Synthesis of 2-Fluoro-1,4-benzoxazines and 2-Fluoro-1,4-benzoxazepin-5-ones by Exploring the Nucleophilic Vinylic Substitution (SNV) Reaction of gem-Difluoroenamides

Article abstract of DOI:10.1021/acs.joc.5b00507

N-Benzoyl β,β-difluoroenamides and N-benzoyl fluoroynamides are novel structural units which have been explored as precursors in heterocyclic synthesis. The presence of two fluorine atoms at the β-position of the enamide moiety endows unique electrophilic

Full text of DOI:10.1021/acs.joc.5b00507

Article
pubs.acs.org/joc
Synthesis of 2‑Fluoro-1,4-benzoxazines and 2‑Fluoro-1,4-
benzoxazepin-5-ones by Exploring the Nucleophilic Vinylic
Substitution (SNV) Reaction of gem-Difluoroenamides
Tamara Meiresonne, Guido Verniest,‡ Norbert De Kimpe,* and Sven Mangelinckx*
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links
653, B-9000 Ghent, Belgium
S
* Supporting Information
ABSTRACT: N-Benzoyl β,β-difluoroenamides and N-benzoyl
fluoroynamides are novel structural units which have been
explored as precursors in heterocyclic synthesis. The presence
of two fluorine atoms at the β-position of the enamide moiety
endows unique electrophilic reactivity. Treatment of these
enamides with oxygen nucleophiles gives rise to a nucleophilic
vinylic substitution (SNV) reaction, which was directed toward
2-fluoro-1,4-benzoxazines and 2-fluoro-1,4-benzoxazepin-5-
ones. Furthermore, fluorinated ynamides, a new type of
building block, were prepared in excellent yields for the first
time. In this case, β-addition of nucleophiles across the triple
bond is observed also.
INTRODUCTION
■
Enamides represent an interesting group of compounds
because they demonstrate an enhanced stability as compared
to enamines but still exhibit a rather nucleophilic reactivity.1 A
significant amount of research has already been devoted to the
class of β,β-dihaloenamines and β,β-dihalogenated enamides.2
In contrast, while some difluorinated enamines have been used
as building blocks, for example, in the synthesis of
difluorocysteine and -serine derivatives,3 dipeptides,4 difluoro-
imines,5 and various α,α-difluoro-β-hydroxycarbonyl com-
pounds,6 the chemistry of difluoroenamides has received only
very limited attention. To our knowledge, this reactivity was
exploited only twice toward the synthesis of fluorinated
heterocycles, more specifically toward isoxazolidines and
dihydropyrans7 or oxazoles.8 Furthermore, one example was
found in which the intermediacy of a difluoroenamide was
postulated in the synthesis of morpholino-fused diketopiper-
azines.9 Also, while gem-difluoroalkenes have been used in a
nucleophilic vinylic substitution (SNV) reaction for the
synthesis of a variety of fluorinated heterocycles,10 their
Figure 1. Comparison between the reactivity of Stork enamines and
nitrogen-substituted analogues have received less attention.
This is remarkable because the presence of two fluorine atoms
at the β-carbon atom of enamide 3 in combination with an
electron-withdrawing acyl or sulfonyl group (R2) at nitrogen
will lead to a highly polarized double bond and an electron-
deficient difluorinated carbon atom (Figure 1). If this effect
could predominate in the electron-donating effect of the
enamide nitrogen atom, enamide 3 would be an example of an
electrophilic enamide readily reacting with nucleophiles. In this
way, the introduction of two fluorine atoms at the β-position
enamides 1, difluoroenamides 3, and fluoroynamides 5.
could be seen as an efficient way to induce umpolung of the
enamide functionality.11 The potential to use this reactivity in a
way that fundamentally deviates from the reactivity of Stork
enamines and enamides 112 is the basis of the present study
Received: March 6, 2015
© XXXX American Chemical Society
A
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Scheme 1. Synthesis of Enamides 8 and 10
(Figure 1). Treatment of these difluoroenamides 3 and the
corresponding hitherto unexplored fluorinated ynamides 5 with
nucleophiles may lead to the formation of β-fluoroenamides 4.
By incorporating the nucleophile in the enamide, this method
could give rise to the formation of fluorinated heterocycles such
as 1,4-benzoxazines and 1,4-benzoxazepin-5-ones.
