3
®
CHH of c,c-2b), 5.10 (d, J = 12.9 Hz, 1H, CHH of c,t-2b), 4.76 (dd, J =
.8, 53.2 Hz, 1H, CHF of t,c-2b), 4.70 (ddd, J = 4.3, 6.0, 53.5 Hz, 1H,
CHF of t,t-2b), 4.69 (d, J = 22.3 Hz, 1H, CH of c,t-2b), 4.68 (dd, J = 4.6,
2
−
1
1
IR (neat): max 1696 cm
4
.
3
4
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201900685
FULL PAPER
3
2
1
2.0 Hz, 1H, CHH), 3.95 (dd, J = 12.2, 25.0 Hz, 1H, CHH), 2.96−2.72 (m,
(dd, J = 5.4, 52.8 Hz, 1H, CHF of cis-2i), 4.83 (dd, J = 5.3, 52.6 Hz, 1H,
CHF*), 4.51 (d, J = 23.5 Hz, 1H, CH*), 4.43 (dd, J = 4.9, 21.6 Hz, 1H, CH
of cis-2i), 3.51 (d, J = 15.0 Hz, 1H, CHH*), 3.45 (d, J = 14.7 Hz, 1H,
1
3
H, CH
2 3
) ppm. C NMR (100 MHz, CDCl ):  170.5 (CO), 137.6 (C),
1
32.0 (2 × CH), 121.4 (2 × CH), 117.9 (C), 85.1 (d,
J
CF = 178.3 Hz,
), 40.1 (d, JCF = 24.0 Hz, CH ) ppm.
):  −173.0 to −173.5 (m, 1F, CHF) ppm. MS:
2
2
CHF), 55.2 (d, JCF = 25.9 Hz, CH
2
2
CHH), 2.85 (ddd, J = 5.5, 18.3, 34.8 Hz, 1H, CHH*), 2.67 (dd, J = 18.3,
1
9
13
F NMR (376 MHz, CDCl
m/z (%) relative intensity MS: m/z (%) relative intensity 257 [(M+H) , 17],
3
3
26.5 Hz, 1H, CHH*) ppm. C NMR (100 MHz, CDCl , trans-2i marked*):
+
3
 171.6 (CO*), 135.1 (C*), 134.8 (C*), 134.1 (d, JCF = 9.1 Hz, C*), 130.4
(2 × CH of cis-2i), 129.6 (2 × CH*), 129.4 (2 × CH of cis-2i), 129.2 (CH of
+
184 (80), 105 (100). HRMS (ESI-TOF) m/z: [M + Na] calcd. for
C
10
H
9
BrFNONa: 279.9744, found 279.9741.
cis-2i), 128.8 (2 × CH*), 128.7 (2 × CH of cis-2i), 128.0 (2 × CH*), 127.8
1
(
CH*), 127.7 (2 × CH*), 126.3 (2 × CH of cis-2i), 92.1 (d, JCF = 184.0 Hz,
1
(
-(2-Chlorophenyl)-4-fluoropyrrolidin-2-one (2f): The reaction of 1f
119.7 mg, 0.5 mmol) with AgNO (127.8 mg, 0.75 mmol) and
Selectfluor (265.7 mg, 0.75 mmol) gave 2f (88.7 mg, 83% yield) after
column chromatography (SiO , 50% EtOAc/hexanes); brown semi-solid;
H NMR (400 MHz, CDCl ):  7.48−7.38 (m,
1
2
CHF of cis-2i), 91.9 (d, JCF = 184.6 Hz, CHF*), 68.0 (d, JCF = 25.8 Hz,
3
2
CH of cis-2i), 67.3 (d, JCF = 26.2 Hz, CH*), 44.3 (CH
2
*), 43.6 (CH
2
of cis-
of cis-2i), 36.9 (d, JCF = 23.6 Hz, CH *)
ppm. Due to low intensity, some proton and carbon peaks of cis-2i could
®
2
2
2
i), 38.4 (d, JCF = 24.5 Hz, CH
2
2
2
−
1
1
IR (neat): max 1688 cm
.
3
19
not be detected. F NMR (376 MHz, CDCl
3
):  −167.4 to −168.0 (m, 1F,
1
4
1
1
H, ArH), 7.32−7.20 (m, 3H, ArH), 5.34 (dt, J = 5.0, 53.1 Hz, 1H, CHF),
.11 (ddd, J = 4.7, 12.1, 32.7 Hz, 1H, CHH), 3.85 (dd, J = 12.0, 25.2 Hz,
H, CHH), 2.86 (ddd, J = 5.3, 18.1, 35.1 Hz, 1H, CHH), 2.76 (dd, J =
CHF of trans-2i), −184.7 to −185.2 (m, 1F, CHF of cis-2i) ppm. MS: m/z
+
(
(
3
%) relative intensity 304 [(M + H) , 23], 283 (10), 151 (17), 132 (100), 91
+
12). HRMS (ESI-TOF) m/z: [M + Na] calcd. for C17
26.0718, found 326.0720.
