Ligand Promoted Olefination of Anilides for Indirectly Introducing Fluorinated Functional Groups via Palladium Catalyst

Article abstract of DOI:10.1021/acs.joc.0c02701

We report a palladium-catalyzed, ligand promoted, C-H fluorine-containing olefination of anilides with 4-bromo-3,3,4,4-tetrafluorobutene as the fluorinated reagent, which has a potential transformation into other compounds due to its -CF2CF2Br functional group. -CF2CF2H was obtained by using the mild reducing agent sodium borohydride. Bioactive compounds such as aminoglutethimide derivative and propham were well-tolerated in this reaction, both of which highlight the synthetic importance of this method.

Full text of DOI:10.1021/acs.joc.0c02701

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Article
Ligand Promoted Olefination of Anilides for Indirectly Introducing
Fluorinated Functional Groups via Palladium Catalyst
Dongjie Wang, Xu Xu, Jingyu Zhang,* and Yingsheng Zhao*
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ABSTRACT: We report a palladium-catalyzed, ligand promoted, C−H
fluorine-containing olefination of anilides with 4-bromo-3,3,4,4-tetrafluorobu-
tene as the fluorinated reagent, which has a potential transformation into other
compounds due to its -CF2CF2Br functional group. -CF2CF2H was obtained by
using the mild reducing agent sodium borohydride. Bioactive compounds such
as aminoglutethimide derivative and propham were well-tolerated in this
reaction, both of which highlight the synthetic importance of this method.
Scheme 1. Synthetic Approaches towards Organofluorinated
Compounds
INTRODUCTION
■
Organofluorinated compounds have important applications in
pharmaceuticals, agrochemicals, and in material science.1 Due
to the unique electronic characteristics of the fluorine atom/
ion, it affects the distribution of the electron cloud within a
molecule as well as the dipole moment, acidity, and alkalinity.
Incorporation of fluorine makes agriculture products more
productive and drugs more efficient; a specific example
includes the antitumor drug epothilone B. In 2003,
Danishefsky and coworkers reported the synthesis of the 12-
trifluoromethyl derivative of epothilone B from trifluoromethyl
building blocks. Studies have shown that the trifluoromethy-
lated derivatives of epothilone B have higher antitumor
activity.2 Consequently, the development of efficient methods
for introducing organofluorine compounds is extremely
valuable in synthetic chemistry.
Several methodologies for introducing fluorine groups to
aromatics and heterocyclics have been extensively explored.3
Functional groups such as F,4 CF3,5 CF2CONR2,6 and
CF2COOR7 are immensely popular fluorinated moieties to
introduce onto prefunctionalized arenes or alkenes and rely on
metal-mediated cross-coupling reactions. These groups have
great appeal for researchers because of the significant potential
potential transformations is important and attractive. One
relatively inexpensive fluorinated reagent, 4-bromo-3,3,4,4-
tetrafluorobutene, reported by Maiti11 previously, has potential
application due to its -CF2CF2Br functional group that could
ring on other kinds of compounds.12
Although ortho-selective olefination of anilides via palladium
catalysis has been studied previously by de Vries and van
Leeuwen,13 the introduction of fluorine groups onto aromatic
compounds via a palladium-catalyzed C−H fluorine-containing
olefination14 of anilides has not been reported. Herein, we
report the development of a synthetic pathway for the
introduction of fluorine groups onto aromatic compounds via
a palladium-catalyzed, ligand promoted C−H fluorine-
containing olefination of anilides with 4-bromo-3,3,4,4-
tetrafluorobutene as the coupling reagent. Various anilides
̂
for postfunctionalization. In 2001 Genet demonstrated an
efficient access to introduce perfluorinated tails onto aromatic
rings by Heck reaction between perfluoroalkenes and
arenediazonium salts catalyzed by palladium, followed by
hydrogenation of the double bond8 (Scheme 1a). In 2016,
Uchiyama and colleagues9 developed an efficient Rh-catalyzed
(perfluoroalkyl) olefination reaction of acetanilides under
slightly modified Glorius10 olefination conditions. RF-anilides
with the saturated C2 spacer were obtained in the presence of
a catalytic amount of Pd/C under atmospheric pressure of H2
gas (Scheme 1b). Aniline is usually the key skeleton of a
variety of important compounds and often plays an important
role in dye work, drug production, and pesticide synthesis. As
impressed by Uchiyama’s work, looking for RF-anilides with
Received: November 12, 2020
Published: January 27, 2021
https://dx.doi.org/10.1021/acs.joc.0c02701
© 2021 American Chemical Society
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were treated and showed good tolerance, yielding the
corresponding fluorinated products in moderate to good
yields. More importantly, some molecules possessing drug
activity, such as aminoglutethimide and propham, were
fluorinated by 4-bromo-3,3,4,4-tetrafluorobutene; this indi-
cated that such an indirect fluorination approach might have
broad potential in pharmaceutical research.
leading to the desired product 3a in 61% yield. Next, oxidants
like Ag2CO3, Cu(OAc)2, and PhIOAc were examined (Table
1, entries 12−14), but none afforded a higher yield than
AgOAc. Interestingly, a slightly improved yield of 3a was
obtained when the reaction was performed under oxygen
(Table 1, entries 15 and 16). This might be because oxygen
acted as a co-oxidant to oxidize Pd(0) to Pd(II) during the
catalytic cycle.16 However, when copper with oxygen or Cu/
AgOAc with oxygen was used as oxidant, we could hardly
obtain the target product (Table 1, entries 17 and 18). A
control experiment showed that the palladium catalyst played a
crucial role in this transformation along with the recovered
starting material (Table 1, entry 19).
RESULTS AND DISCUSSION
■
We began our study by investigating the role of different
ligands; we selected N-(3-methoxyphenyl)pivalamide (1a) as
the model substrate, 4-bromo-3,3,4,4-tetrafluorobutene as the
fluorinated reagent, palladium acetate as the catalyst, and
AgOAc as the oxidant, and the reaction ran for 24 h at 120 °C
in HFIP. To our delight, 3a was obtained in 41% yield (Table
1, entry 1). Several acid additives such as PivOH, MesCOOH,
With the optimized reaction conditions in hand, we
subsequently examined the substrate scope of various
substituted N-phenylpivalamides (Table 2) under optimized
a
a
Table 2. Substrate Scope of Monosubstituted Anilines
Table 1. Optimization of Reaction Conditions
entry
oxidant
AgOAc
ligand
PivOH
MesCOOH
(BuO)2POOH
yield (%)
1
2
3
4
5
6
7
8
41
43
15
nr
45
48
56
48
61
47
45
trace
35
trace
31
72
nr
trace
nr
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
PhIOAc
Ag2CO3
Cu(OAc)2
Cu(OAc)2
AgOAc
Cu
N-Ac-Gly-OH
L1
L2
L3
L4
L5
L6
L4
L4
L4
L4
L4
L4
L4
L4
9
10
11
12
13
14
15
16
17
18
b
b
b
b
a
Cu/AgOAc
AgOAc
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (10
c
19
mol %), AgOAc (2 equiv), L4 (30 mol %), in HFIP (0.5 mL) at 120
°C in an oil bath for 24 h under O2 atm in a sealed tube.
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2(10
mol %), oxidant (2 equiv), ligand (30 mol %), solvent (0.5 mL) at
b
120 °C in an oil bath for 24 h in a sealed tube. O2 (1 atm) was
conditions: catalyst, Pd(OAc)2; oxidant, AgOAc; L4 as the
ligand in HFIP at 120 °C for 24 h under oxygen atmosphere. A
wide variety of N-phenylpivalamides were well-tolerated,
leading to the corresponding fluorinated products in moderate
to good yields. Both electron-withdrawing and electron-
donating functional groups such as Me, MeO, F, Cl, CF3,
and COOMe all worked well for this reaction. The para-
substituted N-phenylpivalamides (1b−1h) reacted well,
affording the corresponding products in moderate to good
yields (3b−3h, 51−79%) along with recovery of the starting
material. It is worth noting the diolefinated product (3h) can
be obtained when the sterically hindered functional group tert-
butyl was applied. The fluorine-containing alkenylation
c
added. No Pd(OAc)2. Key: pivalic acid (PivOH), 2,4,6-trimethyl-
benzoic acid (MesCOOH), N-acetylglycine (N-Ac-Gly-OH), hexa-
fluoroisopropanol (HFIP), AdNH2 = diamantadine.
and (BuO)2POOH were tested; however, none improved the
yield of 3a (Table 1, entries 2−4). Using the well-known
ligand N-Ac-Gly-OH15 improved the yield to 45%, while Ad-
substituted oxalic amide with a free carboxylic acid group
(ligand 1) afforded 3a in 48% yield (Table 1, entries 5 and 6).
Inspired by these results, ligands derived from oxalyl chloride
were examined, and the result showed that ligand 4 proceeded
smoothly for this transformation (Table 1, entries 7−11),
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products were obtained in reasonable to good yields for
substrates containing either electron-donating or -withdrawing
groups at the meta position of the benzene ring (3i−3o) with
the highest yield obtained using a methyl functional group (3i,
90%). It is worth noting that when the functional group was F,
the fluoroolefin could be introduced onto the C2 position (3l′)
in 71% yield and the C6 position (3l) in 19% yield. Further
studies revealed that ortho-substituted (3p−3t) products
performed equally well and led to the fluorine-containing
alkenylation products in 45−83% yields.
Scheme 2. Substrate Scope of Fluoroolefins
We subsequently broadened the scope of aniline substrates
to disubstituted N-phenylpivalamides, N-phenylacetamide, and
tetrahydroquinolines (Table 3), and to our delight, they all
Table 3. Substrate Scope of Disubstituted and Other
a
Anilines
to the formation of the corresponding products in good yields
(73−82%). Substrates like perfluorobutylethylene and per-
fluorooctylethylene performed well in this reaction, and those
reactions yielded the corresponding products in 79% (7b) and
73% (7c) yields, respectively. In addition, drugs like amino-
glutethimide and propham were also examined. Amino-
glutethimide18 is a kind of adrenal cortex hormone inhibitor
and antitumor drug; it inhibits the lyase system that converts
cholesterol to pregnenolone, thereby blocking the synthesis of
adrenal cortex hormones. Furthermore, it inhibits the
production of estrogen by blocking aromatase, thereby
reducing the promoting effect of estrogen on breast cancer
and inhibiting tumor growth. Propham is a kind of pesticide19
that is widely used to control annual gramineous weeds in
soybean, sugar beet, cotton, vegetable, and tobacco fields. To
our delight, the aminoglutethimide derivative and propham
were both compatible with this reaction. The amino-
glutethimide took place under standard reaction conditions
and afforded the desired fluorinated products in yields ranging
from 47 to 61%. Subsequent testing indicated yields of the
corresponding fluorinated products as 47% (7g), 74% (7h),
and 67% (7i) when propham was used under those same
standard conditions.
a
Reaction conditions: 4 (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2(10
mol %), AgOAc (2 equiv), L4 (30 mol %), in HFIP (0.5 mL) at 120
°C in an oil bath for 24 h under O2 atmosphere in a sealed tube.
worked well under these optimized reaction conditions.
