Facile synthesis of fluorovinyl-containing lactams via ring-closing metathesis of N-substituted 2-fluoroallylamides

Article abstract of DOI:10.1016/j.tet.2016.06.054

A cost-efficient method for the preparation of a series of N-substituted 2-fluoroallylamines and their application in the synthesis of fluoroalkene-containing lactams are described. N-substituted 2-fluoroallylamine could be readily synthesized from methyl 2-fluoroacrylate via aminolysis and subsequently selective reduction of the amide group. These amines were further converted into the corresponding amides with diverse acids bearing a terminal double bond. The Ring-Closing Metathesis (RCM) of the resulting amides led to the formation fluorovinyl-containing lactams in good yields.

Full text of DOI:10.1016/j.tet.2016.06.054

Tetrahedron 72 (2016) 4845e4853
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Tetrahedron
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Facile synthesis of fluorovinyl-containing lactams via ring-closing
metathesis of N-substituted 2-fluoroallylamides
,
Yang Li a, Kai Li b, Yue Wu a, Qiaoning Ma a, Xinsheng Lei a
*
a School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong Zone, Shanghai 201203, China
b Forxine Pharmaceutical Co., Ltd, 855 Xiangyang Road, Minhang Zone, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 April 2016
Received in revised form 19 June 2016
Accepted 21 June 2016
Available online 22 June 2016
A cost-efficient method for the preparation of a series of N-substituted 2-fluoroallylamines and their
application in the synthesis of fluoroalkene-containing lactams are described. N-substituted 2-
fluoroallylamine could be readily synthesized from methyl 2-fluoroacrylate via aminolysis and sub-
sequently selective reduction of the amide group. These amines were further converted into the cor-
responding amides with diverse acids bearing a terminal double bond. The Ring-Closing Metathesis
(RCM) of the resulting amides led to the formation fluorovinyl-containing lactams in good yields.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Fluoroolefins
Vinyl fluoride
Ring-closing metathesis
Fluorinated heterocycles
Nitrogen heterocycles
1. Introduction
of expensive fluorine-containing reagents, or formation of in-
separable E/Z isomers.
Fluorinated molecules have a wide range of applications in al-
most all areas of science.1 Of particular relevance is the emergence
of fluoroolefins, which have appeared as peptidomimetics, bio-
active compounds, and materials.2 In the medicinal chemistry field,
monofluorovinyl group has been described as an isopolar and
isosteric mimic of an amide group with increased lipophilicity,
membrane permeability and rigidity.3 Recently such fragments
have been incorporated in a variety of antiviral, antibacterial, an-
tidiabetic and anticancer agents (Fig. 1),4 indicating its importance
in drug discovery. It is also extensively utilized as starting material
in such synthetic reactions as DielseAlder reaction, cyclo-
propanation, polymerization to introduce fluorine atom in the final
products.5
The ring-closing metathesis (RCM) is a well-known and pow-
erful reaction for the preparation of cyclic alkenes owing to its
broad substrate and functional group tolerability, and high regio-
selectivity of the formed double bond.6 However, fluoroalkenes
have scarcely been studied in RCM, because there are two inherent
defects to hinder subsequent turnover in the catalytic trans-
formation: slow phosphine dissociation to form the ruthenium
mono-fluorocarbene complex and abnormal stability of the com-
plex.7 Recently, a pioneering breakthrough in the challenging RCM
reaction of monofluoroolefins has been achieved by Brown and co-
workers,8 and subsequently others have also reported the suc-
cessful RCM reactions with some specific monofluorovinyl de-
rivatives.9 Therefore, further exploration with diverse
monofluorovinyl substrates in RCM remains desirable. Due to their
potential utilities in constrained pseudopeptides and bioactive
heterocycles,10 herein we describe an efficient preparation of
fluorovinyl-containing lactams from 2-fluoroallylamine derivatives
via RCM reaction.
Nowadays, several methods have been developed for preparing
the monofluoroalkenes via direct fluorination of olefin group or
fluorine-containing fragment implanting strategies.6 Nevertheless,
most of those methods have some limitations, such as a narrow
range of substrates, poor functional group tolerance, requirement
2. Results and discussion
Retrosynthetic analysis indicates that fluorolactams 6 would be
prepared from the 2-fluoroallylamides 5, which could in turn come
* Corresponding author. Tel./fax: þ86 21 51980128; e-mail address: leixs@fudan.
edu.cn (X. Lei).
http://dx.doi.org/10.1016/j.tet.2016.06.054
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

4846
Y. Li et al. / Tetrahedron 72 (2016) 4845e4853
Fig. 1. Monofluorovinyl fragments in bioactive compounds.
from the 2-fluoroallylamines 3 through amide formation (Scheme
1). Although 3 could be directly obtained through N-alkylation
between the corresponding amines and expensive 2-fluoroallyl
chloride, it is more attractive to develop a cost-efficient method
for preparation of 3 from the cheap methyl 2-fluoroacrylate
through aminolysis reaction and subsequently selective reduction
of amides.
Table 1
The isolated yields of N-substituted 2-fluoroacrylamides (2) and N-substituted 2-
fluoroallyl amines (3)
Entry
R
Yield
2 (%)
3 (%)a
1
2
3
4
5
6
7
8
9
4-MeOeC6H4CH2
C6H5CH2
4-CF3eC6H4CH2
4-BreC6H4CH2
C6H5
4-MeOeC6H4
4-CF3eC6H4
3-BreC6H4
2a, 64
2b, 54
2c, 56
2d, 55
2e, 75
2f, 70
2g, 85
2h, 75
2i, 67
3a, 52 (32b)
3b, 54
3c, 53
3d, 63
3e, 54
3f, 56
3g, 48
3h, 48
3i, 54
Scheme 1. The approach to fluorovinyl-containing lactams.
As shown in Table 1, the aminolysis reaction of methyl 2-
fluoroacrylate with 4-methoxybenzyl amine was initially tested
under basic conditions. It was noticed that weaker bases such as
K2CO3, Et3N, EtONa, or t-BuOK could hardly initiate the aminolysis
in the presence of a slight excess amount of the amine. After
screening a number of bases, we found that 1.5 equiv of NaHMDS
could promote the reaction and give the desired amide 2a in 64%
yield. Thus, a variety of amines were subjected to this condition and
could smoothly react with methyl 2-fluoroacrylate, providing the
amides 2aei in moderate to good yields (Table 1).
Compared with 4-methoxybenzyl amine, the benzyl amines
with an electron-neutral or withdrawing group on the phenyl ring
resulted in slightly lower yields in the aminolysis reaction (2be2d,
w55%), however, when aryl amines were used, the yields of ami-
nolysis were greatly improved. All of the aryl amines, regardless of
electron-donating or withdrawing substituents on the benzene
ring, afforded the desired N-aryl 2-fluoroacrylamides in good to
excellent yields (2ee2i, 67e85%).
2-CH3eC6H4
a
The isolated yield is obtained by reduction with DIBALH unless otherwise noted.
Reduction with LiAlH4 (4.0 equiv).
b
or THF, thus a solution of 2a in CH2Cl2 was added dropwise to the
suspension of LiAlH4 in Et2O at rt and the selective reduction was
rapidly completed. In comparison, decreasing the temperature or
the amount of the reducing reagent resulted in a sluggish reaction.
In addition, despite the high conversion, the isolated yield was
unfortunately low (3a, 32%), mainly due to the product adsorption
on aluminum salt. On the other hand, the aryl amide (2e or 2g) was
subjected to the same condition, the significant amount of the
olefin-reduction product was observed. Finally, DIBALH was found
as a more suitable reducing reagent for this selective trans-
formation (3a 52%, 3e 54%), and other amides could also be reduced
into 2-fluoroallyl amines in acceptable yields (3be3i, w50%), as
shown in Table 1.
Subsequently, the selective reduction of the amide group in 2a
was attempted with LiAlH4. Due to the poor solubility of 2a in ether

Y. Li et al. / Tetrahedron 72 (2016) 4845e4853
4847
Table 3
With a set of 2-fluoroallyl amines in hand, further acylation was
The acylation of 2-fluoroallyl amines and the subsequent RCM reaction
performed under the routine condition, aiming at preparing a se-
ries of precursors for RCM reaction. The various acids (4ae4e)
tagged with the terminal double bond involving different electronic
properties and distances, were converted into acyl chlorides in situ
with (COCl)2 in the presence of a catalytic amount of DMF. Then the
acyl chlorides were trapped with the amines (3ae3i) to give the
corresponding amides (5aae5fe) in satisfactory yields (61e89%), as
described in Table 2.
Entry
R
R1
n
Yielda
5 (%)
6 (%)
1
2
3
4
5
6
7
8
4-MeOeC6H4CH2
4-MeOeC6H4CH2
4-MeOeC6H4CH2
4-MeOeC6H4CH2
C6H5CH2
4-CF3eC6H4CH2
4-BreC6H4CH2
C6H5
4-MeOeC6H4
4-CF3eC6H4
2-CH3eC6H4
4-MeOeC6H4
H
H
H
H
H
H
H
H
H
H
H
F
0
1
2
3
1
1
1
1
1
1
1
0
5aa, 61
5ab, 76
5ac, 73
5ad, 79
5bb, 82
5cb, 89
5db, 86
5eb, 83
5fb, 82
5gb, 86
5ib, 78
5fe, 76
6aa, 70
6ab, 73
6aa, 48
6ad, 0
6bb, 84
6cb, 81
6db, 60
6ef, 83
6fb, 81
6gb, 35
6ib, 0b
6fe, NRc
Table 2
Optimized conditions of RCM reaction with 5aba
9
10
12
13
a
The isolated yields;
7ib could be isolated instead of 6ib;
No reaction.
b
c
Entry
Cat. (eq.)
Solv.
Temp (oC)
Yield (%)b
1
2
3
4
5
6
7
8
A (0.30)
A (0.10)
A (0.10)
A (0.10)
A (0.10)
A (0.20)
A (0.30)
A (0.05)
A (0.10)
A (0.10)
B (0.10)
C (0.10)
CH2Cl2
THF
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Reflux
Reflux
Reflux
80
100
100
100
100
100
100
8
5
higher amount of catalyst (0.3 equiv) as compared to a lower one
(0.1 equiv), but less amount of catalyst apparently led to a lower
yield (Entries 6, 7, 8). On the other hand, reaction concentration also
affected the reaction yields. Reaction concentration at 0.01 M
appeared to be a better choice than the concentration at 0.005 M
(Entries 9, 10). In addition, catalyst B or C, bearing a non-phosphine
ligand moiety, often has a superior performance in the case of
cross-metathesis with 1-haloethylene or 1,2-dihaloethylene,11 but
they did not enhance the catalytic activity for this transformation
(Entries 11, 12).