Table 1. Reactivity of Difluorinated Enamide 10 toward
Nucleophiles
1,4-Benzoxazines have been shown to possess interesting
biological activities.13 An example of a natural product
containing the 1,4-benzoxazine core is cappamensin A, which
was isolated from the roots of the native Taiwanese shrub
Capparis sikkimensis, and shows promising antitumor activity.14
Another interesting class of benzo-fused heterocycles comprises
1,4-benzoxazepin-5-ones. An important example of this type of
compound is piclozotan, a selective 5-HT1A receptor partial
agonist, showing in vivo neuroprotective effects.15 Due to
fluorine’s unique properties (high electronegativity, small van
der Waals radius),16 its introduction in organic compounds can
induce significant changes in their chemical and pharmaco-
logical properties.17 Therefore, in the pharmaceutical industry,
there is a great interest in the synthesis of fluorinated
compounds, with a profound focus on heterocyclic com-
pounds.18 Although benzoxazines and benzoxazepines contain-
ing a CF3 group have already been synthesized,19 examples of
compounds carrying the fluorine substituent directly attached
to the heterocyclic ring are barely known.20 Only one example
of a 2-fluoro-1,4-benzoxazine derivative was found in the
literature.21 Additionally, no reports were found on the
synthesis of 2- or 3-fluoro-1,4-benzoxazepin-5-ones. In view
of these gaps in the chemistry of fluorinated benzo-fused
heterocycles, a synthetic route toward 2-fluoro-1,4-benzox-
azines and 2-fluoro-1,4-benzoxazepin-5-ones was developed,
exploiting the unique electrophilic reactivity of difluorinated
enamides and elusive fluorinated ynamides.
nucleophile
(equiv)
ratio
compound
a
entry
1
reaction conditions
11:12:13:14
(%)
thiophenol 1.2 equiv of KOH,
(1.2)
8:2:0:0
4:2:1:3
4:2:1:3
8:2:0:0
8:2:0:0
11a (69)
CH3CN, 82 °C, 20 h
1.2 equiv of KOH,
CH3CN, 82 °C, 20 h
1.2 equiv of KOH,
CH3CN, 82 °C, 20 h
THF, rt, 3 h
2
3
4
5
phenol
(1.2)
13b (10) +
b
14b (85)
phenol
(1.2)
11b/12b
c
(32)
NaOMe
11c (57) +
12c (15)
d
(1.1)
KOtBu
(1.1)
THF, 0 °C to rt, 2 h
11d (46)
a
b
Isolated yield. Formed due to hydrolysis of 11b/12b upon
c
prolonged exposure to silica. Ratio 11b:12b = 8:2; the isomers
could not be separated. 1 M in MeOH.
d
enamides 11a and 12a (ratio 11a:12a = 8:2) from which
enamide 11a could be isolated in 69% yield (Table 1, entry 1).
β-Fluoroenamides 11a and 12a are the products of a
nucleophilic substitution at the vinylic CF2 carbon atom of
enamide 10, most probably via a nonconcerted two-step
process (SNV reaction),10a,23 i.e., addition of the nucleophile
across the double bond is followed by elimination of fluoride.
When enamide 10 was treated with 1.2 equiv of phenol in the
presence of KOH, four different products were detected in the
reaction mixture after workup, i.e., the isomeric enamides 11b
and 12b, addition product 13b, and amino ester 14b, in a ratio
of 11b:12b:13b:14b = 4:2:1:3. After purification of this mixture
(column chromatography, SiO2), only two compounds were
isolated, more specifically adduct 13b (10%) and amino ester
14b (85%) (Table 1, entry 2). Apparently, enamides 11b and
12b were not stable upon prolonged exposure to SiO2 and
hydrolyzed toward amino ester 14b. When the reaction of
enamide 10 with phenol was repeated and the reaction mixture
was purified via flash column chromatography (SiO2), a mixture
of isomers 11b and 12b was isolated in 32% total yield (ratio
11b:12b = 8:2) (Table 1, entry 3). Furthermore, the reaction of
RESULTS AND DISCUSSION
■
In the first part of this work, the synthesis of novel
difluoroenamides 8 and 10 was developed (Scheme 1). To
this end, amine 6a22 was protected as benzamide 7 or
tosylamide 9 in good yield by treatment with benzoyl chloride
or p-toluenesulfonyl chloride, respectively, in dichloromethane
in the presence of a base. In the next step, treatment of
benzamide 7 and tosylamide 9 with LiHMDS in THF, to
achieve dehydrobromination, smoothly led to the formation of
new difluorinated enamides 8 and 10 (82−85% yield).
