Nickel-catalysed radical tandem cyclisation/arylation: Practical synthesis of 4-benzyl-3,3-difluoro-γ-lactams

Article abstract of DOI:10.1039/c8ob01389f

Enabled by nickel catalysis, a practical access to the synthesis of 4-benzyl-3,3-difluoro-γ-lactams has been developed via radical tandem cyclisation/arylation. This method features a nickel catalyst, high reaction efficiency, and good substrate tolerance

Full text of DOI:10.1039/c8ob01389f

View Article Online
View Journal
Organic &
Biomol ec ular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: W. Mai, F. Wang,
X. Zhang, S. Wang, Q. Duan and K. Lu, Org. Biomol. Chem., 2018, DOI: 10.1039/C8OB01389F.
Volume 14 Number
1
7
January 2016 Pages 1–372
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Page 1 of 7
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB01389F
Journal Name
RSCPublishing
PAPER
NickelꢀCatalysed Radical Tandem Cyclisation/Arylation:
Practical Synthesis of 4ꢀBenzylꢀ3,3ꢀDifluoroꢀγꢀLactams
Cite this: DOI: 10.1039/x0xx00000x
a*
a
a
a
a
WenꢀPeng Mai, Fei Wang, XiaoꢀFeng Zhang, ShiꢀMin Wang, QunꢀPeng Duan,
and Kui Lu
a,b*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
Enabled by nickel catalysis, a practical access to synthesis of 4ꢀbenzylꢀ3,3ꢀ
difluoroꢀγꢀlactams has been developed via radical tandem cyclisation/arylation.
This method features nickel catalyst, high reaction efficiency, good substrate
tolerance and scope. This protocol proceeds through an intramolecular radical
addition to form a primary alkyl radical followed by intermolecular Suzukiꢀtype
coupling.
www.rsc.org/
Introduction
Fluorineꢀcontaining molecules are of particular interest in the fields
1
of biomedicine, agriculture, and material sciences. Thus, the
development of novel and high efficient methods for the selective
introduction of fluorinated moieties such as F, CF and CF into
2
3
organic molecules has received much attention in the past few
2
years. Conceptually, introduction of a difluoromethylene group
(
CF ) into some heterocycles could lead to the discovery of some
2
3
interesting bioactive molecules. In addition, pyrrolidinone structures
are also very important in many bioactive molecules. Pyrrolidinones
4
containing difluoromethylene moiety may have more attractive
5
properties in drug discovery. Consequently, it is a desirable task to
explore new catalytic strategy to construct fluorinated pyrrolidinones.
In 2012, Chen developed a synthesis of 3,3ꢀdifuloroꢀγꢀlactam via
radical addition of Nꢀaryl halofluoroacetamide to alkyl substituted
Scheme 1The synthesis of 3,3ꢀdifluoropyrrolidinꢀ2ꢀones.
9
radical cyclisation and difluoroalkylation, herein, we describe the
6
alkenes. Recently, highly efficient synthesis for 3,3ꢀDifluoroꢀγꢀ
successful development of the Ni(II)ꢀcatalysed radical tandem
cyclisation/arylation for the synthesis of 4ꢀsubstitutedꢀ3,3ꢀdifluoroꢀγꢀ
lactams (Scheme 1c).
lactams have been achieved in the presence of an iridium
7
photocatalyst (Scheme 1a) or copper catalyst (Scheme 1b). Very
recently, Wang et al also reported
a
Cuꢀcatalysed
1
0bꢀc,e,f
10d,g,j
Up to now, Pd
and Niꢀcatalysed
difluoroalkylations
aminodifluoroalkylation of alkenes for the synthesis of 3,3ꢀDifluoroꢀ
10h
8
and visibleꢀlight photoredox reaction have emerged as a powerful
γꢀlactams which is similar with the work shown in Scheme 1b.
tool for the construction of Ar–CF R bond efficiently. As
2
However, the target of all the works is to develop the synthesis of 5ꢀ
substitutedꢀ3,3ꢀDifluoroꢀγꢀlactams. As a part of our program of
inexpensive catalyst, nickel has proved to be very effective for crossꢀ
couplings, especially for Suzuki–Miyaura and Negishi reactions in
11
the past 20 years. In recent years, the scope of nickelꢀcatalysed
crossꢀcoupling reactions has expanded far beyond simple biꢀaryl
a
School of Materials and Chemical Engineering, Henan University of
12
Engineering, Zhengzhou, 450006, China. E-mail: maiwp@yahoo.com.
synthesis and are rapidly growing, in which, considerable efforts
have been dedicated towards expanding the scope of coupling
partners. Despite the advances, nickelꢀcatalysed an efficient cascade
b
School of Chemical Engineering and Food Science, Zhengzhou
Institute of Technology, Zhengzhou, 450044, China. E-mail:
luckyluke@haue.edu.cnTel: +86-371-67718909
†
Electronic Supplementary Information (ESI) available: [details of any reaction which involves alkenes by a radical pathway to the diverse
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
molecules containing difluoromethylene group is highly attractive.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 1

Organic & Biomolecular Chemistry
Page 2 of 7
View Article Online
PAPER
DOI: 10.1039/C8OB01389F
Journal Name
Results and discussion
Ni(OAc) were found to be not effective (entries 9ꢀ10). However,
2
when the Ni(OTf) was tested, it showed higher catalytic efficiency,
2
giving products 3aa and 3ea in 68% and 37% isolated yields
a
respectively (entry 11). To our delight, significant improvements
Table 1Optimization of reaction conditions
were achieved when 5 mol% PPh was added and the products 3aa
3
and 3ea were obtained in 79% and 56% respectively (entry 12). The
product yield could be increased to 88% when 7.5mol %
a,b
Table 2 Scope of Arylboronic acids 1
b
Entry
[Ni] (mol %)
Ligand (mol %)
Base (eq) Yield (%)
1
2
3
4
5
Ni(NO
Ni(NO
Ni(NO
Ni(NO
3
3
3
3
)
)
)
)
2
2
2
2
•6H
•6H
•6H
•6H
2
2
2
2
O (5)
O (5)
O (5)
O (5)
L1(5)
L2(5)
L3(5)
L4(5)
L2(5)
K
2
K
2
K
2
K
2
K
2
CO
CO
CO
CO
CO
3
3
3
3
3
(3)
(3)
(3)
(3)
(3)
33
51
c
55(0)
trace
32
NiCl
2
•DME (5)
6
7
8
9
NiCl
2
•DME (5)
•DME (5)
•DME (5)
L3(5)
L3(5)/A1(5)
L3(5)/A2(5)
L3(5)
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
3
(3)
(3)
(3)
(3)
(3)
(3)
(3)
(3)
(3)
(3)
(3)
36
40(16)
32
c
NiCl
2
NiCl
2
Ni(acac)
Ni(OAc) •4H
Ni(OTf)
Ni(OTf)
2
(5)
0
10
11
12
13
14
2
2
O (5)
L3(5)
0
c
c
2
(5)
(5)
(5)
L3(5)
68(37)
79(56)
83
2
L3(5)/PPh
3
(5)
Ni(OTf)
2
L3(5)/PPh
3
(10)
Ni(OTf)
Ni(OTf)
Ni(OTf)
2
2
2
(7.5)
(7.5)
(7.5)
L3(7.5)/PPh
L3(7.5)/PPh
L3(7.5)/PPh
3
3
3
(15)
(15)
(15)
88
d
c
15
92(77)
d,e
1
6
27
a
Reaction conditions: 1a or 1e (0.75 mmol, 1.5 equiv), 2a (0.5 mmol), Ni
catalyst (5ꢀ7.5 mol%), Ligand (5ꢀ15 mol %), 1,4ꢀdioxane (3.0 mL), under N
2
b
c
atmosphere, 80℃, 8 h. Isolated yield. The yield in bracket is product 3ea’s.
d
e
1
a or 1e (1.0 mmol), 2a (0.5 mmol). Under air.