Disubstituted N-phenylpivalamides gave corresponding fluori-
nated products in moderate to good yields (5a−5d) along with
the recovered starting material. For N-(naphthalen-1-yl)-
pivalamide (5e) and N-phenylacetamide (5f), the fluorinated
olefin products were obtained in 61 and 60% yields,
respectively. Finally, tetrahydroquinolines were examined for
their tolerance to this reaction due to their great value in
medicinal chemistry;17 they serve as intermediates in
medicinal, pesticide, and chemical industries and some are
also found in several well-known drugs such as oxamniquine
and argatroban. Therefore, we selected several tetrahydroqui-
nolines as substrates for fluorine-containing alkenylation. To
our relief, tetrahydroquinoline substrates with a trimethylacetyl
group as the protecting group smoothly underwent fluorine-
containing alkenylation. Among them, a trimethylacetyl-
protected tetrahydroquinoline (4i) resulted in the target
product (5i) with a yield of 90% and afforded a crystal of 5i
which was used to unambiguously confirm its structure and the
transformation. Unfortunately, a trimethylacetyl-protected
benzomorpholine only formed 5h in poor yield (26%).
To further demonstrate the synthetic utility of our
procedure, a gram-scale reaction was explored (Scheme 3),
and a yield of 75% was obtained (1.51 g) of the corresponding
fluorinated product (3f) when N-(4-fluorophenyl)pivalamide
(1f) was used as the substrate under standard conditions. The
next step in this reaction yielded the target product N-(4-
Scheme 3. Gram-Scale Reaction Conditions
We further investigated the substrate scope concerning
various fluoroolefins by reacting them with N-phenylpivala-
mide under standard conditions (Scheme 2). As expected,
olefins with varying fluoroalkyl chains were compatible and led
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volatiles were evaporated under reduced pressure. The resulting
residue was purified by column chromatography (PE/EA = 10/1) on
silica gel to give the product.
L4 (2 mmol, 0.56 g, 1.0 equiv) was dissolved into EtOH (5 mL)
and H2O (5 mL), and NaOH (2.4 mmol, 96 mg, 1.2 equiv) was
added. The reaction was stirred for 3 h at room temperature, detected
by TLC. Then, the mixture was acidified by 4 M HCl and extracted by
CH2Cl2 (3 × 5 mL). The combined organic extract was washed with
brine, dried with anhydrous Na2SO4, filtered, and concentrated in
vacuo to give the product (L1).
fluoro-2-(3,3,4,4-tetrafluorobut-1-en-1-yl)phenyl)-pivalamide
(8) in 45% yield using the mild reducing agent sodium
borohydride.
CONCLUSIONS
■
In conclusion, we report a C−H fluorine-containing olefination
of anilides with the fluorocarbon compound 4-bromo-3,3,4,4-
tetrafluorobutene and catalyzed by palladium(II). This
reaction is atom-economic, and a variety of fluorinated
products were obtained in high yields based on this process.
Compounds like aminoglutethimide and propham were
modified by fluorinated olefins from this reaction which have
potential application in pharmaceutical research due to the
-CF2CF2Br functional group. Also, -CF2CF2H can be obtained
from -CF2CF2Br by using the mild reducing agent, sodium
borohydride, and more transformations may be conducted
using the -CF2CF2Br functional group.
General Procedure for the Synthesis of L2.23 Diamantadine
hydrochloride (21 mmol, 4.53 g, 2.1 equiv) and triethylamine (50
mmol, 6.9 mL, 5.0 equiv) were added to dichloromethane (50 mL)
solution, and the reaction was stirred in an ice bath for 10 min. A
mixture of oxaloyl chloride (10 mmol, 0.85 mL, 1.0 equiv) and
dichloromethane (20 mL) was then added to the solution slowly
under cooling with an ice−water bath, and the resulting mixture was
stirred at room temperature overnight. The organic layer was
separated, and the aqueous phase was extracted with CH2Cl2 (3 ×
5 mL). The combined organic layer was washed with brine (2 × 5
mL) and dried over anhydrous Na2SO4, and all of the volatiles were
evaporated under reduced pressure. The resulting residue was purified
by column chromatography (PE/EA = 10/1) on silica gel to give the
product.
EXPERIMENTAL SECTION
■
General. Unless otherwise noted, all reagents were purchased from
commercial suppliers and used without further purification. Column
chromatography purifications were performed using 200−300 mesh
silica gel. NMR spectra were recorded on Varian Inova 400 MHz,
Inova 300 MHz, Bruker DRX 400, or Bruker DRX 500 instruments
and calibrated using residual solvent peaks as internal reference.
Multiplicities are recorded as s = singlet, d = doublet, t = triplet, q =
quartet, dd = doublet of doublets, td = triplet of doublets, m =
multiplet. HRMS analysis was carried out using a Bruker microTOF-
Q instrument or a TOF-MS instrument. X-ray crystallographic data
were collected with a Bruker D8 Quest CCD instrument equipped
with graphite-monochromated Mo Kα radiation.
General Procedure for the Synthesis of L5.24 2,6-Difluoroaniline
(20 mmol, 2.2 mL, 1.0 equiv) and dry triethylamine (40 mmol, 5.6
mL, 2.0 equiv) were dissolved in dry THF (10 mL) under nitrogen.
This solution was cooled to 0 °C, and ethyl chlorooxoacetate (24
mmol, 2.7 mL, 1.2 equiv) was added dropwise. Precipitation of a
white solid (triethylamonium chloride) occurred immediately upon
addition. The suspension was allowed to stir for 16 h, warming to
room temperature. The solid was filtered off and washed with diethyl
ether (40 mL), and the combined organic layer was washed with an
aqueous saturated NH4Cl solution until pH 6. This organic layer was
then washed with brine (30 mL) and dried over MgSO4. The solvent
was removed under reduced pressure, leaving a yellow solid that was
washed with hexanes (3 × 3 mL) to afford a yellowish crystalline
solid.
General Procedure for the Compounds 1a−1t, 4b−4i, 6a, and
6d.20 To a stirred solution of anilines (5 mmol, 1.0 equiv) and
triethylamine (15 mmol, 2.1 mL, 3.0 equiv) in anhydrous CH2Cl2 (10
mL), pivaloyl chloride (6 mmol, 0.74 mL, 1.2 equiv) was added
dropwise under an ice bath at 0 °C. After stirring at room
temperature, the mixture was quenched with water and extracted by
CH2Cl2. The combined extracts were washed with brine, dried over
Na2SO4, filtered, and evaporated under reduced pressure to afford the
crude compounds. The crude products were purified by column
chromatography to obtain the desired products. (Note: for synthesis
of 1n, double pivaloyl chloride was added.)
General Procedure for the Synthesis of L6.25 N,N-Diisopropyle-
thylamine (1 mmol, 165 μL), ethanol (1 mL), and 10 mol % Pd/C as
a catalyst in a 100 mL stainless steel autoclave. Then, 9 mL of
acetonitrile was added as a solvent, and the autoclave was closed
tightly and pressurized with oxygen (1 atm) and CO (5 atm) at 100
°C for 24 h. The mixture was stirred with a mechanical stirrer with
450 rpm. After the completion of the reaction, the autoclave cooled to
room temperature, and the remaining pressure was removed carefully.
The reactor vessel was opened, and the catalyst was separated using a
centrifuge tube. Then, the residue was concentrated by a rotary
evaporator. Finally, the crude product was purified by column
chromatography.
General Procedure for the Synthesis of Compounds 3, 5, and 7.
A mixture of N-phenylpivalamides (0.2 mmol, 1.0 equiv), fluorinated
olefin (0.4 mmol, 2.0 equiv), Pd(OAc)2 (0.02 mmol, 4.5 mg, 10 mol
%), AgOAc (0.4 mmol, 67 mg, 2.0 equiv), L4 (0.06 mmol, 8.4 mg, 0.3
equiv), and HFIP (0.5 mL) in a 15 mL glass vial sealed under oxygen
atmosphere was heated at 120 °C in an oil bath for 24 h. The reaction
mixture was cooled to room temperature, filtered through a pad of
Celite, and concentrated in vacuo. The resulting residue was purified
by column chromatography on silica gel to give the pure product.
General Procedure for Gram-Scale Reaction. A mixture of 1f (5
mmol, 1.0 equiv, 0.98g), 2 (10 mmol, 2.0 equiv, 1.5 mL), Pd(OAc)2
(10 mol %, 0.11g), AgOAc (10 mmol, 2.0 equiv, 1.67g), Ligand 4 (1.5
mmol, 0.3 equiv, 0.38g) and HFIP (15 mL) in a 100 mL round
bottomed flask glass was refluxed at 120 °C in an oil bath for 48 h
under oxygen. After cooling to room temperature, the reaction
mixture was filtered through a pad of Celite and concentrated in
vacuo. The resulting residue was purified by column chromatography
on silica gel to give the pure product 3f (1.51 g, 75%).
General Procedure for the Synthesis of the Compound 4a.21 The
reactions were carried out in a one-neck round-bottom flask. 2,3-
Dimethylaniline (5.0 mmol, 0.6 mL, 1.0 equiv) and Na2CO3 (10.0
mmol, 1.06 g 2.0 equiv) were added to a vigorously stirred mixture of
CH2Cl2 (5 mL) and H2O (5 mL). A reflux condenser was attached to
the flask, and pivaloyl chloride (10.0 mmol, 1.2 mL, 2.0 equiv) was
slowly added by syringe through the condenser while maintaining
vigorous stirring. The flask was lowered into an oil bath heated to 80
°C, and the reaction mixture was stirred for 2 h. After cooling to room
temperature, CH2Cl2 (10 mL) and 1 N NaOH (10 mL) were added.
