Visible-Light-Induced, Catalyst-Free Radical Cross-Coupling Cyclization of N-Allylbromodifluoroacetamides with Disulfides or Diselenides

Article abstract of DOI:10.1021/acs.joc.9b03490

A visible-light-induced, catalyst-free radical cross-coupling cyclization of diselenides or disulfides with N-allylbromodifluoroacetamide has been developed. This developed protocol exhibits good functional group tolerance and affords a variety of 4-thio-

Full text of DOI:10.1021/acs.joc.9b03490

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Note
Visible-Light-Induced, Catalyst-Free Radical Cross-Coupling Cyclization
of N-Allylbromodifluoroacetamides with Disulfides or Diselenides
Zhi-Peng Ye, Peng-Ju Xia, Fang Liu, Yuan-Zhuo Hu, Dan Song, Jun-
An Xiao, Ping Huang, Hao-Yue Xiang, Xiao-Qing Chen, and Hua Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03490 • Publication Date (Web): 02 Apr 2020
Downloaded from pubs.acs.org on April 5, 2020
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Visible-Light-Induced, Catalyst-Free Radical Cross-
Coupling Cyclization of N-Allylbromodifluoroacetamides
with Disulfides or Diselenides
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Zhi-Peng Ye,† Peng-Ju Xia,† Fang Liu,† Yuan-Zhuo Hu,† Dan Song,† Jun-
§
,†
,†,‡
⊥
An Xiao, Ping Huang, Hao-Yue Xiang,* Xiao-Qing Chen* and Hua
Yang*,†,‡
†College of Chemistry and Chemical Engineering, Central South University, Changsha
410083, P. R. China
‡Key Laboratory of Hunan Province for Water Environment and Agriculture Product Safety,
Central South University, Changsha 410083, P. R. China
§College of Chemistry and Materials Science, Guangxi Teachers Education University,
Nanning 530001, Guangxi, P. R. China
⊥ Technology Center of Hunan Provincial Tobacco Company, 386, Labor Middle Road,
Changsha 410019, China
E-mail: hyangchem@csu.edu.cn, xianghaoyue@csu.edu.cn, xqchen@csu.edu.cn.
F
X
O
Ar
F
F
base, DMSO
43 examples
N
R
Ar
X
O
Br
+
Ar
X
N
R
F
X
S, Se
=
mild conditions wide scope privileged scaffold
catalyst
metal
YES
NO
ABSTRACT: A visible-light-induced, catalyst-free radical cross-coupling
cyclization of diselenides or disulfides with N-allylbromodifluoroacetamide has been
developed. This developed protocol exhibits good functional group tolerance and
affords a variety of 4-thio-, 4-seleno-substituted 3,3-difluoro-γ-lactams in moderate to
good yields. Based on control experiments, a plausible radical-radical cross coupling
pathway is proposed.
Owing to their unique physical and chemical properties, gem-difluoro
scaffolds have found increasing utilizations in agricultural, medicinal, and
materials sciences.1 Therefore, new synthesis methods for synthesizing difluoro
group-containing compounds have attracted widespread attention in synthetic
chemistry over the past few years.2 In particular, incorporation of
difluoromethylene group (CF2) into γ-lactams has been intensively studied in
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recent years as γ-lactams usually possess interesting biological profiles (Scheme
5
6
1A).3
7
8
9
Scheme 1 Representative Examples of Bioactive γ-Lactams and Synthetic
Profiles Accessing 3,3-Difluoropyrrolidin-2-ones
O
10
11
12
13
14
15
16
17
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A)
Natural products
O
HO
O
NH
N
O
H2N
N
O
H
R
OH
O
CD45 inhibitor
Synthetic bioactive-molecule
Antibacterial agent
HDAC inhibitor
O
O
F
6
NH
O
F
N
COOH
HN
H
N
S
HO
EP4 agonist
R
O
HDAC inhibitors
previous work:
B)
fac-Ir(ppy)3
CuI, bipy
(Zhu's work)ref.4
O
(Nagashima's
work)ref.8
F
Br
F
F
F
N
R2
F
H
Br
Ni(OTf)2
(Lu's work)ref.9
CuI, Phen
O
F
O
N
R
(Zhang's work)ref.5
N
R1
CuI, PMDETA
CuI, Phen
(Zhang's work)ref.10
(Wang's work)ref.6
this work:
Y
O
F
Y
Y
F
F
base
DMSO, Ar
N
Br
R
N
F
O
Y
S, Se
=
R
catalyst-free
metal-free
mild conditions
The current strategies mainly rely on transition-metal or visible-light-
induced photoredox-catalyzed radical difluoromethylation via intramolecular or
intermolecular pathways, resulting in a range of 3,3-difluoro-γ-lactams. Recently,
Zhu,4 Zhang5 and Wang6 group reported the synthesis of 3,3-difluoro-γ-lactams
via visible-light photoredox and copper-catalysed cyclizations between α-
bromodifluoroacetamides and alkenes. More recently, indoles bearing a C-3
bromodifluoroacetamide moiety acted as a CF2 radical precursor were employed
to construct 3,3-difluoro-γ-lactams under visible-light photocatalysis.7
Alternatively, N-allylhalodifluoroacetamides were utilized to proceed a
intramolecular cyclization to generate 3,3-difluoro-γ-lactams developed by
Nagashima,8 Zhang,9 and Lu10 group. Given the fact that the current strategies
heavily rely on the transition-metal catalysis or high temperature, new efficient
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and environmentally benign synthetic protocols accessing CF2-containing γ-
lactams are still highly desirable, especially for catalyst- and metal-free processes
(Scheme 1B).
9
Organosulfides and organoselenides have received increasing attention
because of their interesting biological and medicinal properties.11 In the context
of photocatalysis, disulfides (BDE = 46 kcal/mol) and diselenides (BDE = 41
kcal/mol)12 are able to serve as facile organochalcogen agents in radical-involved
coupling with various pre-functionalized substrates, such as thiols,13 alkynes,14
Olefins,15 indoles,16 etc.. Given their advantageous feature, we envisioned that
the homolytic cleavage of diselenides or disulfides under mild conditions is
expected to facilely generate RS· and RSe·, which would subsequently proceed
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tandem
radical
addition/radical
coupling
process
with
N-
allylhalodifluoroacetamides. Notably, compared to the previous thermal copper-
catalyzed protocol,9 this metal-free, photo-induced strategy for the construction
of sulfo- or seleno-engineered 3,3-difluoro-γ-lactams is more environmentally
benign due to its mild and green reaction conditions. Herein, we disclose an
catalyst-/metal-free strategy for the synthesis of 4-sulfo/seleno-α,α-difluoro-γ-
lactams through a radical-initiated tandem cyclization.
Table 1 Optimization of reaction conditionsa
O
F
F
F
S
N
Br
O
base
F
S
S
N
solvent, Ar, rt
30 W blue LED
3a
1a
2a
CCDC 1963803
Entry
Base
Solvent Yieldb
1
2
3
4
5
6
7
8
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2CO3
DMF
CH3CN Trace
DMSO 71%
THF
CH2Cl2 NR
DMSO 38%
Trace
NR
CH3COOK DMSO Trace
DMAP DMSO 69%
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Et3N
DMSO 60%
DMSO 26%
DMSO 54%
DMSO ND
DMSO ND
DMSO 63%
10c
11d
12
K2HPO4
K2HPO4
-
K2HPO4
K2HPO4
13e
14f
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aUnless otherwise noted, the reaction was carried out at 0.2 mmol scale in solvent (2 mL) at rt with
a molar ratio of 1a/2a = 1:2; w or w/o base (2 equiv.). bIsolated yields. cWith Ru(bpy)3PF6 (5 mol%).
dWith Ir(ppy)2(dtbbpy)PF6 (5 mol%). eIn the dark. fIrradiated by 30W white LED.
Scheme 2 Substrate Scope for the Cyclization of 1 and 2a
X
O
F
X
F
S
F
S
KH2PO4
N
R
1
S
X
Br
O
DMSO, Ar, rt
30 W blue LED
F
2a
2b
2c
X = H
X = Cl
X = Me
N
2
3
R
N-phenyl substrates
F
F
F
F
F
F
O
S
O
O
X
S
S
N
N
N
Br
3a
3b
X = H,
X = F,
(71%)
(61%)
62%)
X
3f
X = Me, (33%)
3c (
X = Br,
X =Me,
3e
(78%)
3g
X = OMe,
(34%)
3d
(57%)
N-benzyl substrates
F
F
F
F
F
F
O
O
X
S
S
O
S
N
N
N
Y
X
X
3k
3l
3m
X = Br,
X = Cl,
X = F,
(55%)
(40%)
(57%)
3h
X = H,
(69%)
3p
3q
X = Br, Y = H
X = F, Y = F
(59%)
(33%)
3i
X = Br, (67%)
3j
X = OMe, (63%)
3n
X = Me,
(77%)
3o
X = OMe,
(65%)
N-alkyl substrates
F
F
F
F
F
F
F
F
O
S
O
S
O
O
S
S
N
N
N
N
3u
(54%)
3t
(49%)
3s
3r
(64%)
(80%)
F
F
F
F
F
F
O
O
O
S
S
S
N
N
N
O
CF3
3x
(52%)
3v
3w
(89%)
F
(64%)
O
variation of disulfide
F
F
F
F
F
R
O
O
O
S
S
S
N
N
N
Ph
N
R = p-ClC6H4, 3aa
R = p-MeC H , 3ab
R = tBu or Bn N.D.
(55%)
(76%)
3y
(54%)
3z
(45%)
6
4
unsuccessful substrates
O
S
O
O
O
N
H
H
H
Br
N
N
Ph
N
Br
Br
3ac
(62%)
H
Ph
H
Ph
H
Ph
scale up
Start
End
start point
2a
, 0.578 g, , 0.872 g)
reaction in progress
( 10 h)
end point
3a
1a
(
(0.324 g, 51% yield)
aReaction conditions: 1 (0.2 mmol), 2 (0.4 mmol, 2equiv.) and K2HPO4 (0.4 mmol, 2
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equiv.) and DMSO (2 mL) were irradiated with 30 W blue LED in Ar at rt for 10 h;
isolated yields. Gram scale: 1 (2 mmol), 2 (4 mmol, 2 equiv.), K2HPO4 (4 mmol, 2
equiv.) and DMSO (20 mL) were irradiated with 30 W blue LED in Ar at rt for 10 h;
isolated yield.
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Originally, N-allyl-2-bromo-2,2-difluoro-N-phenylacetamide (1a) and diphenyl
disulfide (2a) was chosen as the model substrates to verify the designed visible-light-
driven radical tandem cyclization under irradiation of blue light emitting diode (LED).
In the presence of K2HPO4 as a base, a careful survey of different solvents disclosed
that DMSO performed best in this protocol (Table1, entries 1-5). Moreover, K2HPO4
was proven to be the optimal base through cogitative screening of various bases (K2CO3,
CH3COOK, DMAP, Et3N) (Table1, entries 6-9). It is worth mentioning that addition of
Ru(bpy)3PF6 or Ir(ppy)2(dtbbpy)PF6 led to relatively lower yields of 3a (Table1, entries
10-11). Control experiments demonstrated that base and visible light are all essential to
this transformation (Table1, entries 12-13). This reaction can also occur under
irradiation of 3 W blue LEDs but with a prolonged reaction time. Presumably, wide
emission band for white LEDs is more likely to cause the unexpected side reactions,
and irradiation with white LED gave a lower reaction efficiency relative to blue LEDs
(Table1, entry 14). Interestingly, for this photo-induced transformation, the five-exo-
trig cyclization dominated in the process and no six-endo-trig cyclization product was
isolated.
With the optimized reaction conditions in hand, various substituted
bromodifluoroacetamides 1 were examined to evaluate the substrate scope of this
protocol (Scheme 2). As for o-, m- and p-substituted of N-phenyl substrates 1
were tested to give the corresponding sulfo-α,α-difluoro-γ-lactams in moderate
to good chemical yields (3b-3g), whereas ortho-substitution obviously led to
relatively lower yields (3f and 3g). In addition, N-benzyl 3h was also obtained in
good yield (69%). Thus, diverse N-benzyl groups bearing electron-donating (Me,
OMe) and electron-withdrawing (F, Cl, Br) groups were well tolerated and good
yields were generally achieved (3i-3p), except for the ortho-substituted 3q (33%
yield). It is noteworthy that N-cycloalkyl-2-bromo-2,2-difluoro-N-
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phenylacetamides were also suitable for this transformation, providing the
corresponding products 3r-3u in 49%-80% yields. Moreover, N-alkyl substrates
including 2,2,2-trifluoroethyl, butyl, glycine methyl ester, phenylbutyl, pyridin-
2-ylmethyl were all compatible with the reaction conditions, giving the
corresponding products 3v-3z in 45%-89% yields. Ultimately, 4-Cl- and 4-Me-
diphenyl disulfides are also applicable in this protocol, delivering the
corresponding products 3aa and 3ab in good yields (55% and 76%).
Unfortunately, dialkyl disulfides were examined as well in this protocol, which
were unsuitable for this photo-induced process. Possibly, the aryl groups were
essential to stabilize the S/Se-radicals in this transformation. Replacing the gem-
fluoro group with gem-methyl group in 1a had no significant effect on this
procedure, leading to the desired product 3ac in a moderate yield. Otherwise, N-
allyl-2-bromo-N-phenylacetamide was unsuitable substrate. Regrettably, in
contrast to unsubstituted olefin substrate, the Ph-substituted counterpart was
unable to proceed the cyclization, which is probably due to the demanding steric
effect of Ph group. Pleasingly, a scale-up reaction for the synthesis of 3a was
conducted under the standard reaction conditions, which afforded the desired
product 3a in 51% yield.