Subsequently, the reactivity of enamide 10 toward sulfur and
oxygen nucleophiles was investigated (Table 1). Reaction with
thiophenol afforded a mixture of the isomeric fluorinated
B
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enamide 10 with both NaOMe (in MeOH/THF) and KOtBu
(in THF) resulted in smooth conversion toward a mixture of
isomers 11 and 12.
moiety by dehydrofluorination would result in protonation of
the nucleophile and formation of the conjugated acid. For
example, if treatment of enamide 10 with NaOMe (Table 1,
entry 4) would lead to the corresponding ynamide, MeOH
should be a good nucleophile to add across the triple bond.
However, upon stirring ynamide 25a (vide infra) in MeOH for
a prolonged time, no addition of MeOH was observed.
Therefore, it is believed that these transformations operate
through an initial addition of the nucleophile, followed by
elimination of fluoride.
In a next part, this promising methodology was expanded to
the synthesis of novel heterocyclic monofluorinated com-
pounds by incorporating the oxygen nucleophile and the
electrophilic difluoroenamide unit in the same precursor, thus
enabling an intramolecular vinylic nucleophilic substitution. In
view of the synthesis of fluorinated six- and seven-membered
heterocycles, the precursor had to contain a two- or three-
carbon linker between the enamide nitrogen atom and the
nucleophilic oxygen atom. For the synthesis of the six-
membered analogues, i.e., 2-fluoro-1,4-benzoxazines, 2-amino-
phenols 17a and 17b were chosen as the building blocks
(Scheme 3).
These β-fluoroenamides are new compounds and the
differentiation between the two isomeric β-fluoroenamides 11
and 12 could be made based on comparison of the value of the
3
vicinal coupling constant JH,F of the signal of the hydrogen
atom at the α position of the vinylic double bond. More
specifically, in the case of oxygen-substituted monofluorinated
enamides 11b−d and 12b−d, Z-3JH,F (H and F in a Z
configuration) has a value of 0.7−1.7 Hz, while E-3JH,F (H and
F in an E configuration) results in a much larger value of 19−22
Hz. For the sulfur analogues 11a and 12a, larger coupling
constants were observed, with a value of 5.5 Hz for Z-3JH,F and
a larger value of 25.0 Hz for E-3JH,F
.
Furthermore, the reaction of enamide 8 with phenol also led
to the formation of a mixture of enamides 15 and 16, which
could not be separated via column chromatography, in 80%
yield (Scheme 2).
Scheme 2. Reaction of Difluoroenamide 8 with Phenol
In the first step, the reaction of phenols 17 with ethyl
bromodifluoroacetate 18 proceeded selectively toward amides
19. Protection of the phenolic oxygen atom was achieved by
treatment of benzamides 19 with TBDMSCl in the presence of
imidazole. Amides 20 were in turn reduced toward the
secondary amines 21 using an excess of borane dimethylsulfide
complex in CH2Cl2. The next step involved the protection of
the nitrogen atom of amines 21. Because the introduction of a
tosyl group proceeded very slowly, the use of a benzoyl
protecting group was evaluated instead. Treatment of β-bromo-
β,β-difluoroamines 21 with different benzoyl chlorides 22 in the
presence of Et3N led to the formation of N-(2-bromo-2,2-
difluoroethyl)benzamides 23 as suitable precursors for the
synthesis of fluorinated 1,4-benzoxazines.