The layers were separated, and the organic layer was washed with
H2O (2 × 10 mL), dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was subsequently purified by
silica gel chromatography (PE/EA = 10/1) or recrystallization.
General Procedure for the Synthesis of L1, L3, and L4.22
Diamantadine hydrochloride or tert-butylamine (5 mmol, 1.0 equiv)
and triethylamine (15 mmol, 2.1 mL, 3.0 equiv) were added to
dichloromethane (20 mL) solution, and the reaction was stirred in an
ice bath for 10 min. A mixture of ethyl oxalyl monochloride (6 mmol,
0.67 mL, 1.2 equiv) and dichloromethane (5 mL) was then added to
the solution slowly under cooling with an ice−water bath, and the
resulting mixture was stirred at room temperature overnight. Then,
water (20 mL) was added, and the aqueous phase was extracted with
CH2Cl2 (3 × 5 mL). The combined organic layer was washed with
brine (2 × 5 mL) and dried over anhydrous Na2SO4, and all of the
General Procedure for the Synthesis of Compounds 8. A mixture
of 3f (0.4 mmol, 1.0 equiv, 0.16g), NaBH4 (3.2 mmol, 8.0 equiv, 0.12
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g), and anhydrous EtOH (2 mL) in a 15 mL sealed glass vial were
heated at 80 °C in an oil bath for 48 h, detected by TLC. After
cooling to room temperature, the reaction mixture was concentrated
in vacuo. The resulting residue was purified by column chromatog-
raphy on silica gel to give the pure product 8 (57.8 mg, 45%).
N-(4-Ethoxyphenyl)pivalamide (1b). Light green crystalline solid,
13C NMR (101 MHz, CDCl3) δ 176.9, 175.3, 172.4, 137.6, 134.4,
126.9, 120.5, 50.8, 39.8, 33.0, 29.4, 27.7, 27.1, 9.1. HRMS (ESI) m/z:
[M + Na]+ Calcd for C18H24N2O3Na 339.1685; Found: 339.1674.
2-((Adamantan-1-yl)amino)-2-oxoacetic acid (L1). White crys-
talline solid, 0.48 g, 95%. Mp: 61−62 °C. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.08 (s, 1H), 2.19 (s, 1H), 1.86 (s, 2H), 1.66 (q, J =
11.9 Hz, 4H), 1.49−1.08 (m, 6H), 0.87 (s, 6H). 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 54.6, 50.5, 47.0, 42.5, 39.6, 32.6, 30.1. HRMS
(ESI) m/z: [M + Na]+ Calcd for C14H21NO3Na 274.1419; Found:
274.1418.
Ethyl 2-((Adamantan-1-yl)amino)-2-oxoacetate (L4). White
crystalline solid, PE/EtOAc (10:1) as the eluent, 1.37 g, 98%. Mp:
52−53 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 6.83 (s, 1H), 4.27
(q, J = 7.1 Hz, 2H), 2.14 (dt, J = 6.2, 3.1 Hz, 1H), 1.84 (d, J = 1.4 Hz,
2H), 1.64 (q, J = 12.2 Hz, 4H), 1.42−1.23 (m, 7H), 1.20−1.07 (m,
2H), 0.83 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
161.6, 155.4, 63.2, 54.2, 50. 6, 47.0, 42.6, 39.5, 32.5, 30.1, 14.1. HRMS
(ESI) m/z: [M + Na]+ Calcd for C16H25NO3Na 302.1732; Found:
302.1735.
1
PE/EtOAc (10:1) as the eluent, 1.08 g, 98%. Mp: 104−105 °C. H
NMR (400 MHz, CDCl3) δ (ppm) 7.44−7.36 (m, 1H), 7.31 (s, 1H),
6.88−6.76 (m, 2H), 4.10−3.90 (m, 2H), 1.41−1.36 (m, 3H), 1.30−
1.28 (m, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 176.6,
155.8, 131.2, 122.1, 114.8, 63.8, 39.5, 27.8, 14.9. HRMS (ESI) m/z:
[M + H]+ Calcd for C13H20NO2 222.1494; Found: 222.1492.
N-(4-Isopropylphenyl)pivalamide (1d). Light crystalline orange
solid, PE/EtOAc (10:1) as the eluent, 1.08 g, 99%. Mp: 143−144 °C.
1H NMR (400 MHz, CDCl3) δ (ppm) 7.44 (d, J = 8.4 Hz, 2H), 7.33
(s, 1H), 7.17 (d, J = 8.3 Hz, 2H), 2.87 (hept, J = 6.8 Hz, 1H), 1.31 (s,
9H), 1.23 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ
(ppm) 176.6, 145.0, 135.8, 126.9, 120.3, 39.6, 33.7, 27.8, 24.2. HRMS
(ESI) m/z: [M + Na]+ Calcd for C14H21NONa 242.1521; Found:
242.1515.
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-5-
methoxyphenyl)pivalamide (3a). White crystalline solid, PE/EtOAc
N-(4-(Difluoromethoxy)phenyl)pivalamide (1g). Dark brown
1
(40:1) as the eluent, 59.2 mg, 72%. Mp: 81−82 °C. H NMR (400
crystalline solid, PE/EtOAc (10:1) as the eluent, 1.19g, 98%. Mp:
1
MHz, CDCl3): δ (ppm) 7.47 (d, J = 2.6 Hz, 1H), 7.41 (d, J = 8.7 Hz,
1H), 7.33 (s, 1H), 7.18 (dt, J = 15.9, 2.1 Hz, 1H), 6.78 (dd, J = 8.7,
2.6 Hz, 1H), 6.09 (dt, J = 16.0, 11.5 Hz, 1H), 3.86 (s, 3H), 1.36 (s,
9H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 177.0, 161.6,
137.1, 134.7 (C−F, 3JC−F = 9.2 Hz,), 128.5, 119.5, 115.5 (C−F, 2JC−F
= 23.8 Hz), 112.8, 109.1, 55.7, 40.0, 27.7. 19F NMR (376 MHz,
CDCl3) δ (ppm) −65.69 (t, J = 6.4 Hz), −108.77 (t, J = 6.3 Hz,).
HRMS (ESI) m/z: [M + Na]+ Calcd for C16H18BrF4NO2Na
434.0355; Found: 434.0340.
105−106 °C. H NMR (400 MHz, CDCl3) δ (ppm) 7.59 (s, 1H),
7.48 (d, J = 9.0 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H), 6.43 (t, J = 74.1 Hz,
1H), 1.27 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 177.0,
147.3 (C−F, 1JC−F = 2.9 Hz), 135.6, 121.8, 120.2, 118.7, 116.1, 113.5,
39.6, 27.5. 19F NMR (376 MHz, CDCl3) δ (ppm) −80.6. HRMS
(ESI) m/z: [M + Na]+ Calcd for C12H15NO2Na 266.0969; Found:
266.0979.
Methyl 3-Pivalamidobenzoate (1m). White crystalline solid, PE/
EtOAc (10:1) as the eluent, 1.15 g, 98%. Mp: 111−112 °C. 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.00 (s, 1H), 7.76 (d, J = 9.2 Hz, 2H),
7.63 (d, J = 7.7 Hz, 1H), 7.24 (m, 1H), 3.77 (s, 3H), 0.61 (d, J =
487.3 Hz, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 177.1,
166.8, 138.4, 130.6, 128.9, 125.1, 124.9, 121.2, 52.1, 39.6, 27.5.
HRMS (ESI) m/z: [M + Na]+ Calcd for C13H17NO3Na 258.1106;
Found: 258.1100.
3-Pivalamidobenzyl pivalate (1n). White crystalline solid, PE/
EtOAc (10:1) as the eluent, 1.41 g, 97%. Mp: 111−112 °C. 1H NMR
(400 MHz, CDCl3) δ (ppm) 7.60 (s, 1H), 7.46 (s, 1H), 7.38 (d, J =
8.1 Hz, 1H), 7.16 (m, 1H), 6.96 (d, J = 7.6 Hz, 1H), 4.94 (s, 2H),
1.20 (s, 9H), 1.12 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ
(ppm) 178.2, 176.8, 138.3, 137.1, 129.0, 123.3, 119.9, 119.7, 65.8,
39.5, 38.7, 27.5, 27.1. HRMS (ESI) m/z: [M + Na]+ Calcd for
C17H25NO3Na 314.1732; Found: 314.1736.
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-4-
ethoxyphenyl)pivalamide (3b). White crystalline solid, PE/EtOAc
(20:1) as the eluent, 60.4 mg, 71%. Mp: 102−103 °C. 1H NMR (400
MHz, CDCl3): δ (ppm) 7.36(d, J = 8.8 Hz, 1H), 7.18 (dt, J = 15.8,
2.1 Hz, 2H), 6.97 (d, J = 2.8 Hz, 1H), 6.90 (dd, J = 8.8, 2.8 Hz, 1H),
6.13 (dt, J = 16.1, 11.5 Hz, 1H), 4.04 (q, J = 7.0 Hz, 2H), 1.42 (t, J =
7.0 Hz, 3H), 1.31 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 177.6, 157.4, 135.8 (C−F, 3JC−F = 9.1 Hz), 130.6, 128.6, 128.2,
116.9 (C−F, 2JC−F = 23.9 Hz), 116.6, 112.4, 64.0, 39.4, 27.6, 14.9. 19
F
NMR (376 MHz, CDCl3) δ (ppm) −65.70 (t, J = 6.3 Hz), −109.12
(t, J = 6.3 Hz,). HRMS (ESI) m/z: [M + H]+ Calcd for
C17H21BrF4NO2 426.0692; Found: 426.0687.