Initially, we set out to examine the feasibility of the radical
cascade
process
using
Nꢀallylꢀ2ꢀbromoꢀ2,2ꢀdifluoroꢀNꢀ(4ꢀ
a
methoxyphenyl)acetamide (2a) and phenylboronic acid (1a) as
Reaction conditions: 1 (1.0 mmol), 2a or 2b (0.5 mmol), K
2
3
CO (3.0 equiv),
substrates. Selected optimization results are summarized in Table 1
Ni(OTf)
2
(7.5 mol %), L3 (7.5 mol %) and PPh
3
(15 mol %) in 1,4ꢀdioxane
b
(
see Table S1 in SI). We first examined lowꢀcost Ni(NO ) •6H O as
(3.0 mL) at 80 ℃ for 8 h. Isolated yield.
3
2
2
catalyst by using K CO as base (entries 1ꢀ4). Screening the ligands
from L1 to L4, the best result was obtained when L3 was chosen as
ligand (Table 1, entry 3). However, it failed to furnish any of the
2
3
Ni(OTf) and 15 mol % PPh were used as catalyst system (entry 14).
Furthermore, excellent yield (92%) for 3aa and good yield (77%) for
2
3
3
ea could be obtained when the ratio of 1a (1e) to 2a was 2:1 (entry
desired
product
when
electronꢀpoor
3ꢀ(ethoxycarbonyl)ꢀ
1
5).
phenylboronic acid (1e) and 2a were put in the cascade process
under the same condition (entry 3). Thus, the central challenge was
to improve Ni’s catalytic performance in the use of less reactive
With the optimized conditions in hand, we then investigated the
scope of arylboronic acids in this reaction (Table 2). Arylboronic
acids bearing various substituents, including electronꢀdonating (3c,
arylboronic acids. When NiCl •DME was selected as catalyst, the
2
3
f, 3m, 3o) and electronꢀwithdrawing (3b, 3dꢀe, 3gꢀi) performed
similar results were obtained even if some additives (A1 or A2) were
well in the cascade process. Compared with the electronꢀrich
used (entries 5ꢀ8). Other nickel complexes such as Ni(acac) and
2
2
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 3 of 7
Journal Name
Organic & Biomolecular Chemistry
View Article Online
PAPER
DOI: 10.1039/C8OB01389F
arylboronic acids, those electronꢀpoor analogues showed lower product yield. In addition, no obvious changes were found when the
reactivity obviously. Many versatile functional groups, such as substituents on Nꢀsubstituted phenyl ring were electronꢀdonating
ketone, ester and sulphone were all tolerated under the reaction groups such as CH
and OMe, good yields were also obtained (3ac,
3
3
af and 3aj). However, the transformation failed to furnish any of
conditions (3ba, 3da, 3ea and 3ga). Moreover, Bocꢀprotected amine
group was also compatible in this reaction, which provided
possibility of further functionalization (3fa). Pleasingly, aromatic
heterocyclic benzofuranꢀ2ꢀylboronic acid could also perform well in
this transformation and the desired product 3pb was obtained in 80%
yield even in gramꢀscale (5 mmol). The structure of product 3pb was
clearly confirmed by single crystal Xꢀray crystallographic analysis,
which signified the cascade process was 5ꢀexo-trig cyclisation
the desired products when the Nꢀsubstituted groups were alkyl or
allyl analogues (see Scheme S1 and S3 in ESI). The reason for this
result is not clear at present.
In order to acquire further insight into the transformation
mechanism, the standard reaction was performed in the presence of
1
.5 equiv of TEMPO (2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy), a
radical scavenger. To our surprise, the reaction did not proceed at all
and the substrate 2a was recovered in 55% yield (eq 1). The reason
may be TEMPO deactivates the nickel catalyst at the beginning of
the reaction. Addition of the ET scavenger 1,4ꢀdinitrobenzene also
shut down the reaction completely (eq 2). The above studies may
support a SET pathway in the cascade process to a certain extent and
suggest that a radical mechanism may be involved in the catalytic
cycle. However, the substrate 2a could not undergo the cyclisation
and was recovered in 93% yield in the absence of phenylboronic
acid which implied arylboronic acids play an important role in the
transformation (eq 3). As shown in eq 3, it seems that only Ni
catalyst does not initiate the reaction and arylboronic acid may play
a role like activating agent.
(
Table 2). It is noteworthy that alkyl boronic acid is not suitable for
the current reaction. A possible reason is that it is more difficult for
coordination and insertion with nickel catalyst. Furthermore
arylboronic acids containing double bond and nitrogen are not
compatible in this transformation (Table 2). Unfortunately, some
orthoꢀsubstituted aryl boronic acids are not efficient coupling
partners in this reaction (see details in ESI).
Subsequently, the scope of Nꢀsubstituted groups in substrate 2 was
evaluated and found to proceed smoothly in all the cases (Table 3).
The nickelꢀcatalysed cascade reaction between Nꢀphenylacetamide
2
b and boronic acid 1a proceeded efficiently to afford 3ab in 92%
yield. Good result was also obtained when 2b reacted with 1k,
providing 3kb in 80% yield (Table 3).
a
Table 3.Scope of Substrate 2.
1
0
Based on the above studies and previous works, a primary
plausible mechanism for the nickelꢀcatalysed tandem cyclisationꢀ
arylation is described in Scheme 2. Initially, the LNi(I)X complex A
10j
with 1 were translated into species B. Then the Ni(I) complex B
could initiate the generation of radical D from 2 through single
electron transfer (SET), leading Ni(II) intermediate C in the
meanwhile. The radical intermediate D forms radical E rapidly via
5
ꢀexo-trig cyclisation. After an oxidative radical addition, the E and
Reaction conditions: 1a (1.0 mmol), 2bꢀj (0.5 mmol), K
Ni(OTf) (7.5 mol %), L3 (7.5 mol %) and PPh (15 mol %) in 1,4ꢀdioxane
3.0 mL) at 80 ℃ for 8 h.
2 3
CO (3.0 equiv),
C were transferred into Ni(III) complex F. Subsequently, F is
transformed to the final product 3aa, which undergoes reductive
elimination of the nickel catalyst and regenerates species A.
2
3
(
When Nꢀ(3,5ꢀdimethylphenyl)ꢀacetamide 2c was tested under the
current conditions, excellent yield (94%) for 3ac was achieved.
Electronꢀwithdrawing groups such as CF , F and acetyl on the Nꢀ
3
substituted phenyl ring were well tolerated and have no influence on
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 3

Organic & Biomolecular Chemistry
Page 4 of 7
View Article Online
PAPER
DOI: 10.1039/C8OB01389F
Journal Name
MHz, CDCl ) δ: 162.13 (t), 157.67, 136.96, 129.92, 128.97, 128.73,
3
1
27.10, 121.73, 114.95 (t, J = 257 Hz), 114.18, 55.48, 48.54, 41.67
19
(t, J = 21 Hz), 31.53; F NMR (376 MHz, CDCl ) δ: ꢀ109.44 (d, J =
3
2
66.96 Hz), ꢀ117.03 (d, J = 266.96 Hz); HRMS (ESI) calcd for
+
C H F NO [M+H] : 318.1300; found: 318.1308.