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Encouraged by the above results, diphenyl diselenide (4) was also tested to
further evaluate the generality of this protocol and the results are summarized in
Scheme 3. Pleasingly, diverse N-phenyl substituted bromodifluoroamides were
employed in the reaction to afford the corresponding products 5a-5d in moderate
to good chemical yields (37%-69%). Otherwise, good yields (61%-85%) were
obtained for various N-benzyl bromodifluoroamides (5e-5h). Gratifyingly, N-
alkyl substrates were all tolerated well to proceed the title reaction smoothly,
though N-cyclopentyl and N-cyclohexyl analogues (5j and 5k) were achieved in
comparably lower yields. Moreove, N-alkyl substrates including 2,2,2-
trifluoroethyl, glycine methyl ester, pyridin-2-ylmethyl, butyl, phenylbutyl were
applied in reaction conditions to afforded 5l-5p in moderate to good chemical
yields (51%-70%)
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Scheme 3 Substrate Scope for the Cyclization of 1 and Diphenyl Diselenide (4)a
O
7
8
9
KH2PO4
F
F
F
Se
Se
Se
N
R
1
Br
DMSO, Ar, rt
30 W blue LED
O
F
N
4
5
R
10
11
12
13
14
15
16
17
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N-phenyl substrates
F
F
F
F
F
F
O
Se
O
Se
O
Se
N
N
N
Br
X
5c
5d
X = F,
X = Me,
(38%)
(37%)
5a
(51%)
F
5b
(69%)
N-benzyl substrates
F
F
F
F
F
O
Se
O
Se
O
F
Se
N
N
N
X
F
Br
5e
5f
X = H,
(61%)
5g
5h
(85%)
(73%)
X = OMe, (68%)
N-alkyl substrates
F
F
F
F
F
F
O
Se
O
Se
O
Se
N
N
N
5i
5j
(76%)
(43%)
F
5k
(43%)
F
F
F
F
F
O
O
Se
Se
Se
O
N
N
O
O
N
CF3
N
5l
(70%)
5m
(52%)
5n
(51%)
F
F
F
F
O
O
Se
Se
N
N
(CH2)4
5o
(53%)
5p
(61%)
aReaction conditions: 1 (0.2 mmol), 4 (0.4 mmol, 2 equiv.) and K2HPO4 (0.4 mmol, 2
equiv.) were irradiated with 30 W blue LED in Ar at rt for 10 h; isolated yield.
To gain mechanistic insights into this process, several control experiments
were implemented (Figure 1a). The radical inhibition experiments were
conducted by adding 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) under the
standard reaction conditions and the mass analysis of the reaction mixture
indicates that the formation of TEMPO-1a (m/z = 389.1990, calcd 389.2011)
and TEMPO-2a (m/z = 288.1378, calcd 288.1393) can be clearly identified.
Mixing 2a with 2 equiv. of TEMPO under the standard conditions gave the
corresponding TEMPO-2a in 19% yield, while no reaction was observed in the
case of 1a with 2 equiv. of TEMPO. On the other hand, the emission quenching
experiments of 1a and 2a in DMSO were recorded. The 2a solutions was excited at
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340 nm and the emission intensity was collected at 405 nm, moreover, the 1a solutions
was acted as quencher. The Io and I represent the emission in absence and presence of
the quencher. The relevant graph was plotted via the modified Stern–Volmer equation
(Figure 1b).17 The UV-visible spectroscopy studies on 1a and 2a (1×10-4 M, in DMSO)
demonstrate that an absorption at 258 nm can be observed for 1a, whereas the
absorption for 2a shows at 257 nm (Figure 1c). No obvious bathochromic shift was
observed for the mixture of 1a and 2a, indicating that the corresponding electron-
donor−acceptor complexes (EDA) was unlikely formed.
10
11
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13
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S
Ph
Ph
S
a.
O
F
F
F
2a
TEMPO
F
N
O
F
N
O
N
2 equiv
N
O
O
O
Br
F
Ph
S
N
standard reaction
conditions
N
Ph
Ph
Ph
detected by HRMS
1a
detected by HRMS
O
N
standard reaction
conditions
O
N
S
Ph
Ph
S
S
Ph
2a
TEMPO
(2 equiv)
6a
, 19%
O
O
N
standard reaction
conditions
F
N
Br
No Reaction
F
Ph
1a
TEMPO
(2 equiv)
b.
c.
Excition 340 nM
Collection 405 nM
O
F
N
Br
F
Ph
quencher
Figure 1 Control Experiments, Emission Quenching Experiments and UV–Vis
Spectra for Mechanistic Studies
Based on the above-mentioned mechanistic experiments, we propose a
plausible mechanism for this transformation in Scheme 4. Firstly, Ph-X-X-Ph
was excited by visible light to proceed a homolytic cleavage to generate radical
Ph-X· (A) and Ph-XBr (B). Presumably, the base K2HPO4 would consume the
resulting PhXBr to promote this transformation. Subsequently, the abstraction of
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bromine atom from 1a by Ph-X· provided radical C, which would proceed a
rapid 5-exo-trig cyclization to give radical the intermediate D. Finally, a radical-
radical cross-coupling between radical intermediate D and Ph-X· facilely
delivered the final product 3 or 5. Nevertheless, an alternative radical chain
mechanism was unable to be completely ruled out, as the accumulation of the
desired product was observed albeit at an extremely low speed (see Supporting
Information for details).
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Scheme 4 Proposed Mechanism.
O
F
O
N
Br
X
F
F
N
F
1
A
XBr
C
B
5-exo-trig
cyclization
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X = S, Se
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F
O
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N
radical
cross-coupling
N
3/5
D
In summary, we successfully developed a visible-light-induced, catalyst-
free radical cross-coupling cyclization of diselenides or disulfides with N-
allylbromodifluoroacetamide. As a result, a wide range of sulfo- or seleno-
engineered 3,3-difluoro-γ-lactams were facilely installed under mild conditions.
Furthermore, the straightforwardness and environmental benignity of this
developed method would inspire broad exploitation of the hidden potentials of
N-allylhalodifluoroacetamides in the visible-light-induced transformations,
enabling their practical applications in the preparation of valuable fIuorinated
heterocycles.
EXPERIMENTAL SECTION
General Experimental Methods. Unless otherwise noted, all the reagents were purchased
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from commercial suppliers and used without further purification. And the light source used for
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illuminating the reaction vessel (commercial supplier: Synthware) consisted of blue LEDs (λmax
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460 nm) purchased from Taobao (https://gpiled.taobao.com). 1H NMR spectra were recorded at 400
MHz. The chemical shifts were recorded in ppm relative to tetramethylsilane and with the solvent
resonance as the internal standard. Data were reported as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constants (Hz),
integration. 13C NMR data were collected at 100 MHz with complete proton decoupling. Chemical
shifts were reported in ppm from the tetramethylsilane with the solvent resonance as internal
standard. 19F NMR data were collected at 376 MHz with complete proton decoupling. UV–Vis
spectra were recorded using a shimadzu UV-2600. Infrared spectra (IR) were measured by FT-IR
apparatus. High resolution mass spectroscopy (HRMS) was recorded on TOF MS ES+ mass
spectrometer and acetonitrile was used to dissolve the sample. Cyclic Voltammetry (CV)
experiments were recorded on a CHI650D electrochemical workstation. Emission intensities were
recorded using Perkin-Elemer LS 55 Fluorescence Spectrometer. Column chromatography was
carried out on silica gel (200-300 mesh).
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General procedure for the preparation of 1a-1z. Step A: To a mixture of amines (5.0 mmol,
1.0 equiv.) and ytterbium (III) trifluoromethanesulfonate was added ethyl bromodifluoroacetate (0.5
mmol, 1.0 equiv.). The mixture was stirred until the reaction was judged to be completed by TLC
analysis. The obtained crude product was purified by column chromatography (PE:EA = 19:1) on
silica gel to give the corresponding product.
Step B: To a solution of 2-bromo-2,2-difluoro-N-amines (5.0 mmol, 1.0 equiv.) in CH3CN (15
mL) were added K2CO3 (2.07 g, 15 mmol, 3.0 equiv.) and allyl bromide (1.82 g, 15 mmol, 3.0
equiv.). The mixture was heated to reflux under argon atmosphere, until the reaction was judged to
be completed by TLC analysis. The solvent was removed and the obtained residue was purified by
column chromatography (PE:EA = 19:1) on silica gel to give the corresponding product 1.
General procedure for the synthesis of compounds 3a and 5a
Under argon atmosphere, a mixture of N-allyl-2-bromo-2,2-difluoro-N-phenylacetamide 1 (0.2
mmol, 1equiv.), K2HPO4 (0.4 mmol, 2.0 equiv.), diphenyldisulfide (2a) or diphenyldiselenide (2b)
(0.4 mmol, 2 equiv.) in DMSO (2.0 mL) was stirred at room temperature under irradiation of 30 W
blue LEDs (distance app. 3 cm) for 10 h. Thereafter, EtOAc (60 mL) was added to the reaction
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mixture. And the obtained organic layer was washed with brine (3×20 mL), dried over Na2SO4 and
concentrated under reduced pressure. The crude product was further purified by flash
chromatography using silica gel (EtOAc/PE = 1:19 - 1:1) to afford the desired product 3 or 5.
Scale-up reaction Under argon atmosphere, a mixture of N-allyl-2-bromo-2,2-difluoro-N-
phenylacetamide 1a (2.0 mmol, 1.0 equiv.), K2HPO4 (4.0 mmol, 2.0 equiv.), diphenyldisulfide 2a
(4.0 mmol, 2.0 equiv.) in DMSO (20 mL) was stirred at room temperature under irradiation of 30
W blue LEDs (distance app. 8 cm) for 10 h. Thereafter, EtOAc (150 mL) was added to the reaction
mixture. And the obtained organic layer was washed with brine (3×40 mL), dried over Na2SO4 and
concentrated under reduced pressure. The crude products were further purified by flash
chromatography using silica gel (EtOAc/PE = 1:19 - 1:1) to afford the desired products 3a in 50%
yield (326 mg, 1.0 mmol).
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Characterization data of starting materials 1a-1d9,10 1e-1y
N-allyl-2-bromo-N-(3-bromophenyl)-2,2-difluoroacetamide (1e). Pale yellow oil (789 mg, 2.2
mmol, overall yield 43%); IR (neat) ν 1731, 1588, 1439, 1104, 995, 780, 691 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.54 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.30 (J = 8.0 Hz, 1H), 7.21 (d, J = 7.8 Hz,
1H), 5.91 – 5.81 (m, 1H), 5.25 (d, J = 10.1 Hz, 1H), 5.16 (d, J = 17.1 Hz, 1H), 4.30 – 4.29 (m, 2H);
19F {1H} NMR (376 MHz, CDCl3) δ -52.12; 13C {1H} NMR (100 MHz, CDCl3) δ 158.6 (t, JC-F
=
25.3 Hz), 140.8, 132.2, 131.9, 130.4, 127.6, 122.4, 120.3, 111.3 (t, JC-F = 317.3 Hz), 55.4; HRMS
(ESI): C11H9Br2F2NNaO+ [M+Na]+ Calcd 389.8911, found 389.8891.
N-allyl-2-bromo-2,2-difluoro-N-(o-tolyl)acetamide (1f). as an mixture of inseparable
atropisomers: Pale yellow oil (727 mg, 2.4 mmol, overall yield 48%); IR (neat) ν 1686, 1492, 1399,
1150, 981, 899, 660 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.26 (m, 2H), 7.23 – 7.17 (m, 2H),
5.98 – 5.84 (m, 1H), 5.23 – 5.13 (m, 2H), 4.75 (dd, J = 14.1, 5.8 Hz, 1H), 3.69 (dd, J = 14.1, 7.4
Hz, 1H), 2.26 (s, 3H); 19F {1H} NMR (376 MHz, CDCl3) δ -51.78 (d, J = 156.0 Hz, 1.00F), -51.70
(d, J = 157.4 Hz, 0.11F), -55.84 (d, J = 157.4 Hz, 0.09F), -55.41 (d, J = 155.9 Hz, 1.00F); 13C {1H}
NMR (100 MHz, CDCl3) δ 159.1 (dd, JC-F = 26.5, 25.2 Hz), 138.2, 136.0, 131.2, 130.5, 129.6,
129.2, 126.3, 120.1, 111.8 (dd, JC-F = 320.5, 314.5 Hz), 54.5, 17.9; HRMS (ESI):
C12H12BrF2NNaO+ [M+Na]+ Calcd 325.9963, Found 325.9946.
N-allyl-2-bromo-2,2-difluoro-N-(2-methoxyphenyl)acetamide (1g). Pale yellow oil (893 mg,
1
2.8 mmol, overall yield 56%); IR (neat) ν 1687, 1499, 1281, 1150, 924, 938, 662 cm-1; H NMR
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(400 MHz, CDCl3) δ 7.38 – 7.34 (m, 1H), 7.20 (d, J = 7.7 Hz, 1H), 6.96 – 6.93 (m, 2H), 5.90 – 5.80
(m, 1H), 5.16 – 4.64 (m, 2H), 4.69 – 4.64 (dd, J = 14.5, 5.6 Hz, 1H), 3.83 – 3.80 (m, 4H); 19F {1H}
NMR (376 MHz, CDCl3) δ -52.09 (d, J = 154.9 Hz), -54.70 (d, J = 155.1 Hz); 13C {1H} NMR (100
MHz, CDCl3) δ 155.4, 131.3, 130.4, 127.9, 120.1, 119.2, 111.4, 55.5, 54.0; HRMS (ESI):
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+
C12H12BrF2NNaO2 [M+Na]+ Calcd 341.9912, Found 341.9890.
N-allyl-N-benzyl-2-bromo-2,2-difluoroacetamide (1h). as an mixture of inseparable
atropisomers: Pale yellow oil (909 mg, 3.0 mmol, overall yield 60%); IR (neat) ν 1681, 1442, 1153,
1129, 929, 868, 635 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.29 (m, 3H), 7.25 – 7.21 (m, 2H),
5.83 – 5.70 (m, 1H), 5.33 – 5.13 (m, 2H), 4.72 (s, 0.80 H), 4.63 (s, 1.29 H), 4.03 (d, J = 5.6 Hz,
1.28H), 4.03 (d, J = 5.6 Hz, 0.79H); 19F {1H} NMR (376 MHz, CDCl3) δ -53.78 (s, 1.16F), -54.21
(s, 2.00F); 13C {1H} NMR (100 MHz, CDCl3) δ 159.7 (t, JC-F = 26.1 Hz), 135.5, 134.8, 131.6, 130.6,
128.9, 128.8, 128.1, 127.9, 127.2, 119.4, 118.8, 111.0 (t, JC-F = 316.2 Hz), 50.82 (t, JC-F = 3.6 Hz),
49.72 (t, JC-F = 3.5 Hz), 48.8, 48.5; HRMS (ESI): C12H12BrF2NNaO+ [M+Na]+ Calcd 325.9963,
Found 325.9940.