A possible explanation of the moderate stereoselectivity of
this addition−elimination reaction toward enamides 11 and 15
(H and F in a Z configuration) can be found by evaluating the
preferred conformation of the intermediate carbanions after
addition of the nucleophile (Figure 2). To allow fluoride
The key step in the reaction sequence concerned the
conversion of precursors 23 toward the envisioned 1,4-
benzoxazines (Table 2). Therefore, benzamide 23a was treated
with LiHMDS, which led to the formation of a mixture of
difluoroenamide 24a and fluorinated ynamide 25a, resulting
from the LiHMDS-induced elimination of HF from enamide
24a (Table 2, entry 1). Increasing the number of equivalents of
LiHMDS led to a full conversion of amide 23a toward ynamide
25a, which was isolated in an excellent yield of 97% (Table 2,
entry 2). The formation of ynamide 25a can be explained by
C−F bond activation by coordination of fluorine to the silicon
atom in the tert-butyldimethylsilyl protecting group, enhancing
the leaving group capacity of fluoride.10a,25 This could also
explain why amides 7 and 9 were not converted into the
corresponding ynamides upon treatment with LiHMDS. Next,
benzamide 23a was treated with 1 equiv of KOtBu, leading to a
selective conversion toward the envisioned benzoxazine 26a,
which could be isolated in 80% yield (Table 2, entry 3).
Because the use of LiHMDS or KOtBu led to a different
reaction outcome, other bases were evaluated in order to
investigate the possible reaction pathway. It was remarkable
that the cleavage of the silyl ether did not occur upon treatment
of benzamide 23a with 2.2 equiv of LiHMDS, even though
under these conditions fluoride is expelled from the substrate
(Table 2, entry 2). To test the influence of the cation, the
reaction was repeated with NaHMDS and KHMDS (Table 2,
entries 4 and 5). Thus, benzamide 23a was treated with 1 equiv
Figure 2. Possible transition state models in the addition−elimination
reaction.
elimination, the lone pair of the intermediate carbanion and the
fluorine atom must adopt antiperiplanar positions, which is the
case in two possible transition state models TS-A and TS-B. In
TS-B, the substituted nitrogen atom is situated in a gauche
conformation between the two fluorine atoms, generating an
important electronic repulsion. In TS-A, only one repulsive
interaction between the nitrogen atom and fluorine is present,
rendering this conformer energetically more favored. On the
other hand, in TS-A a mild sterical hindrance is present
between the nitrogen atom and the nucleophile. The
combination of these two factors, more specifically electronic
repulsion (which is the main factor) and sterical hindrance,
leads to the moderate stereoselectivity.24
An alternative pathway for the formation of the substituted
enamides 11, 12, 15, and 16 comprises initial formation of the
corresponding ynamide due to a base-promoted elimination of
HF from enamides 8 and 10, followed by the addition of the
nucleophile. In this case, however, formation of the ynamide
C
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Scheme 3. Synthesis of Benzamides 23
Table 2. Reactivity of Benzamide 23a toward Different Bases
a
entry
reaction conditions
ratio 23a:24a:25a:26a
compound (%)
1
2
3
4
5
6
1.1 equiv of LiHMDS, THF, 0 °C, 3 h
2.2 equiv of LiHMDS, THF, rt, 2.5 h
1 equiv of KOtBu, THF, rt, 2 h
3:3:4:0
0:0:1:0
0:0:0:1
0:4:0:6
0:0:0:1
0:1:0:0
−
25a (97)
26a (80)
−
b
2 equiv of NaHMDS , THF, rt, 6 h
b
2 equiv of KHMDS , THF, rt, 6 h
26a (54)
1 equiv of LiOtBu, THF, 66 °C, 1.5 h
24a (73)
a
b
Isolated yield. Second equivalent was added after 3 h.
of NaHMDS. LC-MS analysis of the reaction mixture after 15
min indicated the presence of four compounds, i.e., benzamide
23a, enamide 24a, ynamide 25a, and benzoxazine 26a. Follow-
up via LC-MS indicated no further progress of the reaction, so
an extra 1 equiv of NaHMDS was added after 3 h. After being
stirred for an additional 3 h, the reaction was stopped and a
mixture of enamide 24a and benzoxazine 26a was obtained in a
ratio of 4:6, which could not be separated via column
chromatography (Table 2, entry 4). Subsequently, benzamide
23a was treated with 1 equiv of KHMDS, which also led to the
formation of a mixture of compounds 23a, 24a, 25a, and 26a
after 15 min of reaction at room temperature. Also in this case,
an extra 1 equiv of base was added after 3 h, and the reaction
was stopped after an additional 3 h. After workup, only
benzoxazine 26a was detected, so it was assumed that both
enamide 24a and ynamide 25a were intermediates in the
formation of benzoxazine 26a. It was concluded that the cation
of the base plays an important role in the reaction outcome due
to the different properties of the corresponding fluoride salts.