18
18
2
2
4
ꢀ(3ꢀacetylbenzyl)ꢀ3,3ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)pyrrolidinꢀ2ꢀ
1
one(3ba) White solid; H NMR (400 MHz, CDCl ) δ: 7.88 (d, J =
3
8
(
=
3
.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 4H), 6.92 (d, J = 8.0 Hz, 2H), 3.81
s, 3H), 3.72 (t, J = 8.0 Hz, 1H), 3.59 (t, J = 8.0 Hz, 1H), 3.33 (dd, J
12.0, 4.0 Hz, 1H), 2.97ꢀ3.02 (m, 1H), 2.88ꢀ2.94 (m, 1H), 2.63 (s,
13
H); C NMR (100 MHz, CDCl ) δ: 197.90, 161.93 (t), 157.72,
3
1
37.72, 133.48, 129.27, 128.22, 127.37, 121.75, 117.35 (t, J = 247
1
9
Hz), 114.32, 55.49, 48.49, 41.30 (t, J = 21 Hz), 31.45, 26.71;
F
NMR (376 MHz, CDCl ) δ: ꢀ109.13 (d, J = 266.96 Hz), ꢀ116.60 (d, J
3
+
=
266.96 Hz); HRMS (ESI) calcd for C H F NO [M+H] :
20
20
2
3
3
60.1406; found: 360.1411.
4
ꢀ(3,5ꢀdimethoxybenzyl)ꢀ3,3ꢀdifluoroꢀ1ꢀ(4ꢀethoxyphenyl)pyrroliꢀ
1
dinꢀ2ꢀone(3ca) Pale yellow solid; H NMR (400 MHz, CDCl ) δ:
3
7
.52 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.40 (s, 3H), 3.82
Scheme 2 Proposed mechanism for the reaction
(s, 9H), 3.71 (t, J = 8.0 Hz, 1H), 3.57 (t, J = 8.0 Hz, 1H), 3.24 (dd, J
1
3
=
16.0, 4.0 Hz, 1H), 2.91ꢀ2.96 (m, 1H), 2.70ꢀ2.77 (m, 1H); C NMR
) δ: 161.79, 161.20, 157.67, 139.24, 130.97,
21.75, 117.37 (t, J = 244 Hz), 114.29, 106.81, 98.63, 55.50, 48.53,
Conclusions
(100 MHz, CDCl
3
1
4
19
1.51 (t, J = 21 Hz), 31.77; F NMR (376 MHz, CDCl ) δ: ꢀ109.44
3
In summary, we have disclosed a high efficient synthesis of γꢀ
lactams via inexpensive nickelꢀcatalysed intramolecular radical
cyclisation followed by intermolecular arylation of Nꢀallylꢀ2ꢀbromoꢀ
(
d, J = 366.96 Hz), ꢀ116.97 (d, J = 366.96 Hz); HRMS (ESI) calcd
+
for C H F NO [M+H] : 378.1511; found: 378.1514.
20
22
2
4
2
,2ꢀdifluoroꢀNꢀarylacetamides with arylboronic acids, which
methylꢀ4ꢀ((4,4ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀoxopyrrolidinꢀ3ꢀ
provides a simple and straightforward route to various 4ꢀbenzylꢀ3,3ꢀ
difluoropyrrolidinꢀ2ꢀones. Further applications of this method to
more wide substrates and the study of mechanism are ongoing in our
laboratory.
1
yl)methyl)benzoate(3da) white solid; H NMR (400 MHz, CDCl )
3
δ: 8.05 (d, J = 8.0 Hz, 2.0Hz), 7.50 (d, J = 8.0 Hz, 2.0Hz), 7.36 (d, J
=
8.0 Hz, 2.0Hz), 6.92 (d, J = 8.0 Hz, 2.0Hz), 3.94 (s, 3H), 3.81 (s,
3
1
H), 3.72 (t, J = 8.0 Hz, 1H), 3.59 (t, J = 8.0 Hz, 1H), 3.34 (dd, J =
6.0, 4.0 Hz, 1H), 2.94ꢀ2.98 (m, 1H), 2.86ꢀ2.92 (m, 1H); C NMR
1
3
(
1
5
100 MHz, CDCl ) δ: 166.72, 161.89 (t), 157.72, 142.28, 130.85,
3
Experimental section
30.25, 129.18, 128.81, 121.69, 117.14 (t, J = 255 Hz), 114.32,
19
5.49, 52.18, 48.43 (d), 41.40 (t, J = 21 Hz), 31.57; F NMR (376
General Procedure for the Radical Tandem Cyclisationꢀ
MHz, CDCl ) δ: ꢀ109.24 (d, J = 266.96 Hz), ꢀ116.68 (d, J = 266.96
Hz); HRMS (ESI) calcd for C H F NO [M+H] : 376.1355, found:
3
3
Arylation:
The
synthesis
of
4ꢀbenzylꢀ3,3ꢀdifluoroꢀ1ꢀ(4ꢀ
+
20
20
2
4
methoxyphenyl)pyrrolidinꢀ2ꢀone (3aa). To a 25 mL of Schlenck
tube were added phenylboronic acid 1a (1.0 mmol, 0.122g, 2.0
equiv), 2a (0.5 mmol, 0.16g), Ni(OTf)2 (7.5 mmol %, 13 mg),
76.1355.
ethylꢀ3ꢀ((4,4ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀoxopyrrolidinꢀ3ꢀ
yl)methyl)benzoate(3ea) white solid; H NMR (400 MHz, CDCl ) δ:
7.95ꢀ7.99 (m, 2H), 7.44ꢀ7.50 (m, 4H), 6.91 (d, J = 8.0 Hz), 4.43 (q, J
= 8.0 Hz, 2H), 3.80 (s, 3H), 3.69 (t, J = 8.0 Hz, 1H), 3.59 (t, J = 8.0
Hz, 1H), 3.33 (dd, J = 16.0, 8.0 Hz, 1H), 2.94ꢀ3.00 (m, 1H), 2.86ꢀ
DTBPy (7.5 mmol %, 10 mg), PPh (15 mmol %, 19.6 mg) under air,
1
3
3
followed by K CO (1.5 mmol, 3.0 equiv). The mixture was then
2
3
evacuated and backfilled with N (3 times), dioxane (3 mL) were
2
added subsequently. The tube was put into a preheated oil bath (80
o
C). After stirring for 8 h, the reaction mixture was cooled to room
13
2
.92 (m, 1H), 1.42 (t, J = 8.0 Hz, 3H); C NMR (100 MHz, CDCl3)
temperature and was evaporated under reduced pressure. The residue
was extracted with EtOAc (15 ml x 2) and then dried by Na SO
δ: 166.31, 162.29 (t), 157.70, 137.32, 133.22, 130.88, 129.65, 129.04,
2
4.
128.34, 121.75, 117.45 (t, J = 233 Hz), 114.30, 61.18, 55.48, 48.47
After removing EtOAc, the residue was purified with silica gel
19
(
d), 41.51 (t, J = 21 Hz), 31.33, 14.34; F NMR (376 MHz, CDCl3)
1
chromatography to give product 3aa in 92% yield.White solid; H
δ: ꢀ109.28 (d, J = 266.96 Hz), ꢀ116.67 (d, J = 266.96 Hz); HRMS
NMR (400 MHz, CDCl ) δ: 7.52 (d, J = 12.0 Hz, 2H), 7.30ꢀ7.36 (m,
+
3
(ESI) calcd for C H F NO [M+H] : 390.1511, found: 390.1515.