With the optimized condition in hand, our attention was
turned to 5aa, and the five-membered ring product (6aa) could
smoothly be obtained in 70% yield, similar to the case of the six-
membered ring (6ab). It has been reported the formation of the
five-8,9b,d or seven-9b,d,e membered ring appeared troublesome in
the literature. The RCM reaction could still continue to form the
seven-membered ring albeit in a lower yield (6ac, 48%). However,
our reaction condition failed to provide the eight-membered ring
(8ad, 0%).
38
36
73
67
69
48
16c
60d
46
58
9
10
11
12
Tol
Tol
Tol
100
100
a
Reactions were run for 1 h at the shown temperature after the solution of 5a
(0.5 mmol) in the suitable solvent (0.01 M) had been treated by the catalyst, unless
otherwise noted;
b
The isolated yields;
The reaction concentration was at 0.10 M;
The reaction concentration was at 0.005 M.
c
d
Next, the RCM reaction was carried out on compound 5ab
with catalyst A (Table 2), which was reported to catalyze an ef-
ficient RCM reaction.8,9 The initial attempt failed to produce the
desired 6ab in refluxing CH2Cl2 with 0.1 or 0.3 equiv of catalyst A,
although a negligible yield was obtained overnight (Entry 1).8
When the reaction was conducted in refluxing THF, similar re-
sult was obtained (Entries 2) (see Table 3). However, in refluxing
toluene,9a,b,e the RCM reaction yield was increased (Entries 3).
Extension of reaction time did not improve the yield, and no
reaction was detected at the temperature below 80 ꢀC (Entries 4).
These results suggested that the catalyst could promote the RCM
As expected, the electronic effect on the benzene ring of N-
benzyl substituted substrates hardly had an effect on the formation
of the six-membered ring, and similar yields were obtained from
60% to 84% (6ab, 6bb, 6cb, 6db).
After that, N-aryl substituted amides were next examined (5eb,
5fb, 5gb, 5hb, 5ib). To our best knowledge, this type of substrates
have never been studied in RCM reaction. The results indicated that
the reaction could tolerate diverse functional groups regardless of
their meta or para position on the benzene ring, and smoothly
produced the desired N-aryl fluorovinyl-containing lactams in
moderate to good yields (6eb, 6fb, 6gb, 6hb). However, the with-
drawing electronic group on benzene ring evidently had a detri-
mental effect on the metathesis reaction. To our surprise, the
substrate (5ib) bearing ortho methyl on the benzene ring did not
undergo the RCM reaction, instead, it was partially transformed
reaction at
a higher temperature while it might be easily
decomposed at that temperature. To keep the catalyst’s activity
and life span, a solution of the catalyst in toluene was added to
the diene solution slowly via a syringe pump over 1 h at 100 ꢀC,
and reaction mixture was continued to stir for 1 h. The reaction
yield was greatly improved and 6ab could be obtained in 73%
yield (Entries 5).
into the corresponding ɑ,b-unsaturated amide (7ib) through 1,3-H
shift, suggesting that the ortho methyl might hinder the cyclization
(shown in eq. 1).
Subsequently, the catalyst loading and the reaction concentra-
tion were further evaluated. No improvement was observed with

4848
Y. Li et al. / Tetrahedron 72 (2016) 4845e4853
NMR and 19F NMR spectra were recorded on a 150 MHz or 376 MHz
spectrometer, respectively. HRMS spectra were recorded on
Finnigan-Mat-95 mass spectrometer, equipped with ESI source.
Infrared (IR) spectra were recorded neat on KBr tablets with fre-
quencies expressed in cmꢁ1
.
4.2. Synthetic procedures and characterization data
4.2.1. General procedure for the synthesis of N-substituted ɑ-fluo-
roacrylamides (2aei). A solution of 2.0 M NaHMDS in THF (7.5 mL,
15.0 mmol) was added to the solution of RNH2 (1.2 equiv) in THF
(25 mL) at 0 ꢀC under Ar atmosphere. The reaction solution was
then stirred for 30 min at room temperature, after that, methyl 2-
fluoroacrylate (0.91 mL, 10.0 mmol) was added dropwise at 0 ꢀC.
The resulting solution was then warmed to room temperature and
stirred for overnight. After quenched with saturated NH4Cl aqueous
solution, the mixture was extracted with EtOAc (2ꢂ100 mL), and
the combined organic layers were washed with brine (20 mL) and
dried over NaSO4. After filtration and concentration, the residue
was purified by column chromatography, and the isolated yields
were shown in Table 1.
Although metathesis cyclization between one fluoroalkene and
the other terminal non-fluorinated alkene went smoothly to pro-
vide 5e7 membered lactams, the metathesis between two terminal
fluoroalkene partners (5fe) failed to provide the desired product
(6fe) (eq. 2).
Finally, the application of the fluorovinyl-containing lactams
was demonstrated in a stereo-selective synthesis of an important
building block in the conformation-constrained fluoropseudopep-
4.2.1.1. 2-Fluoro-N-(4-methoxybenzyl)-acrylamide (2a). Eluent
solvent: petroleum ether/ethyl acetate¼2/1. White solid, mp
94e95 ꢀC. IR (neat):
n 3258, 2916, 2848, 1640, 1541, 1514, 1371, 1323,
1251, 1177, 988, 827 cmꢁ1 1H NMR (400 MHz, CDCl3):
. d 7.25 (d,
J¼7.5 Hz, 2H, ArH), 6.88 (d, J¼7.5 Hz, 2H, ArH), 6.51 (brs, 1H, NH),
5.72 (dd, J¼47.8, 1.6 Hz, 1H, CH2]CF), 5.13 (dd, J¼15.3, 1.6 Hz, 1H,
CH2]CF), 4.46 (d, J¼5.6 Hz, 2H, CH2Ar), 3.80 (d, J¼0.5 Hz, 3H,
tides, Fmoc-Gly-J[(E)CF]CH]-Gly-OH, cisoid mimic of Fmoc-Gly-
Gly-OH (eq. 3), which was previously available via poorly stereo-
selective method.2a,d Thus, 6ab was first hydrolyzed in refluxing
hydrochloride aqueous solution (6.0 N) for 3 h to afford the cor-
responding amino acid hydrochloride, and subsequently reacted
with Fmoc chloride under basic conditions, giving rise to the cisoid
mimic 8ab in 76% yield.
OCH3). 13C NMR (150 MHz, CDCl3):
d
159.3 (d, J¼28.8 Hz), 159.2,
156.2 (d, J¼267.8 Hz), 129.3, 114.1, 99.1 (d, J¼15.5 Hz), 55.2, 42.9. 19
F
NMR (376 MHz, CDCl3):
d
ꢁ121.6 (ddd, JHeF(trans)¼47.8 Hz,
JHeF(cis)¼15.3 Hz, J¼1.9 Hz). HRMS (ESI) m/z: calcd for C11H13FNO2þ
[MþH]þ 210.0925, found: 210.0926.
4.2.1.2. 2-Fluoro-N-benzylacrylamide (2b). Eluent solvent: pe-
troleum ether/ethyl acetate¼5/1. White solid, mp 57e58 ꢀC. IR
3. Conclusion
(neat):
n 3319, 2918, 2849, 1649, 1536, 1497, 1357, 1319, 1208, 1186,
In conclusion, a cost-efficient method for preparation of a series
of 2-fluoroallylamines from methyl 2-fluoroacrylate has been de-
veloped through aminolysis and subsequently selective reduction.
Through acylation reaction with diverse acids tagged with terminal
olefin moiety, the 2-fluoroallylamines could be transformed into
the corresponding precursors for RCM reaction. The RCM reaction
with these precursors led to fluorovinyl-containing lactams bearing
five-, six- and seven-membered rings, but the reaction between
two terminal fluoroalkene partners might be a more challenging
task.
697 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d 7.44e7.22 (m, 5H, ArH), 6.60
(brs, 1H, NH), 5.74 (dd, J¼48.0, 3.2 Hz, 1H, CH2]CF), 5.15 (dd,
J¼15.3, 3.2 Hz, 1H, CH2]CF), 4.54 (d, J¼5.8 Hz, 2H, CH2Ph). 13C NMR
(150 MHz, CDCl3)
d
158.8 (d, J¼31 Hz), 155.6 (d, J¼270 Hz), 137.3,
128.8,127.9,127.8, 99.1 (d, J¼15 Hz), 43.6. 19F NMR (376 MHz, CDCl3)
d
ꢁ121.6 (dd, JHeF(trans)¼48.0 Hz, JHeF(cis)¼15.2 Hz). HRMS (ESI) m/z:
calcd for C10H11FNOþ [MþH]þ 180.0819, found 180.0818.
4.2.1.3. 2-Fluoro-N-(4-(trifluoromethyl)benzyl)acrylamide
(2c). Eluent solvent: petroleum ether/ethyl acetate¼8/1. White
solid, mp 100e100 ꢀC. IR (neat):
n 3324, 2917, 2849, 1664, 1540,
4. Experimental section
1333, 1190, 1166, 920, 899 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d7.60 (d,
J¼8.0 Hz, 2H, ArH), 7.40 (d, J¼8.0 Hz, 2H, ArH), 6.70 (brs, 1H, NH),
5.74 (dd, J¼47.4, 3.2 Hz, 1H, CH2]CF), 5.18 (dd, J¼15.0, 3.2 Hz, 1H,
CH2]CF), 4.59 (d, J¼6.0 Hz, 2H, CH2Ar). 13C NMR (150 MHz, CDCl3)
4.1. General methods and materials
Solvents were distilled from the appropriate drying agents be-
fore use. All the reagents were purchased from Acros, Alfa Aesar,
and National Chemical Reagent Group Co. Ltd., P. R. China and used
as received. The progress of the reactions was monitored by TLC
(silica-coated glass plates) and visualized under UV light, and by
using iodine or phosphomolybdic acid. Flash column chromatog-
raphy was performed on silica gel (300e400 mesh). Melting points
were measured on a SGW X-4 microscopy melting point apparatus
without correction. NMR samples were recorded in CDCl3 on
d
159.0 (d, J¼31.2 Hz), 155.4 (d, J¼268 Hz), 140.7, 129.6 (q,
J¼32.2 Hz), 127.3, 125.1 (q, J¼3.3 Hz), 123.6 (q, J¼270 Hz), 98.9 (d,
J¼14.7 Hz), 42.2. 19F NMR (376 MHz, CDCl3) d ꢁ63.10 (s, 3F), ꢁ121.8
(dd, JHeF(trans)¼47.4 Hz, JHeF(cis)¼15.0 Hz, 1F). HRMS (ESI) m/z: calcd
for C11H10F4NOþ [MþH]þ 248.0693, found 248.0693.