Upon use of LiHMDS as the base, the reaction terminates at
the stage of ynamide 25a in which the silyl ether is not
deprotected, so apparently the fluoride anion in LiF is not
available for this reaction. When KHMDS is used, KF is
formed, in which the fluoride anion is available for the
deprotection reaction, because this reaction leads to the
formation of benzoxazine 26a after ring closure. This reactivity
of alkali-metal fluorides may be explained by the higher lattice
energy of LiF in comparison with NaF and KF.26 Following
D
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Scheme 4. Transformation of Benzamides 23 into Ynamides 25 and Benzoxazines 26
Scheme 5. Synthesis of Benzamides 29
these results, the use of LiOtBu should also lead to the
formation of a TBDMS-protected end product. Indeed, the
reaction of benzamide 23a with 1 equiv of LiOtBu afforded
enamide 24a as the sole end product, which was isolated in
73% yield (Table 2, entry 6).
Subsequently, the optimized reaction conditions were used
to convert benzamides 23a−d toward benzoxazines 26 and
ynamides 25 in good to excellent yields (Scheme 4). In an
attempt to prove the intermediacy of ynamides 25 in the
formation of benzoxazines 26, compounds 25 were treated with
TBAF in THF, which led directly to the formation of
benzoxazines 26. The triple bond in ynamides 25 has an
electrophilic reactivity which is prone to nucleophilic attack by
the phenolic oxygen atom, leading to a smooth conversion
toward benzoxazines 26 (Scheme 4).
The chemistry of halogenated ynamides has only been
explored to a limited extent. While 2-iodoynamides have been
used in for example cycloaddition27 and benzannulation28
reactions, the synthesis and reactivity of fluorinated ynamides is
a totally unexplored field in organic chemistry. Only one report
has been published in which the formation of a fluorinated
ynamine was described, albeit in a very low yield of 5%.29 Over
the last years, the chemistry of ynamides has received much
attention.30 Due to the polarization of the triple bond, α-
addition of nucleophiles across the triple bond is more
common than β-addition, although a few examples of β-
addition have been described.31 Umpolung of the ynamide
E
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Scheme 6. Conversion of Benzamides 29 into Benzoxazepinones 32
functionality, leading to addition of nucleophiles at the β-
position, is usually achieved via a metal-catalyzed reaction. In
this work, umpulong is achieved by the presence of a fluorine
substituent at the β-position of the ynamide in combination
with the electron-withdrawing group at nitrogen, leading to
selective addition of the oxygen nucleophile at the β-position
without the need of a metal catalyst.
In the last part of this work, the synthesis of novel fluorinated
benzo-fused seven-membered rings was developed. In the
precursor, a three-carbon atom-containing linker had to be
positioned between the enamide nitrogen atom and the oxygen
nucleophile, in order to be able to form a seven-membered ring
via the vinylic nucleophilic substitution reaction. In the
synthetic route toward benzoxazines 26, the oxygen nucleophile
was already incorporated in the fluorinated secondary amines
21, after which a benzoyl protecting group was introduced at
nitrogen (Scheme 3). In the synthetic route toward the seven-
membered ring analogues, it was chosen to incorporate the
oxygen nucleophile in the aroyl group attached to nitrogen
(Scheme 5). Therefore, a variety of secondary fluorinated
amines was synthesized by reacting ethyl bromodifluoroacetate
acetylsalicyloyl chlorides 28b,c, which were prepared from the
corresponding carboxylic acids by reaction with thionyl
chloride, were reacted with amine 6c, leading to the formation
of benzamides 29d,e (Scheme 5).
To achieve the ring closure, benzamide 29a (R1 = Pr, R2 =
H) was treated with 2.2 equiv of LiHMDS, which led to the
formation of a mixture of three reaction products, i.e.,
benzamide 30a, enamide 31a, and benzoxazepinone 32a
(Scheme 6). The composition of this reaction mixture supports
the intermediacy of enamide 31a in the formation of
benzoxazepinone 32a. Subsequently, the use of KOtBu was
evaluated for the conversion of benzamides 29 into
benzoxazepinones 32. In that regard, benzamides 29a−e were
stirred in THF under reflux in the presence of KOtBu, which
gave a clean conversion toward the envisioned benzoxazepi-
nones 32a−e (Scheme 6). In a last step, the deprotection of
benzoxazepinones 32c,e was achieved by heating in the
presence of 5 equiv of boron(III) fluoride etherate resulting
in 4H-benzoxazepinones 33a,b, enabling further functionaliza-
tion of this scaffold.