N-allyl-2-bromo-N-(3-bromobenzyl)-2,2-difluoroacetamide (1i). as an mixture of inseparable
atropisomers: Pale yellow oil (1.33 g, 3.5 mmol, overall yield 70%); IR (neat) ν 1681, 1419, 1155,
1071, 930, 873, 641 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.36 (m, 1H), 7.39 – 7.36 (m, 1H),
7.27 – 7.14 (m, 2H), 5.84 – 5.71 (m, 1H), 5.35 – 5.14 (m, 2H), 4.69 (s, 0.67H), 4.59 (s, 1.32H), 4.05
(d, J = 5.3 Hz, 1.33H), 4.05 (d, J = 5.6 Hz, 0.69H); 19F {1H} NMR (376 MHz, CDCl3) δ -53.96 (s,
1.00F), -54.39 (s, 2.00F); 13C {1H} NMR (100 MHz, CDCl3) δ 159.7 (t, JC-F = 26.8 Hz), 137.8,
137.2, 131.4, 131.3, 131.1, 131.0, 130.5, 130.4, 130.3, 130.2, 126.6, 125.7, 123.1, 122.9, 119.7,
119.1, 110.8 (t, JC-F = 315.0 Hz), 50.4 – 49.9 (m), 48.7, 48.3; HRMS (ESI): C12H11Br2F2NNaO+
[M+Na]+ Calcd 403.9068, Found 403.9064.
N-allyl-2-bromo-2,2-difluoro-N-(3-methoxybenzyl)acetamide (1j). as an mixture of
inseparable atropisomers: Pale yellow oil (1.43 g, 4.3 mmol, overall yield 86%); IR (neat) ν 1681,
1436, 1262, 1150, 1008, 871, 691 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.24 (m, 1H), 6.86 –
6.75 (m, 3H), 5.83 – 5.71 (m, 1H), 5.33 – 5.14 (m, 2H), 4.69 (s, 0.74H), 4.61 (s, 1.33H), 4.03 (d, J
= 5.3 Hz, 1.30H), 3.94 (d, J = 5.6 Hz, 0.77H), 3.80 – 3.79 (m, 3H); 19F {1H} NMR (376 MHz,
CDCl3) δ -53.77 (s, 1.15F), -54.28 (s, 2.00F); 13C {1H} NMR (100 MHz, CDCl3) δ 160.1 – 159.1
(m), 137.0, 136.4, 131.1, 130.4, 130.0, 129.9, 120.3, 119.5, 119.4, 118.8, 113.5, 113.4, 113.2, 113.0,
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111.0 (t, JC-F = 315.2 Hz), 55.3, 55.2, 50.7 (t, JC-F = 3.7 Hz), 49.8 (t, JC-F = 3.6 Hz), 48.6, 48.5;
HRMS (ESI): C13H14BrF2NNaO2+ [M+Na]+ Calcd 356.0068, Found 356.0045.
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N-allyl-2-bromo-N-(4-bromobenzyl)-2,2-difluoroacetamide (1k). as an mixture of inseparable
atropisomers: Pale yellow oil (1.49 g, 3.9 mmol, overall yield 78%); IR (neat) ν 1686, 1492, 1399,
1150, 981, 899, 660 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.49 (m, 2H), 7.14 – 7.09 (m, 2H),
5.83 – 5.69 (m, 1H), 5.34 – 5.12 (m, 2H), 4.67 (s, 0.65H), 4.57 (s, 1.32H), 4.02 (d, J = 5.3 Hz,
1.35H), 3.94 (d, J = 5.6 Hz, 0.67H); 19F {1H} NMR (376 MHz, CDCl3) δ -53.90 (s, 0.98F), -54.35
(s, 2.00F); 13C {1H} NMR (100 MHz, CDCl3) δ159.7 (t, JC-F = 26.8 Hz), 134.6, 133.9, 132.1, 132.0,
131.5, 130.4, 129.9, 128.9, 122.1, 122.0, 119.7, 119.0, 110.9 (t, JC-F = 315.0 Hz), 50.2 (t, JC-F = 3.7
Hz), 50.0 (t, JC-F = 3.7 Hz), 48.5, 48.4; HRMS (ESI):C12H11Br2F2NNaO+ [M+Na]+ Calcd 403.9068,
Found 403.9051.
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N-allyl-2-bromo-N-(4-chlorobenzyl)-2,2-difluoroacetamide (1l). as an mixture of inseparable
atropisomers: Pale yellow oil (1.01 g, 3.0 mmol, overall yield 60%); IR (neat) ν 1681, 1407, 1130,
1015, 924, 800, 682 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.31 (m, 2H), 7.20 – 7.15 (m, 2H),
5.83 – 5.69 (m, 1H), 5.34 – 5.12 (m, 2H), 4.69 (s, 0.68H), 4.59 (s, 1.36H), 4.02 (d, J = 5.3 Hz,
1.34H), 3.92 (d, J = 5.6 Hz, 0.67H); 19F {1H} NMR (376 MHz, CDCl3) δ -53.90 (s, 0.98F), -54.35
(s, 2.00F); 13C {1H} NMR (100 MHz, CDCl3) δ 159.7 (t, JC-F = 26.6 Hz), 134.0, 133.9, 133.3, 131.5,
130.4, 129.5, 129.2, 129.1, 128.6, 119.6, 119.0, 110.9 (t, JC-F = 315.0 Hz), 50.2 (t, JC-F = 3.7 Hz),
49.9 (t, JC-F = 3.7 Hz), 48.5, 48.3; HRMS (ESI): C12H11BrClF2NNaO+ [M+Na]+ Calcd 359.9573,
Found 359.9551.
N-allyl-2-bromo-2,2-difluoro-N-(4-fluorobenzyl)acetamide (1m). as an mixture of inseparable
atropisomers: Pale yellow oil (1.09 g, 3.4 mmol, overall yield 68%); IR (neat) ν 1681, 1415, 1224,
115, 923, 820, 621 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.27 – 7.19 (m, 2H), 7.09 – 7.01 (m, 2H),
5.83 – 5.69 (m, 1H), 5.34 – 5.12 (m, 2H), 4.69 (s, 0.66H), 4.59 (s, 1.37H), 4.02 (d, J = 5.4 Hz,
1.40H), 3.91 (d, J = 5.7 Hz, 0.69H); 19F {1H} NMR (376 MHz, CDCl3) δ -53.80 (s, 1.55F), -54.31
(s, 3.15F), -113.83 (s, 0.50F), -114.10 (s, 1.01F); 13C {1H} NMR (100 MHz, CDCl3) δ 162.5 (d, JC-F
= 247.3 Hz), 162.5 (d, JC-F = 246.7 Hz), 159.6 (d, JC-F = 26.6 Hz), 159.3 (d, JC-F = 26.5 Hz), 131.5,
131.3 (d, JC-F = 3.3 Hz), 130.51, 130.47, 130.0 (d, JC-F = 8.2 Hz), 129.0 (d, JC-F = 8.2 Hz), 119.5,
118.9, 115.9 (d, JC-F = 21.7 Hz), 115.8 (d, JC-F = 21.5 Hz), 110.9 (t, J = 315.0 Hz), 50.1 (t, JC-F
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3.6 Hz), 49.8 (t, JC-F = 3.7 Hz), 48.3, 48.2; HRMS (ESI): C12H11BrF3NNaO+ [M+Na]+ Calcd
343.9868, Found 343.9844.
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N-allyl-2-bromo-2,2-difluoro-N-(4-methylbenzyl)acetamide (1m). as an mixture of inseparable
atropisomers: Pale yellow oil (1.32 g, 4.2 mmol, overall yield 83%); IR (neat) ν 1681, 1443, 1155,
1008, 923, 868, 677 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.19 – 7.09 (m, 4H), 5.83 – 5.69 (m, 1H),
5.32 – 5.13 (m, 2H), 4.67 (s, 0.80H), 4.59 (s, 1.26H), 4.00 (d, J = 5.5 Hz, 1.24H), 3.91 (d, J = 5.7
Hz, 0.80H), 2.35 (s, 1.18H), 2.34 (s, 1.77H); 19F {1H} NMR (376 MHz, CDCl3) δ -53.63 (s, 1.27F),
-54.01 (s, 2.00F); 13C {1H} NMR (100 MHz, CDCl3) δ 159.6 (t, JC-F = 26.1 Hz), 137.9, 137.7, 132.4,
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131.7, 130.6, 129.6, 129.5, 128.2, 127.2, 119.4, 118.7, 111.1 (t, JC-F = 315.0 Hz), 111.0 (t, JC-F
=
315.0 Hz), 50.6 (t, JC-F = 3.8 Hz), 49.6 (t, JC-F = 3.7 Hz), 48.5, 48.3, 21.13, 21.09; HRMS (ESI):
C13H14BrF2NNaO+ [M+Na]+ Calcd 340.0119, Found 340.0101.
N-allyl-2-bromo-2,2-difluoro-N-(4-methoxybenzyl)acetamide (1o). as an mixture of
inseparable atropisomers: Pale yellow oil (1.02 g, 3.1 mmol, overall yield 61%); IR (neat) ν 1681,
1
1435, 1260, 1150, 927, 781, 691 cm-1; H NMR (400 MHz, CDCl3) δ 7.19 – 7.13 (m, 2H), 6.9 –
6.87 (m, 2H), 5.83 – 5.68 (m, 1H), 5.33 – 5.12 (m, 2H), 4.65 (s, 0.74H), 4.56 (s, 1.25H), 4.00 (d, J
= 5.5 Hz, 1.25H), 3.91 (d, J = 5.7 Hz, 0.76H), 3.81 (s, 1.18H), 3.80 (s, 1.79H); 19F {1H} NMR (376
MHz, CDCl3) δ -53.63 (s, 1.19F), -54.01 (s, 2.00F); 13C {1H} NMR (100 MHz, CDCl3) δ 159.6 (d,
JC-F = 26.5 Hz), 159.5, 159.4, 159.1 (d, JC-F = 26.2 Hz), 159.6 – 159.3 (m), 131.7, 130.7, 129.7,
128.7, 127.5, 126.6, 119.3, 118.7, 114.3, 114.2, 111.1 (t, JC-F = 315.1 Hz), 111.0 (t, JC-F = 315.0
Hz), 55.3, 55.2, 50.3 (t, JC-F = 3.9 Hz), 49.4 (t, JC-F = 3.7 Hz), 48.2, 48.1; HRMS (ESI):
C13H14BrF2NNaO2+ [M+Na]+ Calcd 356.0068, Found 356.0041.
N-allyl-2-bromo-N-(2-bromobenzyl)-2,2-difluoroacetamide (1p). as an mixture of inseparable
atropisomers: Pale yellow oil (1.51 g, 4.0 mmol, overall yield 79%); IR (neat) ν 1692, 1440, 1132,
1027, 873, 746, 682 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.60 – 7.56 (m, 1H), 7.36 – 7.30 (m, 1H),
7.21 – 7.13 (m, 2H), 5.86 – 5.75 (m, 1H), 5.32 – 5.19 (m, 2H), 4.79 (s, 0.73H), 4.74 (s, 1.37H), 4.07
(d, J = 5.4 Hz, 1.33H), 3.98 (d, J = 5.7 Hz, 0.74H); 19F {1H} NMR (376 MHz, CDCl3) δ -54.22 (s,
2.00F), -54.58 (s, 1.08F); 13C {1H} NMR (100 MHz, CDCl3) δ 159.9 (d, JC-F = 26.6 Hz), 159.6 (d,
JC-F = 26.5 Hz), 134.6, 134.3, 133.2, 133.1, 131.4, 130.3, 129.3, 128.5, 127.9, 127.8, 127.4, 123.6,
122.7, 119.6, 119.1, 111.8 (t, JC-F = 315.1 Hz), 111.7 (t, JC-F = 315.0 Hz), 51.2 (t, JC-F = 3.8 Hz),
50.5 (t, JC-F = 3.6 Hz), 49.7, 49.2; HRMS (ESI): C12H11Br2F2NNaO+ [M+Na]+ Calcd 403.9068,
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N-allyl-2-bromo-N-(2,4-difluorobenzyl)-2,2-difluoroacetamide (1q). as an mixture of
inseparable atropisomers: Pale yellow oil (1.46 g, 4.3 mmol, overall yield 86%); IR (neat) ν 1682,
1505, 1136, 1092, 967, 849, 606 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.33 (m, 0.80H), 6.93
– 6.80 (m, 0.27H), 6.93 – 6.80 (m, 2H), 5.84 – 5.72 (m, 1H), 5.34 – 5.24 (m, 2H), 4.74 (s, 0.55H),
4.62 (s, 1.60H), 4.07 (d, J = 5.6 Hz, 1.60H), 3.93 (d, J = 5.7 Hz, 0.56H); 19F {1H} NMR (376 MHz,
CDCl3) δ -54.11 (s, 0.66F), -54.36 (s, 1.97F), -109.76 (d, J = 7.6 Hz, 0.24F), -109.82 (d, J = 7.7 Hz,
0.65F), -114.02 (d, J = 7.6 Hz, 0.87F), -114.06 (d, J = 7.6 Hz, 0.31F); 13C {1H} NMR (100 MHz,
CDCl3) δ 164.1 – 161.2 (m), 160.2 – 159.3 (m), 131.5 (dd, JC-F = 9.7, 5.4 Hz), 131.3, 130.2, 129.5
– 129.3 (m), 119.7, 119.0, 118.6 (dd, JC-F = 15.2, 4.0 Hz), 111.9 (dd, JC-F = 21.3, 3.6 Hz), 109.3 (t,
JC-F = 315.0 Hz), 104.2 (t, JC-F = 25.4 Hz), 103.9 (t, JC-F = 25.7 Hz), 50.4, 49.0, 44.3 – 44.2 (m),
42.4 (d, JC-F = 3.5 Hz); HRMS (ESI): C12H10BrF4NNaO+ [M+Na]+ Calcd 361.9774, Found 361.9758.