4.2.1.4. 2-Fluoro-N-(4-bromobenzyl) acrylamide (2d). Eluent
solvent: petroleum ether/ethyl acetate¼5/1. White solid, mp
108e109 ꢀC. IR (neat):
n 3329, 2918, 2849, 1650, 1537, 1316, 1207,
400 MHz spectrometers. Chemical shifts (
using TMS (
d
) are reported in ppm
1186, 920, 895 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d 7.50e7.30 (m, 2H,
d
¼0.0) as an internal standard. Multiplicities of NMR
ArH), 7.20e7.10 (m, 2H, ArH), 6.65 (brs, 1H, NH), 5.33 (dd, J¼48.0,
signals are designated as s (singlet), d (doublet), t (triplet), q
(quartet), br (broad), m (multiplet, for unresolved lines), etc. 13C
2.2 Hz, 1H, CH2]CF), 4.76 (dd, J¼15.6, 2.1 Hz, 1H, CH2]CF), 4.08 (m,
2H, CH2Ar). 13C NMR (150 MHz, CDCl3)
d
158.9 (d, J¼31.0 Hz), 155.4

Y. Li et al. / Tetrahedron 72 (2016) 4845e4853
4849
(d, J¼268 Hz), 135.7, 131.3, 128.9, 121.1, 98.8 (d, J¼14.7 Hz), 42.2. 19
F
(40 mL, 40 mmol) was added dropwise to the solution of compound
2aei (8.0 mmol) in dichloromethane (80 mL) within 20 min at 0 ꢀC
under Ar atmosphere. The reaction solution was then warmed to
room temperature and stirred for overnight. After quenched with
saturated NH4Cl aqueous solution (50 mL), the mixture was filtered,
and the filtrate was then extracted with EtOAc (3ꢂ100 mL), washed
with brine (100 mL) and dried over NaSO4. After filtration and
concentration. The residue was purified by column chromatogra-
phy, and the isolated yields were shown in Table 1.
NMR (376 MHz, CDCl3)
d
ꢁ121.7 (ddd, JHeF(trans)¼47.7 Hz,
JHeF(cis)¼15.4 Hz, J¼2.2 Hz). HRMS (ESI) m/z: calcd for
C
10H10BrFNOþ [MþH]þ 257.9924, found 257.9928.
4.2.1.5. 2-Fluoro-N-phenylacrylamide (2e). Eluent solvent: pe-
troleum ether/ethyl acetate¼20/1. White solid, mp 57e58 ꢀC. IR
(neat):
n 3349, 2917, 1682, 1661, 1530, 1445, 1329, 1164, 888, 747,
690 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d 7.96 (brs, 1H, NH), 7.59 (d,
J¼8.0 Hz, 2H, ArH), 7.37 (m, 2H, ArH), 7.22 (t, J¼7.6 Hz, 1H, ArH),
5.81 (dd, J¼47.9, 3.3 Hz, 1H, CH2]CF), 5.26 (dd, J¼15.4, 3.3 Hz, 1H,
4.2.2.1. 2-Fluoro-N-(4-methoxybenzyl)-prop-2-en-1-amine
CH2]CF). 13C NMR (150 MHz, CDCl3)
d
156.6 (d, J¼31.0 Hz),155.8 (d,
(3a). Eluent solvent: dichloromethane/acetone¼200/1. Colorless
J¼268 Hz), 135.9, 128.5, 124.6, 119.6, 99.3 (d, J¼15.0 Hz). 19F NMR
oil. IR (neat): n 3409, 2955, 2917, 1677, 1662, 1513, 1464, 1247, 1176,
(376 MHz, CDCl3)
d
ꢁ121.1 (ddd, JHeF(trans)¼47.9 Hz,
1036, 847 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
7.25 (d, J¼8.7 Hz, 2H,
JHeF(cis)¼15.4 Hz, J¼5.1 Hz). HRMS (ESI) m/z: calcd for C9H9FNOþ
ArH), 6.87 (d, J¼8.7 Hz, 2H, ArH), 4.70 (dd, J¼17.4, 2.8 Hz, 1H, CH2]
CF), 4.45 (dd, J¼49.6, 2.8 Hz, 1H, CH2]CF), 3.80 (s, 3H, OCH3), 3.75
[MþH]þ 166.0663, found 166.0662.
(s, 2H, CH2Ar), 3.32 (d, J¼14.3 Hz, 2H, CH2NH), 1.60 (brs, 1H, NH). 13
C
4.2.1.6. 2-Fluoro-N-(4-methoxyphenyl)acrylamide
solvent: petroleum ether/ethyl acetate¼8/1. White solid, mp
128e109 ꢀC. IR (neat):
3438, 3339, 2962, 1680, 1655, 1528, 1414,
1031, 901, 822, 690 cmꢁ1. 1H NMR (400 MHz, CDCl3)
7.94 (brs, 1H,
(2f). Eluent
NMR (400 MHz, CDCl3)
d
163.9 (d, J¼260 Hz), 158.6, 131.6, 129.3,
113.7, 91.4 (d, J¼10.0 Hz), 55.2, 51.7, 48.4 (d, J¼30.2 Hz). 19F NMR
n
(376 MHz, CDCl3)
d
ꢁ104.4 (ddt, JHeF(trans)¼49.7 Hz,
d
JHeF(cis)¼17.4 Hz, J¼14.3 Hz). HRMS (ESI) m/z: calcd for
NH), 7.49 (d, J¼9.0 Hz, 2H, ArH), 6.87 (d, J¼9.0 Hz, 2H, ArH), 5.79
C
11H14FNONaþ [MþNa]þ 218.0952, found 218.0953.
(dd, J¼47.9, 3.3 Hz, 1H, CH2]CF), 5.21 (dd, J¼15.4, 3.3 Hz, 1H, CH2]
CF), 3.79 (s, 3H, OCH3). 13C NMR (150 MHz, CDCl3)
d
156.5 (d,
4.2.2.2. 2-Fluoro-N-benzyl-prop-2-en-1-amine (3b). Eluent sol-
J¼34.8 Hz), 154.8 (d, J¼270 Hz), 128.9, 121.4, 113.6, 98.9 (d,
vent: Petroleum ether/ethyl acetate¼2/1. Colorless oil. IR (neat):
3338, 3028, 2918, 2846, 1677, 1495, 1454, 1196, 1119, 932, 738,
698 cmꢁ1. 1H NMR (400 MHz, CDCl3)
7.34 (m, 5H, ArH), 4.70 (dd,
n
J¼15.0 Hz), 54.8. 19F NMR (376 MHz, CDCl3)
d
ꢁ121.1 (ddd,
JHeF(trans)¼47.9 Hz, JHeF(cis)¼15.4 Hz, J¼4.9 Hz). HRMS (ESI) m/z:
d
calcd for C10H11FNOþ2 [MþH]þ 196.0768, found 196.0770.
J¼17.1, 2.8 Hz, 1H, CH2]CF), 4.46 (dd, J¼49.7, 2.8 Hz, 1H, CH2]CF),
3.82 (s, 2H, CH2Ph), 3.34 (d, J¼14.3 Hz, 2H, CH2NH). 13C NMR
4.2.1.7. 2-Fluoro-N-(4-trifluoromethylphenyl)acrylamide
(2g). Eluent solvent: petroleum ether/ethyl acetate¼8/1. Colorless
(150 MHz, CDCl3)
d
163.3 (d, J¼257 Hz), 139.1, 127.8, 127.5, 126.5,
90.8 (d, J¼18.4 Hz), 51.8, 48.1 (d, J¼30.3 Hz). 19F NMR (376 MHz,
oil. 1H NMR (400 MHz, CDCl3)
d
8.10 (brs, 1H, NH), 7.73 (d, J¼8.4 Hz,
CDCl3)
d
ꢁ103.5 (ddt, JHeF(trans)¼49.7 Hz, JHeF(cis)¼17.1 Hz,
2H, ArH), 6.87 (d, J¼8.4 Hz, 2H, ArH), 5.85 (dd, J¼47.6, 3.6 Hz, 1H,
J¼14.3 Hz). HRMS (ESI) m/z: calcd for C10H13FNþ [MþH]þ 166.1027,
CH2]CF), 5.21 (dd, J¼15.2, 3.6 Hz,1H, CH2]CF). 13C NMR (150 MHz,
found 166.1024.
CDCl3)
d
157.5 (d, J¼30.0 Hz), 155.8 (d, J¼270 Hz), 139.6, 127.1 (q,
J¼32.7 Hz), 126.4 (q, J¼3.4 Hz), 123.9 (q, J¼270 Hz), 119.9, 100.7 (d,
4.2.2.3. 2-Fluoro-N-(4-(trifluoromethyl)benzyl)-prop-2-en-1-
amine (3c). Eluent solvent: dichloromethane. Colorless oil. IR
J¼15.0 Hz). 19F NMR (376 MHz, CDCl3)
d
ꢁ121.3 (dd,
JHeF(trans)¼47.9 Hz, JHeF(cis)¼15.2 Hz, 1F), ꢁ62.7 (s, 3F). HRMS (ESI)
(neat):
n 3423, 2955, 2921, 2849, 1677, 1620, 1326, 1164, 1126, 1019,
m/z: calcd for C10H11FNO2þ [MþH]þ 196.0768, found 196.0770.
850 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
7.59 (d, J¼8.0 Hz, 2H, ArH),
7.46 (d, J¼7.9 Hz, 2H, ArH), 4.71 (dd, J¼17.0, 2.9 Hz, 1H, CH2]CF),
4.45 (dd, J¼49.5, 2.9 Hz, 1H, CH2]CF), 3.87 (s, 2H, CH2Ar), 3.33 (d,
4.2.1.8. 2-Fluoro-N-(3-bromophenyl)acrylamide (2h). Recrystal-
lization: dichloromethane/ethyl acetate¼5/30. White solid, mp
J¼14.5 Hz, 2H,CH2NH). 13C NMR (150 MHz, CDCl3)
d 163.6 (d,
93e94 ꢀC. IR (neat):
n
3438, 3304, 2917,1682,1661,1592,1536,1425,
J¼257 Hz), 143.2, 128.8 (q, J¼32.4 Hz), 127.7, 124.7 (q, J¼4.0 Hz),
1162, 776, 681 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
7.96 (brs, 1H, NH),
123.6 (q, J¼270 Hz), 91.1 (d, J¼18.4 Hz), 51.1, 48.1 (d, J¼30.3 Hz). 19
F
7.86 (d, J¼2.1 Hz, 1H, ArH), 7.21 (d, J¼8.1 Hz, 1H, ArH), 6.96 (m, 2H,
NMR (376 MHz, CDCl3)
d
ꢁ62.8 (s, 3F), ꢁ100.0 (ddt,
ArH), 5.79 (dd, J¼47.8, 3.4 Hz, 1H, CH2]CF), 5.27 (dd, J¼16.1, 3.4 Hz,
JHeF(trans)¼49.5 Hz, JHeF(cis)¼17.0 Hz, J¼14.5 Hz, 1F). HRMS (ESI) m/z:
1H, CH2]CF). 13C NMR (150 MHz, CDCl3)
d
156.6 (d, J¼29.7 Hz),
calcd for C11H12F4Nþ [MþH]þ 234.0900, found 234.0905.