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-4-
methoxyphenyl)pivalamide (3c). White crystalline solid, PE/EtOAc
(10:1) as the eluent, 41.8 mg, 51%. Mp: 108−109 °C. 1H NMR (400
MHz, CDCl3): δ (ppm) 7.32 (s, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.16
(dt, J = 16.1, 2.1 Hz, 1H), 6.92 (d, J = 2.8 Hz, 1H), 6.87 (dd, J = 8.7,
2.8 Hz, 1H), 6.10 (dt, J = 16.1, 11.5 Hz, 1H), 3.81 (s, 3H), 1.28 (s,
9H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 177.6, 157.9, 135.7
(C−F, 3JC−F = 9.2 Hz), 130.6, 128.6, 128.2, 116.8 (C−F, 2JC−F = 23.9
Hz), 116.1, 111.5, 55.5, 39.3, 27.5. 19F NMR (376 MHz, CDCl3) δ
(ppm) −65.69 (t, J = 6.3 Hz,), −109.07 (t, J = 6.3 Hz). HRMS (ESI)
m/z: [M + Na]+ Calcd for C16H18BrF4NO2Na 434.0355; Found:
434.0343.
N-(3-Chloro-4-methylphenyl)pivalamide (4b). White crystalline
solid, PE/EtOAc (10:1) as the eluent, 1.07 g, 95%. Mp: 160−161 °C.
1H NMR (400 MHz, CDCl3) δ (ppm) 7.63 (d, J = 1.9 Hz, 1H),
7.28−7.25 (m, 2H), 7.14 (d, J = 8.2 Hz, 1H), 2.31 (s, 3H), 1.29 (s,
9H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 176.7, 136.9, 134.6,
131.9, 131.0, 120.7, 118.3, 39.8, 27.73, 19.6. HRMS (ESI) m/z: [M +
Na]+ Calcd for C12H16ClNONa 226.0999; Found: 226.0988.
N-(4-Fluoro-2-methylphenyl)pivalamide (4d). Pink crystalline
solid, PE/EtOAc (10:1) as the eluent, 1.02 g, 98%. Mp:94−95 °C.
1H NMR (400 MHz, CDCl3) δ (ppm) 7.59−7.56 (m, 1H), 7.21 (s,
1H), 6.86 (d, J = 9.1 Hz, 2H), 2.19 (s, 3H), 1.31−1.30 (m, 9H).
13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 176.9, 160.1 (C−F 1JC−F
= 244.0 Hz,), 132.8 (C−F, 3JC−F = 8.2 Hz,), 131.8 (C−F, 3JC−F = 2.6
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-4-
isopropylphenyl)pivalamide (3d). White crystalline solid, PE/EtOAc
(80:1) as the eluent, 51.6 mg, 61%. Mp: 138−139 °C. 1H NMR (400
MHz, CDCl3): δ (ppm) 7.55 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 1.9 Hz,
1H), 7.27−7.21 (m, 2H), 7.20 (s, 1H), 6.17 (dt, J = 16.1, 11.5 Hz,
1H), 2.92 (m, 1H), 1.32 (s, 9H), 1.25 (d, J = 6.9 Hz, 6H). 13C{1H}
4
2
Hz,), 125.7 (C−F, JC−F = 8.5 Hz,), 117.0 (C−F, JC−F = 22.5 Hz,),
113.2 (C−F, 2JC−F = 22.0 Hz,), 40.0, 27.7, 17.9. 19F NMR (376 MHz,
CDCl3) δ (ppm) −117.6. HRMS (ESI) m/z: [M + Na]+ Calcd for
C12H16FNONa 232.1114; Found: 232.1117.
3
NMR (100 MHz, CDCl3): δ (ppm) 177.1, 147.1, 136.0 (C−F, JC−F
= 9.1 Hz), 133.4, 128.8, 128.2, 125.8, 125.2, 117.3 (C−F, 2JC−F = 23.9
Hz), 39.7, 33.9, 27.7, 24.1. 19F NMR (376 MHz, CDCl3) δ (ppm)
−65.64 (t, J = 6.2 Hz,), −108.97 (t, J = 6.2 Hz,). HRMS (ESI) m/z:
[M + H]+ Calcd for C18H23BrF4NO 424.0899; Found: 424.0891.
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-4-
chlorophenyl)pivalamide (3e). White crystalline solid, PE/EtOAc
(60:1) as the eluent, 62.2 mg, 75%. Mp: 146−147 °C. 1H NMR (400
MHz, CDCl3): δ (ppm) 7.58 (d, J = 8.6 Hz, 1H), 7.41 (d, J = 2.4 Hz,
N-(4-(3-Ethyl-2,6-dioxopiperidin-3-yl)phenyl)pivalamide (6d).
White crystalline solid, PE/EtOAc (5:1) as the eluent, 1.55 g, 98%.
1
Mp:204−205 °C. H NMR (400 MHz, CDCl3) δ (ppm) 8.25 (s,
1H), 7.54 (d, J = 8.7 Hz, 2H), 7.44 (s, 1H), 7.20 (d, J = 8.7 Hz, 2H),
2.63−2.53 (m, 1H), 2.43−2.31 (m, 2H), 2.23−2.15 (m, 1H), 2.01 (tt,
J = 14.7, 7.5 Hz, 1H), 1.88 (dq, J = 14.6, 7.4 Hz, 1H), 1.30 (s, 9H),
0.84 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm)
2700
https://dx.doi.org/10.1021/acs.joc.0c02701
J. Org. Chem. 2021, 86, 2696−2705

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1H), 7.36−7.27 (m, 2H), 7.14 (dt, J = 16.0, 2.1 Hz, 1H), 6.17 (dt, J =
NMR (400 MHz, CDCl3): δ (ppm) 7.93 (s, 1H), 7.61−7.47 (m, 2H),
7.42 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 16.1 Hz, 1H), 6.20 (dt, J = 16.0,
11.3 Hz, 1H), 1.31 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 177.4, 136.1, 134.6 (C−F, 3JC−F = 9.1 Hz), 132.4 (C−F, 1JC−F
16.0, 11.3 Hz, 1H), 1.31 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3):
3
δ (ppm) 177.2, 134.5 (C−F, JC−F = 9.2 Hz), 134.2, 131.7, 130.5,
2
129.8, 127.0, 118.9 (C−F, JC−F = 24.1 Hz), 39.7, 27.6. 19F NMR
(376 MHz, CDCl3) δ (ppm) −65.8 (t, J = 6.2 Hz, 1H), −109.3 (t, J =
6.2 Hz, 2H). HRMS (ESI) m/z: [M + Na]+ Calcd for
C15H15BrClF4NONa 437.9859; Found: 437.9864.
= 33.1 Hz), 131.4, 127.8, 124.9, 123.3−121.6, 119.9 (C−F, 2JC−F =
24.1 Hz), 39.8, 27.5. 19F NMR (376 MHz, CDCl3) δ (ppm) −62.9,
−65.9 (t, J = 6.2 Hz), −109.5 (t, J = 6.2 Hz). HRMS (ESI) m/z: [M
+ H]+ Calcd for C16H16BrF7NO 450.0303; Found: 450.0313.
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-5-
chlorophenyl)pivalamide (3k). White crystalline solid, PE/EtOAc
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-4-fluorophenyl)-
pivalamide (3f). White crystalline solid, PE/EtOAc (100:1) as the
eluent, 63.0 mg, 79%. Mp: 136−137 °C. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.49 (s, 1H), 7.33 (dd, J = 8.8, 5.2 Hz, 1H), 7.21−
7.06 (m, 2H), 7.05−6.96 (m, 1H), 6.10 (dt, J = 16.1, 11.4 Hz,1H),
1.27 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 177.6,
1
(200:1) as the eluent, 34.8 mg, 42%. Mp: 124−125 °C. H NMR
(400 MHz, CDCl3): δ (ppm) 7.84 (d, J = 2.1 Hz, 1H), 7.37 (d, J =
8.4 Hz, 1H). 7.28 (s, 1H), 7.22−7.11 (m, 2H), 6.17 (dt, J = 16.0, 11.3
Hz, 1H), 1.33 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
177.0, 136.6, 136.4, 134.5 (C−F, 3JC−F = 9.2 Hz), 128.4, 126.2, 126.0,
125.0, 118.5 (C−F, 2JC−F = 24.1 Hz), 39.9, 27.6. 19F NMR (376 MHz,
CDCl3) δ (ppm) −65.8 (t, J = 6.3 Hz), −109.3 (t, J = 6.3 Hz). HRMS
(ESI) m/z: [M + Na]+ Calcd for C15H15BrClF4NONa 437.9859;
Found: 437.9869.
1
3
160.6 (C−F, JC−F = 246.6 Hz), 134.6 (C−F, JC−F = 9.1 Hz), 131.6
(C−F, 4JC−F= 2.8 Hz), 131.0 (C−F, 3JC−-F = 8.0 Hz), 128.5 (C−F, 3J
C−F= 8.4 Hz), 118.0 (C−F, 2JC−F= 24.1 Hz), 117.3 (C−F, 2JC−F
=
22.5 Hz), 113.2 (C−F, 2JC−F= 23.6 Hz), 39.4, 27.4. 19F NMR (376
MHz, CDCl3) δ (ppm) −65.8, −109.3 (dt, J = 11.2, 5.3 Hz), −111.7,
−117.5. HRMS (ESI) m/z: [M + Na]+ Calcd for C15H15BrF5NONa
422.0155; Found: 422.0143.
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-5-fluorophenyl)-
pivalamide (3l). White crystalline solid, PE/EtOAc (80:1) as the
eluent, 15.2 mg, 19%. Mp: 130−131 °C. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.56 (d, J = 8.2 Hz, 1H), 7.38 (s, 1H), 7.31 (m,
1H), 7.03 (dt, J = 16.5, 2.3 Hz, 1H), 6.99−6.90 (m, 1H), 6.38 (dt, J =
16.5, 11.3 Hz, 1H), 1.32 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3):
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-4-
(difluoromethoxy)phenyl)pivalamide (3g). White crystalline solid,
1
PE/EtOAc (40:1) as the eluent, 46.6 mg, 52%. Mp: 94−95 °C. H
NMR (400 MHz, CDCl3): δ (ppm) 7.51 (s, 1H), 7.41 (d, J = 8.8 Hz,
1H), 7.24−6.98 (m, 6H). 6.50 (t, J = 73.4 Hz, 1H), 6.12 (dt, J = 15.9,
11.4 Hz, 1H), 1.27 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ
2
1
δ (ppm) 177.1 (C−F, JC−F = 3.7 Hz), 160.93 (C−F, JC−F = 251.1
3
2
1
Hz), 137.1 (C−F, JC−F = 4.6 Hz), 130.9 (C−F, JC−F = 10.3 Hz),
129.5 (C−F, 3JC−F = 9.8 Hz), 122.3−121.4, 120.7, 113.4−112.5, 39.9,
27.6. 19F NMR (376 MHz, CDCl3) δ (ppm) −60.5, −70.3, −110.0 (t,
J = 6.2 Hz), −112.2. HRMS (ESI) m/z: [M + Na]+ Calcd for
C15H15BrF5NONa 422.0155; Found: 422.0142.