N-allyl-2-bromo-N-cyclopropyl-2,2-difluoroacetamide (1r). as an mixture of inseparable
atropisomers with EtOAc : Pale yellow oil (924 mg, 3.7 mmol, overall yield 73%); IR (neat) ν 1682,
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1405, 1148, 986, 912, 841, 665 cm-1; H NMR (400 MHz, CDCl3) δ 5.87 – 5.79 (m, 1H), 5.21 –
5.18 (m, 2H), 4.15 – 4.08 (m, 2H), 3.04 – 2.93 (m, 0.66H), 2.81 – 2.70 (m, 0.31H), 1.00 – 0.72 (m,
4H); 19F {1H} NMR (376 MHz, CDCl3) δ -53.01 (s, 2.00F), -54.26 (s, 0.96F); 13C {1H} NMR (100
MHz, CDCl3) δ 132.5, 132.2, 118.4, 117.3, 51.6, 31.2, 30.8, 8.7, 7.4; HRMS (ESI):
C8H10BrF2NNaO+ [M+Na]+ Calcd 275.9806, Found 275.9789.
N-allyl-2-bromo-N-cyclobutyl-2,2-difluoroacetamide (1s). as an mixture of inseparable
atropisomers: Pale yellow oil (1.18 g, 4.4 mmol, overall yield 88%); IR (neat) ν 1681, 1418, 1269,
1106, 985, 877, 686 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.89 – 5.76 (m, 1H), 5.23 – 5.13 (m, 2H),
4.74 (p, J = 8.3 Hz, 0.66H), 4.42 (p, J = 8.7 Hz, 0.35H), 4.12 – 4.11 (m, 2H), 2.32 – 2.14 (m, 4H),
1.80 – 1.60 (m, 2H); 19F {1H} NMR (376 MHz, CDCl3) δ -54.13 (s, 2.00F), -54.16 (s, 1.08F); 13
C
{1H} NMR (100 MHz, CDCl3) δ 159.2 (t, JC-F = 26.4 Hz), 158.6 (t, JC-F = 26.4 Hz), 133.7, 133.6,
117.3, 116.2, 111.1 (t, JC-F = 315.1 Hz), 110.8 (t, JC-F = 315.1 Hz), 53.0, 52.0 (t, JC-F = 4.2 Hz), 47.6
(t, JC-F = 3.5 Hz), 44.8, 28.9, 28.2, 15.1, 14.4; HRMS (ESI): C9H12BrF2NNaO+ [M+Na]+ Calcd
289.9963, Found 289.9941.
N-allyl-2-bromo-N-cyclopentyl-2,2-difluoroacetamide (1t). as an mixture of inseparable
atropisomers: Pale yellow oil (1.15 g, 4.1 mmol, overall yield 82%); IR (neat) ν 1682, 1444, 1108,
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1008, 923, 800, 645 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.91 – 5.78 (m, 1H), 5.24 – 5.16 (m, 2H),
4.62 – 4.48 (m, 0.73H), 4.19 – 4.13 (m, 0.28H), 4.08 (d, J = 3.4 Hz, 0.60H), 3.90 (d, J = 4.6 Hz,
1.47H), 1.98 – 1.93 (m, 2H), 1.78 – 1.74 (m, 2H), 1.57 – 1.55 (m, 4H); 19F {1H} NMR (376 MHz,
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CDCl3) δ -53.72 (s, 2.00F), -54.09 (s, 0.78F); 13C {1H} NMR (100 MHz, CDCl3) δ 159.1 (t, JC-F
=
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26.4 Hz), 158.9 (t, JC-F = 26.4 Hz), 133.9, 133.7, 117.5, 116.5, 111.3 (t, JC-F = 315.1 Hz), 110.9 (t,
JC-F = 315.1 Hz), 60.6, 59.3 (t, JC-F = 3.7 Hz), 49.6 (t, JC-F = 3.6 Hz), 45.5, 29.5, 28.5, 24.2, 24.0;
HRMS (ESI): C10H14BrF2NNaO+ [M+Na]+ Calcd 304.0119, Found 304.0103.
N-allyl-2-bromo-N-cyclohexyl-2,2-difluoroacetamide (1u). as an mixture of inseparable
atropisomers: Pale yellow oil (1.18 g, 4.0 mmol, overall yield 80%); IR (neat) ν 1675, 1420, 1171,
1119, 901, 844, 692 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.87 – 5.77 (m, 1H), 5.24 – 5.15 (m, 2H),
4.08 – 3.99 (m, 1H), 3.95 – 3.93 (m, 2H), 1.88 – 1.81 (m, 4H), 1.77 – 1.63 (m, 2H), 1.54 – 1.47 (m,
1H), 1.39 – 1.47 (m, 2H), 1.17 – 1.05 (m, 1H); 19F {1H} NMR (376 MHz, CDCl3) δ -53.83 (s,
0.73F), -54.10 (s, 2.00F); 13C {1H} NMR (100 MHz, CDCl3) δ 159.0 (t, JC-F = 26.4 Hz), 158.7 (t,
JC-F = 26.4 Hz), 134.6, 132.9, 117.5, 117.0, 111.3 (t, JC-F = 315.1 Hz), 110.8 (t, JC-F = 315.1 Hz),
58.4, 58.1 (t, JC-F = 3.7 Hz), 48.1 (t, JC-F = 3.7 Hz), 45.5, 31.2, 29.6, 25.8, 25.6, 25.3, 25.0; HRMS
(ESI): C11H16BrF2NNaO+ [M+Na]+ Calcd 318.0276, Found 318.0254.
N-allyl-2-bromo-2,2-difluoro-N-(2,2,2-trifluoroethyl)acetamide (1v). as an mixture of
inseparable atropisomers: Pale yellow oil (1.25 g, 4.3 mmol, overall yield 85%); IR (neat) ν 1695,
1417, 1106, 1011, 991, 875, 685 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.82 – 5.72 (m, 1H), 5.41 –
5.28 (m, 2H), 4.27 (d, J = 5.7 Hz, 1.58H), 4.19 (d, J = 5.3 Hz, 0.43H), 4.09 – 4.01 (m, 2H); 19F {1H}
NMR (376 MHz, CDCl3) δ -53.92 (q, J = 7.5 Hz, 0.50F), -55.03 (s, 2.00F), -68.57 (t, J = 7.5 Hz,
0.72F), -68.72 (s, 3.11F); 13C {1H} NMR (100 MHz, CDCl3, major) δ 160.1 (t, JC-F = 27.8 Hz),
130.5, 124.1 (q, JC-F = 280.9 Hz), 120.8, 110.2 (t, JC-F = 314.3 Hz), 51.5, 45.7 (q, JC-F = 34.5 Hz);
HRMS (ESI): C7H7BrF5NNaO+ [M+Na]+ Calcd 317.9523, Found 317.9498.
Methyl N-allyl-N-(2-bromo-2,2-difluoroacetyl)glycinate (1x). as an mixture of inseparable
atropisomers: Pale yellow oil (613 mg, 2.2 mmol, overall yield 43%); IR (neat) ν 1685, 1439, 1214,
1118, 991, 876, 674 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.79 – 5.65 (m, 1H), 5.26 – 5.15 (m, 2H),
4.17 – 4.01 (m, 4H), 3.71 – 3.69 (m, 3H); 19F {1H} NMR (376 MHz, CDCl3) δ -55.09 (s, J = 0.86F),
-55.10 (s, J = 2.00F); 13C {1H} NMR (100 MHz, CDCl3) δ 168.3, 168.2, 161.5 – 157.4 (m), 131.2,
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130.6, 119.9, 119.4, 110.7, 110.4 (t, JC-F = 314.3 Hz), 52.7, 52.5, 52.3 (t, JC-F = 3.8 Hz), 51.0, 48.4
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(t, JC-F = 4.1 Hz), 47.6; HRMS (ESI): C8H10BrF2NNaO3 [M+Na]+ Calcd 307.9704, Found 307.9681.
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N-allyl-2-bromo-2,2-difluoro-N-(4-phenylbutyl)acetamide (1y). as an mixture of inseparable
atropisomers: Pale yellow oil (1.19 g, 3.5 mmol, overall yield 69%); IR (neat) ν 1681, 1452, 1143,
983, 868, 745, 698 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.12 (m, 2H), 7.21 – 7.16 (m, 3H),
5.81 – 5.70 (m, 1H), 5.28 – 5.17 (m, 2H), 4.05 (d, J = 5.4 Hz, 1.14H), 3.97 (d, J = 5.6 Hz, 0.91H),
3.44 – 3.38 (m, 2H), 2.68 – 2.56 (m, 2H), 1.64 – 1.63 (m, 4H); 19F {1H} NMR (376 MHz, CDCl3)
δ -54.07 (s, 2.00F), -54.13 (s, 1.58F); 13C {1H} NMR (100 MHz, CDCl3) δ 159.1 (t, JC-F = 26.4 Hz),
159.0 (t, JC-F = 26.3 Hz), 141.9, 141.5, 132.1, 131.2, 128.44, 128.40, 128.38, 128.33, 126.0, 125.9,
118.9, 118.2, 111.1 (t, JC-F = 315.1 Hz), 110.0 (t, JC-F = 315.0 Hz), 50.8 (t, JC-F = 3.8 Hz), 49.4, 48.0
(t, JC-F = 3.5 Hz), 46.7, 35.5, 35.4, 28.4, 28.3, 27.9, 26.0; HRMS (ESI): C15H18BrF2NNaO+ [M+Na]+
Calcd 368.0432, Found 368.0411.
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N-allyl-2-bromo-2,2-difluoro-N-(pyridin-2-ylmethyl)acetamide (1z). as an mixture of
inseparable atropisomers: Pale yellow oil (897 mg, 295 mmol, overall yield 59%); IR (neat) ν
1681, 1436, 1133, 993, 930, 750, 603 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.59 – 8.55 (m, 1H), 7.73
– 7.66 (m, 1H), 7.27 – 7.19 (m, 2H), 5.87 – 5.74 (m, 1H), 5.31 – 5.17 (m, 2H), 4.84 (s, 0.72H), 4.71
(s, 1.28H), 4.22 (d, J = 5.4 Hz, 1.28H), 4.07 (d, J = 5.6 Hz, 0.74H); 19F NMR (376 MHz, CDCl3) δ
-54.11 (s, J = 1.09F), -54.31 (s, J = 2.00F); 13C NMR (100 MHz, CDCl3) δ 159.9, 159.6, 155.7,
155.4, 149.7, 149.4, 137.0, 131.4, 130.4, 122.8, 122.7, 122.2, 120.9, 119.5, 118.9, 111.0, 52.6 (t, J
= 3.3 Hz), 51.2 – 51.1 (m), 49.9; HRMS (ESI): C11H11BrF2N2NaO+ [M+Na]+ Calcd 326.9915,
Found 326.9894.
Characterization data of products 3 and 5
3,3-difluoro-1-phenyl-4-((phenylthio)methyl)pyrrolidin-2-one (3a). Pale yellow solid (45 mg,
0.14 mmol, yield 71%); m.p. 82 – 83 ℃; IR (neat) ν 2924, 1722, 1494, 1202, 1147, 1022, 757, 693
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.63 – 7.61 (m, 2H), 7.43 – 7.41 (m, 4H), 7.36 – 7.32 (m, 2H),
7.29 – 7.28 (m, 1H), 7.24 – 7.23 (m, 1H), 4.02 – 3.97 (m, 1H), 3.72 – 3.68 (m, 1H), 3.50 (dd, J =
13.6, 4.0 Hz, 1H), 2.99 (dd, J = 13.5, 11.0 Hz, 1H), 2.91 – 2.76 (m, 1H); 19F {1H} NMR (376 MHz,
CDCl3) δ -109.46 (d, J = 268.8 Hz), -116.89 (d, J = 268.5 Hz); 13C {1H} NMR (100 MHz, CDCl3)
δ 163.1 – 161.3 (m), 137.8, 133.7, 130.6, 129.5, 129.2, 127.5, 126.3, 112.0, 116.9 (dd, JC-F = 255.2,
250.0 Hz), 48.1 (d, JC-F = 5.9 Hz), 39.3 (t, JC-F = 20.9 Hz), 30.2 (d, JC-F = 7.6 Hz); HRMS (ESI):
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C17H15F2NNaOS+ [M+Na]+ Calcd 342.0735, Found 342.0729.
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3,3-difluoro-1-(4-fluorophenyl)-4-((phenylthio)methyl)pyrrolidin-2-one (3b). Pale yellow oil
(40 mg, 0.12 mmol, yield 61%); IR (neat) ν 2917, 1728, 1509, 1230, 1024, 833, 741, 690 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.62 – 7.58 (m, 2H), 7.43 – 7.41 (m, 2H), 7.36 – 7.33 (m, 2H), 7.30 –
7.28 (m, 1H), 7.13 – 7.08 (m, 2H), 3.97 (t, J = 9.0 Hz, 1H), 3.68 (t, J = 8.7 Hz, 1H), 3.50 (dd, J =
13.7, 4.2 Hz, 1H), 2.99 (dd, J = 13.4, 11.1 Hz, 1H), 2.92 – 2.77 (m, 1H); 19F {1H} NMR (376 MHz,
CDCl3) δ -109.47 (d, J = 269.2 Hz), -114.87, -116.80 (d, J = 269.0 Hz); 13C {1H} NMR (100 MHz,
CDCl3) δ 160.4 (d, JC-F = 246.9 Hz), 133.9, 133.6, 130.6, 129.5, 127.5, 121.8 (d, JC-F = 8.2 Hz),
116.1 (d, JC-F = 22.7 Hz), 48.3 (d, JC-F = 5.9 Hz), 39.4 (t, JC-F = 21.0 Hz), 30.22 (d, JC-F = 7.6 Hz);
HRMS (ESI): C17H14F3NNaOS+ [M+Na]+ Calcd 360.0640, Found 360.0645.
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1-(4-bromophenyl)-3,3-difluoro-4-((phenylthio)methyl)pyrrolidin-2-one (3c) Pale yellow oil
(48 mg, 0.12 mmol, yield 62%); IR (neat) ν 2918, 1710, 1493, 1296, 1075, 970, 750, 691 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.56 – 7.51 (m, 4H), 7.42 (d, J = 7.3 Hz, 2H), 7.35 (t, J = 7.4 Hz, 2H),
7.29 (d, J = 7.2 Hz, 1H), 3.96 (t, J = 9.0 Hz, 1H), 3.67 (t, J = 8.4 Hz, 1H), 3.50 (dd, J = 13.8, 4.1
Hz, 1H), 2.99 (dd, J = 13.4, 11.2 Hz, 1H), 2.91 – 2.76 (m, 1H); 19F {1H} NMR (376 MHz, CDCl3)
δ -109.58 (d, J = 269.6 Hz), -116.73 (d, J = 269.2 Hz); 13C {1H} NMR (100 MHz, CDCl3) δ 161.9
(t, JC-F = 31.2 Hz), 136.8, 133.5, 132.2, 130.6, 129.5, 127.6, 121.3, 119.3, 116.7 (dd, JC-F = 255.6,
250.1 Hz), 47.9 (d, JC-F = 6.0 Hz), 39.2 (t, JC-F = 21.0 Hz), 30.1 (d, JC-F = 7.6 Hz); HRMS (ESI):
C17H14BrF2NNaOS+ [M+Na]+ Calcd 419.9840, Found 419.9863.