155.1 (d, J¼270 Hz), 137.1, 129.8, 127.6, 122.5, 122.1, 118.0, 99.8 (d,
J¼14.9 Hz). 19F NMR (376 MHz, CDCl3)
d
ꢁ121.4 (ddd,
4.2.2.4. 2-Fluoro-N-(4-bromobenzyl)-acrylamide
solvent: petroleum ether/ethyl acetate¼10/1. Colorless oil. IR
(neat): 3338, 2919, 2836, 1677, 1487, 1461, 1197, 1120, 1070, 1011,
932, 855, 799 cmꢁ1. 1H NMR (400 MHz, CDCl3)
(3d). Eluent
JHeF(trans)¼47.8 Hz, JHeF(cis)¼16.3 Hz, J¼5.3 Hz). HRMS (ESI) m/z:
calcd for C9H8BrFNOþ [MþH]þ 243.9768, found 243.9774.
n
d
7.45 (d, J¼8.0 Hz,
4.2.1.9. 2-Fluoro-N-(o-tolyl)acrylamide (2i). Eluent solvent: pe-
troleum ether/ethyl acetate¼20/1. White solid, mp 60e61 ꢀC. IR
2H, ArH), 7.22 (d, J¼8.0 Hz, 2H, ArH), 4.69 (d, J¼17.0 Hz, 1H, CH2]
CF), 4.44 (d, J¼49.7 Hz, 1H, CH2]CF), 3.77 (s, 2H, CH2Ph), 3.31 (d,
(neat):
n
3443, 3294, 2927, 1687, 1659, 1590, 1530, 1458, 1318, 933,
J¼14.6 Hz, 2H, CH2NH). 13C NMR (150 MHz, CDCl3)
d 164.0 (d,
897, 750 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
7.94 (d, J¼8.0 Hz, 1H,
J¼257 Hz),138.1,130.9,129.3,120.3, 91.0 (d, J¼18.5 Hz), 51.0, 48.0 (d,
ArH), 7.84 (brs, 1H, NH), 7.30e7.13 (m, 3H, ArH), 5.83 (dd, J¼48.1,
3.2 Hz, 1H, CH2]CF), 5.26 (dd, J¼15.4, 3.2 Hz, 1H, CH2]CF), 2.29 (s,
J¼30.0 Hz). 19F NMR (376 MHz, CDCl3)
d
ꢁ63.0 (s, 3F), ꢁ103.5 (ddt,
JHeF(trans)¼49.6 Hz, JHeF(cis)¼17.0 Hz, J¼14.6 Hz, 1F). HRMS (ESI) m/z:
3H, ArCH3). 13C NMR (150 MHz, CDCl3)
d
156.6 (d, J¼29.3 Hz), 155.7
calcd for C10H12BrFNþ [MþH]þ 244.0132, found 244.0127.
(d, J¼270 Hz), 133.8, 129.9, 128.3, 126.3, 125.1, 122.1, 99.2 (d,
J¼15.0 Hz), 16.8. 19F NMR (376 MHz, CDCl3)
d
ꢁ121.2 (dd,
4.2.2.5. 2-Fluoroallyl-N-aniline (3e). Eluent solvent: petroleum
JHeF(trans)¼48.2 Hz, JHeF(cis)¼15.6 Hz). HRMS (ESI) m/z: calcd for
ether/ethyl acetate¼50/1. Colorless oil. IR (neat):
2836, 1677, 1487, 1461, 1197, 1120, 1070, 1011, 932, 855, 799 cmꢁ1. 1H
NMR (400 MHz, CDCl3) 7.25e7.20 (m, 2H, ArH), 6.77 (m, 1H, ArH),
n 3338, 2919,
C
10H11FNOþ [MþH]þ 180.0819, found 180.0821.
d
4.2.2. General procedure for the synthesis of N-substituted 2-
fluoroallyl amines (3aei). A solution of 1.0 M DIBALH in THF
6.69e6.62 (m, 2H, ArH), 4.71 (dd, J¼17.3, 3.2 Hz, 1H, CH2]CF), 4.54
(dd, J¼49.5, 3.2 Hz, 1H, CH2]CF), 3.90 (brs, NH), 3.88 (d, J¼8.3 Hz,

4850
Y. Li et al. / Tetrahedron 72 (2016) 4845e4853
2H, CH2NH). 13C NMR (150 MHz, CDCl3)
d
163.5 (d, J¼258 Hz), 146.4,
concentration, the residue was purified by column chromatography
to give the acylated product with two rotamers, and the isolated
yields were shown in Table 2.
128.6, 117.6, 112.5, 90.4 (d, J¼17.3 Hz), 43.7 (d, J¼34.9 Hz). 19F NMR
(376 MHz, CDCl3)
d
ꢁ104.5 (ddt, JHeF(trans)¼49.5 Hz,
JHeF(cis)¼17.3 Hz, J¼8.3 Hz). HRMS (ESI) m/z: calcd for C9H11FNþ
[MþH]þ 152.0870, found 152.0869.
4.2.3.1. 2-Fluoroallyl-N-(4-(trifluoromethyl)-N-phenyl-acrylam-
ide (5aa). Eluent solvent: petroleum ether/ethyl acetate¼1/1. Col-
4.2.2.6. 2-Fluoroallyl-N-4-methoxyaniline (3f). Eluent solvent:
petroleum ether/dichloromethane/ethyl acetate¼45/10/1. Colorless
orless oil. IR (neat): n 2933, 1651, 1613, 1513, 1441, 1284, 1205, 1176,
1033, 847 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
7.20 (d, J¼8.8 Hz, 1H,
oil. IR (neat):
n
3410, 2934, 2834, 1680, 1514, 1464, 1441, 1236, 1201,
ArH, one rotamer), 7.08 (d, J¼8.4 Hz, 1H, ArH, the other rotamer),
6.87 (d, J¼8.8 Hz, 1H, ArH, one rotamer), 6.84 (d, J¼8.4 Hz, 2H, ArH,
the other rotamer), 6.55e6.51 (m, 1H), 6.48e6.38 (m, 1H),
5.78e5.68 (m, 1H), 4.83e4.67 (m, 1H), 4.61 (m, 1H), 4.59 (m, 1H),
4.52e4.48 (m, 0.5H), 4.40e4.36 (m, 0.5H). 4.13 (d, J¼12.8 Hz, 1H),
3.89 (d, J¼8.8 Hz, 1H), 3.78 (s, 1.5H), 3.77 (s, 1.5H). 13C NMR
1180, 1036, 932, 855, 820 cmꢁ1 1H NMR (400 MHz, CDCl3)
.
d
6.89e6.71 (m, 2H, ArH), 6.63 (m, 2H, ArH), 4.70 (dd, J¼17.3, 2.7 Hz,
1H, CH2]CF), 4.52 (dd, J¼49.7 Hz, 2.7, 1H, CH2]CF), 3.82 (d,
J¼8.9 Hz, 2H, CH2NH), 3.76 (s, 3H, OCH3), 3.70e3.50 (brs, 1H, NH).
13C NMR (150 MHz, CDCl3)
d
163.7 (d, J¼258 Hz), 152.1, 140.6, 114.1
(d, J¼48.8 Hz), 90.4 (d, J¼17.7 Hz), 55.1, 44.7 (d, J¼34.2 Hz). 19F NMR
(150 MHz, CDCl3)
d
166.8, 161.2 (d, J¼258 Hz, one rotamer), 160.7 (d,
(376 MHz, CDCl3)
d
ꢁ104.2 (ddt, JHeF(trans)¼49.7, JHeF(cis)¼17.3,
J¼258 Hz, one rotamer), 159.2, 159.0, 129.8, 129.5, 129.1, 128.8,
127.9, 127.7, 127.3, 127.2, 114.3, 114.0, 93.0 (d, J¼17.3 Hz, one
rotamer), 92.4 (d, J¼17.2 Hz, one rotamer), 55.3, 50.0, 47.8, 46.3,
45.0 (d, J¼32.0 Hz, one rotamer). 19F NMR (376 MHz, CDCl3)
J¼8.9 Hz). HRMS (ESI) m/z: calcd for C10H13FNOþ [MþH]þ 182.0976,
found 182.0972.
4.2.2.7. 2-Fluoroallyl-4-(trifluoromethyl)-N-aniline (3g). Eluent
solvent: petroleum ether/ethyl acetate¼65/1. Colorless oil. IR
d
ꢁ103.0 to ꢁ103.3 (m),
d
ꢁ104.0 to ꢁ104.3 (m). HRMS (ESI) m/z:
calcd for C14H17FNOþ2 [MþH]þ 250.1238, found 250.1239.
(neat):
(400 MHz, CDCl3)
n
3410, 1617, 1528, 1328, 1187, 1162, 1065, 829 cmꢁ1. 1H NMR
d
7.43 (d, J¼8.6 Hz, 2H, ArH), 6.65 (d, J¼8.6 Hz, 2H,
4.2.3.2. 2-Fluoroallyl-N-(4-methoxybenzyl)-N-but-3-enamide
ArH), 4.70 (dd, J¼16.8, 3.2 Hz,1H, CH2]CF), 4.52 (dd, J¼49.2, 3.2 Hz,
(5ab). Eluent solvent: petroleum ether/ethyl acetate¼1/1. Colorless
1H, CH2]CF), 4.29 (brs, 1H, NH), 3.89 (d, J¼8.0 Hz, 2H, CH2NH). 13
C
oil. IR (neat): n 2955, 2923, 2850, 1651, 1612, 1513, 1456, 1247, 1174,
NMR (150 MHz, CDCl3)
d
162.3 (d, J¼258 Hz), 148.9, 126.7 (q,
1033, 930, 847 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
7.20 (d, J¼8.4 Hz,
J¼3.4 Hz), 124.1 (q, J¼269 Hz), 119.3 (q, J¼32.5 Hz), 111.6, 91.6 (d,
1H, ArH, one rotamer), 7.09 (d, J¼8.4 Hz, 1H, ArH, the other
rotamer), 6.87 (d, J¼8.4 Hz, 1H, ArH, the other rotamer), 6.84 (d,
J¼8.4 Hz, 1H, ArH, one rotamer), 6.09e5.90 (m, 1H), 5.21e5.16 (m,
1H), 5.21e5.16 (m, 1H), 4.83e4.67 (m, 1H), 4.56 (s, 1H), 4.52 (s, 1H),
4.51e4.33 (m, 1H), 4.08 (d, J¼14.4 Hz, 1H), 3.84 (d, J¼8.4 Hz, 1H),
3.80 (s, 1.5H), 3.79 (s, 1.5H), 3.25e3.20 (m, 2H). 13C NMR (150 MHz,
J¼17.2 Hz), 44.7 (d, J¼34.2 Hz). 19F NMR (376 MHz, CDCl3)
ꢁ61.7 (s,
d
3F), 104.2 (ddt, JHeF(trans)¼49.2, JHeF(cis)¼16.8, J¼8.0 Hz, 1F). HRMS
(ESI) m/z: calcd for C10H10F4Nþ [MþH]þ 220.0749, found 220.0735.