H15ClFNONa:
1
3
8.0, 26.4 Hz, 1H, CHH) ppm. C NMR (100 MHz, CDCl
3
):  171.4 (CO),
1
J
35.1 (C), 132.2 (C), 130.6 (CH), 129.6 (2 × CH), 127.9 (CH), 86.4 (d,
1
2
2
CF = 178.3 Hz, CHF), 56.5 (d, JCF = 24.9 Hz, CH
2
), 38.6 (d, JCF = 23.9
1-Benzyl-4-fluoro-5-(p-tolyl)pyrrolidin-2-one (2j): The reaction of rac-
1j (dr = 90:10) (309.1 mg, 1 mmol) with AgNO (254.3 mg, 1.5 mmol) and
Selectfluor (531.4 mg, 1.5 mmol) gave a mixture of trans-2j and cis-2j
(127.6 mg, 45% yield, 93:7) after column chromatography (SiO , 20%
H NMR (400
, integrated equally for both isomers, trans-2j marked*): 
.38−7.29 (m, 3H, ArH*), 7.23 (d, J = 7.8 Hz, 2H, ArH*), 7.17 (d, J = 6.9
19
Hz, CH
CHF) ppm. MS: m/z (%) relative intensity 214 [(M+H) , 17], 178 (100),
2
) ppm. F NMR (376 MHz, CDCl
3
):  −173.0 to −173.6 (m, 1F,
3
+
®
+
140 (30), 77 (11). HRMS (ESI-TOF) m/z: [M
+
Na] calcd. for
2
−
1
1
C
10
H
9
ClFNONa: 236.0249, found 236.0250.
acetone/hexanes); brown oil; IR (neat): max 1693 cm
MHz, CDCl
.
3
4-Fluoro-1-propylpyrrolidin-2-one (2g): The reaction of 1g (85.7 mg,
7
®
3
0.5 mmol) with AgNO (127.8 mg, 0.75 mmol) and Selectfluor (265.9
Hz, 2H, ArH*), 7.02 (d, J = 7.9 Hz, 2H, ArH*), 5.27 (d, J = 15.0 Hz, 1H,
CHH*), 5.21 (d, J = 14.4 Hz, 1H, CHH of cis-2j), 4.94 (dd, J = 5.3, 52.8
Hz, 1H, CHF*), 4.61 (d, J = 23.8 Hz, 1H, CH*), 4.53 (dd, J = 5.0, 21.2 Hz,
mg, 0.75 mmol) gave 2g (54.6 mg, 75% yield) after column
chromatography (SiO , 50% EtOAc/hexanes); pale-yellow oil; IR (neat):
max 1668 cm . H NMR (400 MHz, CDCl ):  5.19 (dt, J = 5.1, 53.2 Hz,
H, CHF), 3.61 (ddd, J = 4.8, 12.2, 32.2 Hz, 1H, CHH), 3.51 (dd, J =
1.0, 25.0 Hz, 1H, CHH), 3.32−3.21 (m, 1H, CHH), 3.21−3.12 (m, 1H,
), 1.55−1.45 (m, 2H, CH ), 0.85 (t, J = 7.4
) ppm. C NMR (100 MHz, CDCl ):  171.4 (CO), 86.1 (d,
CF = 178.2 Hz, CHF), 54.0 (d, JCF = 25.9 Hz, CH ), 43.8 (CH ), 38.9 (d,
) ppm. F NMR (376 MHz,
2
−
1 1

1
1
3
1H, CH of cis-2j), 3.60 (d, J = 15.0 Hz, 1H, CHH*), 2.96 (ddd, J = 5.4,
1
8.3, 35.6 Hz, 1H, CHH*), 2.75 (dd, J = 18.2, 26.4 Hz, 1H, CHH*), 2.42
13
(
3 3
s, 3H, CH of cis-2j), 2.39 (s, 3H, CH *) ppm. C NMR (100 MHz,
CHH), 2.76−2.52 (m, 2H, CH
2
2
CDCl
3
, trans-2j marked*):  171.7 (CO*), 138.7 (C*), 135.5 (C*), 132.4 (d,
1
3
Hz, 3H, CH
3
3
3
JCF = 9.4 Hz, C*), 130.0 (2 × CH*), 129.6 (CH of cis-2j), 129.3 (2 × CH of
1
2
J
J
2
2
cis-2j), 129.0 (CH of cis-2j), 128.7 (2 × CH*), 128.6 (2 × CH of cis-2j),
2
19
CF = 23.9 Hz, CH
2
), 20.4 (CH
2
), 11.1 (CH
3
1
2
1
2
2
28.5 (2 × CH of cis-2j), 128.0 (2 × CH*), 127.6 (CH*), 126.7 (CH of cis-
CDCl
3
):  −172.6 to −173.2 (m, 1F, CHF) ppm. MS: m/z (%) relative
1
1
j), 126.3 (2 × CH*), 92.2 (d,
85.6 Hz, CHF of cis-2j), 67.7 (d,
0.3 Hz, CH of cis-2j), 44.1 (CH *), 43.9 (CH
J
CF = 183.7 Hz, CHF*), 86.9 (d,
J
CF
=
=
=
+
+
intensity 146 [(M+H) , 100], 145 (M , 10), 116 (36), 96 (65), 53 (79).