3,3-difluoro-4-((phenylthio)methyl)-1-(p-tolyl)pyrrolidin-2-one (3d). Pale yellow solid (38 mg,
0.11 mmol, yield 57%); m.p. 82 – 83 ℃; IR (neat) ν 2922, 1725, 1439, 1252, 1100, 1000, 739, 691
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 7.2 Hz, 2H), 7.34 (t, J=
7.2 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 3.96 (t, J = 9.1 Hz, 1H), 3.67 (t, J =
8.7 Hz, 1H), 3.49 (dd, J = 13.7, 4.2 Hz, 1H), 2.98 (dd, J = 13.5, 11.0 Hz, 1H), 2.90 – 2.75 (m, 1H),
2.35 (s, 3H); 19F {1H} NMR (376 MHz, CDCl3) δ -109.33 (d, J = 268.5 Hz), -116.82 (d, J = 268.4
Hz); 13C {1H} NMR (100 MHz, CDCl3) δ 161.7 (t, JC-F = 31.2 Hz), 136.2, 135.3, 133.7, 130.6,
129.7, 129.4, 127.5, 120.0, 117.0 (dd, JC-F = 255.0, 249.9 Hz), 48.1 (d, JC-F = 5.9 Hz), 39.4 (t, JC-F
= 21.1 Hz), 30.3 (d, JC-F = 7.7 Hz), 20.9; HRMS (ESI): C18H17F2NNaOS+ [M+Na]+ Calcd 356.0891,
Found 356.0889.
1-(3-bromophenyl)-3,3-difluoro-4-((phenylthio)methyl)pyrrolidin-2-one (3e). Pale yellow oil
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(62 mg, 0.16 mmol, yield 78%); IR (neat) ν 2922, 1731, 1478, 1147, 1024, 934, 741, 679 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 7.3 Hz, 2H), 7.39 –
7.33 (m, 3H), 7.30 – 7.27 (m, 2H), 3.97 (t, J = 9.0 Hz, 1H), 3.67 (t, J = 8.6 Hz, 1H), 3.49 (dd, J =
13.8, 4.2 Hz, 1H), 2.99 (dd, J = 13.5, 11.1 Hz, 1H), 2.91 – 2.76 (m, 1H); 19F {1H} NMR (376 MHz,
CDCl3) δ -109.58 (d, J = 269.2 Hz), -116.86 (d, J = 269.5 Hz); 13C {1H} NMR (100 MHz, CDCl3)
δ 162.0 (t, JC-F = 31.4 Hz) 139.0, 133.6, 130.7, 130.5, 129.5, 129.2, 127.6, 122.9, 122.7, 118.4, 116.6
(dd, JC-F = 255.7, 250.3 Hz), 47.9 (d, JC-F = 5.9 Hz), 39.3 (t, JC-F = 20.8 Hz), 30.2 (d, JC-F = 7.4 Hz);
HRMS (ESI): C17H14BrF2NNaOS+ [M+Na]+ Calcd 419.9840, Found 419.9870.
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3,3-difluoro-4-((phenylthio)methyl)-1-(o-tolyl)pyrrolidin-2-one (3f). Pale yellow oil (22 mg,
0.070 mmol, yield 33%); IR (neat) ν 2919, 1732, 1493, 1195, 1023, 851, 762, 691 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.41 (d, J = 7.4 Hz, 2H), 7.35 (t, J = 7.2 Hz, 2H), 7.30 – 7.28 (m, 4H), 7.11
(d, J = 7.1 Hz, 1H), 3.86 – 3.81 (m, 1H), 3.63 – 3.59 (m, 1H), 3.52 (dd, J = 13.6, 4.0 Hz, 1H), 3.04
– 2.98 (m, 1H), 2.94 – 2.83 (m, 1H), 2.20 (s, 3H); 19F {1H} NMR (376 MHz, CDCl3) δ -110.28 (d,
J = 269.4 Hz), -117.20 (d, J = 269.1 Hz); 13C {1H} NMR (100 MHz, CDCl3) δ 162.2, 135.5, 135.2,
133.9, 131.5, 130.5, 129.4, 129.0, 127.4, 127.1, 126.1, 50.4 (d, JC-F = 5.8 Hz), 40.4 (t, JC-F = 21.0
Hz), 30.4 (d, JC-F = 7.9 Hz), 17.7; HRMS (ESI): C18H17F2NNaOS+ [M+Na]+ Calcd 356.0891, Found
356.0893.
3,3-difluoro-1-(2-methoxyphenyl)-4-((phenylthio)methyl)pyrrolidin-2-one (3g). Pale yellow
oil (24 mg, 0.070 mmol, yield 34%); IR (neat) ν 2954, 1733, 1504, 1160, 1022, 851, 741, 691 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.6 Hz, 2H), 7.36 – 7.29 (m, 4H), 7.25 (s, 1H), 7.01 –
6.96 (m, 2H), 3.89 – 3.87 (m, 1H), 3.82 (s, 3H), 3.73 – 3.68 (m, 1H), 3.48 (dd, J = 13.5, 4.2 Hz,
1H), 3.04 – 2.98 (m, 1H), 2.91 – 2.80 (m, 1H); 19F {1H} NMR (376 MHz, CDCl3) δ -110.33 (d, J =
268.5 Hz), -117.84 (d, J = 268.5 Hz); 13C {1H} NMR (100 MHz, CDCl3) δ 154.4, 134.1, 130.5,
129.8, 129.3, 127.9, 127.3, 125.2, 121.0, 112.2, 55.7, 49.6 (d, JC-F = 5.3 Hz), 40.3 (t, JC-F = 21.0
Hz), 30.3 (d, JC-F = 7.9 Hz); HRMS (ESI): C18H17F2NNaO2S+ [M+Na]+ Calcd 372.0840, Found
372.0866.
1-benzyl-3,3-difluoro-4-((phenylthio)methyl)pyrrolidin-2-one (3h). Pale yellow oil (46 mg,
1
0.14 mmol, yield 69%); IR (neat) ν 2918, 1735, 1251, 1080, 1025, 995, 739, 692 cm-1; H NMR
(400 MHz, CDCl3) δ 7.36 – 7.28 (m, 7H), 7.23 – 7.21 (m, 3H), 4.55 (d, J = 14.6 Hz, 1H), 4.45 (d, J
= 14.6 Hz, 1H), 3.44 – 3.36 (m, 2H), 3.10 – 3.06 (m, 1H), 2.85 – 2.79 (m, 1H), 2.74 – 2.57 (m, 1H);
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19F {1H} NMR (376 MHz, CDCl3) δ -110.01 (d, J = 268.8 Hz), -116.88 (d, J = 269.1 Hz); 13C {1H}
NMR (100 MHz, CDCl3) δ 163.1 (t, JC-F = 30.4 Hz), 134.4, 133.8, 130.4, 129.3, 129.1, 128.3, 127.3,
47.4, 46.5 (d, JC-F = 6.2 Hz) 39.6 (t, JC-F = 21.1 Hz), 30.4 (d, JC-F = 8.2 Hz); HRMS (ESI):
C18H17F2NNaOS+ [M+Na]+ Calcd 356.0891, Found 356.0909.
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1-(3-bromobenzyl)-3,3-difluoro-4-((phenylthio)methyl)pyrrolidin-2-one (3i). Pale yellow oil
(55 mg, 0.13 mmol, yield 67%); IR (neat) ν 2918, 1727, 1439, 1251, 1134, 997, 741, 690 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.8 Hz, 1H), 7.39 – 7.29 (m, 6H), 7.23 – 7.21 (m, 1H), 7.15
(d, J = 7.6 Hz, 1H), 4.50 (d, J = 14.7 Hz, 1H), 4.42 (d, J = 14.7 Hz, 1H), 3.44 – 3.36 (m, 2H), 3.11
– 3.07 (m, 1H), 2.88 – 2.81 (m, 1H), 2.76 – 2.61 (m, 1H); 19F {1H} NMR (376 MHz, CDCl3) δ -
110.17 (d, J = 269.7 Hz), -116.91 (d, J = 269.4 Hz); 13C {1H} NMR (100 MHz, CDCl3) δ 163.2 (t,
JC-F = 31.1 Hz), 136.7, 133.8, 131.6, 131.3, 130.7, 130.5, 129.4, 127.4, 126.9, 123.0, 117.1 (dd, JC-
F = 249.5, 253.9 Hz), 46.9, 46.6 (d, JC-F = 6.1 Hz), 39.8 (t, JC-F = 21.2 Hz), 30.4 (d, JC-F = 7.0 Hz);
HRMS (ESI): C18H16BrF2NNaOS+ [M+Na]+ Calcd 433.9996, Found 434.0009.
3,3-difluoro-1-(3-methoxybenzyl)-4-((phenylthio)methyl)pyrrolidin-2-one (3j). Pale yellow oil
(46 mg, 0.13 mmol, yield 63%); IR (neat) ν 2925, 1726, 1438, 1042, 1255, 995, 692 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.35 – 7.24 (m, 6H), 6.86 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 6.74
(s, 1H), 4.51 (d, J = 14.6 Hz, 1H), 4.42 (d, J = 14.5 Hz, 1H), 3.79 (s, 3H), 3.44 – 3.35 (m, 2H), 3.11
– 3.06 (m, 1H), 2.86 – 2.80 (m, 1H), 2.74 – 2.59 (m, 1H); 19F {1H} NMR (376 MHz, CDCl3) δ -
110.00 (d, J = 269.0 Hz), -116.94 (d, J = 269.4 Hz); 13C {1H} NMR (100 MHz, CDCl3) δ 163.1 (t,
JC-F = 30.8 Hz), 160.1, 135.9, 133.9, 130.4, 130.1, 129.3, 127.3, 120.5, 117.3 (dd, JC-F = 255.7,
250.9 Hz), 113.8, 113.7, 55.3, 47.4, 46.5 (d, JC-F = 6.1 Hz), 39.7 (t, JC-F = 21.1 Hz), 30.4 (d, JC-F
=
8.1 Hz); HRMS (ESI): C19H19F2NNaO2S+ [M+Na]+ Calcd 386.0997, Found 386.1011.
1-(4-bromobenzyl)-3,3-difluoro-4-((phenylthio)methyl)pyrrolidin-2-one (3k). Pale yellow oil
(45 mg, 0.11 mmol, yield 55%); IR (neat) ν 2924, 1725, 1488, 1252, 1069, 739, 691 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.48 (d, J = 8.4 Hz, 2H), 7.34 – 7.27 (m, 5H), 7.10 (d, J = 8.4 Hz, 2H), 4.50
(d, J = 14.7 Hz, 1H), 4.39 (d, J = 14.7 Hz, 1H), 3.42 – 3.36 (m, 2H), 3.10 – 3.05 (m, 1H), 2.86 –
2.79 (m, 1H), 2.74 – 2.59 (m, 1H); 19F NMR (376 MHz, CDCl3) δ -110.13 (d, J = 269.7 Hz), -
116.97 (d, J = 269.6 Hz); 13C NMR (100 MHz, CDCl3) δ 133.8, 133.4, 132.2, 130.4, 130.0, 129.4,
127.4, 122.5, 46.4, 46.5 (d, JC-F = 6.1 Hz), 39.7 (t, JC-F = 21.3 Hz), 30.4 (d, JC-F = 8.0 Hz); HRMS
(ESI): C18H16BrF2NNaOS+ [M+Na]+ Calcd 433.9996, Found 434.0013.
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1-(4-chlorobenzyl)-3,3-difluoro-4-((phenylthio)methyl)pyrrolidin-2-one (3l). Pale yellow oil
(29 mg, 0.080 mmol, yield 40%); IR (neat) ν 2920, 1726, 1491, 1253, 1015, 802, 691 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.38 – 7.29 (m, 7H), 7.16 (d, J = 8.3 Hz, 2H), 4.51 (d, J = 14.7 Hz, 1H), 4.41
(d, J = 14.7 Hz, 1H), 3.42 – 3.36 (m, 2H), 3.11 – 3.05 (m, 1H), 2.85 – 2.79 (m, 1H), 2.74 – 2.59 (m,
1H); 19F {1H} NMR (376 MHz, CDCl3) δ -110.12 (d, J = 269.2 Hz), -116.99 (d, J = 269.3 Hz); 13C
{1H} NMR (100 MHz, CDCl3) δ 163.2 (t, JC-F = 32.0 Hz), 134.4, 133.8, 132.9, 130.5, 129.7, 129.4,
129.3, 127.4, 46.8, 46.5 (d, JC-F = 7.4 Hz), 39.7 (t, JC-F = 21.5 Hz), 30.4 (d, JC-F = 8.0 Hz); HRMS
(ESI): C18H16ClF2NNaOS+ [M+Na]+ Calcd 390.0501, Found 390.0501.
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3,3-difluoro-1-(4-fluorobenzyl)-4-((phenylthio)methyl)pyrrolidin-2-one (3m). Pale yellow oil
(40 mg, 0.11 mmol, yield 57%); IR (neat) ν 2918, 1725, 1509m 1223, 1096, 819, 691 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.34 – 7.29 (m, 5H), 7.22 – 7.19 (m, 2H), 7.04 (t, J = 8.5 Hz, 2H), 4.52 (d, J
= 14.6 Hz, 1H), 4.42 (d, J = 14.6 Hz, 1H), 3.43 – 3.36 (m, 2H), 3.10 – 3.05 (m, 1H), 2.85 – 2.79 (m,
1H), 2.74 – 2.59 (m, 1H); 19F {1H} NMR (376 MHz, CDCl3) δ -110.10 (d, J = 269.4 Hz), -113.39,
-117.03 (d, J = 269.2 Hz); 13C {1H} NMR (100 MHz, CDCl3) δ 163.1 (t, JC-F = 30.3 Hz), 162.7 (d,
JC-F = 247.3 Hz), 133.8, 130.5, 130.3 (d, J = 3.3 Hz), 130.1 (d, J = 8.4 Hz), 129.4, 127.4, 116.05 (d,
JC-F = 21.7 Hz), 46.7, 46.4 (d, JC-F = 6.2 Hz), 39.7 (t, JC-F = 20.6 Hz), 30.39 (d, JC-F = 8.1 Hz);
HRMS (ESI): C18H16F3NNaOS+ [M+Na]+ Calcd 374.0797, Found 374.0813.