4.2.2.8. 2-Fluoroally-3-bromo-N-aniline (3h). Eluent solvent:
petroleum ether/acetone¼50:1. Colorless oil. IR (neat):
2923, 1681, 1596, 1575, 1505, 1482, 1203, 987, 852, 765 cmꢁ1
NMR (400 MHz, CDCl3) 7.10e6.90 (m, 1H, ArH), 6.80e6.75 (m, 1H,
ArH), 6.70e6.60 (m, 1H, ArH), 6.55 (dd, J¼8.2, 2.1 Hz, 1H, ArH), 4.72
(dd, J¼17.2, 3.3 Hz, 1H, CH2]CF), 4.52 (dd, J¼49.3, 3.3 Hz, 1H, CH2]
CF), 4.03 (brs, 1H, NH), 3.93e3.72 (m, 2H,CH2NH). 13C NMR
n
3426,
.
CDCl3)
d
171.6, 171.5, 161.4 (d, J¼261 Hz, one rotamer), 161 (d,
1H
J¼260 Hz, the other rotamer), 159.5, 159.3, 131.6, 131.5, 130.0, 129.2,
128.0, 127.9, 118.3, 118.2, 114.6, 114.2, 93.2 (d, J¼18.1 Hz), 92.8 (d,
J¼18.1 Hz), 55.6, 55.5, 50.3, 47.6, 46.5 (d, J¼34.8 Hz), 44.8 (d,
d
J¼35.4 Hz), 38.9, 38.6. 19F NMR (376 MHz, CDCl3)
ꢁ103.1 to ꢁ103.5
d
(m), ꢁ104.0 to ꢁ104.3 (m). HRMS (ESI) m/z: calcd for C15H19FNO2þ
(150 MHz, CDCl3)
d
161.7 (d, J¼258 Hz), 147.7, 129.9, 122.6, 120.4,
[MþH]þ 264.1394, found 264.1395.
115.1, 111.2, 90.8 (d, J¼17.1 Hz), 43.48 (d, J¼35.0 Hz) 19F NMR
(376 MHz, CDCl3)
d
ꢁ103.0 to ꢁ103.5.0 (m). HRMS (ESI) m/z: calcd
4.2.3.3. 2-Fluoroallyl-N-(4-methoxybenzyl)-N-pent-4-enamide
for C9H10BrFNþ [MþH]þ 229.9975, found 229.9979.
(5ac). Eluent solvent: petroleum ether/ethyl acetate¼2/1. Colorless
oil. IR (neat): n 3443, 2955, 2923, 2850, 1651, 1612, 1513, 1456, 1247,
4.2.2.9. 2-Fluoroallyl-N-2-methylaniline (3i). Eluent solvent:
1174, 1033, 930, 847 cmꢁ1 1H NMR (400 MHz, CDCl3)
. d7.16 (d,
petroleum ether: Acetone¼200:1. Colorless oil. IR (neat):
3061, 1657,1537,1441, 1314, 1206,1184, 1045, 920, 893, 748 cmꢁ1. 1H
NMR (400 MHz, CDCl3) 7.20e7.00 (m, 2H, ArH), 6.80e6.50 (m, 2H,
n
3311,
J¼8.4 Hz,1H, ArH, one rotamer), 7.07 (d, J¼8.4 Hz,1H, ArH, the other
rotamer), 6.88 (d, J¼8.4 Hz, 1H, ArH, the other rotamer), 6.84 (d,
J¼8.4 Hz, 1H, ArH, one rotamer), 5.92e5.77 (m, 1H), 5.10e5.03 (m,
1H), 5.01e4.96 (m, 1H), 4.81e4.67 (m, 1H), 4.57 (s, 1H), 4.53 (s, 1H),
4.49e4.33 (m, 1H), 4.08 (d, J¼13.6 Hz, 1H), 3.84 (d, J¼8.8 Hz, 1H),
3.80 (s, 1.5H), 3.78 (s, 1.5H), 2.53e2.40 (m, 4H). 13C NMR (150 MHz,
d
ArH), 4.73 (dd, J¼17.2, 3.2 Hz, 1H, CH2]CF), 4.55 (dd, J¼49.6, 3.2 Hz,
1H, CH2]CF), 4.02 (brs, 1H, NH), 3.94 (d, J¼8.3 Hz, 2H, CH2NH), 2.20
(s, 3H, ArCH3). 13C NMR (150 MHz, CDCl3)
d
162.6 (d, J¼257 Hz),
144.4, 129.6, 126.5, 121.7, 117.2, 109.6, 90.4 (d, J¼17.3 Hz), 43.70 (d,
CDCl3)
d
172.6, 172.5, 161.4 (d, J¼260 Hz, one rotamer), 160.8 (d,
J¼34.8 Hz), 16.8. 19F NMR (376 MHz, CDCl3)
d
ꢁ104.4 (ddt,
J¼260 Hz, the other rotamer), 159.1, 159.0, 137.3, 137.2, 129.7, 129.0,
127.9, 127.6, 115.4, 115.3, 114.3, 114.0, 93.8 (d, J¼17.5 Hz), 92.8 (d,
J¼17.1 Hz), 55.3, 55.2, 49.9, 47.3, 46.2 (d, J¼33.4 Hz), 44.7 (d,
J¼32.0 Hz), 32.5, 32.2, 29.2, 29.1. 19F NMR (376 MHz, CDCl3):
JHeF(trans)¼49.6 Hz, JHeF(cis)¼17.2 Hz, J¼8.3 Hz). HRMS (ESI) m/z:
calcd for C10H13FNþ [MþH]þ 166.1027, found 166.1028.
4.2.3. General procedure for the acylation of 2-fluoroallyl amines
(5aae5fe). Oxalyl dichloride (1.56 mmol, 0.14 mL) was added to
the solution of the tested acid (1.72 mmol) in CH2Cl2 (5 mL) and
DMF (a drop, about 0.05 mL) at 0 ꢀC under Ar atmosphere within
10 min. After the solution was stirred for 3 h at the room temper-
ature, a solution of 3aei (1.32 mmol) in dichloromethane (8.0 mL)
was added at 0 ꢀC. The reaction solution was then warmed to room
temperature and stirred for overnight. After quenched with satu-
rated NaHCO3 aqueous solution, the mixture was extracted with
EtOAc (2ꢂ15 mL), and the combined organic layers were washed
with brine (20 mL) and dried over NaSO4. After filtration and
d
ꢁ103.3 to ꢁ103.6 (m), ꢁ104.1 to e104.4 (m). HRMS (ESI) m/z:
calcd for C16H21FNOþ2 [MþH]þ 278.1151, found 278.1156.
4.2.3.4. 2-Fluoroallyl-N-benzyl-N-hex-5-enamide (5ad). Eluent
solvent: petroleum ether/ethyl acetate¼5/1. Colorless oil. 1H NMR
(400 MHz, CDCl3)
d
7.17 (d, J¼8.4 Hz, 1H, ArH, one rotamer), 7.07 (d,
J¼8.4 Hz, 1H, ArH, the other rotamer), 6.88 (d, J¼8.4 Hz, 1H, ArH,
one rotamer), 6.84 (d, J¼8.4 Hz, 1H, ArH, the other rotamer),
5.92e5.77 (m, 1H), 5.10e4.96 (m, 2H), 4.81e4.67 (m, 1H), 4.57 (s,
1H), 4.53 (s, 1H), 4.49e4.33 (m, 1H), 4.08 (d, J¼13.6 Hz, 1H), 3.84 (d,
J¼8.8 Hz, 1H), 3.80 (s, 1.5H), 3.78 (s, 1.5H), 2.53e2.40 (m, 2H),

Y. Li et al. / Tetrahedron 72 (2016) 4845e4853
4851
2.30e2.00 (m, 2H), 1.90e1.70 (m, 2H). 13C NMR (150 MHz, CDCl3)
ꢁ104.0 (m). HRMS (ESI) m/z: calcd for C13H15FNOþ [MþH]þ
d
173.3, 173.1, 162.0 (d, J¼260 Hz, one rotamer), 160.8 (d, J¼260 Hz,
220.1132, found 220.1134.
the other rotamer), 159.1, 159.0, 138.1, 138.0, 129.7, 129.2, 128.1,
127.7, 115.4, 115.2, 114.3, 114.0, 92.7 (d, J¼17.5 Hz), 92.3 (d,
J¼17.1 Hz), 55.3, 55.2, 50.0, 47.3, 46.2 (d, J¼33.4 Hz), 44.7 (d,
J¼32.0 Hz), 33.2, 33.1, 32.4, 32.1, 24.3. 19F NMR (376 MHz, CDCl3):
4.2.3.9. 2-Fluoroallyl-N-(4-methoxyphenyl)-N-but-3-enamide
(5fb). Eluent solvent: petroleum ether/ethyl acetate¼10/1. Col-
orless oil. IR (neat):
n 3078, 2935, 2839, 1665, 1512, 1249, 1195,
d
ꢁ103.3 to ꢁ103.6 (m), ꢁ104.1 to ꢁ104.4 (m). HRMS (ESI) m/z:
1025, 841 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
7.11 (d, J¼8.8 Hz, 2H,
calcd for C17H23FNOþ2 [MþH]þ 292.1707, found 292.1709.
ArH), 6.90 (d, J¼8.8 Hz, 2H, ArH), 5.84 (m, 1H, CH]CH2), 5.05 (dd,
J¼10.2, 1.6 Hz, 1H, CH]CH2), 4.92 (dd, J¼17.1, 1.6 Hz, 1H, CH]CH2),
4.63 (dd, JHeF(cis)¼16.2 Hz, J¼3.1 Hz, 1H, CF]CH2), 4.37 (d,
J¼15.6 Hz, 2H, CH2NAr), 4.35 (dd, JHeF(trans)¼48.1 Hz, J¼3.1 Hz, 1H,
CF]CH2), 3.81 (s, 3H, OCH3), 2.85 (m, 2H, CH2CO). 13C NMR
4.2.3.5. 2-Fluoroallyl-N-benzyl-N-but-3-enamide (5bb). Eluent
solvent: petroleum ether/ethyl acetate¼5/1. Colorless oil. IR (neat):
n
3065, 3030, 2982, 2930, 1651, 1495, 1445, 1202, 932, 848,
700 cmꢁ1
.