(ppm) 177.8 (C−F, 2JC−F = 9.7 Hz), 148.9 (C−F, JC−F = 2.7 Hz),
134.8 (C−F, 3JC−F= 9.2 Hz), 133.1, 130.7 (C−F, 3JC−F = 12.5 Hz),
128.0 (C−F, 2JC−F = 11.9 Hz), 121.6 (C−F, 2JC−F = 5.7 Hz), 119.0−
117.9, 115.8, 39.5 (C−F, 3JC−F = 3.2 Hz), 27.5 ppm (C−F, 4JC−F
=
2.8 Hz). 19F NMR (376 MHz, CDCl3) δ (ppm) −65.8 (t, J = 6.0
Hz,), −81.1 (d, J = 10.4 Hz), −109.3 (q, J = 6.3 Hz). HRMS (ESI)
m/z: [M + Na]+ Calcd for C16H16BrF6NO2Na 470.0166; Found:
470.0164.
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-3-fluorophenyl)-
pivalamide (3l′). White crystalline solid, PE/EtOAc (300:1) as the
eluent, 56.6 mg, 71%. Mp: 99−100 °C. 1H NMR (400 MHz, CDCl3):
δ (ppm) 7.71 (dd, J = 10.4, 2.6 Hz, 1H), 7.41 (dd, J = 8.6, 6.1 Hz,
1H), 7.31 (s, 1H), 7.17 (d, J = 16.0 Hz, 1H), 6.92 (m, 1H), 6.14 (dt, J
= 16.0, 11.4 Hz, 1H), 1.33 (s, 9H). 13C{1H} NMR (100 MHz,
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-4-(tert-butyl)-
phenyl)pivalamide (3hmono). White crystalline solid, PE/EtOAc
1
(150:1) as the eluent, 55.8 mg, 64%. Mp: 130−131 °C. H NMR
CDCl3): δ (ppm) 177.1 (C−F, 2JC−F = 3.8 Hz), 163.7 (C−F, 2JC−F
=
(400 MHz, CDCl3): δ (ppm) 7.57 (d, J = 8.3 Hz, 1H), 7.42 (d, J =
7.8 Hz, 2H), 7.24 (dd, J = 17.2, 4.8 Hz, 2H), 6.16 (dt, J = 16.0, 11.5
Hz, 1H), 1.33 (d, J = 3.5 Hz, 18H). 13C{1H} NMR (100 MHz,
3
2
250.1 Hz), 137.3 (C−F, JC−F = 11.2 Hz), 134.5 (C−F, JC−F = 9.1
Hz,), 128.8 (C−F, 3JC−F = 9.4 Hz), 123.4 (C−F, 3JC−F = 9.1, 3.1 Hz),
118.5−117.4, 113.1 (C−F, 2JC−F = 22.1, 2.5 Hz), 112.1 (C−F, 2JC−F
=
3
CDCl3): δ (ppm) 177.1, 149.4, 136.3 (C−F, JC−F = 9.1 Hz), 133.1,
25.5, 7.4 Hz), 39.9 (C−F, 3JC−F = 1.2 Hz), 27.5. 19F NMR (376 MHz,
CDCl3) δ (ppm) −65.8 (t, J = 6.2 Hz), −108.3, −109.2 (t, J = 6.3
Hz). HRMS (ESI) m/z: [M + Na]+ Calcd for C15H15BrF5NONa
422.0155; Found: 422.0144.
2
128.0, 127.8, 125.4, 124.0, 117.2 (C−F, JC−F = 23.8 Hz), 39.6, 34.7,
31.4, 27.7. 19F NMR (376 MHz, CDCl3) δ (ppm) −65.6 (t, J = 6.1
Hz), −108.9 (t, J = 6.2 Hz). HRMS (ESI) m/z: [M + Na]+ Calcd for
C19H24BrF4NONa 460.0875; Found: 460.0860.
Methyl-4-(4-bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-3-pivalami-
dobenzoate (3m). White crystalline solid, PE/EtOAc (40:1) as the
eluent, 50.8 mg, 58%. Mp: 114−115 °C. 1H NMR (400 MHz,
CDCl3): δ (ppm) 8.24 (d, J = 1.6 Hz, 1H), 7.87 (dd, J = 8.1, 1.5 Hz,
1H), 7.52 (d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 7.22 (dt, J = 16.1, 2.1 Hz,
1H), 6.25 (dt, J = 16.1, 11.3 Hz, 1H), 3.92 (s, 3H), 1.34 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 177.2, 166.2, 135.8,
N-(2,6-Bis((E)-4-bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-4-(tert-
butyl)phenyl)pivalamide (3hdi). White crystalline solid, PE/EtOAc
(150:1) as the eluent, 41.2 mg (0.8 mmol), 8%. Mp: 253−254 °C. 1H
NMR (400 MHz, CDCl3): δ (ppm) 7.57 (s, 2H), 7.39−7.09 (m, 2H),
6.97 (s, 1H), 6.17 (dt, J = 16.1, 11.4 Hz, 2H), 1.36 ppm (d, J = 8.4
Hz, 18H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 177. 6, 151.5,
136.2 (C−F, JC−F = 9.2 Hz), 132.6, 131.6, 125.5, 117.4 (C−F, JC−F
= 23.9 Hz), 39.5, 35.0, 31.3, 27.6 ppm. 19F NMR (376 MHz, CDCl3)
δ (ppm) −65.6 (C−F, J = 6.2 Hz), −109.0 (C−F, J = 6.2 Hz). HRMS
(ESI) m/z: [M + Na]+ Calcd for C23H25Br2F8NONa 666.0052;
Found: 666.0036.
3
2
135.0 (C−F, 3JC−F = 9.1 Hz), 132.8, 132.1, 127.3 126.9, 119.5 (C−F,
2JC−F = 24.1 Hz), 52.5, 39.7, 27.6. 19F NMR (376 MHz, CDCl3) δ
(ppm) −65.8 (t, J = 6.2 Hz), −109.4 (t, J = 6.2 Hz). HRMS (ESI) m/
z: [M + H]+ Calcd for C17H19BrF4NO3 440.0484; Found: 440.0488.
4-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-3-pivalamidoben-
zylpivalate (3n). White crystalline solid, PE/EtOAc (10:1) as the
eluent, 58.4 mg, 59%. Mp: 112−113 °C. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.56 (s, 1H), 7.45 (dd, J = 17.6, 11.1 Hz, 2H),
7.23−7.13 (m, 2H), 6.14 (dt, J = 16.0, 11.5 Hz, 1H), 5.05 (s, 2H),
1.30 (s, 9H), 1.21 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 178.3, 177.2, 139.3, 135.8, 135.2 (C−F, 3JC−F = 9.1 Hz), 127.9,
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-5-
methylphenyl)pivalamide (3i). White crystalline solid, PE/EtOAc
1
(80:1) as the eluent, 71.0 mg, 90%. Mp: 88−89 °C. H NMR (400
MHz, CDCl3): δ (ppm) 7.39 (d, J = 15.3 Hz, 2H), 7.32 (d, J = 8.0
Hz, 1H), 7.15 (d, J = 16.1 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.08 (dt,
J = 15.9, 11.6 Hz, 1H), 2.33 (s, 3H), 1.29 (s, 9H). 13C{1H} NMR
(100 MHz, CDCl3): δ (ppm) 177.3, 141.0, 136.9−134.4, 127.2,
2
2
126.9, 126.5, 125.7, 116.0 (C−F, JC−F = 23.8 Hz), 39.6, 27.6, 21.4.
127.5, 125.3, 124.9, 117.6 (C−F, JC−F = 23.9 Hz), 65.3, 39.7, 38.9,
19F NMR (376 MHz, CDCl3) δ (ppm) −65.66 (t, J = 6.4 Hz),
27.6, 27.2. 19F NMR (376 MHz, CDCl3) δ (ppm) −65.8 (t, J = 6.2
Hz), −109.2 (t, J = 6.2 Hz). HRMS (ESI) m/z: [M + Na]+ Calcd for
C21H26BrF4NO3Na 518.0930; Found: 518.0920.
−108.92 (t, J = 6.3 Hz). HRMS (ESI) m/z: [M + H]+ Calcd for
C16H19BrF4NO 396.0586; Found: 396.0599.
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-5-
N-(5-Acetyl-2-(4-bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)phenyl)-
pivalamide (3o). Yellow crystalline solid, PE/EtOAc (10:1) as the
eluent, 27.0 mg, 32%. Mp: 135−136 °C. 1H NMR (400 MHz,
(trifluoromethyl)phenyl)pivalamide (3j). White crystalline solid, PE/
1
EtOAc (120:1) as the eluent, 45.8 mg, 51%. Mp: 171−172 °C. H
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CDCl3): δ (ppm) 8.24 (d, J = 1.7 Hz, 1H), 7.80 (dd, J = 8.1, 1.6 Hz,
1H), 7.55 (d, J = 8.1 Hz, 1H), 7.37 (s, 1H), 7.23 (d, J = 16.1 Hz, 1H),
6.26 (dt, J = 16.1, 11.3 Hz, 1H), 2.61 (s, 3H), 1.35 (s, 9H). 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 197.3, 177.3, 138.7, 136.0, 134.8
(C−F, 3JC−F = 9.2 Hz), 132.6, 127.6, 125.6, 119.7 (C−F, 3JC−F = 24.1
Hz), 39.8, 27.6, 26.9. 19F NMR (376 MHz, CDCl3) δ (ppm) −65.8
(t, J = 6.2 Hz), −109.4 (t, J = 6.2 Hz). HRMS (ESI) m/z: [M + H]+
Calcd for C17H19BrF4NO2 424.0535; Found: 424.0547.