3,3-difluoro-1-(4-methylbenzyl)-4-((phenylthio)methyl)pyrrolidin-2-one (3n). Pale yellow oil
(53 mg, 0.15 mmol, yield 77%); IR (neat) ν 2918, 1726, 1439, 1210, 1060, 740, 691 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.36 – 7.28 (m, 5H), 7.16 (d, J = 7.9 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 4.50
(d, J = 14.5 Hz, 1H), 4.41 (d, J = 14.5 Hz, 1H), 3.43-3.35 (m, 2H), 3.09 – 3.04 (m, 1H), 2.85 – 2.78
(m, 1H), 2.73 – 2.57 (m, 1H), 2.35 (s, 3H); 19F {1H} NMR (376 MHz, CDCl3) δ -109.91 (d, J =
269.0 Hz), -116.93 (d, J = 268.9 Hz); 13C {1H} NMR (100 MHz, CDCl3) δ 163.0 (t, JC-F = 30.7 Hz),
138.1, 133.9, 131.3, 130.4, 129.7, 129.3, 128.3, 127.3, 47.2, 46.4 (d, JC-F = 6.1 Hz), 39.6 (t, JC-F
=
21.1 Hz), 30.4 (d, JC-F = 8.1 Hz), 21.1; HRMS (ESI): C19H19F2NNaOS+ [M+Na]+ Calcd 370.1048,
Found 370.1057.
3,3-difluoro-1-(4-methoxybenzyl)-4-((phenylthio)methyl)pyrrolidin-2-one 3o: Pale yellow oil
(47 mg, 0.13 mmol, yield 65%); IR (neat) ν 2918, 1727, 1489, 1257, 1042, 876, 692 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.31 – 7.28 (m, 4H), 7.24 – 7.22 (m, 1H), 7.15 (d, J = 8.6 Hz, 2H), 6.87 (d, J
= 8.6 Hz, 2H), 4.48 (d, J = 14.5 Hz, 1H), 4.39 (d, J = 14.5 Hz, 1H), 3.81 (s, 3H), 3.42 – 3.31 (m,
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2H), 3.08 – 3.03 (s, 1H), 2.86 – 2.78 (m, 1H), 2.71 – 2.57 (m, 1H); 19F {1H} NMR (376 MHz,
CDCl3) δ -109.86 (d, J = 268.9 Hz), -116.94 (d, J = 30.5 Hz); 13C {1H} NMR (100 MHz, CDCl3) δ
163.0 (t, JC-F = 30.6 Hz), 159.6, 133.9, 130.42, 129.8, 129.3, 127.8, 126.4, 117.3 (dd, JC-F = 249.5,
254.0 Hz), 114.4, 55.3, 46.9, 46.3 (d, JC-F = 6.0 Hz), 39.6 (t, JC-F = 21.1 Hz), 30.4 (d, JC-F = 8.1 Hz);
HRMS (ESI): C19H19F2NNaO2S+ [M+Na]+ Calcd 386.0997, Found 386.1011.
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1-(2-bromobenzyl)-3,3-difluoro-4-((phenylthio)methyl)pyrrolidin-2-one (3p). Pale yellow oil
(49 mg, 0.12 mmol, yield 59%); IR (neat) ν 2926, 1728, 1439, 1252, 1136, 992, 741, 690 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.9 Hz, 1H), 7.36 – 7.29 (m, 5H), 7.24 – 7.18 (m, 3H), 4.70
(d, J = 15.0 Hz, 1H), 4.62 (d, J = 15.0 Hz, 1H), 3.50 – 3.41 (m, 1H), 3.38 (dd, J = 13.6, 4.5 Hz, 1H),
3.13 – 3.08 (m, 1H), 2.86 (dd, J = 13.3, 10.9 Hz, 1H), 2.77 – 2.61 (m, 1H); 19F {1H} NMR (376
MHz, CDCl3) δ -110.17 (d, J = 269.1 Hz), -117.02 (d, J = 269.5 Hz); 13C {1H} NMR (100 MHz,
CDCl3) δ 163.2 (t, JC-F = 30.6 Hz), 133.9, 133.7, 133.2, 130.5, 130.4, 130.0, 129.3, 128.1, 127.3,
124.0, 117.1 (dd, JC-F = 255.7, 251.0 Hz), 47.2, 46.8 (d, JC-F = 6.0 Hz), 39.9 (t, JC-F = 20.8 Hz), 30.4
(d, JC-F = 8.1 Hz); HRMS (ESI): C18H16BrF2NNaOS+ [M+Na]+ Calcd 433.9996, Found 434.0022.
1-(2,4-difluorobenzyl)-3,3-difluoro-4-((phenylthio)methyl)pyrrolidin-2-one (3q). Pale yellow
1
oil (25 mg, 0.07 mmol, yield 33%); IR (neat) ν 2920, 1728, 1506, 1254, 1095, 850, 691 cm-1; H
NMR (400 MHz, CDCl3) δ 7.36 – 7.29 (m, 6H), 6.91 – 6.82 (m, 2H), 4.57 (d, J = 14.7 Hz, 1H),
4.48 (d, J = 14.7 Hz, 1H), 3.47 (t, J = 9.1 Hz, 1H), 3.38 (dd, J = 13.6, 4.3 Hz, 1H), 3.15 – 3.11 (m,
1H), 2.84 (dd, J = 13.3, 11.1 Hz, 1H), 2.76 – 2.60 (m, 1H); 19F {1H} NMR (376 MHz, CDCl3) δ -
108.73 (d, J = 7.9 Hz), -110.25 (d, J = 269.8 Hz), -114.14 (d, J = 7.8 Hz), -117.12 (d, J = 269.4 Hz);
13C {1H} NMR (100 MHz, CDCl3) δ 164.3 – 159.8 (m), 133.8, 131.95 (dd, JC-F = 9.7, 5.2 Hz),
130.5, 129.4, 127.4, 120.20 – 113.52 (m), 112.18 (dd, JC-F = 21.4, 3.8 Hz), 104.19 (t, JC-F = 25.5
Hz), 46.8 (d, JC-F = 5.9 Hz), 40.4 (d, JC-F = 3.2 Hz), 39.8 (t, JC-F = 20.7 Hz), 30.4 (d, JC-F = 8.1 Hz);
HRMS (ESI): C18H15F4NNaOS+ [M+Na]+ Calcd 392.0703, Found 392.0721.
1-cyclopropyl-3,3-difluoro-4-((phenylthio)methyl)pyrrolidin-2-one (3r). Pale yellow oil (45
mg, 0.16 mmol, yield 80%); IR (neat) ν 2928, 1724, 1439, 1208, 1101, 984, 740, 691 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.39 – 7.38 (m, 2H), 7.35 – 7.32 (m, 2H), 7.28 – 7.25 (m, 1H), 3.50 – 3.45 (m,
1H), 3.39 (dd, J =13.7, 4.4 Hz, 1H), 3.18 – 3.13 (m, 1H), 2.86 (dd, J = 13.2, 11.3 Hz, 1H), 2.75 –
2.57 (m, 2H), 0.85 – 0.81 (m, 2H), 0.79 – 0.73 (m, 2H); 19F {1H} NMR (376 MHz, CDCl3) δ -
109.84 (d, J = 268.9 Hz), -117.16 (d, J = 268.6 Hz); 13C {1H} NMR (100 MHz, CDCl3) δ 164.0 (t,
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JC-F = 30.3 Hz), 133.9, 130.4, 129.4, 127.3, 117.4 (dd, J = 255.4, 250.7 Hz), 47.4 (d, JC-F = 6.0 Hz),
39.7 (t, JC-F = 20.9 Hz), 30.3 (d, JC-F = 8.2 Hz), 26.2, 5.1, 4.9; HRMS (ESI): C14H15F2NNaOS+
[M+Na]+ Calcd 306.0735, Found 306.0747.
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1-cyclobutyl-3,3-difluoro-4-((phenylthio)methyl)pyrrolidin-2-one (3r). Pale yellow oil (38 mg,
0.13 mmol, yield 64%); IR (neat) ν 2921, 1717, 1480, 1269, 1100, 1012, 971, 691 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.42 – 7.40 (m, 2H), 7.37 – 7.33 (m, 2H), 7.29 – 7.27 (m, 1H), 4.61 (p, J = 8.8
Hz, 1H), 3.66 (ddd, J = 10.0, 8.1, 1.8 Hz, 1H), 3.43 (dd, J = 13.7, 4.3 Hz, 1H), 3.33 – 3.19 (m, 1H),
2.89 (dd, J = 13.4, 11.2 Hz, 1H), 2.76 – 2.62 (m, 1H), 2.22 – 2.14 (m, 4H), 1.78 – 1.70 (m, 2H); 19F
{1H} NMR (376 MHz, CDCl3) δ -109.87 (d, J = 268.4 Hz), -116.96 (d, J = 268.6 Hz); 13C {1H}
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NMR (100 MHz, CDCl3) δ 162.4 (t, JC-F = 30.7 Hz), 133.9, 130.4, 129.4, 127.3, 117.6 (dd,
=
C-F
255.5, 250.5 Hz), 47.1, 43.6 (d, JC-F = 6.2 Hz), 39.6 (t, JC-F = 21.0 Hz), 30.4 (d, JC-F = 8.1 Hz), 27.0,
26.8, 15.1; HRMS (ESI): C15H17F2NNaOS+ [M+Na]+ Calcd 320.0891, Found 320.0909.
1-cyclopentyl-3,3-difluoro-4-((phenylthio)methyl)pyrrolidin-2-one (3t). Pale yellow oil (30 mg,
1
0.10 mmol, yield 49%); IR (neat) ν 2918, 1720, 1439, 1254, 1133, 991, 741, 691 cm-1; H NMR
(400 MHz, CDCl3) δ 7.40 – 7.39 (m, 2H), 7.36 – 7.32 (m, 2H), 7.29 – 7.25 (m, 1H), 4.47 (p, J = 8.1
Hz, 1H), 3.52 (t, J = 8.9 Hz, 1H), 3.42 (dd, J = 13.7, 4.2 Hz, 1H), 3.18 – 3.14 (m, 1H), 2.91 – 2.85
(m, 1H), 2.75 – 2.60 (m, 1H), 1.94 – 1.82 (m, 2H), 1.76 – 1.62 (m, 4H), 1.56 – 1.46 (m, 2H); 19
F
{1H} NMR (376 MHz, CDCl3) δ -110.04 (d, J = 268.3 Hz), -117.37 (d, J = 268.3 Hz); 13C {1H}
NMR (100 MHz, CDCl3) δ 162.9 (t, JC-F = 30.3 Hz), 134.0, 130.4, 129.3, 127.3, 53.4, 43.2 (d, JC-F
= 6.1 Hz), 39.8 (t, JC-F = 21.3 Hz), 31.5 (d, JC-F = 8.0 Hz), 28.7, 24.1; HRMS (ESI):
C16H19F2NNaOS+ [M+Na]+ Calcd 334.1048, Found 334.1047.
1-cyclohexyl-3,3-difluoro-4-((phenylthio)methyl)pyrrolidin-2-one (3t). Pale yellow oil (35 mg,
1
0.11 mmol, yield 54%); IR (neat) ν 2918, 1711, 1453, 1257, 1056, 976, 733, 688 cm-1; H NMR
(400 MHz, CDCl3) δ 7.40 – 7.38 (m, 2H), 7.36 – 7.32 (m, 2H), 7.28 – 7.24 (m, 1H), 3.99 – 3.95 (m,
1H), 3.55 (t, J = 9.0 Hz, 1H), 3.42 (dd, J = 13.6, 4.2 Hz, 1H), 3.16 (t, J = 8.2 Hz, 1H), 2.89 – 2.83
(m, 1H), 2.73 – 2.58 (m, 1H), 1.83 – 1.81 (m, 2H), 1.74 – 1.68 (m, 3H), 1.43 – 1.34 (m, 5H); 19
F
{1H} NMR (376 MHz, CDCl3) δ -110.13 (d, J = 268.1 Hz), -117.30 (d, J = 267.9 Hz); 13C {1H}
NMR (100 MHz, CDCl3) δ 134.0, 130.3, 129.4, 127.3, 51.6, 43.1 (d, JC-F = 6.2 Hz), 39.7 (t, JC-F
=
21.5 Hz), 30.3 (d, JC-F = 8.3 Hz), 29.8, 29.6, 25.2, 25.1; HRMS (ESI): C17H21F2NNaOS+ [M+Na]+
Calcd 348.1204, Found 348.1216.
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3,3-difluoro-4-((phenylthio)methyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-2-one (3v). Pale yellow
oil (58 mg, 0.18 mmol, yield 89%); IR (neat) ν 2918, 1743, 1489, 1259, 1081, 905, 742, 659 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.41 – 7.39 (m, 2H), 7.36 – 7.33 (m, 2H), 7.30 – 7.28 (m, 1H), 4.02
(dq, J = 17.7, 8.9 Hz, 1H), 3.85 (dq, J = 17.2, 8.7 Hz, 1H), 3.70 (t, J = 9.0 Hz, 1H), 3.41 (dt, J =
16.0, 7.9 Hz, 2H), 2.91 (dd, J = 13.4, 11.0 Hz, 1H), 2.83 – 2.68 (m, 1H); 19F{1H} NMR (376 MHz,
CDCl3) δ -69.45, -111.43 (d, J = 271.0 Hz), -117.56 (d, J = 271.3 Hz); 13C {1H} NMR (100 MHz,
CDCl3) δ 163.9 (t, JC-F = 31.6 Hz), 133.6, 130.7, 129.5, 127.6, 123.4 (q, JC-F = 280.4 Hz), 116.2 (dd,
JC-F = 255.9, 250.9 Hz), 48.1 (d, JC-F = 5.9 Hz), 44.8 (q, JC-F = 35.1 Hz), 40.1 (t, JC-F = 20.9 Hz),
30.1 (d, 7.8 Hz); HRMS (ESI): C13H12F5NNaOS+ [M+Na]+ Calcd 348.0452, Found 348.0455.