1H NMR (400 MHz, CDCl3)
d
7.51e7.03 (m, 5H, ArH),
(150 MHz, CDCl3)
d
170.7, 161.4 (d, J¼259 Hz), 158.7, 133.7, 131.0,
6.10e5.50 (m, 1H), 5.50e5.10 (m, 2H), 4.80e4.60 (m, 1H), 4.60e4.50
(m, 2H), 4.50e4.40 (m, 1H), 4.12 (d, J¼13.8 Hz,1H), 3.87 (d, J¼9.1 Hz,
128.7, 117.1, 114.1, 93.0 (d, J¼17.9 Hz), 54.8, 48.7 (d, J¼30.4 Hz),
38.6. 19F NMR (376 MHz, CDCl3)
d
ꢁ102.0 to ꢁ104.0 (m). HRMS
1H), 3.23e3.10 (m, 2H). 13C NMR (150 MHz, CDCl3)
d
170.8, 170.7,
(ESI) m/z: calcd for C14H16FNO2Naþ [MþNa]þ 272.1057, found
160.7 (d, J¼259 Hz, one rotamer), 159.3 (d, J¼259 Hz, the other
rotamer), 136.3, 135.5, 130.7, 128.4, 128.1, 127.7, 127.2, 127.0, 125.7,
117.5, 92.3 (d, J¼17.6 Hz), 92.2 (d, J¼17.4 Hz), 50.0, 47.4, 45.9 (d,
J¼34.2 Hz), 44.4 (d, J¼31.7 Hz), 37.9, 37.7. 19F NMR (376 MHz, CDCl3)
272.1064.
4.2.3.10. 2-Fluoroallyl-N-(4-(trifluoromethyl)phenyl-N-but-3-
enamide (5gb). Eluent solvent: petroleum ether/ethyl acetate¼10/
d
ꢁ102.0 to ꢁ104.0 (m), ꢁ104.0 to ꢁ106.0 (m). HRMS (ESI) m/z:
1. Colorless oil. IR (neat): n 3082, 2932, 1674, 1614, 1423, 1381, 1326,
calcd for C14H17FNOþ [MþH]þ 234.1289, found 234.1291.
1169, 1128, 1107, 852 cmꢁ1 1H NMR (400 MHz, CDCl3)
. d 7.71 (d,
J¼8.2 Hz, 2H, ArH), 7.37 (d, J¼8.2 Hz, 2H, ArH), 5.90e5.70 (m, 1H,
CH¼CH2), 5.11 (d, JHeH(cis)¼10.1 Hz, 1H, CH]CH2), 4.97 (d,
JHeH(trans)¼17.2 Hz, 1H, CH]CH2), 4.69 (dd, JHeF(cis)¼16.1 Hz,
J¼3.1 Hz, 1H, CF]CH2), 4.45 (dd, JHeF(trans)¼47.6 Hz, J¼3.1 Hz, 1H,
CF]CH2), 4.40 (d, J¼15.2 Hz, 2H, CH2NAr), 2.89 (d, J¼6.7 Hz, 2H,
4.2.3.6. 2-Fluoroallyl-N-(4-(trifluoromethyl)phenyl-N-but-3-
enamide (5cb). Eluent solvent: petroleum ether/dichloro-
methane/ethyl acetate¼35/15/1. Colorless oil. IR (neat):
1656, 1413, 1326, 1165, 1125, 1067, 934, 849 cmꢁ1 1H NMR
(400 MHz, CDCl3)
7.60 (d, J¼8.0 Hz, 1H, ArH, one rotamer), 7.57
n 2925,
.
d
CH2CO). 13C NMR (150 MHz, CDCl3)
d
170.0, 160.9 (d, J¼276 Hz),
(d, J¼8.0 Hz, 1H, ArH, the other rotamer), 7.35 (d, J¼8.0 Hz, 1H,
ArH, the other rotamer), 7.29 (d, J¼8.0 Hz, 1H, ArH, one rotamer),
6.10e5.80 (m, 1H), 5.38e5.00 (m, 2H), 4.82e4.70 (m, 2H),
4.70e4.60 (m, 2H), 4.45e4.25 (m, 1H), 4.12 (d, J¼14.4 Hz, 1H), 3.89
(d, J¼9.2 Hz, 1H), 3.26 (d, 6.5 Hz, 1H), 3.17 (d, 6.5 Hz, 1H). 13C NMR
145.0, 131.1, 130.7 (q, J¼32.7 Hz), 128.9, 127.0, 123.7 (q, J¼270 Hz),
118.4, 94.3 (d, J¼17.7 Hz), 49.3 (d, J¼30.5 Hz), 39.4. 19F NMR
(376 MHz, CDCl3)
d
ꢁ62.9 (s, 3F), ꢁ103.2 (ddt, JHeF(trans)¼47.6 Hz,
JHeF(cis)¼16.1 Hz, J¼15.2 Hz, 1F). HRMS (ESI) m/z: calcd for
C
13H14F4NO [MþH]þ 288.1006, found 288.1006.
(150 MHz, CDCl3)
d
170.9, 160.6 (d, J¼259 Hz, one rotamer), 159.8
(d, J¼259 Hz, the other rotamer), 140.3, 139.7, 130.4, 130.2, 129.0
(q, J¼32.3 Hz), 127.8, 125.9, 125.4, 125.0 (q, J¼3.1 Hz), 123.4 (q,
J¼270 Hz, one rotamer), 117.7, 117.6, 92.9 (d, J¼17.7 Hz), 92.5(d,
J¼17.5 Hz), 49.7, 47.2, 46.5 (d, J¼33.6 Hz), 44.6 (d, J¼30.9 Hz), 37.9,
4.2.3.11. 2-Fluoroallyl-N-(3-bromophenyl)-N-but-3-enamide
(5hb). Eluent solvent: petroleum ether/ethyl acetate¼10/1. Color-
less oil. 1H NMR (400 MHz, CDCl3)
d
7.53 (d, J¼8.0 Hz, 1H, ArH), 7.40
(s, 1H, ArH), 7.32 (m, 1H, ArH), 7.18 (d, J¼8.4 Hz, 1H, ArH), 6.00e5.80
(m, 1H, CH]CH2), 5.11 (d, J¼10.1 Hz, 1H, CH]CH2), 4.97 (d,
J¼17.2 Hz, 1H, CH]CH2), 4.69 (dd, JHeF(cis)¼16.1, 3.1 Hz, 1H, CF]
CH2), 4.41 (dd, JHeF(trans)¼47.6 Hz, J¼3.1 Hz, 1H, CF]CH2), 4.40 (d,
J¼15.6 Hz, 2H, CH2NAr), 2.89 (d, J¼6.7 Hz, 2H, CH2CO). 13C NMR
37.6. 19F NMR (376 MHz, CDCl3)
d
ꢁ62.9 to ꢁ63.0 (m, 3F), ꢁ103 to
ꢁ105 (m, 1F). HRMS (ESI) m/z: calcd for C15H15F4NONaþ [MþNa]þ
324.0982, found 324.0986.
4.2.3.7. 2-Fluoroallyl-N-(4-bromobenzyl)-N-but-3-enamide
(5db). Eluent solvent: petroleum ether/dichloromethane/ethyl
(150 MHz, CDCl3)
d
170.0, 160.9 (d, J¼259 Hz), 142.3, 131.1, 130.9,
130.5, 130.3, 126.5, 122.3, 117.6, 93.4 (d, J¼17.7 Hz), 48.6 (d,
acetate¼30/10/4. Colorless oil. IR (neat):
2932, 1651, 1592, 1488, 1445, 1403, 1220, 1071, 1011, 932, 848,
794 cmꢁ1. 1H NMR (400 MHz, CDCl3)
7.53e7.39 (m, 2H, ArH), 7.08
n
3491, 3080, 3022, 2981,
J¼30.5 Hz), 38.7. 19F NMR (376 MHz, CDCl3)
ꢁ102.0 to ꢁ103.0 (m).
d
HRMS (ESI) m/z: calcd for C13H14BrFNONaþ [MþNa]þ 320.0057,
d
found 320.0059.
(m, 2H, ArH), 6.06e5.90 (m, 1H), 5.23e5.06 (m, 2H), 4.80e4.60 (m,
1H), 4.50e4.40 (m, 2H), 4.40e4.20 (m, 1H), 4.12 (d, J¼14.0, 1H), 3.85
(d, J¼9.5 Hz, 1H), 3.24e3.20 (m, 1H), 3.19e3.15 (m, 1H). 13C NMR
4.2.3.12. 2-Fluoroallyl-N-(o-tolyl)-N-but-3-enamide (5ib). Elu-
ent solvent: petroleum ether/ethyl acetate¼10/1. White solid, mp
(150 MHz, CDCl3)
d
170.8, 160.3 (d, J¼259 Hz), 159.9 (d, J¼259 Hz),
60e61 ꢀC. IR (neat):
n 3424, 2919, 2849,1666,1492,1393,1378,1187,
135.4, 134.5, 131.5, 131.1, 130.5, 130.4, 129.4, 127.4, 121.1, 120.9, 117.6,
92.7 (d, J¼17.7 Hz), 92.3 (d, J¼17.3 Hz), 49.5, 46.9, 46.2 (d,
J¼34.0 Hz), 44.4 (d, J¼31.5 Hz), 37.8, 37.6. 19F NMR (376 MHz, CDCl3)
935, 848, 730 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d 7.40e7.01 (m, 4H,
ArH), 5.89 (m, 1H, CH]CH2), 5.06e5.0 (m, 1H, CH]CH2), 4.97e4.73
(m, 2H, CH]CH2, CH2NAr), 4.65 (dd, JHeF(cis)¼16.0 Hz, J¼3.0 Hz, 1H,
CFCH2), 4.38 (dd, JHeF(trans)¼47.9 Hz, J¼3.0 Hz, 1H, CFCH2), 3.82 (dd,
J¼18.6, 15.0 Hz, 1H, CH2NAr), 2.94e2.60 (m, 2H, CH2CO), 2.22 (s, 3H,
d
ꢁ102.0 to ꢁ103.0 (m), ꢁ103.0 to ꢁ106.0 (m). HRMS (ESI) m/z:
calcd for C14H16BrFNOþ [MþH]þ 312.0394, found 312.0395.
CH3). 13C NMR (150 MHz, CDCl3)
d
170.6, 161.4 (d, J¼259 Hz), 139.6,
4.2.3.8. 2-Fluoroallyl-N-phenyl-N-but-3-enamide (5eb). Eluent
solvent: petroleum ether/ethyl acetate¼10/1. White solid, mp
135.2, 130.8, 130.7, 128.7, 128.2, 126.6, 117.3, 93.5 (d, J¼17.9 Hz), 47.6
(d, J¼30.1 Hz), 38.4, 16.8. 19F NMR (376 MHz, CDCl3)
d
ꢁ101.5 to
66e67 ꢀC. IR (neat):
n
3497, 3079, 2981, 2933, 1667, 1596, 1495,
ꢁ102.0 (m). HRMS (ESI) m/z: calcd for C14H17FNOþ [MþH]þ
1423, 1393, 1195, 933, 848, 702 cmꢁ1
7.52e7.06 (m, 5H, ArH), 5.89e5.70 (m, 1H), 5.07e4.90 (m, 1H),
4.90e4.70 (m, 1H), 4.65e4.50 (m, 1H), 4.50e4.20 (m, 3H),
2.87e2.70 (m, 2H). 13C NMR (150 MHz, CDCl3)
170.4, 160.4 (d,
.