21
22
2
4
2
3
8
H), 7.26ꢀ7.30 (m, 3H), 6.93 (dd, J = 8.0, 4.0 Hz, 2H), 3.82 (s, 3H),
.69 (t, J = 8.0 Hz, 1H), 3.60 (t, J = 8.0 Hz, 1H), 3.30 (dd, J = 16.0,
.0 Hz, 1H), 2.95ꢀ2.99 (m, 1H), 2.79ꢀ2.85 (m, 1H); C NMR (100
tertꢀbutyl(4ꢀ((4,4ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀoxopyrrolidinꢀ
1
3
1
3
ꢀyl)methyl)phenyl)carbamate(3fa) white solid; H NMR (400
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 5 of 7
Journal Name
Organic & Biomolecular Chemistry
View Article Online
PAPER
DOI: 10.1039/C8OB01389F
MHz, CDCl ) δ: 7.51 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), Hz), ꢀ117.07 (d, J = 266.96 Hz); HRMS (ESI) calcd for
3
+
7
.19 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 6.58 (s, 1H), 3.81 C H F NO [M+H] : 332.1457, found: 332.1460.
19
20
2
2
(s, 3H), 3.69 (t, J = 8.0 Hz, 1H), 3.56 (t, J = 8.0 Hz, 1H), 3.24 (dd, J
=
12.0, 8.0 Hz, 1H), 2.85ꢀ2.93 (m, 1H), 2.72ꢀ2.78 (m, 1H), 1.54 (s, 4ꢀ(4ꢀchlorobenzyl)ꢀ3,3ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)pyrrolidinꢀ
13
1
9
1
H); C NMR (100 MHz, CDCl ) δ: 162.16 (t), 157.64, 152.83, 2ꢀone(3ka) white solid; H NMR (400 MHz, CDCl ) δ: 7.51 (d, J =
3 3
37.42, 131.33, 130.98, 129.24, 121.69, 119.86, 117.55 (t, J = 231 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.94
Hz), 114.29, 80.64, 55.49, 48.49, 41.70 (t, J = 21 Hz), 30.82, 28.34; (d, J = 8.0, 4.0 Hz, 2H), 3.82 (s, 3H), 3.73 (t, J = 8.0 Hz, 1H), 3.57 (t,
1
9
F NMR (376 MHz, CDCl ) δ: ꢀ109.26 (d, J = 266.96 Hz), ꢀ116.99 J = 8.0 Hz, 1H), 3.27 (dd, J = 8.0, 4.0 Hz, 1H), 2.88ꢀ2.95 (m, 1H),
3
+
13
(d, J = 266.96 Hz); HRMS (ESI) calcd for C H F N O [M+H] : 2.78ꢀ2.84 (m, 1H); C NMR (100 MHz, CDCl ) δ: 161.95 (t),
2
3
27
2
2
4
3
4
33.1933, found: 433.1930.
157.71, 135.39, 133.03, 130.87, 130.08, 129.13, 121.70, 119.87 (t, J
1
9
=
269 Hz), 114.33, 55.51, 48.43, 41.58 (t, J = 21 Hz), 30.97;
F
3
,3ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀ(4ꢀ
NMR (376 MHz, CDCl ) δ: ꢀ109.07 (d, J = 266.96 Hz), ꢀ116.78 (d, J
3
+
(
methylsulfonyl)benzyl)pyrrolidinꢀ2ꢀone(3ga) Pale yellow solid; = 266.96 Hz); HRMS (ESI) calcd for C H ClF NO [M+H] :
18
17
2
2
1
H NMR (400 MHz, CDCl ) δ: 7.95 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 352.0910, found: 352.0915.
3
8
.0 Hz, 4H), 6.93 (d, J = 8.0 Hz, 2H), 3.82 (s, 3H), 3.75 (t, J = 8.0
Hz, 1H), 3.58 (t, J = 8.0 Hz, 1H), 3.36 (dd, J = 12.0, 4.0 Hz, 1H), 3,3ꢀdifluoroꢀ4ꢀ(3ꢀfluoroꢀ4ꢀmethylbenzyl)ꢀ1ꢀ(4ꢀ
1
3
1
3
1
.08 (s, 3H), 2.93ꢀ3.00 (m, 2H); C NMR (100 MHz, CDCl ) δ: methoxyphenyl)pyrrolidinꢀ2ꢀone(3la) white solid; H NMR (400
3
61.69 (t), 157.79, 143.51, 139.53, 130.71, 129.81, 128.07, 121.71, MHz, CDCl ) δ: 7.52 (d, J = 12 Hz, 2.0Hz), 7.17 (t, J = 8.0 Hz, 1H),
3
1
17.24 (t, J = 248 Hz), 114.36, 55.51, 48.38, 44.48, 41.26 (t, J = 21 6.91ꢀ6.95 (m, 4H), 3.82 (s, 3H), 3.71 (t, J = 12 Hz, 1H), 3.58 (t, J =
19
Hz), 31.59; F NMR (376 MHz, CDCl ) δ: ꢀ108.85 (d, J = 266.96 12 Hz, 1H), 3.25 (dd, J = 12.0, 8.0 Hz, 1H), 2.87ꢀ2.93 (m, 1H), 2.75ꢀ
Hz), ꢀ116.31 (d, J = 266.96 Hz); HRMS (ESI) calcd for 2.81 (m, 1H), 2.28 (s, 3H); C NMR (100 MHz, CDCl ) δ: 162.63,
C H F NO S [M+H] : 396.1076, found: 396.1080.
3
13
3
+
162.03 (t, J = 32 Hz), 160.19, 157.69, 136.5(d), 131.96, 130.93,
24.11, 123.51, 121.72, 117.26 (t, J = 252 Hz), 115.35(d), 114.31,
55.49, 48.47, 41.54 (t, J = 21 Hz), 30.97(d), 14.22(d); F NMR (376
1
9
20
2
4
1
19
4
ꢀ(4ꢀ(tertꢀbutyl)benzyl)ꢀ3,3ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)pyroliꢀ
1
dinꢀ2ꢀone(3ha) white solid; H NMR (400 MHz, CDCl ) δ: 7.52 (d, MHz, CDCl ) δ: ꢀ109.26 (d, J = 266.96 Hz), ꢀ116.74, ꢀ116.86 (d, J =
J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 266.96 Hz); HRMS (ESI) calcd for C H F NO [M+H] : 350.1362,
3
3
+
19
19
3
2
6
.93 (d, J = 8.0 Hz, 2H), 3.82 (s, 3H), 3.72 (t, J = 8.0 Hz, 1H), 3.56 found: 350.1366.
(
1
1
t, J = 8.0 Hz, 1H), 3.28 (dd, J = 16.0, 12.0 Hz, 1H), 2.91ꢀ2.99 (m,
H), 2.76ꢀ2.82 (m, 1H), 1.35 (s, 9H); C NMR (100 MHz, CDCl ) δ: 3,3ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀ(4ꢀ
3
62.20 (t), 157.67, 150.03, 133.80, 131.04, 128.39, 125.86, 121.80, (trifluoromethyl)benzyl)pyrrolidinꢀ2ꢀone(3ma) white solid;
1
3
1
H
1
3
17.60 (t, J = 235 Hz), 114.29, 55.49, 48.65, 41.46 (t, J = 21 Hz), NMR (400 MHz, CDCl ) δ: 7.65 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0
4.49, 31.35; F NMR (376 MHz, CDCl ) δ: ꢀ109.31 (d, J = 266.96 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 3.82 (s,
3
3
19
Hz), ꢀ117.16 (d, J = 266.96 Hz); HRMS (ESI) calcd for 3H), 3.73 (t, J = 8.0 Hz, 1H), 3.62 (t, J = 8.0 Hz, 1H), 3.34 (dd, J =
+
13
C H F NO [M+H] : 374.1926; found: 374.1923.