1-butyl-3,3-difluoro-4-((phenylthio)methyl)pyrrolidin-2-one (3w). Pale yellow oil (38 mg, 0.13
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mmol, yield 64%); IR (neat) ν 2917, 1727, 1510, 1293, 1098, 836, 739, 691 cm-1; H NMR (400
MHz, CDCl3) δ 7.39 (d, J = 7.2 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.29 – 7.25 (m, 1H), 3.55 – 3.50
(m, 1H), 3.42 (ddd, J = 16.6, 11.3, 5.8 Hz, 2H), 3.30 – 3.21 (m, 2H), 2.91 – 2.85 (m, 1H), 2.77 –
2.58 (m, 1H), 1.53 (p, J = 7.4 Hz, 2H), 1.34 – 1.28 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H); 19F {1H} NMR
(376 MHz, CDCl3) δ -110.10 (d, J = 268.5 Hz), -116.98 (d, J = 268.5 Hz); 13C {1H} NMR (100
MHz, CDCl3) δ 163.0 (t, JC-F = 30.0 Hz), 133.9, 130.4, 129.4, 127.3, 117.4 (dd, JC-F = 255.0, 250.4
Hz), 46.9 (d, JC-F = 6.6 Hz), 43.2, 39.7 (t, JC-F = 21.2 Hz), 30.4 (d, JC-F = 8.4 Hz), 28.8, 19.9, 13.6;
HRMS (ESI): C15H19F2NNaOS+ [M+Na]+ Calcd 322.1048, Found 322.1031.
Methyl 2-(3,3-difluoro-2-oxo-4-((phenylthio)methyl)pyrrolidin-1-yl)acetate (3x). Pale yellow
oil (33 mg, 0.10 mmol, yield 52%); IR (neat) ν 2920, 1728, 1438, 1207, 1101, 1023, 852, 692 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.5 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.29 – 7.25 (m,
1H), 4.18 (d, J = 17.5 Hz, 1H), 4.06 (d, J = 17.6 Hz, 1H), 3.76 (s, 3H), 3.65 (t, J = 8.9 Hz, 1H), 3.45
– 3.40 (m, 2H), 2.94 (dd, J = 13.2, 11.4 Hz, 1H), 2.85 – 2.70 (m, 1H); 19F {1H} NMR (376 MHz,
CDCl3) δ -110.38 (d, J = 270.4 Hz), -117.37 (d, J = 270.3 Hz); 13C {1H} NMR (100 MHz, CDCl3)
δ 167.7, 163.7 (t, JC-F = 30.8 Hz), 133.8, 130.5, 129.4, 127.4, 116.8 (dd, JC-F = 255.1, 251.4 Hz),
52.6, 47.78 (d, JC-F = 5.8 Hz), 44.3, 39.8 (t, JC-F = 21.3 Hz), 30.3 (d, JC-F = 8.0 Hz); HRMS (ESI):
C14H15F2NNaO3S+ [M+Na]+ Calcd 338.0633, Found 338.0637.
3,3-difluoro-1-(4-phenylbutyl)-4-((phenylthio)methyl)pyrrolidin-2-one (3y). Pale yellow oil
(41 mg, 0.11 mmol, yield 54%); IR (neat) ν 2919, 1725, 1439, 1253, 1143, 1066, 980, 698 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.39 – 7.37 (m, 2H), 7.34 – 7.31 (m, 2H), 7.29 – 7.26 (m, 4H), 7.20 –
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7.18 (m, 1H), 7.16 – 7.14 (m, 1H), 3.48 – 3.38 (m, 3H), 3.31 – 3.24 (m, 1H), 3.17 – 3.13 (m, 1H),
2.85 (dd, J = 13.3, 11.2 Hz, 1H), 2.74 – 2.61 (m, 3H), 1.62 – 1.56 (m, 4H); 19F {1H} NMR (376
MHz, CDCl3) δ -110.05 (d, J = 268.4 Hz), -116.89 (d, J = 268.6 Hz); 13C {1H} NMR (100 MHz,
CDCl3) δ 163.1 (t, JC-F = 30.0 Hz), 141.6, 133.9, 130.4, 129.4, 128.42, 128.40, 127.3, 126.0, 117.3
(dd, JC-F = 255.3, 250.3 Hz), 47.0 (d, JC-F = 6.2 Hz), 43.2, 39.7 (t, JC-F = 21.1 Hz), 35.2, 30.4 (d, JC-F
= 8.1 Hz), 28.2, 26.1; HRMS (ESI): C21H23F2NNaOS+ [M+Na]+ Calcd 398.1361, Found 398.1367.
3,3-difluoro-4-((phenylthio)methyl)-1-(pyridin-2-ylmethyl)pyrrolidin-2-one (3z). Pale yellow
oil (30 mg, 0.90 mmol, yield 45%); IR (neat) ν 2919, 1726, 1437, 1210, 1097, 1001, 741, 691 cm-1;
1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 4.4 Hz, 1H), 7.68 (td, J = 7.7, 1.6 Hz, 1H), 7.37 – 7.29
(m, 4H), 7.26 – 7.22 (m, 3H), 4.68 (d, J = 15.0 Hz, 1H), 4.57 (d, J = 15.0 Hz, 1H), 3.76 – 3.55 (m,
1H), 3.40 (dd, J = 13.6, 4.4 Hz, 1H), 3.34 – 3.31 (m, 1H), 2.89 (dd, J = 13.2, 11.0 Hz, 1H), 2.80 –
2.66 (m, 1H); 19F {1H} NMR (376 MHz, CDCl3) δ -110.00 (d, J = 269.1 Hz), -117.09 (d, J = 269.1
Hz); 13C {1H} NMR (100 MHz, CDCl3) δ 163.3 (t, JC-F = 30.1 Hz), 154.6, 149.6, 137.2, 134.0,
130.5, 129.3, 127.3, 123.0, 122.5, 117.3 (dd, JC-F = 255.5, 251.1 Hz), 49.0, 47.5 (d, JC-F = 5.8 Hz),
39.8 (t, JC-F = 21.1 Hz), 30.4 (d, JC-F = 8.1 Hz); HRMS (ESI): C17H16F2N2NaOS+ [M+Na]+ Calcd
357.0844, Found 357.0853.
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4-(((4-chlorophenyl)thio)methyl)-3,3-difluoro-1-phenylpyrrolidin-2-one (3aa). Pale yellow
solid (39 mg, 0.11 mmol, yield 55%); m.p. 116 – 117 ℃; IR (neat) ν 2918, 1722, 1476, 1202, 1057,
809, 760, 691 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 8.0 Hz, 2H),
7.36 – 7.30 (m, 4H), 7.27 – 7.23 (m, 1H), 4.00 (t, J = 8.8 Hz, 1H), 3.70 (t, J = 8.4 Hz, 1H), 3.46 (dd,
J = 13.7, 4.4 Hz, 1H), 2.99 (dd, J = 13.5, 10.9 Hz, 1H), 2.89 – 2.74 (m, 1H); 19F {1H} NMR (376
MHz, CDCl3) δ -109.26 (d, J = 269.0 Hz), -116.85 (d, J = 268.7 Hz); 13C {1H} NMR (100 MHz,
CDCl3) δ 161.8 (t, JC-F = 31.1 Hz), 137.7, 133.7, 132.2, 131.9, 129.6, 129.2, 126.3, 119.9, 116.8
(dd, JC-F = 255.4, 250.3 Hz), 48.0 (d, JC-F = 5.8 Hz), 39.2 (t, JC-F = 20.8 Hz), 30.5 (d, JC-F = 7.6 Hz);
HRMS (ESI): C17H14ClF2NNaOS+ [M+Na]+ Calcd 376.0345, Found 376.0371.
3,3-difluoro-1-phenyl-4-((p-tolylthio)methyl)pyrrolidin-2-one (3ab). Pale yellow solid (51 mg,
0.15 mmol, yield 76%); m.p. 72 – 73 ℃; IR (neat) ν 2920, 1723, 1494, 1200, 1035, 802, 756, 690
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.4 Hz, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.33 (d, J =
8.0 Hz, 2H), 7.24 – 7.23 (m, 1H), 7.15 (d, J = 8.0 Hz, 2H), 3.99 (t, J = 8.8 Hz, 1H), 3.70 (t, 8.4 Hz,
1H), 3.44 (dd, J = 13.7, 4.1 Hz, 1H), 2.94 (dd, J = 13.6, 11.1 Hz, 1H),, 2.87 – 2.71 (m, 1H), 2.34 (s,
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3H); 19F {1H} {1H} NMR (376 MHz, CDCl3) δ -109.46 (d, J = 268.7 Hz), -116.87 (d, J = 268.5
Hz); 13C {1H} {1H} NMR (100 MHz, CDCl3) δ 162.0 (t, JC-F = 31.1 Hz), 137.90, 137.85, 131.3,
130.2, 129.8, 129.2, 126.2, 119.9, 117.0 (dd, JC-F = 254.9, 250.1 Hz), 48.1 (d, JC-F = 5.9 Hz), 39.3
(t, JC-F = 20.9 Hz), 30.9 (d, JC-F = 7.4 Hz), 21.1; HRMS (ESI): C18H17F2NNaOS+ [M+Na]+ Calcd
356.0891, Found 356.0909.
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3,3-dimethyl-1-phenyl-4-((phenylthio)methyl)pyrrolidin-2-one (3ac) Yellow oil (39 mg, 0.12
mmol, yield 62%); IR (neat) ν 2963, 1693, 1492, 1394, 1298, 1022, 759, 690 cm-1; 1H NMR (400
MHz, CDCl3) 1H NMR (400 MHz, Chloroform-d) δ 7.62 (d, J = 8.2 Hz, 2H), 7.46 – 7.20 (m, 7H),
7.13 (t, J = 7.4 Hz, 1H), 3.92 (dd, J = 9.8, 7.5 Hz, 1H), 3.54 (t, J = 9.5 Hz, 1H), 3.23 (dd, J = 12.9,
4.3 Hz, 1H), 2.87 (dd, J = 12.9, 10.8 Hz, 1H), 2.35 (tdd, J = 11.0, 8.1, 4.2 Hz, 1H), 1.27 (s, 3H),
1.11 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 178.2, 139.5, 135.3, 129.8, 129.2, 128.8, 126.7,
124.4, 119.7, 50.4 , 44.8, 42.3, 33.2, 24.1, 18.8; HRMS (ESI): C19H21NNaOS+ [M+Na]+ Calcd
334.1236, Found 3334.1211.
3,3-difluoro-1-phenyl-4-((phenylselanyl)methyl)pyrrolidin-2-one (5a). Pale yellow solid (37
mg, 0.10 mmol, yield 51%); m.p. 86 – 87 ℃; IR (neat) ν 2917, 1724, 1495, 1285, 1098, 848, 765,
692 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.0 Hz, 2H), 7.57 – 7.55 (m, 2H), 7.41 (t, J =
8.0 Hz, 2H), 7.33 – 7.332 (m, 3H), 7.24 – 7.23 (m, 1H), 3.90 (t, J = 8.8 Hz, 1H), 3.63 (t, J = 8.4 Hz,
1H), 3.39 (dd, J = 12.7, 3.9 Hz, 1H), 2.94 (t, J = 11.7 Hz, 1H), 2.89 – 2.73 (m, 1H); 19F {1H} NMR
(376 MHz, CDCl3) δ -109.86 (d, J = 268.0 Hz), -116.89 (d, J = 267.9 Hz); 13C {1H} NMR (100
MHz, CDCl3) δ 162.1 (t, JC-F = 31.0 Hz), 137.8, 133.6, 126.9, 129.2, 128.1, 127.9, 126.3, 119.9,
116.9 (dd, JC-F = 253.3, 248.0 Hz), 48.9 (d, JC-F = 6.1 Hz), 40.3 (t, JC-F = 21.1 Hz), 22.3 (d, JC-F
=
7.0 Hz); HRMS (ESI): C17H15F2NNaOSe+ [M+Na]+ Calcd 390.0179, Found 390.0153.
1-(3-bromophenyl)-3,3-difluoro-4-((phenylselanyl)methyl)pyrrolidin-2-one (5b). Pale yellow
oil (62 mg, 0.14 mmol, yield 69%); IR (neat) ν 2954, 1729, 1478, 1209, 1036, 851, 737, 691 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.63 – 7.60 (m, 1H), 7.57 – 7.55 (m, 2H), 7.38-7.36 (m,
1H), 7.33 – 7.32 (m, 3H), 7.29 – 7.27 (m, 1H)，3.95 (t, J = 9.2 Hz, 1H), 3.58 (t, J = 8.8 Hz, 1H),
3.38 (dd, J = 12.7, 4.0 Hz, 1H), 2.93 (t, J = 11.8 Hz, 1H), 2.87 – 2.74 (m, 1H); 19F {1H} NMR (376
MHz, CDCl3) δ -110.00 (d, J = 268.7 Hz), -116.84 (d, J = 268.5 Hz); 13C {1H} NMR (100 MHz,
CDCl3) δ 162.1 (t, JC-F = 31.0 Hz), 139.0, 133.6, 130.5, 129.6, 129.2, 128.2, 127.8, 122.9, 122.6,
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118.3, 116.7 (dd, JC-F = 254.4, 249.0 Hz), 48.7 (d, J = 6.0 Hz), 40.2 (t, JC-F = 21.1 Hz), 22.2 (d, JC-
F = 6.9 Hz); HRMS (ESI): C17H14BrF2NNaOSe+ [M+Na]+ Calcd 467.9284, Found 467.9305.