1H NMR (400 MHz, CDCl3)
234.1289, found 234.1289.
d
4.2.3.13. 2-Fluoro-N-(2-fluoroallyl)-N-(4-methoxyphenyl)-acryl-
amide (5fe). Eluent solvent: petroleum ether/dichloromethane/
d
J¼259 Hz), 141.1, 130.9, 129.0, 127.8, 127.7, 117.3, 93.0 (d, J¼17.8 Hz),
ethyl acetate¼15/4/1. Colorless oil. IR (neat):
n
3415, 2916, 2848,
48.6 (d, J¼30.7 Hz), 38.7. 19F NMR (376 MHz, CDCl3)
d
ꢁ102.0 to
1667, 1644, 1512, 1400, 1249, 1172, 934, 838, 769 cmꢁ1
.
1H NMR

4852
Y. Li et al. / Tetrahedron 72 (2016) 4845e4853
(400 MHz, CDCl3)
d
7.13e7.11 (m, 2H, ArH), 6.89e6.86 (m, 2H, ArH),
CH2CO). 13C NMR (150 MHz, CDCl3)
d
165.6, 150.6 (d, J¼250 Hz),
5.26 (dd, JHeF(trans)¼45.6 Hz, J¼3.2 Hz, 1H, COCFCH2), 4.98 (dd,
JHeF(cis)¼12.8 Hz, J¼3.2 Hz,1H, COCFCH2), 4.70 (dd, JHeF(cis)¼16.0 Hz,
J¼3.2 Hz, 1H, CFCH2), 4.43 (dd, JHeF(trans)¼48.0 Hz, J¼3.2 Hz, 1H,
CFCH2), 4.42 (d, J¼14.8 Hz, 1H, CH2N), 3.80 (d, J¼1.6 Hz, 3H, OCH3).
135.3, 128.2, 127.6, 127.2, 97.4 (d, J¼14.8 Hz), 49.3, 45.3 (d,
J¼39.1 Hz), 29.2 (d, J¼8.3 Hz). 19F NMR (376 MHz, CDCl3)
ꢁ116.0 to
d
ꢁ116.9 (m). HRMS (ESI) m/z: calcd for C12H13FNOþ [MþH]þ
206.0976, found 206.0974.
13C NMR (150 MHz, CDCl3)
d
161.1 (d, J¼28.9 Hz), 159.8 (d,
J¼259 Hz), 158.5, 156.3 (d, J¼271 Hz), 133.4, 127.4, 113.8, 100.5 (d,
4.2.4.5. 5-Fluoro-1-(4-(trifluoromethyl)benzyl)-1,6-
dihydropyridin-2(3H)-one (6cb). Eluent solvent: petroleum ether/
J¼15.3 Hz), 93.5 (d, J¼17.6 Hz), 54.8, 49.9 (d, J¼30.8 Hz). 19F NMR
(376 MHz, CDCl3)
d
ꢁ102.8 to ꢁ103.0 (m), ꢁ105.9 to ꢁ106.1 (m).
ethyl acetate¼5/3. White solid, mp 70e71 ꢀC. IR (neat):
n 3453,
HRMS (ESI) m/z: calcd for C13H14F2NOþ2 [MþH]þ 254.0987, found
2924, 1651, 1620, 1489, 1419, 1325, 1169, 1124, 1066, 819 cmꢁ1. 1H
254.0992.
NMR (400 MHz, CDCl3)
d
7.61 (d, J¼8.0 Hz, 2H, ArH), 7.40 (d,
J¼8.0 Hz, 2H, ArH), 5.31 (d, J¼16.0 Hz, 1H, CH]CF), 4.69 (s, 2H,
4.2.4. General procedure for the synthesis of compound (6aae6fe). A
solution of Grubbs’ II (0.145 g, 0.17 mmol) in Tol (40 mL) was added
via a syringe pump over 1 h to a solution of compound 5abeib
(1.70 mmol) in Tol (150 mL) at 100 ꢀC under Ar atmosphere. After
that, the solution continued to stir for another 30 min at the same
temperature. The solvent was removed under reduced pressure and
the residue was purified by silica gel chromatography, and the
isolated yields were shown in Table 2.
CH2Ar), 3.89e3.86 (m, 2H, CH2N), 3.16e3.12 (m, 2H, CH2CO). 13C
NMR (150 MHz, CDCl3)
d
165.8, 150.3 (d, J¼250 Hz), 139.4, 129.6 (q,
J¼32.3 Hz), 127.7, 125.2e125.1 (q, J¼3.8 Hz), 123.4 (q, J¼270 Hz),
97.6 (d, J¼15 Hz), 48.9, 45.7 (d, J¼39.5 Hz), 29.1 (d, J¼8.4 Hz). 19
F
NMR (376 MHz, CDCl3)
d
ꢁ63.1 (s, 3F), ꢁ116.0 to ꢁ116.6 (m, 1F).
HRMS (ESI) m/z: calcd for C12H10F4NOþ [MþH]þ 260.0693, found
260.0695.
4.2.4.6. 5-Fluoro-1-(4-bromobenzyl)-1,6-dihydropyridin-2(3H)-
4.2.4.1. 4-Fluoro-1-(4-methoxybenzyl)-1H-pyrrol-2(5H)-one
one (6db). Eluent solvent: petroleum ether/ethyl acetate¼5/2.
(6aa). Eluent solvent: petroleum ether/ethyl acetate¼2/1. White
White solid, mp 78e79 ꢀC. IR (neat):
n 3455, 2920, 1649, 1488, 1181,
solid, mp 69e70 ꢀC IR (neat):
n
3447, 2929, 2837, 1652, 1613, 1513,
1070, 1012, 817 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
7.45 (d, J¼7.6 Hz,
1441, 1248, 1205, 1038, 933, 847, 819, 794 cmꢁ1. 1H NMR (400 MHz,
CDCl3)
7.27 (d, J¼8.6 Hz, 2H, ArH), 6.97 (d, J¼8.6 Hz, 2H, ArH), 5.62
(s, 1H, CH]CF), 4.63 (s, 2H, CH2Ar), 3.93 (s, 2H, CH2N), 3.89 (s, 3H,
OCH3). 13C NMR (100 MHz, CDCl3)
173.5 (d, J¼291 Hz), 169.4 (d,
J¼15 Hz), 159.1, 129.4, 128.6, 114.2, 102.3, 55.3, 48.2 (d, J¼25.5 Hz).
2H, ArH), 7.15 (d, J¼8.0 Hz, 2H, ArH), 5.27 (d, J¼12.4 Hz,1H, CH]CF),
d
4.57 (s, 2H, CH2Ar), 3.84e3.82 (m, 2H, CH2N), 3.12e3.07 (m, 2H,
CH2CO). 13C NMR (150 MHz, CDCl3)
d
165.6, 150.4 (d, J¼250 Hz),
d
134.4, 131.3, 129.4, 121.2, 97.5 (d, J¼14.9 Hz), 48.8, 45.4 (d,
J¼39.5 Hz), 29.2 (d, J¼8.3 Hz). 19F NMR (376 MHz, CDCl3)
ꢁ116.0 to
d
19F NMR (376 MHz, CDCl3)
d
ꢁ108.6 (s). HRMS (ESI) m/z: calcd for
ꢁ116.9 (m). HRMS (ESI) m/z: calcd for C12H12BrFNOþ2 [MþH]þ
C
12H12FNO2Naþ [MþNa] 244.0744, found 244.0744.
284.0081, found 284.0083.
4.2.4.2. 5-Fluoro-1-(4-methoxybenzyl)-1,6-dihydropyridin-
2(3H)-one (6ab). Eluent solvent: petroleum ether/ethyl acetate¼2/
1. White solid, mp 73e74 ꢀC IR (neat):
3442, 2955, 2923, 2850,
1651, 1513, 1456, 1247, 1198, 1174, 1038, 930, 847 cmꢁ1 1H NMR
(400 MHz, CDCl3)
4.2.4.7. 5-Fluoro-1-phenyl-1,6-dihydropyridin-2(3H)-one
(6eb). Eluent solvent: dichloromethane/ethyl acetate¼30/1. White
n
solid, mp 102e103 ꢀC. IR (neat):
n 3421, 2917, 2849,1645,1595,1441,
.
1368, 1277, 1174, 1140, 749 cmꢁ1
7.46e7.42 (m, 2H, ArH), 7.35e7.26 (m, 3H, ArH), 5.40 (dt, J¼14,
1.2 Hz, 1H, CH]CF), 4.33e4.31 (m, 2H, CH2N), 3.25e3.20 (m, 2H,
CH2CO). 13C NMR (150 MHz, CDCl3)
165.8, 150.8 (d, J¼250 Hz),
.
1H NMR (400 MHz, CDCl3)
d
7.21 (d, J¼8.4 Hz, 2H, ArH), 6.86 (d, J¼8.4 Hz, 2H,
d
ArH), 5.25 (d, J¼14.0 Hz, 1H, CH]CF), 4.57 (s, 2H, CH2Ar), 3.83e3.81
(m, 2H, CH2N), 3.79 (s, 3H, OCH3), 3.11e3.00 (m, 2H, CH2CO). 13C
d
NMR (100 MHz, CDCl3):
d
166.1, 159.2, 151.5 (d, J¼250 Hz), 129.7,
140.8, 128.9, 127.0, 125.7, 97.6 (d, J¼14.7 Hz), 49.4 (d, J¼39.0 Hz),
127.8, 114.1, 97.7 (d, J¼15.0 Hz), 55.2, 49.2, 45.7 (d, J¼40.0 Hz), 29.9
29.7(d, J¼8.7 Hz). 19F NMR (376 MHz, CDCl3)
ꢁ117.0 to ꢁ118.1 (m).
d
(d, J¼12.3 Hz). 19F NMR (376 MHz, CDCl3):
d
ꢁ117.7 to ꢁ116.0 (m).
HRMS (ESI) m/z: calcd for C11H11FNOþ [MþH]þ 192.0819, found
HRMS (ESI) m/z: calcd for C13H15FNOþ2 [MþH] 236.1081, found
192.0821.
236.1080.