HRMS (ESI-TOF) m/z: [M + Na] calcd. for C
found 168.0791.
2
2
J
CF = 25.7 Hz, CH*), 65.3 (d, JCF
+
7
H
12FNONa: 168.0795,
2
2
2
of cis-2j), 38.4 (d,
of cis-2j), 37.1 (d, JCF = 23.7 Hz, CH *), 21.1 (CH
J
CF
2
4.2 Hz, CH
2
2
3
*) ppm.
Due to low intensity, some proton and carbon peaks of cis-2j could not
1
-Butyl-4-fluoropyrrolidin-2-one (2h): The reaction of 1h (92.6 mg, 0.5
1
9
®
be detected. F NMR (376 MHz, CDCl
3
):  −167.2 to −167.8 (m, 1F,
3
mmol) with AgNO (127.4 mg, 0.75 mmol) and Selectfluor (265.9 mg,
CHF of trans-2j), −184.9 to −185.3 (m, 1F, CHF of cis-2j) ppm. MS: m/z
0.75 mmol) gave 2g (54.2 mg, 68% yield) after column chromatography
+
−
1
(
%) relative intensity 284 [(M + H) , 3], 91 (100), 83 (51), 81 (30), 77 (20).
(
SiO
2
, 50% EtOAc/hexanes); pale-yellow oil; IR (neat): max 1678 cm
.
+
1
HRMS (ESI-TOF) m/z: [M + H] calcd. for C18
84.1448.
H19FNO: 283.1445, found
3
H NMR (400 MHz, CDCl ):  5.19 (dt, J = 4.9, 53.7 Hz, 1H, CHF), 3.61
2
(
ddd, J = 4.7, 12.1, 32.1 Hz, 1H, CHH), 3.51 (dd, J = 11.8, 26.6 Hz, 1H,
CHH), 3.36−3.25 (m, 1H, CHH), 3.25−3.16 (m, 1H, CHH), 2.74−2.50 (m,
(
[
4S,5R)- and (4R,5R)-4-Fluoro-5-methyl-5-phenylpyrrolidin-2-one
2
H, CH
2
), 1.50−1.39 (m, 2H, CH
2
), 1.32−1.19 (m, 2H, CH
) ppm. C NMR (100 MHz, CDCl ):  171.2 (CO), 86.1
), 41.9 (CH ), 38.9
), 13.7 (CH ) ppm.
):  −172.6 to −173.2 (m, 1F, CHF) ppm. MS: m/z
2
), 0.87 (t, J =
(4S,5R)- and (4R,5R)-2k]: The reaction of (2S,3S)-1j (dr >99:1) (109.7
13
7.4 Hz, 3H, CH
3
3
®
3
mg, 0.5 mmol) with AgNO (127.5 mg, 0.75 mmol) and Selectfluor
(
2
EtOAc/hexanes).
(
1
7
1
2
(
(
d, JCF = 177.3 Hz, CHF), 54.0 (d, JCF = 24.9 Hz, CH
d, JCF = 23.9 Hz, CH
2
2
265.7 mg, 0.75 mmol) gave (4S,5R)-2k (40 mg, 42% yield) and (4R,5R)-
k (28.6 mg, 29% yield) after column chromatography (SiO , 60%
2
2
19
2
), 29.2 (CH
2
), 19.9 (CH
2
3
F
NMR (376 MHz, CDCl
3
+
(
(
%) relative intensity 160 [(M+H) , 100], 117 (30), 96 (39), 53 (51). HRMS
ESI-TOF) m/z: [M + Na] calcd. for C
25
4S,5R)-2k: semi-solid; [] −233.7 (c 1.0, CHCl
3
). IR (neat): max 3206,
+
D
8
H14FNONa: 182.0952, found
−1
1
689 cm
.
H NMR (400 MHz, CDCl
3
):  7.38−7.30 (m, 4H, ArH),
182.0954.