3,3-difluoro-1-(4-fluorophenyl)-4-((phenylselanyl)methyl)pyrrolidin-2-one (5c). Pale yellow
oil (29 mg, 0.08 mmol, yield 38%); IR (neat) ν 2918, 1725, 1509, 1223, 1096, 819, 739, 691 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.60 – 7.55 (m, 4H), 7.33 – 7.32 (m, 3H), 7.12 – 7.08 (m, 2H), 3.96
(t, J = 9.2 Hz, 1H), 3.61 (t, J = 8.4 Hz, 1H), 3.39 (dd, J = 12.8, 4.0 Hz, 1H), 2.96 – 2.90 (m, 1H),
2.88 – 2.75 (m, 1H); 19F {1H} NMR (376 MHz, CDCl3) δ -109.88 (d, J = 268.2 Hz), -114.90, -
116.75 (d, J = 268.4 Hz);13C {1H} NMR (100 MHz, CDCl3) δ 162.0 (t, JC-F = 31.1 Hz), 160.4 (d, J
= 245.3 Hz), 133.9 (d, JC-F = 3.1 Hz), 133.5, 129.6, 128.1, 127.8, 121.7 (d, JC-F = 8.2 Hz), 116.9
(dd, JC-F = 255.2, 249.7 Hz), 116.1 (d, JC-F = 22.7 Hz), 49.1 (d, JC-F = 6.1 Hz), 40.2 (t, JC-F = 21.1
Hz), 22.3 (d, JC-F = 7.0 Hz); HRMS (ESI): C17H14F3NNaOSe+ [M+Na]+ Calcd 408.0085, Found
408.0105.
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3,3-difluoro-4-((phenylselanyl)methyl)-1-(p-tolyl)pyrrolidin-2-one (5d). Pale yellow solid (28
mg, 0.07 mmol, yield 37%); m.p. 91 – 92 ℃; IR (neat) ν 2918, 1706, 1514, 1284, 1028, 829, 739,
691 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.55 (m, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.33 – 7.31
(m, 3H), 7.20 (d, J = 8.4 Hz, 2H), 3.96 (t, J = 9.2 Hz, 1H), 3.60 (t, J = 8.8 Hz, 1H), 3.39 (dd, J =
12.8, 4.0 Hz, 1H), 2.96 – 2.90 (m, 1H), 2.88 – 2.73 (m, 1H), 2.35 (s, 3H); 19F {1H} NMR (376 MHz,
CDCl3) δ -109.77 (d, J = 267.8 Hz), -116.80 (d, J = 267.8 Hz); 13C {1H} NMR (100 MHz, CDCl3)
δ 161.9 (t, JC-F = 30.6 Hz), 136.1, 135.3, 133.5, 129.7, 129.6, 128.1, 127.9, 119.9, 116.9 (dd, JC-F
=
255.2, 249.7 Hz), 49.9 (d, JC-F = 6.0 Hz), 40.2 (t, JC-F = 21.1 Hz), 22.4 (d, JC-F = 7.1 Hz), 21.0;
HRMS (ESI): C18H17F2NNaOSe+ [M+Na]+ Calcd 404.0336, Found 404.0363.
1-benzyl-3,3-difluoro-4-((phenylselanyl)methyl)pyrrolidin-2-one (5e). Pale yellow oil (47 mg,
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0.12 mmol, yield 61%); IR (neat) ν 2919, 1724, 1437, 1249, 1057, 994, 737, 692 cm-1; H NMR
(400 MHz, CDCl3) δ 7.47 – 7.45 (m, 2H), 7.36 – 7.33 (m, 3H), 7.28 – 7.27 (m, 3H), 7.22 – 7.20 (m,
2H), 4.53 (d, J = 14.6 Hz, 1H), 4.45 (d, J = 14.6 Hz, 1H), 3.43 – 3.38 (m, 1H), 3.27 (dd, J = 12.6,
4.3 Hz, 1H), 3.04 – 3.00 (m, 1H), 2.77 (t, J = 11.7 Hz, 1H), 2.74 – 2.57 (m, 1H); 19F {1H} NMR
(376 MHz, CDCl3) δ -110.43 (d, J = 268.2 Hz), -116.89 (d, J = 268.2 Hz); 13C {1H} NMR (100
MHz, CDCl3) δ 163.3 (t, JC-F = 30.1 Hz), 134.4, 133.4, 129.5, 129.1, 128.3, 128.0, 127.9, 117.4 (dd,
JC-F = 255.8, 250.7 Hz), 47.1, 47.3 (d, JC-F = 6.2 Hz), 40.6 (t, JC-F = 21.2 Hz), 22.6 (d, JC-F = 7.5
Hz); HRMS (ESI): C18H17F2NNaOSe+ [M+Na]+ Calcd 404.0336, Found 404.0357.
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3,3-difluoro-1-(4-methoxybenzyl)-4-((phenylselanyl)methyl)pyrrolidin-2-one (5f). Pale yellow
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oil (56 mg, 0.14 mmol, yield 68%); IR (neat) ν 2918, 1724, 1513, 1245, 1029, 818, 691 cm-1; H
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NMR (400 MHz, CDCl3) δ 7.47 – 7.45 (m, 2H), 7.31 – 7.28 (m, 3H), 7.14 (d, J = 8.4 Hz, 2H), 6.87
(d, J = 8.4 Hz, 2H), 4.47 (d, J = 14.5 Hz, 1H), 4.37 (d, J = 14.4 Hz, 1H), 3.81 (s, 3H), 3.41 – 3.36
(m, 1H), 3.26 (dd, J = 12.6, 4.3 Hz, 1H), 3.01 – 2.96 (m, 1H), 2.76 (t, J = 11.7 Hz, 1H), 2.71 – 2.56
(m, 1H); 19F {1H} NMR (376 MHz, CDCl3) δ -110.25 (d, J = 268.2 Hz), -116.88 (d, J = 267.9 Hz);
13C {1H} NMR (100 MHz, CDCl3) δ 163.1 (t, JC-F = 30.7 Hz), 159.5, 133.4, 129.7, 129.4, 128.0,
127.9, 126.4, 117.4 (dd, JC-F = 255.8, 250.8 Hz), 114.4, 55.3, 47.1 (d, JC-F = 6.3 Hz), 46.8, 40.5 (t,
JC-F = 21.2 Hz), 22.6 (d, JC-F = 7.6 Hz); HRMS (ESI): C19H19F2NNaO2Se+ [M+Na]+ Calcd 434.0441,
Found 434.0464.
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1-(2,4-difluorobenzyl)-3,3-difluoro-4-((phenylselanyl)methyl)pyrrolidin-2-one (5g). Pale
yellow oil (71 mg, 0.17 mmol, yield 85%); IR (neat) ν 2918, 1728, 1505, 966, 850, 737, 691 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.49 – 7.47 (m, 2H), 7.29-7.24 (m, 4H), 6.90 – 6.81 (m, 2H), 4.56
(d, J = 14.7 Hz, 1H), 4.46 (d, J = 14.7 Hz, 1H), 3.46 (t, J = 9.0 Hz, 1H), 3.27 (dd, J = 12.6, 4.2 Hz,
1H), 3.05 (t, J = 8.4 Hz, 1H), 2.78 (t, J = 11.7 Hz, 1H), 2.69 – 2.59 (m, 1H); 19F {1H} NMR (376
MHz, CDCl3) δ -108.76 (d, J = 8.0 Hz), -110.63 (d, J = 268.6 Hz), -114.09 (d, J = 7.7 Hz), -117.02
(d, J = 268.8 Hz); 13C {1H} NMR (100 MHz, CDCl3) δ 163.3 (t, JC-F = 30.8 Hz), 162.9 (dd, JC-F
=
250.5, 11.9 Hz), 161.1 (dd, JC-F = 249.7, 12.0 Hz), 133.5, 131.9 (dd, JC-F = 9.8, 5.3 Hz), 129.5,
128.0, 117.6 (dd, JC-F = 15.4, 3.8 Hz), 117.1 (dd, JC-F = 256.2, 250.9 Hz), 112.2 (dd, JC-F = 21.3, 3.8
Hz), 104.2 (t, JC-F = 25.5 Hz), 47.5 (d, JC-F = 6.3 Hz), 40.7 (t, JC-F = 21.2 Hz), 40.4 (d, JC-F = 3.3
Hz), 22.5 (d, JC-F = 7.5 Hz); HRMS (ESI): C18H15F4NNaOSe+ [M+Na]+ Calcd 440.0147, Found
440.0163.
1-(2-bromobenzyl)-3,3-difluoro-4-((phenylselanyl)methyl)pyrrolidin-2-one (5h). Pale yellow
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oil (67 mg, 0.15 mmol, yield 73%); IR (neat) ν 2919, 1437, 1251, 1134, 1026, 737, 691 cm-1; H
NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 1H), 7.48 – 7.47 (m, 2H), 7.35 – 7.31 (m, 2H), 7.27
– 7.26 (m, 2H), 7.24 – 7.18 (m, 2H), 4.67 (d, J = 15.0 Hz, 1H), 4.61 (d, J = 14.9 Hz, 1H), 3.45 (t, J
= 9.0 Hz, 1H), 3.27 (dd, J = 12.6, 4.3 Hz, 1H), 3.03 (t, J = 8.5 Hz, 1H), 2.80 (t, J = 11.6 Hz, 1H),
2.76 – 2.61 (m, 1H); 19F {1H} NMR (376 MHz, CDCl3) δ -110.59 (d, J = 268.3 Hz), -116.94 (d, J
= 268.3 Hz); 13C {1H} NMR (100 MHz, CDCl3) δ 163.4 (t, JC-F = 30.1 Hz), 133.7, 133.5, 133.2,
130.4, 130.0, 129.5, 128.2, 128.04, 127.99, 124.0, 117.2 (dd, JC-F = 254.3, 249.0 Hz), 47.6 (d, JC-F
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The Journal of Organic Chemistry
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= 6.2 Hz), 47.2, 40.8 (t, JC-F = 21.2 Hz), 22.5 (d, JC-F = 7.5 Hz); HRMS (ESI): C18H16BrF2NNaOSe+
Calcd 481.9441, Found 481.9466.
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1-cyclobutyl-3,3-difluoro-4-((phenylselanyl)methyl)pyrrolidin-2-one (5i). Pale yellow oil (52
mg, 0.15 mmol, yield 76%); IR (neat) ν 2917, 1721, 1438, 1268, 1065, 968, 738, 691 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.60 – 7.51 (m, 2H), 7.33 – 7.31 (m, 3H), 4.61 (p, J = 8.6 Hz, 1H), 3.70 – 3.59
(m, 1H), 3.33 (dd, J = 12.8, 4.3 Hz, 1H), 3.22 – 3.09 (m, 1H), 2.90 – 2.78 (m, 1H), 2.74 – 2.60 (m,
1H), 2.20 – 2.11 (m, 4H), 1.77 – 1.70 (m, 2H); 19F {1H} NMR (376 MHz, CDCl3) δ -110.24 (d, J =
267.8 Hz), -116.97 (d, J = 268.0 Hz); 13C {1H} NMR (100 MHz, CDCl3) δ 162.3 (t, JC-F = 30.6 Hz),
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133.4, 129.5, 128.0, 47.0, 44.4 (d, JC-F = 6.4 Hz), 40.5 (t, JC-F = 21.2 Hz), 27.0, 26.9, 22.7 (d, JC-F
=
7.4 Hz), 15.1; HRMS (ESI): C15H17F2NNaOSe+ [M+Na]+ Calcd 368.0336, Found 368.0357.
1-cyclopentyl-3,3-difluoro-4-((phenylselanyl)methyl)pyrrolidin-2-one (5j). Pale yellow oil (31
mg, 0.09 mmol, yield 43%); IR (neat) ν 2918, 1717, 1250, 1080, 851, 775, 738, 691 cm-1;1H NMR
(400 MHz, CDCl3) δ 7.55 – 7.53 (m, 2H), 7.33 – 7.31 (m, 3H), 4.47 (p, J = 8.1 Hz, 1H), 3.53 – 3.49
(m, 1H), 3.32 (dd, J = 12.8, 4.3 Hz, 1H), 3.11 – 3.06 (m, 1H), 2.86 – 2.80 (m, 1H), 2.74 – 2.59 (m,
1H), 1.88 – 1.83 (m, 2H), 1.75 – 1.61 (m, 4H), 1.54 – 1.45 (m, 2H); 19F {1H} NMR (376 MHz,
CDCl3) δ -110.43 (d, J = 267.6 Hz), -117.34 (d, J = 267.6 Hz); 13C {1H} NMR (100 MHz, CDCl3)
δ 163.1 (t, JC-F = 30.6 Hz), 133.4, 129.5, 128.2, 128.0, 117.52 (dd, JC-F = 255.0, 250.2 Hz), 53.3,
44.0 (d, JC-F = 6.2 Hz), 40.8 (t, JC-F = 21.2 Hz), 28.7, 24.1, 22.7 (d, JC-F = 7.5 Hz); HRMS (ESI):
C16H19F2NNaOSe+ [M+Na]+ Calcd 382.0492, Found 382.0501.
1-cyclohexyl-3,3-difluoro-4-((phenylselanyl)methyl)pyrrolidin-2-one (5k). Pale yellow oil (32
mg, 0.09 mmol, yield 43%); IR (neat) ν 2927, 1716, 1438, 1248, 1057, 976, 739, 691 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.54 – 7.52 (m, 2H), 7.32 – 7.31 (m, 3H), 3.98 – 3.93 (m, 1H), 3.56 – 3.51 (m,
1H), 3.32 (dd, J = 12.7, 4.3 Hz, 1H), 3.11 – 3.06 (m, 1H), 2.81 (t, J = 11.9 Hz, 1H), 2.71 – 2.56 (m,
1H), 1.82-1.80 (m, 2H), 1.73 – 1.67 (m, 3H), 1.37 – 1.32 (m, 4H), 1.26 (m, 1H); 19F {1H} NMR
(376 MHz, CDCl3) δ -110.46 (d, J = 267.0 Hz), -117.33 (d, J = 267.3 Hz); 13C {1H} NMR (100
MHz, CDCl3) δ 162.6 (t, JC-F = 30.3 Hz), 133.4, 129.5, 128.2, 127.9, 117.7 (dd, JC-F = 255.3, 250.6
Hz), 51.6, 43.9 (d, JC-F = 6.2 Hz), 40.7 (t, JC-F = 21.2 Hz), 29.8, 29.5, 25.18, 25.16, 25.10, 22.8 (d,
JC-F = 7.5 Hz); HRMS (ESI): C17H21F2NNaOSe+ [M+Na]+ Calcd 396.0649, Found 396.0663.
3,3-difluoro-4-((phenylthio)methyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-2-one (5l). Pale yellow
oil (46 mg, 0.14 mmol, yield 70%); IR (neat) ν 2918, 1741, 1439, 1256, 1081, 851, 738, 691 cm-1;
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