8.0, 4.0 Hz, 1H), 2.88ꢀ2.99 (m, 2H); C NMR (100 MHz, CDCl ) δ:
3
2
2
26
2
2
1
61.79 (t), 157.76, 141.07, 130.79, 129.13, 125.88 (d, J = 4.0 Hz),
3
2
8
,3ꢀdifluoroꢀ4ꢀ(4ꢀfluorobenzyl)ꢀ1ꢀ(4ꢀmethoxyphenyl)pyrrolidinꢀ
121.72, 117.18 (t, J = 274 Hz), 114.35, 55.50, 48.41, 41.24 (t, J = 20
1
19
ꢀone(3ia) white solid; H NMR (400 MHz, CDCl ) δ: 7.51 (d, J = Hz), 31.47; F NMR (376 MHz, CDCl ) δ: ꢀ62.53, ꢀ109.15 (d, J =
3
3
.0 Hz, 2H), 7.22ꢀ7.23 (m, 2H), 7.05 (t, J = 8.0 Hz, 2H), 6.91ꢀ6.94 266.96 Hz), ꢀ116.66 (d, J = 266.96 Hz); HRMS (ESI) calcd for
+
(m, 2H), 3.82 (s, 3H), 3.71 (t, J = 8.0 Hz, 1H), 3.56 (t, J = 8.0 Hz, C H F NO [M+H] : 386.1174; found: 386.1172.
19 17 5 2
1
H), 3.25 (dd, J = 12.0, 4.0 Hz, 1H), 2.87ꢀ2.95 (m, 1H), 2.78ꢀ2.84
13
(m, 1H); C NMR (100 MHz, CDCl ) δ: 163.14 (d, J = 244 Hz), 3,3ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀ(naphthalenꢀ2ꢀ
3
1
1
2
62.02 (t), 157.71, 132.64, 130.92, 130.19, 121.71, 117.40 (t, J = ylmethyl)pyrrolidinꢀ2ꢀone(3na) white solid; H NMR (400 MHz,
43 Hz), 115.72, 114.32, 55.49, 48.47, 41.53 (t, J = 21 Hz), 30.80; CDCl ) δ: 7.83ꢀ7.88 (m, 3H), 7.72 (s, 1H), 7.50ꢀ7.52 (m, 4H), 7.41
3
1
9
F NMR (376 MHz, CDCl ) δ: ꢀ109.14 (d, J = 266.96 Hz), ꢀ115.54, (d, J = 12 Hz, 1H), 6.92 (d, J = 12 Hz, 2H), 3.81 (s, 3H), 3.59ꢀ3.70
3
ꢀ
[
116.90 (d, J = 266.96 Hz); HRMS (ESI) calcd for C H F NO
2
M+H] : 336.1206, found: 336.1211.
(m, 2H), 3.48 (dd, J = 12.0, 4.0 Hz, 1H), 3.06ꢀ3.11 (m, 1H), 2.98ꢀ
18
17
3
+
13
3.04 (m, 1H); C NMR (100 MHz, CDCl ) δ: 162.13 (t), 157.65,
3
1
34.38, 133.55, 132.45, 130.98, 128.82, 127.75, 127.53, 127.37,
3
2
,3ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀ(3ꢀmethylbenzyl)pyrrolidinꢀ
126.49, 125.97, 121.68, 117.31 (t, J = 214 Hz), 114.29, 55.49, 48.55,
1
19
ꢀone(3ja) pale white solid; H NMR (400 MHz, CDCl ) δ: 7.52 (d, 41.59 (t, J = 21 Hz), 31.70; F NMR (376 MHz, CDCl ) δ: ꢀ109.29
3
3
J = 8.0 Hz, 2H), 7.24ꢀ7.28 (m, 1H), 7.05ꢀ7.10 (m, 3H), 6.94 (d, J = (d, J = 266.96 Hz), ꢀ116.82 (d, J = 266.96 Hz); HRMS (ESI) calcd
+
1
2.0 Hz, 2H), 3.82 (s, 3H), 3.69 (t, J = 8.0 Hz, 1H), 3.57 (t, J = 8.0 for C H F NO [M+H] : 368.1457, found: 368.1455.
22 20 2 2
Hz, 1H), 3.28 (dd, J = 16.0, 4.0 Hz, 1H), 2.91ꢀ2.98 (m, 1H), 2.74ꢀ
1
3
2
1
1
3
.80 (m, 1H), 2.38 (s, 3H); C NMR (100 MHz, CDCl ) δ: 162.19, 3,3ꢀdifluoroꢀ4ꢀ(4ꢀmethoxybenzyl)ꢀ1ꢀ(4ꢀ
3
1
57.65, 138.68, 136.87, 131.01, 129.48, 128.84, 127.84, 125.70, methoxyphenyl)pyrrolidinꢀ2ꢀone(3oa) white solid; H NMR (400
21.75, 117.48 (t, J = 242 Hz), 55.50, 48.59, 41.69 (t, J = 21 Hz), MHz, CDCl ) δ: 7.52 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H),
1.42, 21.42; F NMR (376 MHz, CDCl ) δ: ꢀ109.48 (d, J = 266.96 6.93 (t, J = 8.0 Hz, 2H), 3.82 (s, 3H), 3.69 (t, J = 8.0 Hz, 1H), 3.58 (t,
3
19
3
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

Organic & Biomolecular Chemistry
Page 6 of 7
View Article Online
PAPER
DOI: 10.1039/C8OB01389F
Journal Name
J = 8.0 Hz, 1H), 3.25 (dd, J = 16.0, 8.0 Hz, 1H), 2.85ꢀ2.94 (m, 1H), 3.71 (t, J = 8.0 Hz, 1H), 3.60 (t, J = 8.0 Hz, 1H), 3.32 (dd, J = 16.0,
1
3
13
2
1
.73ꢀ2.79 (m, 1H); C NMR (100 MHz, CDCl ) δ: 162.19 (t), 8.0 Hz, 1H), 2.91ꢀ3.04 (m, 1H), 2.80ꢀ2.86 (m, 1H); C NMR (100
3
58.65, 157.64, 131.02, 129.71, 128.82, 121.70, 121.61, 117.58 (t, J MHz, CDCl ) δ: 162.36 (t), 161.6 (d, J = 245 Hz), 136.78, 133.97,
3
=
244 Hz), 114.34, 114.29, 55.50 (d, J = 20 Hz), 48.53, 41.85 (t, J = 129.03, 128.72, 127.19, 121.90, 117.30 (t, J = 249 Hz), 116.09,
19
19
2
2
0 Hz), 30.65; F NMR (376 MHz, CDCl ) δ: ꢀ109.25 (d, J = 115.87, 48.40, 41.42 (t, J = 21 Hz), 31.44; F NMR (376 MHz,
66.96 Hz), ꢀ117.07 (d, J = 266.96 Hz); HRMS (ESI) calcd for CDCl ) δ: ꢀ109.63 (d, J = 266.96 Hz), ꢀ115.10, ꢀ117.14 (d, J =
3
3
+
+
C H F NO [M+H] : 348.1406, found: 348.1406.
266.96 Hz); HRMS (ESI) calcd for C H F NO [M+H] : 306.1100,
17 15 3
1
9
20
2
3
found: 306.1108.