.30−7.24 (m, 1H, ArH), 6.91 (br, 1H, NH), 4.96 (dd, J = 4.2, 53.0 Hz, 1H,
CHF), 2.83 (ddd, J = 5.2, 18.0, 31.4 Hz, 1H, CHH), 2.59 (ddd, J = 1.9,
1
-Benzyl-5-(4-chlorophenyl)-4-fluoropyrrolidin-2-one
(2i):
The
1
3
1
8.0, 23.7 Hz, 1H, CHH), 1.60 (d, J = 1.6 Hz, 3H, CH
3
) ppm. C NMR
reaction of rac-1i (dr = 97:3) (165 mg, 0.5 mmol) with AgNO
3
(127.4 mg,
3
®
(
100 MHz, CDCl
3
):  174.1 (CO), 139.0 (d, JCF = 5.7 Hz, C), 128.5 (2 ×
0
.75 mmol) and Selectfluor (265.7 mg, 0.75 mmol) gave a mixture of
trans-2i and cis-2i (62.7 mg, 21% yield, 91:9) after column
chromatography (SiO , 20% acetone/hexanes); pale-yellow oil; IR (neat):
H NMR (400 MHz, CDCl , integrated equally for both
1
CH), 127.9 (CH), 125.9 (2 × CH), 93.9 (d, JCF = 188.8 Hz, CHF), 65.8 (d,
2
2
3
J
CF = 20.1 Hz, C), 37.6 (d, JCF = 23.9 Hz, CH
2
), 27.0 (d, JCF = 2.9 Hz,
2
1
9
−
1
1
CH
ppm. MS: m/z (%) relative intensity 194 [(M + H) , 4], 178 (100), 158 (18),
) ppm. F NMR (376 MHz, CDCl ):  −174.6 to −175.1 (m, 1F, CHF)
3 3
max 1692 cm
.
3
+
isomers, trans-2i marked*):  7.37−7.28 (m, 2H, ArH*), 7.27−7.15 (m, 3H,
ArH*), 7.06 (d, J = 6.6 Hz, 2H, ArH*), 6.98 (d, J = 8.3 Hz, 2H, ArH*), 5.18
+
130 (23), 104 (31), 77 (11). HRMS (ESI-TOF) m/z: [M + Na] calcd. for
11
C H12FNONa: 216.0795, found 216.0796.
(
d, J = 14.7 Hz, 1H, CHH of cis-2i), 5.16 (d, J = 15.0 Hz, 1H, CHH*), 4.87
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201900685
FULL PAPER
2
6
+
(

4R,5R)-2k: yellow semi-solid; [] −177.4 (c 1.0, CHCl
3
). IR (neat):
intensity 236 [(M + H) , 1], 167 (59), 149 (100), 55 (2). HRMS (ESI-TOF)
D
−1
1
+
max 3211, 1695 cm
.
H NMR (400 MHz, CDCl
3
):  7.38−7.22 (m, 4H,
m/z: [M + Na] calcd. for C14H18FNONa: 258.1265, found 258.1270.
ArH), 7.28−7.22 (m, 1H, ArH), 6.62 (br, 1H, NH), 5.01 (dd, J = 4.8, 53.6
2
6
(
4R,5R)-2m: semi-solid; [] −115.7 (c 0.5, CHCl
3
). IR (neat): max
):  7.37−7.29 (m, 2H, ArH),
.29−7.21 (m, 3H, ArH), 6.71 (br, 1H, NH), 5.05 (ddd, J = 1.2, 4.6, 54.0
Hz, 1H, CHF), 2.52 (ddd, J = 5.1, 17.7, 34.1 Hz, 1H, CHH), 2.43 (ddd, J =
1.6, 17.8, 24.6 Hz, 1H, CHH), 2.01 (dt, J = 1.6, 8.6 Hz, 2H, CH ),
.30−1.13 (m, 2H, CH ), 1.07−0.95 (m, 1H, CHH), 0.95−0.81 (m, 1H,
CHH), 0.76 (t, J = 7.2 Hz, 3H, CH
174.5 (CO), 141.2 (C), 129.0 (2 × CH), 127.8 (CH), 125.3 (2 × CH), 96.0
Hz, 1H, CHF), 2.56 (ddd, J = 4.8, 18.0, 34.4 Hz, 1H, CHH), 2.43 (dd, J =
D
−
1 1
1
3
3182, 1699 cm . H NMR (400 MHz, CDCl
3
1
8.0, 23.2 Hz, 1H, CHH), 1.63 (d, J = 4.0 Hz, 3H, CH
3
) ppm. C NMR
7
(
1
100 MHz, CDCl ):  174.4 (CO), 142.9 (C), 129.0 (2 × CH), 128.0 (CH),
3
1
2
24.9 (2 × CH), 95.6 (d, JCF = 191.7 Hz, CHF), 66.1 (d, JCF = 21.0 Hz,
2
3
19
2
C), 37.3 (d, JCF = 23.0 Hz, CH
2
), 22.8 (d, JCF = 10.6 Hz, CH
3
) ppm.
F
1
2
NMR (376 MHz, CDCl ):  −180.1 to −180.7 (m, 1F, CHF) ppm. MS: m/z
3
1
3
+
3 3
) ppm. C NMR (100 MHz, CDCl ): 
(
(
2
%) relative intensity 194 [(M + H) , 1], 178 (100), 158 (13), 130 (15), 104
+
18), 77 (3). HRMS (ESI-TOF) m/z: [M + Na] calcd. for C11
16.0795, found 216.0798.