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-6-
methoxyphenyl)pivalamide (3p). White crystalline solid, PE/EtOAc
(60:1) as the eluent, 44.2 mg, 54%. Mp: 102−103 °C. 1H NMR (400
MHz, CDCl3): δ (ppm) 7.23 (m, 1H), 7.20−7.13 (m, 3H), 6.92 (dd,
J = 8.1, 1.0 Hz, 1H), 6.15 (dt, J = 16.1, 11.6 Hz, 1H), 3.84 (s, 3H),
1.34 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 177.7,
153.8, 137.0 (C−F, 3JC−F = 9.3 Hz), 132.1, 127.3, 125.2, 118.6, 115.4
(C−F, 2JC−F = 23.9 Hz), 111.9, 56.1, 39.6, 27.7. 19F NMR (376 MHz,
CDCl3) δ (ppm) −65.5 (t, J = 6.3 Hz), −109.0 (t, J = 6.3 Hz). HRMS
(ESI) m/z: [M + Na]+ Calcd for C16H18BrF4NO2Na 434.0355;
Found: 434.0340.
Hz), 135.1, 134.1, 129.6, 129.1, 123.4, 114.8 (C−F, JC−F = 23.6, 5.1
Hz), 39.2, 27.5, 20.6, 14.1. 19F NMR (376 MHz, CDCl3) δ (ppm)
−65.5 (t, J = 5.7 Hz), −108.8 (t, J = 6.1 Hz). HRMS (ESI) m/z: [M
+ Na]+ Calcd for C17H20BrF4NONa 432.0562; Found: 432.0569.
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-5-chloro-4-
methylphenyl)pivalamide (5b). White crystalline solid, PE/EtOAc
1
(200:1) as the eluent, 82.2 mg, 96%. Mp: 158−159 °C. H NMR
(400 MHz, CDCl3): δ (ppm) 7.63 (s, 1H), 7.29 (d, J = 10.2 Hz, 2H),
7.11 (dt, J = 16.1, 2.1 Hz, 1H), 6.13 (dt, J = 16.1, 11.4 Hz, 1H), 2.35
(s, 3H), 1.31 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
3
2
177.2, 136.2, 134.6 (C−F, JC−F = 9.1 Hz), 134.1 (C−F, JC−F = 4.3
Hz), 128.8, 126.7, 126.1, 117.8−117.0, 39.6, 27.5, 19.6. 19F NMR
(376 MHz, CDCl3) δ (ppm) −65.7 (t, J = 6.2 Hz), −109.2 (t, J = 6.3
Hz). HRMS (ESI) m/z: [M + Na]+ Calcd for C16H17BrClF4NONa
452.0016; Found: 452.0007.
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-4,5-
dimethoxyphenyl)pivalamide (5c). Yellow crystalline solid, PE/
EtOAc (5:1) as the eluent, 61.8 mg, 70%. Mp: 156−157 °C. 1H NMR
(400 MHz, CDCl3): δ (ppm) 7.25 (s, 1H), 7.15 (d, J = 14.6 Hz, 2H),
6.88 (s, 1H), 6.03 (dt, J = 16.0, 11.5 Hz, 1H), 3.89 (d, J = 3.8 Hz,
6H), 1.33 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
177.4, 151.0, 147.4, 134.8 (C−F, 3JC−F = 9.2 Hz), 129.8, 120.3, 114.8
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-6-
chlorophenyl)pivalamide (3q). White crystalline solid, PE/EtOAc
(40:1) as the eluent, 39.0 mg, 47%. Mp: 154−155 °C. 1H NMR (400
MHz, CDCl3): δ (ppm) 7.43 (m, 2H), 7.34 (s, 1H), 7.22 (m, 1H),
7.13 (dt, J = 16.2, 2.0 Hz, 1H), 6.15 (dt, J = 16.1, 11.5 Hz, 1H), 1.34
(s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 177.3, 136.3
(C−F, 3JC−F = 9.4 Hz), 133.9, 133.2, 132.0, 130.7, 128.0, 125.4, 116.8
(C−F, 2JC−F = 23.9 Hz), 109.2, 108.7, 56.3, 56.2, 39.7, 27.7 ppm. 19
F
NMR (376 MHz, CDCl3) δ (ppm) −65.6 (t, J = 6.2 Hz), −108.5 (t, J
6.2 Hz). HRMS (ESI) m/z: [M
Na]+ Calcd for
C17H20BrF4NO3Na 464.0460; Found: 464.0461.
=
+
2
(C−F, JC−F = 24.0 Hz), 39.7, 27.6. 19F NMR (376 MHz, CDCl3) δ
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-4-fluoro-6-
methylphenyl)pivalamide (5d). White crystalline solid, PE/EtOAc
(40:1) as the eluent, 38.8 mg, 47%. Mp: 158−159 °C. 1H NMR (400
MHz, CDCl3): δ (ppm) 7.51 (s, 1H), 7.04 (d, J = 16.0 Hz, 1H), 6.93
(dd, J = 8.9, 2.6 Hz, 1H), 6.81 (dd, J = 8.7, 2.5 Hz, 1H), 6.02 (dt, J =
16.1, 11.4 Hz, 1H), 2.00 (s, 3H), 1.23 (s, 9H). 13C{1H} NMR (100
(ppm) −65.6 (t, J = 6.3 Hz), −109.2 (ddd, J = 8.7, 6.8, 3.3 Hz).
HRMS (ESI) m/z: [M + Na]+ Calcd for C15H15BrClF4NONa
437.9859; Found: 437.9866.
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-6-
methylphenyl)pivalamide (3r). White crystalline solid, PE/EtOAc
(80:1) as the eluent, 65.6 mg, 83%. Mp: 165−166 °C. 1H NMR (400
MHz, CDCl3): δ (ppm) 7.34 (s, 1H), 7.31 (dd, J = 6.3, 2.8 Hz, 1H),
7.15 (dd, J = 9.2, 5.1 Hz, 3H), 6.06 (dt, J = 16.1, 11.6 Hz, 1H), 2.08
1
MHz, CDCl3): δ (ppm) 177.9, 161.2 (C−F, J = 246.4 Hz), 139.3
3
3
(C−F, JC−F = 8.6 Hz), 135.6 (C−F, JC−F = 9.1 Hz), 133.7 (C−F,
3JC−F = 8.7 Hz), 130.6 (C−F, JC−F = 2.5 Hz), 118.6 (C−F, JC−F
=
4
2
(s, 3H), 1.25 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
2
2
22.2 Hz), 117.0 (C−F, JC−F = 24.0 Hz), 110.5 (C−F, JC−F = 23.3
2
Hz), 39.3, 27.5, 18.1 (C−F, JC−F = 1.0 Hz). 19F NMR (376 MHz,
3
177.4, 137.9−135.9, 134.5, 132.1, 127.6, 124.3, 115.9 (C−F, JC−F
=
23.8 Hz), 39.3, 27.6, 18.0. 19F NMR (376 MHz, CDCl3) δ (ppm)
−65.6 (t, J = 6.2 Hz), −109.0 (t, J = 6.3 Hz). HRMS (ESI) m/z: [M
+ H]+ Calcd for C16H19BrF4NO 396.0586; Found: 396.0585.
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-6-ethylphenyl)-
pivalamide (3s). White crystalline solid, PE/EtOAc (80:1) as the
eluent, 56.4 mg, 69%. Mp: 159−160 °C. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.36 (m, 1H), 7.28 (s, 1H), 7.23 (d, J = 4.9 Hz,
2H), 7.17 (dt, J = 16.1, 2.0 Hz, 1H), 6.08 (dt, J = 16.1, 11.6 Hz, 1H),
2.48 (q, J = 7.6 Hz, 2H), 1.26 (s, 9H), 1.12 (t, J = 7.6 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 177.6, 142.1, 136.8 (C−
CDCl3) δ (ppm) −65.7 (dd, J = 13.4, 7.2 Hz), −109.1 (dt, J = 11.3,
6.1 Hz), −114.5 (d, J = 45.5 Hz). HRMS (ESI) m/z: [M + H]+ Calcd
for C16H18BrF5NO 414.0492; Found: 414.0499.
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)naphthalen-1-
yl)pivalamide (5e). White crystalline solid, PE/EtOAc (50:1) as the
eluent, 52.4 mg, 61%. Mp: 166−167 °C. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.72 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.58 (dd, J =
16.1, 8.5 Hz, 2H), 7.50−7.36 (m, 2H), 7.31 (d, J = 8.7 Hz, 1H), 7.19
(d, J = 16.2 Hz, 1H), 6.06 (dt, J = 16.1, 11.6 Hz, 1H), 1.30 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 178.1, 135.9 (C−F,
3
3JC−F = 9.2 Hz), 134.5, 132.3, 130.6, 128.5, 128.3, 128.0, 127.1, 123.2,
F, JC−F = 9.2 Hz), 134.0, 132.5, 130.3, 127.9, 124.4, 115.9 (C−F,
2JC−F = 23.8 Hz), 39.3, 27.6, 24.7, 14.2. 19F NMR (376 MHz, CDCl3)
122.5, 115.8 (C−F, 2JC−F = 23.8 Hz), 39.5, 27.6. 19F NMR (376 MHz,
CDCl3) δ (ppm) −65.5 (t, J = 6.2 Hz), −108.8 (t, J = 6.2 Hz). HRMS
(ESI) m/z: [M + H]+ Calcd for C19H19BrF4NO 432.0586; Found:
432.0580.
δ (ppm) −65.6 (t, J = 6.3 Hz), −109.0 (ddd, J = 11.1, 6.6, 4.8 Hz).
HRMS (ESI) m/z: [M + H]+ Calcd for C17H21BrF4NO 410.0743;
Found: 410.0756.