4
ꢀ(benzofuranꢀ2ꢀylmethyl)ꢀ3,3ꢀdifluoroꢀ1ꢀphenylpyrrolidinꢀ2ꢀ
1
one(3pb) pure crystal; H NMR (400 MHz, CDCl ) δ: 7.65 (d, J = 4ꢀbenzylꢀ1ꢀ(4ꢀchlorophenyl)ꢀ3,3ꢀdifluoropyrrolidinꢀ2ꢀone(3ae)
8
3
1
.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.40ꢀ7.47 (m, 3H), 7.24ꢀ7.32 white solid; H NMR (400 MHz, CDCl ) δ: 7.65 (d, J = 8.0 Hz, 2H),
3
(m, 3H), 6.60 (s, 1H), 3.96 (t, J = 8.0 Hz, 1H), 3.76 (t, J = 8.0 Hz, 7.31ꢀ7.40 (m, 5H), 7.28 (d, J = 8.0 Hz, 2H), 3.71 (t, J = 8.0 Hz, 1H),
1
H), 3.43 (dd, J = 16.0, 4.0 Hz, 1H), 3.15ꢀ3.22 (m, 1H), 3.05ꢀ3.11 3.59 (t, J = 8.0 Hz, 1H), 3.32 (dd, J = 16.0, 8.0 Hz, 1H), 2.92ꢀ2.98
13
13
(m, 1H); C NMR (100 MHz, CDCl ) δ: 162.02 (t), 154.96, 153.69, (m, 1H), 2.80ꢀ2.86 (m, 1H); C NMR (100 MHz, CDCl ) δ: 162.44
3
3
1
37.80, 129.22, 128.33, 126.29, 124.14, 123.01, 120.76, 120.01, (t), 136.70, 136.45, 131.44, 129.23, 129.05, 128.71, 127.22, 117.13
1
9
117.17 (t, J = 241 Hz), 111.01, 104.54, 48.28 (d), 38.94 (t, J = 21 (t, J = 241 Hz), 48.05 (d), 41.55 (t, J = 21 Hz), 31.42 (d); F NMR
19
Hz), 24.89; F NMR (376 MHz, CDCl ) δ: ꢀ110.64 (d, J = 266.96 (376 MHz, CDCl ) δ: ꢀ111.20 (d, J = 266.96 Hz), ꢀ118.70 (d, J =
Hz), ꢀ118.80 (d, J = 266.96 Hz); HRMS (ESI) calcd for 266.96 Hz); HRMS (ESI) calcd for C H ClF NO [M+H] :
C H F NO [M+H] : 328.1144, found: 328.1141.
3
3
+
17
15
2
+
322.0805, found: 322.0800.
1
9
16
2
2
4
ꢀ(4ꢀchlorobenzyl)ꢀ3,3ꢀdifluoroꢀ1ꢀphenylpyrrolidinꢀ2ꢀone(3kb)
4ꢀbenzylꢀ3,3ꢀdifluoroꢀ1ꢀ(pꢀtolyl)pyrrolidinꢀ2ꢀone(3af) white solid;
1
1
white solid; H NMR (400 MHz, CDCl ) δ: 7.62 (d, J = 8.0 Hz, 2H),
H NMR (400 MHz, CDCl ) δ: 7.50 (d, J = 8.0 Hz, 2H), 7.40 (t, J =
3
3
7
3
8
.42 (t, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.21ꢀ7.28 (m, 3H), 8.0 Hz, 2H), 7.27ꢀ7.33 (m, 3H), 7.20 (d, J = 8.0 Hz, 2H), 3.74 (t, J =
.76 (t, J = 8.0 Hz, 1H), 3.59 (t, J = 8.0 Hz, 1H), 3.28 (dd, J = 16.0, 8.0 Hz, 1H), 3.61 (t, J = 8.0 Hz, 1H), 3.32 (dd, J = 16.0, 8.0 Hz, 1H),
.0 Hz, 1H), 2.89ꢀ2.97 (m, 1H), 2.79ꢀ2.85 (m, 1H); C NMR (100 2.89ꢀ3.02 (m, 1H), 2.79ꢀ2.85 (m, 1H), 2.36 (s, 3H); C NMR (100
1
3
13
MHz, CDCl ) δ: 162.25 (t), 137.81, 135.32, 133.07, 130.08, 129.21, MHz, CDCl ) δ: 162.49 (t), 136.95, 136.07, 135.40, 129.68, 128.99,
3
3
1
2
2
29.15, 126.26, 119.96, 117.18 (t, J = 249 Hz), 48.04, 41.32 (t, J = 128.73, 127.12, 119.98, 114.92 (t, J = 252 Hz), 48.26, 41.66 (t, J =
19
19
1 Hz), 30.92; F NMR (376 MHz, CDCl ) δ: ꢀ109.17 (d, J = 21 Hz), 31.52, 20.96; F NMR (376 MHz, CDCl ) δ: ꢀ111.00 (d, J =
3
3
66.96 Hz), ꢀ117.49 (d, J = 266.96 Hz); HRMS (ESI) calcd for 266.96 Hz), ꢀ118.73 (d, J = 266.96 Hz); HRMS (ESI) calcd for
+
+
C H ClF NO [M+H] : 322.0805, found: 322.0801.
C H F NO [M+H] : 302.1351, found: 302.1357.
18 18 2
1
7
15
2
4
ꢀbenzylꢀ3,3ꢀdifluoroꢀ1ꢀphenylpyrrolidinꢀ2ꢀone(3ab) pure crystal; 4ꢀbenzylꢀ3,3ꢀdifluoroꢀ1ꢀ(4ꢀ(trifluoromethyl)phenyl)pyrrolidinꢀ2ꢀ
1
1
H NMR (400 MHz, CDCl ) δ: 7.63 (d, J = 8.0 Hz, 2H), 7.33ꢀ7.41 one(3ag) white solid; H NMR (400 MHz, CDCl ) δ: 7.78 (d, J = 8.0
3
3
(m, 4H), 7.23ꢀ7.29 (m, 4H), 3.74 (t, J = 8.0 Hz, 1H), 3.62 (t, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.39 (t, J = 8.0 Hz, 2H), 7.28ꢀ7.34
Hz, 1H), 3.32 (dd, J = 12.0, 4.0 Hz, 1H), 2.92ꢀ3.01 (m, 1H), 2.80ꢀ (m, 3H), 3.78 (t, J = 8.0 Hz, 1H), 3.64 (t, J = 8.0 Hz, 1H), 3.33 (dd, J
1
3
13
2
1
=
.86 (m, 1H); C NMR (100 MHz, CDCl ) δ: 162.87 (t), 137.91, = 12.0, 4.0 Hz, 1H), 2.94ꢀ3.09 (m, 1H), 2.82ꢀ2.88 (m, 1H); C NMR
3
36.89, 129.17, 129.01, 128.72, 127.15, 126.18, 119.99, 117.33 (t, J (100 MHz, CDCl ) δ: 162.79 (t), 140.79, 136.59, 129.07, 128.70,
21 Hz), 48.16 (d), 41.65 (t, J = 21 Hz), 31.48 (d); F NMR (376 127.27, 126.37 (q), 116.96 (t, J = 244 Hz), 47.88, 41.30 (t, J = 21
MHz, CDCl ) δ: ꢀ109.57 (d, J = 266.96 Hz), ꢀ117.24 (d, J = 266.96 Hz), 31.36; F NMR (376 MHz, CDCl ) δ: ꢀ62.46, ꢀ109.87 (d, J =
Hz); HRMS (ESI) calcd for C H F NO [M+H] : 288.1194, found: 266.96 Hz), ꢀ117.29 (d, J = 266.96 Hz); HRMS (ESI) calcd for
3
1
9
19
3
3
+
1
7
16 2
+
2
88.1192.
C H F NO [M+H] : 356.1068, found: 356.1065.