H12FNONa:
1
2
2
(
2
d,
J
CF = 191.6 Hz, CHF), 69.4 (d,
J
CF = 20.2 Hz, C), 36.9 (d,
), 34.6 (d, JCF = 9.6 Hz, CH ), 26.0 (CH ), 22.9 (CH
3 3
) ppm. F NMR (376 MHz, CDCl ):  −182.8 to −183.3 (m, 1F, CHF)
CF
J =
2
), 13.8
3
4.0 Hz, CH
2
19
2
2
(
[
4S,5R)-
and
(4R,5R)-5-Ethyl-4-fluoro-5-phenylpyrrolidin-2-one
(CH
ppm. MS: m/z (%) relative intensity 236 [(M + H) , 1], 178 (100), 160 (33),
+
(4S,5R)- and (4R,5R)-2l]: The reaction of (2S,3S)-1h (dr = 95:5) (116.6
®
+
mg, 0.5 mmol) with AgNO
(
(
3
(127.4 mg, 0.75 mmol) and Selectfluor
265.8 mg, 0.75 mmol) gave (4S,5R)-2l (40.9 mg, 40% yield) and
4R,5R)-2l (9.8 mg, 10% yield) after column chromatography (SiO , 60%
130 (26), 77 (1). HRMS (ESI-TOF) m/z: [M
14
C H18FNONa: 258.1265, found 258.1275.
5: yellow viscous oil; IR (neat): max 3210, 1682 cm . H NMR (400 MHz,
+
Na] calcd. for
−
1
1
2
EtOAc/hexanes).
CDCl
NH of two isomers), 4.65−4.39 (m, 2H, CHF of two isomers), 2.40−2.20
(m, 8H, 4 × CH ), 2.23−2.12 (m, 1H, CHH), 2.12−1.90 (m, 2H, CH ),
1.89−1.77 (m, 1H, CHH), 1.55−1.38 (m, 2H, CH ), 1.38−1.28 (m, 2H,
CH ), 1.25−1.20 (m, 3H, CH ), 1.20−1.15 (m, 3H, CH
(100 MHz, CDCl , interpreted for two major isomers):  178.2 (2 × CO),
144.9 (C), 144.6 (C), 128.7 (4 × CH), 127.1 (2 × CH), 124.8 (4 × CH),
3
, interpreted for two major isomers):  7.40−7.10 (m, 12H, ArH and
2
6
(
2
4S,5R)-2l: white solid; m.p. 130−131 °C (Et O/hexanes). [] −123.7 (c
D
−1 1
1

1
1
1
.0, CHCl
3
). IR (neat): max 3184, 1698 cm . H NMR (400 MHz, CDCl
3
):
2
2
7.62 (br, 1H, NH), 7.38−7.21 (m, 5H, ArH), 5.02 (dd, J = 4.4, 53.2 Hz,
H, CHF), 2.83 (ddd, J = 5.6, 18.2, 31.8 Hz, 1H, CHH), 2.59 (ddd, J =
.6, 18.0, 24.6 Hz, 1H, CHH), 2.15−1.98 (m, 1H, CHH), 1.75−1.63 (m,
2
1
3
2
3
3
) ppm. C NMR
3
1
3
H, CHH), 0.75 (t, J = 7.2 Hz, 3H, CH
3
) ppm. C NMR (100 MHz,
3
1
1
CDCl
3
):  174.7 (CO), 137.1 (d, JCF = 5.7 Hz, C), 128.5 (2 × CH), 127.6
90.7 (d, JCF = 164.8 Hz, CHF), 90.6 (d, JCF = 165.8 Hz, CHF), 64.9 (C),
1
2
3
3
(
CH), 126.1 (2 × CH), 93.5 (d, JCF = 187.8 Hz, CHF), 70.2 (d, JCF = 20.2
64.8 (C), 38.0 (d, JCF = 2.9 Hz, CH
2
), 37.8 (d, JCF = 3.9 Hz, CH
2
), 36.5
2
19
2
2
Hz, C), 37.8 (d,
J
CF = 23.9 Hz, CH
):  −174.7 to −175.2 (m, 1F, CHF) ppm. MS: m/z
%) relative intensity 178 (100), 158 (19), 149 (33), 130 (5), 81 (7), 55 (8).
2
), 32.3 (CH
2
), 7.7 (CH
3
) ppm.
F
(CH
CH
Hz, CH
2
), 36.3 (CH
2
), 31.8 (d, JCF = 21.1 Hz, CH
2
), 31.7 (d, JCF = 21.1 Hz,
), 21.0 (d, JCF = 23.0 Hz, CH
2
2
NMR (376 MHz, CDCl
(
3
2
), 30.1 (2 × CH
2
3
), 20.9 (d, JCF = 23.0
1
9
3
) ppm. F NMR (376 MHz, CDCl
3
, interpreted for two major
+
HRMS (ESI-TOF) m/z: [M + Na] calcd. for C12
found 230.0953.