Methyl 3-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-2-pivalami-
dobenzoate (3t). White crystalline solid, PE/EtOAc (40:1) as the
eluent, 39.4 mg, 45%. Mp: 77−78 °C. 1H NMR (400 MHz, CDCl3):
δ (ppm) 9.74 (s, 1H), 8.01 (dd, J = 7.9, 1.4 Hz, 1H), 7.74 (dd, J = 7.8,
1.3 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.07 (dt, J = 16.1, 2.1 Hz, 1H),
6.17 (dt, J = 16.1, 11.5 Hz, 1H), 3.92 (s, 3H), 1.35 (s, 9H). 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 177.7, 167.6, 138.4, 137.2 (C−F,
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)phenyl)-
acetamide (5f). White crystalline solid, PE/EtOAc (10:1) as the
eluent, 40.7 mg, 60%. Mp: 116−117 °C. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.86 (s, 1H), 7.43 (m, 1H), 7.30 (d, J = 7.4 Hz,
1H), 7.18 (dd, J = 17.4, 9.8 Hz, 2H), 6.29−5.88 (m, 1H), 2.12 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 169.8, 137.9−
2
134.1, 130.4, 128.4, 126.8, 126.5−126.4, 116.4 (C−F, JC−F = 23.8
2
3JC−F = 9.3 Hz), 132.0, 131.7, 131.5, 125.3, 123.0, 115.0 (C−F, JC−F
Hz), 23.6. 19F NMR (376 MHz, CDCl3) δ (ppm) −65.7 (t, J = 6.3
Hz), −109.0 (t, J = 6.3 Hz). HRMS (ESI) m/z: [M + Na]+ Calcd for
C12H10BrF4NONa 361.9780; Found: 361.9783.
= 24.1 Hz), 52.7, 39.9, 27.5 ppm. 19F NMR (376 MHz, CDCl3) δ
(ppm) −65.5 (t, J = 6.3 Hz), −108.9 (t, J = 6.4 Hz). HRMS (ESI) m/
z: [M + H]+ Calcd for C17H19BrF4NO3 440.0484; Found: 440.0479.
N-(6-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-2,3-
dimethylphenyl)pivalamide (5a). White crystalline solid, PE/EtOAc
(40:1) as the eluent, 53.2 mg, 65%. Mp: 137−138 °C. 1H NMR (400
MHz, CDCl3): δ (ppm) 7.29 (s, 1H), 7.24 (d, J = 7.9 Hz, 1H), 7.15
(dt, J = 16.1, 2.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.04 (dt, J = 16.1,
11.7 Hz, 1H), 2.26 (s, 3H), 2.00 (s, 3H), 1.28 (s, 9H). 13C{1H} NMR
1-(8-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-6-methyl-3,4-di-
hydroquinolin-1(2H)-yl)-2,2-dimethylpropan-1-one (5g). White
crystalline solid, PE/EtOAc (180:1) as the eluent, 60.9 mg, 70%.
1
Mp: 117−118 °C. H NMR (400 MHz, CDCl3): δ (ppm) 7.20 (s,
1H), 7.00 (s, 2H), 6.15 (dd, J = 23.7, 10.9 Hz, 1H), 4.42 (s, 1H), 3.23
(s, 1H), 2.72 (s, 2H), 2.21 (d, J = 97.3 Hz, 3H), 2.04 (d, J = 40.8 Hz,
2H), 1.36 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
178.7, 138.4, 136.5, 130.6, 129.7, 124.6, 120.6, 118.4−116.7, 114.5
3
(100 MHz, CDCl3): δ (ppm) 177.3, 139.6, 136.6 (C−F, JC−F = 9.1
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(C−F, JC−F = 40.7, 22.2 Hz), 45.4, 39.8, 28.5, 25.6, 24.5, 21.0. 19F
J = 5.9 Hz), −109.0 (t, J = 5.9 Hz). HRMS (ESI) m/z: [M + Na]+
Calcd for C22H25BrF4N2O3Na 543.0882; Found: 543.0883.
NMR (376 MHz, CDCl3) δ (ppm) −59.93, −74.24, −108.75. HRMS
(ESI) m/z: [M + Na]+ Calcd for C19H22BrF4NONa 458.0719;
Found: 458.0722.
N-(4-(3-Ethyl-2,6-dioxopiperidin-3-yl)-2-(3,3,4,4,5,5,6,6,6-nona
fluorohex-1-en-1-yl)phenyl)pivalamide (7e). White crystalline solid,
1
PE/EtOAc (5:1) as the eluent, 62 mg, 61%. Mp: 170−171 °C. H
1-(5-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-2,3-dihydro-4H-
benzo[b][1,4]oxazin-4-yl)-2,2-dimethylpropan-1-one (5h). White
crystalline solid, PE/EtOAc (40:1) as the eluent, 22.0 mg, 26%.
Mp: 144−145 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.16−7.01
(m, 2H), 6.99−6.78 (m, 2H), 6.15 (dt, J = 16.0, 11.7 Hz, 1H), 4.96−
3.14 (m, 4H), 1.37 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 178.5, 148.7, 136.4 (C−F, 3JC−F = 9.4 Hz), 130.8, 126.7, 118.7,
118.5, 114.7 (C−F, 2JC−F = 23.7 Hz), 67.0, 44.6, 40.2, 28.5. 19F NMR
(376 MHz, CDCl3) δ (ppm) −65.5 (dd, J = 11.1, 5.5 Hz), −108.8
(dt, J = 23.3, 5.5 Hz). HRMS (ESI) m/z: [M + H]+ Calcd for
C17H19BrF4NO2 424.0535; Found: 424.0545.
1-(8-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-3,4-dihydro-
quin-olin-1(2H)-yl)-2,2-dimethylpropan-1-one (5i). White crystal-
line solid, PE/EtOAc (180:1) as the eluent, 75.8 mg, 90%. Mp: 132−
133 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.49−7.37 (m, 1H),
7.17 (dd, J = 8.4, 5.2 Hz, 2H), 7.05 (d, J = 15.3 Hz, 1H), 6.16 (dd, J =
27.4, 11.9 Hz, 1H), 4.42 (s, 1H), 3.28 (s, 1H), 2.76 (s, 2H), 2.04 (s,
2H), 1.35 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
178.8, 141.0, 138.5−135.7, 130.2, 130.0, 126.1, 124.2, 115.6−114.1,
45.4, 40.0, 28.6, 25.7, 24.6. 19F NMR (376 MHz, CDCl3) δ (ppm)
−65.5 (td, J = 6.0, 3.2 Hz), −103.1, −117.7. HRMS (ESI) m/z: [M +
H]+ Calcd for C18H21BrF4NO 422.0743; Found: 422.0737.
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)phenyl)-
pivalamide (7a). White crystalline solid, PE/EtOAc (60:1) as the
eluent, 62.5 mg, 82%. Mp: 106−107 °C. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.58 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H),
7.35 (dd, J = 12.2, 4.6 Hz, 1H), 7.25−7.14 (m, 2H), 6.15 (dt, J = 16.0,
11.5 Hz, 1H), 1.31 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 177.2, 135.7 (C−F, 3JC−F = 9.1 Hz), 130.6, 128.4, 127.2, 126.3,
125.8, 117.4 (C−F, 2JC−F = 23.9 Hz), 39.6, 27.6. 19F NMR (376 MHz,
CDCl3) δ (ppm) −65.7 (t, J = 6.3 Hz), −109.1 (t, J = 6.4 Hz). HRMS
(ESI) m/z: [M + Na]+ Calcd for C15H16BrF4NONa 404.0249;
Found: 404.0248.
NMR (400 MHz, CDCl3): δ (ppm) 8.00 (s, 1H), 7.80 (d, J = 9.2 Hz,
1H), 7.38−7.29 (m, 2H), 7.24−7.16 (m, 1H), 6.13 (dt, J = 16.0, 11.7
Hz, 1H), 2.72−2.54 (m, 1H), 2.49−2.32 (m, 2H), 2.31−2.20 (m,
2H), 2.14−1.98 (m, 1H), 1.91 (m, 1H), 1.32 (s, 9H), 0.88 (t, J = 7.4
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 177.1, 174.8,
172.0, 136.6, 135.5 (C−F, 3JC−F = 9.8 Hz), 135.2, 128.4, 128.1, 125.5,
2
118.8 (C−F, JC−F = 23.2 Hz), 50.9, 39.8, 33.1, 29.3, 27.6, 26.9, 9.1.
19F NMR (376 MHz, CDCl3) δ (ppm) −80.1, −82.2, −111.5 (t, J =
11.5 Hz), −123.8 (dd, J = 17.3, 9.6 Hz), −124.8, −126.7. HRMS
(ESI) m/z: [M + Na]+ Calcd for C24H25F9N2O3Na 583.1619; Found:
583.1618.
N-(4-(3-Ethyl-2,6-dioxopiperidin-3-yl)-2-(3,3,4,4,5,5,6,6,7,7,8,8,9,
9,10,10,10-heptadecafluorodec-1-en-1-yl)phenyl)pivalamide (7f).
White crystalline solid, PE/EtOAc (5:1) as the eluent, 71 mg, 47%.
1
Mp: 159−160 °C. H NMR (400 MHz, CDCl3): δ (ppm) 8.09 (s,
1H), 7.79 (d, J = 9.2 Hz, 1H), 7.36−7.27 (m, 3H), 7.20 (d, J = 16.1
Hz, 1H), 6.13 (dt, J = 16.0, 11.6 Hz, 1H), 2.80−2.54 (m, 1H), 2.50−
2.33 (m, 2H), 2.33−2.18 (m, 1H), 2.05 (dt, J = 14.7, 7.3 Hz, 1H),
2.02−1.87 (m, 1H), 1.32 (s, 9H), 0.88 (t, J = 7.4 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 177.0, 174.7, 171.9, 136.5, 135.4
(C−F, 3JC−F = 9.7 Hz), 135.1, 128.3, 128.0, 125.3, 118.7 (C−F, 2JC−F
= 23.0 Hz), 50.7, 39.7, 32.9, 29.2, 27.4, 26.8, 9.0. 19F NMR (376
MHz, CDCl3) δ (ppm) −80.8 (t, J = 9.8 Hz), −111.3 (t, J = 12.9 Hz),
−121.3, −121.9), −122.8 (d, J = 11.1 Hz), −126.1 (d, J = 13.6 Hz).
HRMS (ESI) m/z: [M + Na]+ Calcd for C28H25F17N2O3Na
783.1491; Found: 783.1492.