18 15 5
4
ꢀbenzylꢀ1ꢀ(3,5ꢀdimethylphenyl)ꢀ3,3ꢀdifluoropyrrolidinꢀ2ꢀ
1ꢀ(4ꢀacetylphenyl)ꢀ4ꢀbenzylꢀ3,3ꢀdifluoropyrrolidinꢀ2ꢀone(3ah)
1
1
one(3ac) white solid; H NMR (400 MHz, CDCl ) δ: 7.41 (t, J = 8.0 white solid; H NMR (400 MHz, CDCl ) δ: 7.98 (d, J = 8.0 Hz, 2H),
3
3
Hz, 2H), 7.27ꢀ7.33 (m, 3H), 7.21 (s, 2H), 6.90 (s, 1H), 3.74 (t, J = 7.75 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 8.0 Hz, 2H), 7.27ꢀ7.33 (m, 3H),
8
2
.0 Hz, 1H), 3.61 (t, J = 8.0 Hz, 1H), 3.32 (dd, J = 16.0, 8.0 Hz, 1H), 3.79 (t, J = 8.0 Hz, 1H), 3.65 (t, J = 8.0 Hz, 1H), 3.32 (dd, J = 12.0,
.90ꢀ3.00 (m, 1H), 2.79ꢀ2.85 (m, 1H), 2.34 (s, 6H); C NMR (100 4.0 Hz, 1H), 2.92ꢀ3.03 (m, 1H), 2.81ꢀ2.87 (m, 1H); C NMR (100
1
3
13
MHz, CDCl ) δ: 162.68 (t), 138.93, 137.76, 136.98, 128.99, 128.74, MHz, CDCl ) δ: 196.80, 163.11 (t), 141.75, 141.76, 136.61, 134.26,
3
3
1
2
2
28.01, 127.10, 118.00, 117.42 (t, J = 245 Hz), 48.44, 41.68 (t, J = 129.52, 129.07, 128.71, 127.25, 119.12, 117.04 (t, J = 249 Hz),
1
9
19
1 Hz), 31.55, 21.43; F NMR (376 MHz, CDCl ) δ: ꢀ109.50 (d, J = 47.86, 41.26 (t, J = 21 Hz), 31.37, 26.55; F NMR (376 MHz,
3
66.96 Hz), ꢀ117.29 (d, J = 266.96 Hz); HRMS (ESI) calcd for CDCl ) δ: ꢀ109.82 (d, J = 266.96 Hz), ꢀ117.17 (d, J = 266.96 Hz);
3
+
+
C H F NO [M+H] : 316.1507, found: 316.1504.
HRMS (ESI) calcd for C H F NO [M+H] : 330.1300, found:
19 18 2 2
1
9
20
2
3
30.1308.
4
ꢀbenzylꢀ3,3ꢀdifluoroꢀ1ꢀ(4ꢀfluorophenyl)pyrrolidinꢀ2ꢀone(3ad)
1
white solid; H NMR (400 MHz, CDCl ) δ: 7.60 (q, J = 4.0 Hz, 2H), 4ꢀbenzylꢀ3,3ꢀdifluoroꢀ1ꢀ(3ꢀfluoroꢀ4ꢀmethylphenyl)pyrrolidinꢀ2ꢀ
7
3
1
.38 (t, J = 8.0 Hz, 2H), 7.27ꢀ7.31 (m, 3H), 7.12 (t, J = 8.0 Hz, 2H), one(3ai) white solid; H NMR (400 MHz, CDCl ) δ: 7.17ꢀ7.46 (m,
3
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 7 of 7
Journal Name
Organic & Biomolecular Chemistry
View Article Online
PAPER
DOI: 10.1039/C8OB01389F
8
1
1
H), 3.71 (t, J = 8.0 Hz, 1H), 3.57 (t, J = 8.0 Hz, 1H), 3.30 (dd, J =
5
(a) T. Sifferlen, A. Boller, A. Chardonneau, E. Cottreel, J. Gatfield, A.
Treiber, C. Roch, F. Jenck, H. Aissaoui, J. T. Williams, C. Brotschi, B.
Heidmann, R. Siegrist, C. Boss, Bioorg. Med. Chem. Lett. 2015, 25,
2.0, 4.0 Hz, 1H), 2.91ꢀ2.99 (m, 1H), 2.79ꢀ2.85 (m, 1H), 2.28 (s,
13
H); C NMR (100 MHz, CDCl ) δ: 162.79 (t), 162.24 (d, J = 243
3
1
884. (b) H. Nagashima, Y. Isono, S.ꢀi. Iwamatsu, J. Org. Chem. 2001,
6, 315; (c) S. Fustero, B. Fernández, P. Bello, C. del Pozo, S. Arimitsu,
Hz), 136.93, 131.62, 129.03, 128.71, 127.19, 122.81, 117.25 (t, J =
6
2
1
48 Hz), 114.82, 107.36, 107.07, 48.08, 41.31 (t, J = 21 Hz), 31.45,
19
G. B. Hammond, Org. Lett. 2007, 9, 4251; (d) Z. Zhang, X. Tang, C. S.
Thomoson, W. R. Dolbier, Org. Lett. 2015, 17, 3528.
4.19; F NMR (376 MHz, CDCl ) δ: ꢀ111.15 (d, J = 266.96 Hz), ꢀ
3
1
15.99, ꢀ118.66 (d, J = 266.96 Hz); HRMS (ESI) calcd for
+
C H F NO [M+H] : 320.1257, found: 320.1253.
1
8
17
3
6
7
B.ꢀH. Li, K.ꢀL. Li, Q.ꢀY. Chen, J. Fluorine Chem. 2012, 133, 163.
(a) M. Zhang, W. Li, Y. Duan, P. Xu, S. Zhang, C. Zhu,Org. Lett. 2016,
4
ꢀbenzylꢀ1ꢀ(4ꢀchloroꢀ3ꢀmethoxyphenyl)ꢀ3,3ꢀdifluoropyrrolidinꢀ2ꢀ
1
8, 3266; (b) Y. Lv, W. Pu, Q. Wang, Q. Chen, J. Niu, Q. Zhang, Adv.
1
one(3aj) white solid; H NMR (400 MHz, CDCl ) δ: 7.74 (s, 1H),
3
Synth. Catal. 2017, 359, 3114.
7
8
2
.27ꢀ7.33 (m, 6H), 6.78 (d, J = 8.0 Hz, 1H), 3.93 (s, 3H), 3.74 (t, J =
.0 Hz, 1H), 3.59 (t, J = 8.0 Hz, 1H), 3.32 (dd, J = 16.0, 4.0 Hz, 1H),
.91ꢀ2.98 (m, 1H), 2.80ꢀ2.86 (m, 1H); C NMR (100 MHz, CDCl3)
8
9
H. Chen, X. Wang, M. Guo, W. Zhao, X. Tang, G. G. Wang,
1
3
Org.Chem.Front. 2017, 4, 2403.
(a) W.ꢀP. Mai, J.ꢀT. Wang, L.ꢀR. Yang, J.ꢀW. Yuan, Y.ꢀM. Xiao, P. Mao,
L.ꢀB. Qu, Org. Lett. 2014, 16, 204; (b) W.ꢀP. Mai, G.ꢀC. Sun, J.ꢀT. Wang,
G. Song, P. Mao, L.ꢀR. Yang, J.ꢀW. Yuan, Y.ꢀM. Xiao, L.ꢀB. Qu, J. Org.
Chem. 2014, 79, 8094; (c) W.ꢀP. Mai, B. Sun, G.ꢀS. Qian, J.ꢀW. Yuan, P.