4.2.4.8. 5-Fluoro-1-(4-methoxyphenyl)-1,6-dihydropyridin-
4.2.4.3. 6-Fluoro-1-(4-methoxybenzyl)-3,4-dihydro-1H-azepin-
2(3H)-one (6fb). Eluent solvent: petroleum ether/ethyl acetate¼1/
2(7H)-one (6ac). Eluent solvent: petroleum ether/ethyl acetate¼3/
2. White solid, mp 138e139 ꢀC. IR (neat):
n 3442, 2995, 2916, 1650,
2. Colorless oil. IR (neat):
n
2920, 2849, 1652, 1611, 1513, 1473, 1246,
1606, 1513, 1475, 1446, 1276, 1248, 1171, 1140, 1031, 821, 778 cmꢁ1
1H NMR (400 MHz, CDCl3)
7.20e7.18 (m, 2H, ArH), 6.95e6.93 (m,
.
1110, 1032, 839, 815 cmꢁ1
.
1H NMR (400 MHz, CDCl3)
d
7.18 (d,
d
J¼12 Hz, 2H, ArH), 6.85 (d, J¼8.4 Hz, 2H, ArH), 5.43 (dt, J¼20.4 Hz,
J¼4.0 Hz, 1H, CH]CF), 4.59 (s, 2H, CH2Ar), 3.92 (d, J¼12 Hz, 2H,
CH2N), 3.79 (s, 3H, OCH3), 2.75e2.72 (t, J¼6.0 Hz, 2H, CH2CO),
2H, ArH), 5.38 (d, J¼13.6 Hz, 1H, CH]CF), 4.28e4.26 (m, 2H,
CH2N), 3.81 (s, 3H, OCH3), 3.22e3.17 (m, 2H, CH2CO). 13C NMR
(150 MHz, CDCl3)
d
165.9, 158.1, 150.8 (d, J¼251 Hz), 133.6, 126.9,
2.43e2.40 (m, 2H, CH2CH2CO). 13C NMR (100 MHz, CDCl3):
d
173.7,
114.2, 97.6 (d, J¼15.0 Hz), 54.8, 49.8 (d, J¼38.6 Hz), 29.6(d,
159.0, 156.6 (d, J¼252 Hz), 129.2, 128.7, 114.0, 106.0 (d, J¼20 Hz),
J¼8.6 Hz). 19F NMR (376 MHz, CDCl3)
ꢁ116.9 to ꢁ117.3 (m). HRMS
d
55.2, 50.6, 46.4 (d, J¼42 Hz), 33.7, 21.4. 19F NMR (376 MHz, CDCl3):
(ESI) m/z: calcd for
C
12H13FNOþ2 [MþH]þ 222.0925, found
d
ꢁ98.9 to ꢁ99.0 (m). HRMS (ESI) m/z: calcd for C14H17FNOþ2 [MþH]
222.0927.
250.1238, found 250.1239.
4.2.4.9. 5-Fluoro-1-(4-(trifluoromethyl)phenyl)-1,6-dihydro pyr-
idin-2(3H)-one (6gb). Eluent solvent: petroleum ether/ethyl
4.2.4.4. 5-Fluoro-1-benzyl-1,6-dihydropyridin-2(3H)-one
(6bb). Eluent solvent: petroleum ether/dichloromethane/ethyl
acetate¼15/1. White solid, mp 127e128 ꢀC. IR (neat):
n 3441, 2954,
acetate¼10/5/2. White solid, mp 62e63 ꢀC. IR (neat):
n
3462, 2920,
.
2917, 2849, 1648, 1610, 1442, 1324, 1277, 1165, 1116, 821, 783 cmꢁ1
.
1650, 1489, 1453, 1252, 1181, 1064, 819, 710 cmꢁ1
1H NMR
1H NMR (400 MHz, CDCl3)
d
7.70 (d, J¼8.0 Hz, 2H, ArH), 7.45 (d,
(400 MHz, CDCl3)
d
7.41e7.22 (m, 5H, ArH), 5.29e5.24 (m, 1H, CH]
J¼8.0 Hz, 2H, ArH), 5.42 (d, J¼13.6 Hz, 1H, CH]CF), 4.35e4.33 (m,
CF), 4.63 (s, 2H, ArCH2), 3.85e3.82 (m, 2H, CH2N), 3.13e3.08 (m, 2H,
2H, CH2N), 3.25e3.21 (m, 2H, CH2CO). 13C NMR (150 MHz, CDCl3)

Y. Li et al. / Tetrahedron 72 (2016) 4845e4853
4853
d
166.7, 151.2 (d, J¼251 Hz), 144.6, 129.7 (q, J¼32.7 Hz), 126.7 (q,
Acknowledgements
J¼3.5 Hz), 126.6, 123.9 (q, J¼270 Hz), 98.4 (d, J¼15.1 Hz), 49.6 (d,
J¼39.6 Hz), 30.5 (d, J¼8.4 Hz). 19F NMR (376 MHz, CDCl3)
d
ꢁ63.13
We gratefully acknowledge National Natural Science Foundation
of China (No. 21472024 and No. 21242008) for the research finan-
cial support.
(s, 3F), ꢁ116.5 to ꢁ116.6 (m, 1F). HRMS (ESI) m/z: calcd for
C
12H10F4NOþ [MþH]þ 261.0711, found 261.0711.
4.2.4.10. 5-Fluoro-1-(3-bromophenyl)-1,6-dihydropyridin-2(3H)-
Supplementary data
one (6hb). Eluent solvent: petroleum ether/ethyl acetate¼5:2.
White solid, mp 126e127 ꢀC. IR (neat):
3414, 2955, 2918, 2849,
1663, 1580, 1573, 1476, 1362, 1259, 1178, 1143, 1028, 769 cmꢁ1. 1H
NMR (400 MHz, CDCl3) 7.47e7.45 (m, 2H, ArH), 7.33e7.24 (m, 2H,
n
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2016.06.054.
d
ArH), 5.43e5.37 (dt, J¼13.8, 1.4 Hz, 1H, CH]CF), 4.31e4.28 (m, 2H,
CH2N), 3.23e3.19 (m, 2H, CH2CO). 13C NMR (150 MHz, CDCl3)
References and notes
d
165.8, 150.6 (d, J¼251 Hz), 141.9, 130.1, 130.0, 128.9, 124.4, 122.1,
97.6 (d, J¼14.8 Hz), 49.2 (d, J¼39.3 Hz), 29.6 (d, J¼8.6 Hz). 19F NMR
1. Fluorine in Medicinal Chemistry and Chemical Biology; Ojima, I., Ed.; Wiley:
Chichester, 2009.
(376 MHz, CDCl3)
C
d
ꢁ116.7 to ꢁ116.8 (m). HRMS (ESI) m/z: calcd for
11H11BrFNOþ [MþH]þ 269.9924, found 269.9931.
2. (a) Couve-Bonnaire, S.; Cahard, D.; Pannecoucke, X. Org. Biomol. Chem. 2007, 5,
1151; (b) Dutheuil, G.; Couve-Bonnaire, S.; Pannecoucke, X. Angew. Chem., Int.
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4.2.4.11. (E)-N-(2-Fluoroallyl)-N-(o-tolyl)but-2-enamide
(7ib). Eluent solvent: petroleum ether/ethyl acetate¼10:1. White
solid, mp 62e63 ꢀC. IR (neat):
3484, 2924, 2852, 1669, 1633, 1492,
1445, 1375, 1206, 1188, 966, 935, 849, 729 cmꢁ1. 1H NMR (400 MHz,
CDCl3) 7.47e7.45 (m, 2H, ArH), 7.33e7.10 (m, 4H, ArH), 7.10e6.90
n
3. (a) Urban, J. J.; Tillman, B. G.; Cronin, W. A. J. Phys. Chem. A 2006, 110, 11120; (b)
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d
(m, 1H, MeCH¼CH), 5.60e5.50 (dq, J¼14.8, 1.4 Hz, 1H, MeCH]CH),
4.90e4.70 (dd, J¼15.2,15.2 Hz,1H, CH2N), 4.66 (dd, J¼16.0, 3.2 Hz, 1H,
CH2]CF), 4.41 (dd, J¼48, 3.2 Hz, 1H, CH2]CF), 3.96 (dd, J¼48, 3.2 Hz,
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Otto, M. J.; Sofia, M. J. Bioorg. Med. Chem. Lett. 2012, 22, 2938; (b) Edmondson, S.
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1H, CH2N), 2.19 (s, 3H, ArCH3), 1.72 (d, J¼3.4 Hz, 3H, MeCH]CH). 13
C
NMR (150 MHz, CDCl3)
d
165.5,160.8 (d, J¼260 Hz),142.2,139.4,135.7,
130.6, 128.6, 127.9, 126.5, 121.1, 93.3 (d, J¼18 Hz), 47.7 (d, J¼30 Hz),
17.4, 16.9. 19F NMR (376 MHz, CDCl3)
d
ꢁ101.0 to ꢁ102.0 (m). HRMS
(ESI) m/z: calcd for C14H16FNONaþ [MþH]þ 256.1108, found 256.1111.
4.2.4.12. (E)-5-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-
fluoropent-3-enoic acid (8ab). 6ab (0.235 g, 1.0 mmol) was added to
a solution of 6 N HCl aqueous (10 mL), and the mixture was refluxed
for 3 h and then concentrated under reduced pressure to dryness,
giving a quantitative white solid, mp 52e53 ꢀC. 1H NMR (400 MHz,
D2O)
d
5.51 (dt, J¼20, 8.0 Hz, 1H, CF]CH), 4.41 (d, J¼20 Hz, 2H,
CH2CF), 3.04 (d, J¼8.0 Hz, 2H, CH2CO), MS (ESI) m/z: 143 [MþH]þ.
The crude mixture was used in the next step without further
purification.
Fmoc-Cl (0.310 g,1.2 mmol) was added at 0 ꢀC to a mixture of the
amine hydrochloride (1.0 mmol) in THF and 10% Na2CO3 aqueous
solution (10/10 mL) and the reaction mixture was stirred at 0 ꢀC for
3 h and was then poured into ice-cooled HCl aqueous solution (1 N,
30 mL) and extracted with AcOEt (3ꢂ30 mL). The combined organic
layers were washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude mixture was pu-
rified by column chromatography to afford 8ab (0.269 g, 76%). El-
uent solvent: petroleum ether/ethyl acetate¼10:1. White solid, mp
7. Takahira, Y.; Morizawa, Y. J. Am. Chem. Soc. 2015, 137, 7031.
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123e124 ꢀC; 1H NMR (400 MHz, (CD3)2CO):
d
3.23 (d, J¼7.6 Hz, 2H,
CH2CO), 3.90e4.00 (m, 2H, OCH2CH), 4.00e4.30 (m, 1 H, OCH2CH),
4.30e4.40 (m, 2 H, CH2CF), 5.35 (dt, J¼19.6, 7.6 Hz, 1H, CF]CH),
6.90 (brs, 1 H, NH), 7.25e7.50 (m, 4 H, ArH), 7.60e7.80 (m, 2H, ArH),
7.64e7.66 (m, 2H, ArH); MS (ESI) m/z: 356.1 [MþH]þ. The data is
consistent with the reported literature.2d