H
14FNONa: 230.0952,
isomers):  −172.8 to −173.3 (m, 1F, CHF), −173.3 to −173.9 (m, 1F,
+
CHF) ppm. MS: m/z (%) relative intensity 236 [(M + H) , 7], 160 (100),
+
117 (9), 115 (9). HRMS (ESI-TOF) m/z: [M
+
Na] calcd. for
2
6
(
1
4R,5R)-2l: semi-solid; [] −62.0 (c 0.6, CHCl
698 cm . H NMR (400 MHz, CDCl ):  7.57 (br, 1H, NH), 7.38−7.21
3
). IR (neat): max 3182,
D
14
C H18FNONa: 258.1265, found 258.1267.
−
1
1
3
(m, 5H, ArH), 5.08 (ddt, J = 1.5, 4.8, 53.9 Hz, 1H, CHF), 2.54 (ddd, J =
(4S,5R)- and (4R,5R)-5-Butyl-4-fluoropyrrolidin-2-one [(4S,5R)- and
5
.0, 17.8, 33.4 Hz, 1H, CHH), 2.44 (ddd, J = 1.8, 17.8, 24.2 Hz, 1H,
(4R,5R)-2n]: The reaction of (2R,3S)-1n (dr = 75:25) (92.6 mg, 0.5
1
3
®
CHH), 2.16−1.97 (m, 2H, CH
2
), 0.69 (t, J = 7.6 Hz, 3H, CH
3
) ppm.
C
mmol) with AgNO
3
(127.5 mg, 0.75 mmol) and Selectfluor (265.8 mg,
NMR (100 MHz, CDCl
3
):  174.8 (CO), 141.0 (C), 129.0 (2 × CH), 127.8
0.75 mmol) gave (4S,5R)-2n (30.1 mg, 38% yield) and (4R,5R)-2n (8.2
1
2
(
CH), 125.5 (2 × CH), 95.8 (d, JCF = 191.6 Hz, CHF), 70.0 (d, JCF = 20.2
mg, 10% yield) along with a racemic mixture of 6 (10 mg, 11% yield, 1:1,
2
3
19
Hz, C), 37.2 (d,
(
J
CF = 24.0 Hz, CH
2
), 27.9 (d,
J
CF = 9.6 Hz, CH
2
), 8.1
determined by F NMR analysis) after column chromatography (SiO
40-90% EtOAc/hexanes).
2
,
19
CH
) ppm. F NMR (376 MHz, CDCl ):  −183.0 to −183.8 (m, 1F, CHF)
3 3
+
ppm. MS: m/z (%) relative intensity 230 [(M + H) , 5], 178 (100), 158 (40),
2
5
+
(4S,5R)-2n: pale yellow oil; []
−140.1 (c 1.0, CHCl
H NMR (400 MHz, CDCl ):  6.95 (br, 1H, NH), 4.93
dd, J = 6.0, 53.2 Hz, 1H, CHF), 3.74 (dt, J = 6.8, 25.2 Hz, 1H, CH), 2.73
(ddd, J = 5.8, 18.2, 31.6 Hz, 1H, CHH), 2.54 (ddd, J = 1.6, 18.4, 26.4 Hz,
1H, CHH), 1.56−1.39 (m, 2H, CH ), 1.38−1.27 (m, 4H, 2 × CH ), 0.90 (t,
) ppm. C NMR (100 MHz, CDCl ):  175.0 (CO),
3
). IR (neat): max
130 (42), 77 (3). HRMS (ESI-TOF) m/z: [M + H] calcd. for C12
H15FNO:
D
−
1 1
3232, 1690 cm
.
3
208.1132, found 208.1131.
(
(
[
(
4S,5R)-
(4S,5R)- and (4R,5R)-2m]: The reaction of (2S,3S)-1m (dr = 93:7)
130.7 mg, 0.5 mmol) with AgNO (127.5 mg, 0.75 mmol) and
and
(4R,5R)-5-Butyl-4-fluoro-5-phenylpyrrolidin-2-one
2
2
1
3
3
J = 7.0 Hz, 3H, CH
3
3
®
1
2
2
Selectfluor (266.0 mg, 0.75 mmol) gave (4S,5R)-2m (35.6 mg, 30%
yield) and (4R,5R)-2m (8.4 mg, 7% yield) along with a racemic mixture of
92.5 (d, JCF = 181.1 Hz, CHF), 61.5 (d, JCF = 24.0 Hz, CH), 37.1 (d, JCF
3
= 23.0 Hz, CH
13.8 (CH ) ppm. F NMR (376 MHz, CDCl
CHF) ppm. MS: m/z (%) relative intensity 160 [(M + H) , 62], 102 (43), 82
2
), 33.1 (d,
J
CF = 7.7 Hz, CH
2 2 2
), 27.5 (CH ), 22.3 (CH ),
):  −170.6 to −171.2 (m, 1F,
1
9
5
(14.6 mg, 12% yield, 1:1) after column chromatography (SiO
2
, 60%
3
3
+
EtOAc/hexanes).