Mao, L.ꢀR. Yang, Y.ꢀM. Xiao, Tetrahedron. 2015, 71, 8416; (d) W.ꢀP.
Mai, J.ꢀT. Wang, Y.ꢀM. Xiao, P. Mao, K. Lu, Tetrahedron. 2015, 71,
δ: 162.55 (t), 155.30, 137.63, 136.69, 130.06, 129.05, 128.71, 127.22,
19.82, 117.29 (t, J = 236 Hz), 111.36, 104.81, 56.30, 48.19, 41.27 (t,
1
19
J = 21 Hz), 31.44; F NMR (376 MHz, CDCl ) δ: ꢀ109.48 (d, J =
2
C H ClF NO [M+H] : 352.0910, found: 352.0913.
3
66.96 Hz), ꢀ117.48 (d, J = 266.96 Hz); HRMS (ESI) calcd for
+
1
8
17
2
2
8
041; (e) J.ꢀW. Yuan, S.ꢀN. Liu, W.ꢀP. Mai, Org. Biomol. Chem. 2017,
5, 7654.
Acknowledgements
1
1
0 (a) A. Tarui, S. Shinohara, K. Sato, M.Omote, A. Ando, Org. Lett. 2016,
8, 1128;(b) J. W. Gu, Q.ꢀQ. Min, L. C. Yu, X. Zhang, Angew. Chem.Int.
This work was supported by National Natural Science
Foundation of China (21572046). Financial support from the
Program of “543 team” of Henan University of Engineering and
the Youth Doctoral Funding of Henan University of Engineering
1
Ed. 2016, 55,12270; (c) Z. Feng, Q.ꢀQ. Min, Y.ꢀL. Xiao, B. Zhang, X.
Zhang, Angew. Chem.Int. Ed. 2014, 53, 1669; (d) Y.ꢀL. Xiao, W.ꢀH. Guo,
G.ꢀZ. He, Q. Pan, X. Zhang, Angew. Chem, Int. Ed. 2014, 53, 9909; (e) Z.
Feng, Q.ꢀQ. Min, X.ꢀP. Fu, L. An, X. Zhang, Nature Chem. 2017, 9, 918;
(
2015017) is gratefully acknowledged.
(
f) H.ꢀY. Zhao, F. Zhang, Z. Luo, X. Zhang, Angew.Chem.Int. Ed. 2016,
Notes and references
5
5, 10401; (g) Y.ꢀL. Xiao, Q.ꢀQ. Min, C. Xu, R.ꢀW. Wang, X. Zhang,
Angew. Chem.Int. Ed. 2016, 55, 5873; (h) Y.ꢀM. Su, Y. Hou, F. Yin, Y.ꢀ
M. Xu, Y. Li, X. Zheng, X.ꢀS. Wang, Org.Lett.2014, 16, 2958; (i) J.
Sheng, H.ꢀQ. Ni, G. Liu, Y. Li, X.ꢀS. Wang, Org. Lett. 2017, 19, 4480; (j)
G. Li, T. Wang, F. Fei, Y.ꢀM. Su, Y. Li, Q. Lan, X.ꢀS. Wang, Angew.
Chem. Int. Ed. 2016, 55, 3491.
1
(a) K. Müller, C. Faeh, F. Diederich, Science. 2007, 317, 1881; (b) S.
Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev
008, 37, 320.
.
2
2
(a) T. Furuya, A. S.Kamlet, T. Ritter, Nature. 2011, 473, 470; (b)
O.A.Tomashenko, V. V. Grushin, Chem. Rev. 2011, 111, 4475; (c) T.
Chatterjee, N. Iqbal, Y. You, E. J. Cho, Acc. Chem. Res. 2016, 49,2284;
1
1 J. Yamaguchi, K. Muto, K. Itami, Eur. J. Org. Chem. 2013, 2013, 19.
2 (a) J. Wang, T. Qin, T.ꢀG. Chen, L. Wimmer, J. T. Edwards, J. Cornella,
B. Vokits, S. A. Shaw, P. S. Baran, Angew. Chem, Int. Ed. 2016, 55,
9676; (b) S. Rezazadeh, V. Devannah, D. A. Watson, J. Am. Chem. Soc.
2017, 139, 8110; (c) H. Yue, C. Zhu, M. Rueping, Angew. Chem. Int. Ed.
2018,57,1371; (d) A. Chatupheeraphat, H.ꢀH. Liao, W. Srimontree, L.
Guo, Y. Minenkov, A. Poater, L. Cavallo, M. Rueping, J. Am. Chem.
Soc.2018, 140, 3724; (e) W. Srimontree, A. Chatupheeraphat, H.ꢀH. Liao,
M. Rueping, Org. Lett.2017, 19, 3091; (f) K. M. Cobb, J. M. RabbꢀLynch,
E. H. Hoerrner, A. Manders, Q. Zhou, M. P. Watson, Org. Lett. 2017, 19,
1
(
d) S. L. Shi, S. L. Buchwald, Angew. Chem., Int. Ed. 2015, 54, 1646;
e) P. Novák, A. Lishchynskyi, V. V. Grushin, J. Am. Chem. Soc. 2012,
(
1
34, 16167; (f) P. S. Fier, J. F. Hartwig, Science. 2013, 342, 956; (g) W.
Liu, X. Huang, M.ꢀJ. Cheng, R. J. Nielsen, W. A. Goddard III, J. T.
Groves, Science. 2012, 337, 1322; (h) E. J. Cho, T. D. Senecal, T.
Kinzel, Y. Zhang, D. A. Watson, S. L. Buchwald, Science. 2010, 328,
1
679; (i) Y. Zeng, C. Ni, J. Hu, Chem. Eur. J. 2016, 22, 3210; (j) Z. Li,
L. Song, C. Li, J. Am. Chem. Soc. 2013, 135, 4640; (k) Z. Li, Z. Wang,
L. Zhu, X. Tan, C. Li, J. Am. Chem. Soc. 2014, 136, 16439; (l) F. Yin,
Z. Wang, Z. Li, C. Li, J. Am. Chem. Soc. 2012, 134, 10401; (m) Y. Ye,
M. S. Sanford, J. Am. Chem. Soc. 2013, 135, 4648.
4
1
2
355; (g) C. H. Basch, K. M. Cobb, M. P. Watson, Org. Lett. 2016, 18,
36; (h) Q. Zhou, K. M. Cobb, T. Tan, M. P. Watson, J. Am. Chem. Soc.
016, 138, 12057; (i) A. G. Domίnguez, S. Mgller, C. Nevado, Angew.
3
4
(a) C. Han, A. E. Salyer, E. H. Kim, X. Jiang, R. E. Jarrard, M. S.
Powers, A. M. Kirchhoff, T. K. Salvador, J. A. Chester, G. H.
Hockerman, D. A. Colby, J. Med. Chem. 2013, 56, 2456; (b) J. Li, S. Y.
Chen, B. J. Murphy, N. Flynn, R. Seethala, D. Slusarchyk, M. Yan, P.
Sleph, H. Zhang, W. G. Humphreys, W. R. Ewing, J. A. Robl, D.
Gordon, J. A. Tino, Bioorg. Med. Chem. Lett. 2008, 18, 4072.
Chem. Int. Ed. 2017, 56, 9949; (j) Z. Li, A. G. Domίnguez, C. Nevado,
Angew. Chem. Int. Ed. 2016, 55, 6938.
(a) S. Larsson, N. Rønsted, Curr. Top. Med. Chem. 2014,14, 274; (b) A.
K. Mailyan, J. A. Eickhoff, A. S.Minakova, Z. Gu, P. Lu, A. Zakarian,
Chem. Rev. 2016,116, 4441.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 7