Isopropyl-(2-(4-bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)phenyl)-
carbamate (7g). White crystalline solid, PE/EtOAc (400:1) as the
eluent, 36.0 mg, 47%. Mp: 58−59 °C. 1H NMR (400 MHz, CDCl3):
δ (ppm) 7.70 (d, J = 8.1 Hz, 1H), 7.46 (dd, J = 7.8, 1.2 Hz, 1H),
7.41−7.36 (m, 1H), 7.33 (dt, J = 16.1, 2.3 Hz, 1H), 7.18 (t, J = 7.5
Hz,1H), 6.41 (s, 1H), 6.19 (dt, J = 16.0, 11.7 Hz, 1H), 5.02 (m, 1H),
1.31 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 153.8, 135.9, 135.2 (C−F, 3JC−F = 8.9 Hz), 130.8, 129.2, 127.4,
N-(2-(3,3,4,4,5,5,6,6,6-Nonafluorohex-1-en-1-yl)phenyl)-
pivalamide (7b). White crystalline solid, PE/EtOAc (60:1) as the
eluent, 66.5 mg, 79%. Mp: 81−82 °C. 1H NMR (400 MHz, CDCl3):
δ (ppm) 7.52 (d, J = 8.0 Hz, 1H), 7.48−7.39 (m, 2H), 7.38−7.30 (m,
1H), 7.24−7.15 (m, 2H), 6.10 (dt, J = 16.0, 11.9 Hz, 1H), 1.30 (s,
9H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 177.3, 135.8 (C−
F, 3JC−F = 4.8 Hz), 135.7, 130.7, 128.6, 127.2, 126.4, 126.0, 117.1 (C−
2
125.4, 123.9, 117.5 (C−F, JC−F = 23.7 Hz), 69.6, 22.2. 19F NMR
(376 MHz, CDCl3) δ (ppm) −65.7 (t, J = 6.5 Hz), −109.2 (t, J = 6.3
Hz). HRMS (ESI) m/z: [M + Na]+ Calcd for C14H14BrF4NO2Na
406.0042; Found: 406.0041.
Isopropyl-(2-(3,3,4,4,5,5,6,6,6-nonafluorohex-1-en-1-yl)phenyl)-
carbamate (7h). White crystalline solid, PE/EtOAc (400:1) as the
eluent, 62.6 mg, 74%. Mp: 80−81 °C. 1H NMR (400 MHz, CDCl3):
δ (ppm) 7.70 (d, J = 7.4 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.43−7.36
(m, 1H), 7.32 (dt, J = 15.9, 2.2 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.39
(s, 1H), 6.16 (dt, J = 15.9, 12.1 Hz, 1H), 5.02 (m, 1H), 1.31 (d, J =
6.3 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 153.8,
136.0, 135.3 (C−F, 3JC−F = 9.5 Hz), 130.9, 129.2, 127.4, 125.4, 124.0,
F, JC−F = 23.1 Hz), 39.6, 27.5. 19F NMR (376 MHz, CDCl3) δ
2
(ppm) −74.2, −84.3, −111.5 (dd, J = 17.4, 7.2 Hz), −124.1 (dt, J =
16.5, 4.7 Hz), −125.1, −127.0. HRMS (ESI) m/z: [M + Na]+ Calcd
for C17H16F9NONa 444.0980; Found: 444.0964.
N-(2-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodec-1-
en-1-yl)phenyl)pivalamide (7c). White crystalline solid, PE/EtOAc
1
(60:1) as the eluent, 90.7 mg, 73%. Mp: 88−89 °C. H NMR (400
2
117.3 (C−F, JC−F = 23.1 Hz), 69.6, 22.1. 19F NMR (376 MHz,
MHz, CDCl3): δ (ppm) 7.53 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.40
(d, J = 7.6 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.24−7.12 (m, 2H), 6.07
(dt, J = 15.7, 11.9 Hz, 1H), 1.27 (s, 9H). 13C{1H} NMR (100 MHz,
CDCl3) δ (ppm) −74.8, −85.7, −111.5 (t, J = 11.4 Hz), −124.1 (dd,
J = 16.8, 8.8 Hz), −124.9, −127.2. HRMS (ESI) m/z: [M + Na]+
Calcd for C16H14F9NO2Na 446.0779; Found: 446.0779.
3
CDCl3): δ (ppm) 177.5, 135.9, 135.7 (C−F, JC−F = 9.9 Hz), 130.6,
2
128.8, 127.1, 126.4, 126.2, 117.1 (C−F, JC−F = 23.0 Hz), 39.5, 27.4.
Isopropyl-(2-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluor-
odec-1-en-1-yl)phenyl)carbamate (7i). White crystalline solid, PE/
EtOAc (400:1) as the eluent, 83.5 mg, 67%. Mp: 89−90 °C. 1H NMR
(400 MHz, CDCl3): δ (ppm) 7.70 (d, J = 7.2 Hz, 1H), 7.46 (d, J =
7.8 Hz, 1H), 7.43−7.36 (m, 1H), 7.32 (d, J = 16.0 Hz, 1H), 7.19 (t, J
= 7.6 Hz, 1H), 6.40 (s, 1H), 6.17 (dt, J = 15.9, 12.1 Hz, 1H), 5.02 (m,
1H), 1.31 ppm (d, J = 6.3 Hz, 6H). 13C{1H} NMR (100 MHz,
19F NMR (376 MHz, CDCl3) δ (ppm) −81.1, −111.4, −121.5,
−122.1, −123.1 (d, J = 123.2 Hz), −125.9, −127.0. HRMS (ESI) m/
z: [M + Na]+ Calcd for C21H16F17NONa 644.0858; Found: 644.0855.
N-(2-(4-Bromo-3,3,4,4-tetrafluorobut-1-en-1-yl)-4-(3-ethyl-2,6-
dioxopiperidin-3-yl)phenyl)pivalamide (7d). White crystalline solid,
1
PE/EtOAc (5:1) as the eluent, 52.1 mg, 51%. Mp: 248−249 °C. H
3
NMR (400 MHz, CDCl3): δ (ppm) 7.94 (s, 1H), 7.83 (d, J = 9.2 Hz,
1H), 7.37−7.30 (m, 2H), 7.21 (d, J = 16.1 Hz, 1H), 6.15 (dt, J = 16.1,
11.2 Hz, 1H), 2.64 (dd, J = 16.1, 3.3 Hz, 1H), 2.49−2.33 (m, 2H),
2.31−2.19 (m, 1H), 2.06 (m, 1H), 1.91 (m, 1H), 1.32 (s, 9H), 0.88
(t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
177.0, 174.7, 171.9, 136.5, 135.4 (C−F, 3JC−F = 9.3 Hz), 135.1, 128.3,
CDCl3): δ (ppm) 153.8, 136.0, 135.3 (C−F, JC−F = 9.6 Hz), 130.9,
2
127.4, 125.4, 124.0, 117.4 (C−F, JC−F = 22.9 Hz), 69.6, 22.1. 19F
NMR (376 MHz, CDCl3) δ (ppm) −80.8 (t, J = 10.0 Hz), −111.2 (t,
J = 12.6 Hz), −121.3, −121.9, −122.7, −123.1 (d, J = 11.7 Hz),
−125.4, −127.6. HRMS (ESI) m/z: [M + Na]+ Calcd for
C20H14F17NO2Na 646.0645; Found: 646.0630.
2
128.1, 125.5, 125.3, 119.1 (C−F, JC−F = 24.0 Hz), 50.9, 39.9, 33.1,
N-(4-Fluoro-2-(3,3,4,4-tetrafluorobut-1-en-1-yl)phenyl)-
pivalamide (8). Yellow liquid, PE/EtOAc (100:1) as the eluent, 57.8
29.4, 27.7, 27.0, 9.1. 19F NMR (376 MHz, CDCl3) δ (ppm) −65.7 (t,
2703
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J. Org. Chem. 2021, 86, 2696−2705

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Article
1
mg, 45%. H NMR (400 MHz, CDCl3): δ (ppm) 7.54 (dd, J = 8.9,
Science Found for Distinguished Young Scholars
(BK20180041), and the PAPD Project. The project was also
supported by Open Research Fund of the School of Chemistry
and Chemical Engineering, Henan Normal University.
5.3 Hz, 1H), 7.24 (s, 1H), 7.15 (d, J = 2.9 Hz, 1H), 7.13−7.00 (m,
2H), 6.12 (dt, J = 16.2, 11.6 Hz, 1H), 5.83 (m, 1H), 1.32 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 177.4, 160.6 (C−F,
1JC−F = 246.1 Hz), 133.6 (C−F, 3JC−F = 9.8 Hz), 131.5, 130.9 (C−F,
3JC−F = 8.0 Hz), 127.9 (C−F, JC−F = 8.3 Hz), 119.6 (C−F, JC−F
=
3
2
2
2
REFERENCES
23.9 Hz), 117.2 (C−F, JC−F = 22.5 Hz), 113.6 (C−F, JC−F = 23.7
Hz), 39.6, 27.6. 19F NMR (376 MHz, CDCl3) δ (ppm) −113.2 (d, J =
3.0 Hz), −115.4, −134.1 (d, J = 2.4 Hz). HRMS (ESI) m/z: [M +
Na]+ Calcd for C15H16F5NONa 344.1050; Found: 344.1061.
■
̌
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02701.
■
sı
1H, 13C and 19F NMR spectra for all compounds (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1b, 1d, 1g, 1m, 1n, 4b, 4d, 6d, 2a, 3a−3t
(3h includes 3h (mono) and 3h (di), 3l includes 3l and
3l′), 5a−5i, 7a−7i, 8, L1, and L4 (ZIP)
Accession Codes
CCDC 2035074 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Jingyu Zhang − College of Energy, Soochow Institute for
Energy and Materials Innovations, Soochow University,
Suzhou 215006, P.R. China; School of Chemistry and
Chemical Engineering, Henan Normal University, Xinxiang
453000, P.R. China; Email: jyzhang@suda.edu.cn
Yingsheng Zhao − Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry, Chemical Engineering
and Materials Science, Soochow University, Suzhou 215123,
P.R. China; School of Chemistry and Chemical Engineering,
Henan Normal University, Xinxiang 453000, P.R. China;
orcid.org/0000-0002-6142-7839; Email: yszhao@
suda.edu.cn
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Authors
Dongjie Wang − College of Energy, Soochow Institute for
Energy and Materials Innovations and Key Laboratory of
Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow
University, Suzhou 215006, P.R. China
Xu Xu − College of Energy, Soochow Institute for Energy and
Materials Innovations and Key Laboratory of Organic
Synthesis of Jiangsu Province, College of Chemistry, Chemical
Engineering and Materials Science, Soochow University,
Suzhou 215006, P.R. China
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02701
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Natural Science Foundation
of China (Grants 21772139), the Jiangsu Province Natural
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