2
6
+
(
(
4S,5R)-2m: white solid; m.p. 142−143 °C (Et
c 1.0, CHCl ). IR (neat): max 3173, 3090, 1702 cm . H NMR (400 MHz,
):  7.38−7.30 (m, 2H, ArH), 7.30−7.20 (m, 3H, ArH), 7.04 (br, 1H,
2
O/hexanes). [] −132.0
8
(100), 55 (57). HRMS (ESI-TOF) m/z: [M + H] calcd. for C H15FNO:
D
−1 1
3
160.1138, found 160.1130.
CDCl
3
2
5
(
1
4
4R,5R)-2n: semi-solid; [] −240.8 (c 0.5, CHCl
3
). IR (neat): max 3178,
):  6.34 (br, 1H, NH), 5.09 (dt, J =
.4, 53.6 Hz, 1H, CHF), 3.69 (ddt, J = 3.9, 7.1, 24.5 Hz, 1H, CH), 2.60
NH), 4.99 (dd, J = 5.2, 52.8 Hz, 1H, CHF), 2.82 (ddd, J = 5.7, 17.7, 31.7
Hz, 1H, CHH), 2.58 (ddd, J = 1.4, 18.0, 24.6 Hz, 1H, CHH), 2.04 (dt, J =
D
−
1 1
699 cm . H NMR (400 MHz, CDCl
3
4
(
.1, 12.8 Hz, 1H, CHH), 1.62 (dt, J = 4.3, 12.7 Hz, 1H, CHH), 1.28−1.16
m, 2H, CH ), 1.16−1.06 (m, 1H, CHH), 1.06−0.94 (m, 1H, CHH), 0.77 (t,
J = 7.0 Hz, 3H, CH
(
ddd, J = 4.8, 17.8, 36.4 Hz, 1H, CHH), 2.52 (dd, J = 17.2, 25.2 Hz, 1H,
2
1
3
CHH), 1.75−1.62 (m, 1H, CHH), 1.62−1.51 (m, 1H, CHH), 1.38−1.25 (m,
3
) ppm. C NMR (100 MHz, CDCl
37.4 (C), 128.6 (2 × CH), 127.7 (CH), 126.0 (2 × CH), 93.6 (d,
3
):  174.3 (CO),
1
3
1
4H, 2 × CH
CDCl ):  174.7 (CO), 89.4 (d,
2 2
21.1 Hz, CH), 38.8 (d, JCF = 24.9 Hz, CH ), 28.3 (d, JCF = 9.5 Hz, CH
2 3
), 0.87 (t, J = 7.0 Hz, 3H, CH ) ppm. C NMR (100 MHz,
1
1
2
J
CF
=
1
2
2
2
3
J
CF = 185.0 Hz, CHF), 59.3 (d,
J
CF
=
),
88.8 Hz, CHF), 69.5 (d, JCF = 19.1 Hz, C), 39.1 (CH
4.9 Hz, CH ), 25.4 (CH ), 22.8 (CH ), 13.8 (CH
):  −174.7 to −175.1 (m, 1F, CHF) ppm. MS: m/z (%) relative
2
), 37.6 (d, JCF
=
2
3
1
9
2
2
2
3
) ppm. F NMR (376
1
9
2 2 3 3
28.1 (CH ), 22.6 (CH ), 13.9 (CH ) ppm. F NMR (376 MHz, CDCl ): 
MHz, CDCl
3
−193.4 to −194.3 (m, 1F, CHF) ppm. MS: m/z (%) relative intensity 160
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201900685
FULL PAPER
+
[
(M + H) , 14], 102 (33), 82 (100), 55 (55). HRMS (ESI-TOF) m/z: [M +
N–F based reagents; e) G. S. Lal, G. P. Pez, R. G. Syvret, Chem. Rev.
1996, 96, 1737−1756; f) A. S. Kiselyov, Chem. Soc. Rev. 2005, 34,
+
8
Na] calcd. for C H14FNONa: 182.0957, found 182.0958.
1
031−1037; g) P. T. Nyffeler, S. G. Durón, M. D. Burkart, S. P. Vincent,
C.-H. Wong, Angew. Chem. Int. Ed. 2005, 44, 192−212; Angew. Chem.
005, 117, 196−217; h) J. N. Capilato, D. D. Bume, W. H. Lee, L. E. S.
Hoffenberg, R. T. Jokhai, T. Lectka, J. Org. Chem. 2018, 83,
−
1
1
6
: pale-yellow oil; IR (neat): max 3224, 1692 cm
.
H NMR (400 MHz,
CDCl
3
, interpreted for two major isomers): δ = 6.57 (br, 1H, NH), 6.51 (br,
H, NH), 4.89 (dd, J = 5.4, 53.0 Hz, 2H, 2 × CHF of two isomers),
2
1
4
2
.74−4.50 (m, 2H, 2 × CHF of two isomers), 3.74 (dt, J = 6.4, 24.8 Hz,
H, 2 × CH of two isomers), 2.68 (ddd, J = 6.0, 18.4, 30.8 Hz, 2H, 2 ×
CHH of two isomers), 2.50 (dd, J = 18.2, 27.4 Hz, 2H, 2 × CHH of two
isomers), 1.78−1.51 (m, 6H, 2 × CHH and 2 × CH of two isomers),
.51−1.38 (m, 2H, 2 × CHH of two isomers), 1.29 (dd, J = 6.0, 23.6 Hz,
H, 2 × CH of two isomers) ppm. C NMR (100 MHz, CDCl , interpreted
3 3
for two major isomers): δ = 174.5 (2 × CO of two isomers), 92.4 (d, JCF
81.1 Hz, CHF), 92.3 (d, JCF = 181.1 Hz, CHF), 90.4 (d, JCF = 164.8 Hz,
CHF), 90.0 (d, JCF = 164.8 Hz, CHF), 61.2 (d, JCF = 24.0 Hz, 2 × CH of
14234−14244; i) M. Li, H. Zheng , X. Xue, J. Cheng, Tetrahedron Lett.
2018, 59, 1278−1285, and references cited therein. See also, j) Y. Zhu,
J. Han, J. Wang, N. Shibata, M. Sodeoka, V. A. Soloshonok, J. A. S.
Coelho, F. D. Toste, Chem. Rev. 2018, 118, 3887−3964; k) P. A.
Champagne, J. Desroches, J. Hamel, M. Vandamme, J. Paquin, Chem.
Rev. 2015, 115, 9073−9174; l) X. Yang, T. Wu, R. J. Phipps, F. D.
Toste, Chem. Rev. 2015, 115, 826−870, and references cited therein.
See, for example, a) R. P. Singh, J. M. Shreeve, Synthesis 2002,
2
1
6
1
3
1
=
1
1
1
[
[
3]
4]
1
2
2561−2578; b) X. Bi, Synlett 2006, 15, 2515−2516; c) J. Wu;
2
2
two isomers), 37.1 (d, JCF = 23.0 Hz, CH
2
), 37.0 (d, JCF = 24.1 Hz, CH
2
),
Tetrahedron Lett. 2014, 55, 4289–4294; d) D. E. Yerien, S. Bonesi, A.
Postigo, Org. Biomol. Chem. 2016, 14, 8398–8427; e) S. Liang, G. B.
Hammond, B. Xu, Chem. Eur. J. 2017, 23, 17850–17861.
2
2
32.8 (d,
J
CF = 21.1 Hz, CH
2
), 32.6 (d,
J
CF = 21.1 Hz, CH
), 21.1 (d, JCF = 22.1 Hz, CH ), 20.8 (d, JCF
) ppm. F NMR (376 MHz, CDCl , interpreted for two
2
), 29.4−29.3
2
2
(m, CH
2
), 29.1−29.0 (m, CH
22.0 Hz, CH
2
3
1
9
=
3
3
For recent reviews, see, a) C. Chatalova-Sazepin, R. Hemelaere, J.
Paquin, G. M. Sammis, Synthesis 2015, 47, 2554−2569; b) B. Lantaño,
A. Postigo, Org. Biomol. Chem. 2017, 15, 9954−9973; c) L. Yang, T.
Dong, H. M. Revankar, C.-P. Zhang, Green Chem. 2017, 19,
major isomers): δ = −170.8 to −171.6 (m, 2F, 2 × CHF of two isomers),
173.0 to −173.5 (m, 1F, CHF), −173.5 to −174.1 (m, 1F, CHF) ppm. MS:
m/z (%) relative intensity 178 [(M + H) , 54], 157 (10), 102 (48), 82 (100),
−
+
+
5
8 14 2
5 (58). HRMS (ESI-TOF) m/z: [M + H] calcd. for C H F NO: 178.1043,
39513992; d) H. Yan, C. Zhu, SelectFluor Radical Fluorination for
found 178.1041.
Preparing Alkyl Fluorides. In Fluorination. Synthetic Organofluorine
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The authors acknowledge financial support from the Thailand
Research Fund (RSA6180025 and IRN58W0005), the Center of
Excellence for Innovation in Chemistry (PERCH-CIC), Ministry of
Higher Education, Science, Research and Innovation, the Office
of the Higher Education Commission and Mahidol University
under the National Research Universities Initiative, CNRS-PICS
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Entry for the Table of Contents
FULL PAPER

-fluorinated -butyrolactams*
Supasorn Phae-nok, Manat Pohmakotr,
Chutima Kuhakarn, Vichai Reutrakul,
and Darunee Soorukram*
Page No. – Page No.
Site-specific Synthesis of -
Fluorinated -Butyrolactams via
Decarboxylative Fluorination of -
Carboxyl--Butyrolactams
The direct and site-specific synthesis of -fluorinated -butyrolactams via AgNO
3
®
mediated decarboxylative fluorination of -carboxyl--butyrolactams using Selectfluor
as a fluorine source was described. The -fluorinated -butyrolactams including chiral
derivatives were obtained in moderate to good yields.
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