CONCLUSIONS
18 with different amines, leading to amides 27, which in turn
■
were reduced using borane dimethylsulfide complex in
dichloromethane under reflux. Subsequently, a functionalized
benzoyl group was introduced at the nitrogen atom by
treatment with O-acetylsalicyloyl chloride 28a, leading to the
formation of benzamides 29a−c. Benzamides 29 are suitable
precursors for the synthesis of fluorinated seven-membered
rings, because there is a three-carbon linker in between the
nitrogen and oxygen atom. An advantage of this synthetic route
is the possibility of a late stage functionalization, because
various derivatives of 2-acetylsalicylic acid can be used for the
introduction of the group at nitrogen. For example,
In conclusion, a straightforward synthesis toward novel 2-
fluoro-1,4-benzoxazines and 2-fluoro-1,4-benzoxazepin-5-ones
was developed. The key step in this reaction sequence is a base-
induced ring closure of the corresponding difluorinated
benzamides, via an SNV reaction, which either proceeds via
an addition−elimination reaction at the vinylic CF2 carbon
atom or via formation of fluorinated ynamides which undergo
nucleophilic attack by the phenolic oxygen in a second step.
The synthesis of these fluorinated ynamides comprises the first
example of an efficient route toward this unexplored class of
fluorinated compounds.
F
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procedure.22 The synthesis of amine 6c is given as a representative
example.
EXPERIMENTAL SECTION
■
Synthesis of N-Propyl-2-bromo-2,2-difluoroacetamide 27a.
To an ice-cooled solution of ethyl bromodifluoroacetate 18 (5.07 g, 25
mmol) in CH2Cl2 (40 mL) was added a solution of propylamine (1.77
g, 30 mmol, 1.2 equiv) in CH2Cl2 (20 mL). This mixture was warmed
to room temperature, and after being stirred for 17 h at this
temperature, the solvent and excess propylamine were removed in
vacuo, affording N-propyl-2-bromo-2,2-difluoroacetamide 27a (5.35 g)
in 99% yield.
To a solution of N-(4-methoxybenzyl)-2-bromo-2,2-difluoroaceta-
mide 27c (1.94 g, 6.9 mmol) in anhydrous THF (40 mL) was added
borane dimethylsulfide complex (1.58 g, 21 mmol, 3 equiv) with a
syringe. Subsequently, this mixture was stirred at reflux for 17 h after
which it was slowly quenched with a mixture of water and methanol
(H2O/MeOH: 1/1, 50 mL). After extraction with EtOAc (3 × 50
mL), drying (MgSO4), filtration, and evaporation of the solvent, the
residue was redissolved in MeOH and stirred in the presence of Pd/C
at room temperature for 2 h. After filtration, the crude amide 6c was
purified by column chromatography (SiO2, PE/EtOAc 92/8) and
obtained in 73% yield (1.41 g).
N-Propyl-2-bromo-2,2-difluoroacetamide 27a. Colorless oil.
1
Yield: 99% (5.35 g). H NMR (300 MHz, CDCl3): δ 0.97 (3H, t, J =
7.2 Hz), 1.63 (2H, sextet, J = 7.2 Hz), 3.34 (2H, q, J = 6.8 Hz), 6.31
(1H, br s). 13C NMR (75 MHz, CDCl3): δ 11.1, 22.3, 41.9, 111.9 (t, J
= 316.1 Hz), 160.3 (t, J = 27.1 Hz). 19F NMR (282 MHz, CDCl3): δ
N-Benzyl-2-bromo-2,2-difluoroethylamine 6b. Yellow oil. Rf
1
0.42 (petroleum ether/EtOAc 9/1). Yield: 85% (5.40 g). H NMR
−60.40 (2F, s). IR (ATR, cm−1): νNH = 3304, νCO = 1698, νmax
=
(400 MHz, CDCl3): δ 1.86 (1H, br s), 3.36 (2H, t, JH,F = 12.5 Hz),
3.95 (2H, s), 7.27−7.37 (5H, m). 13C NMR (100.6 MHz, ref =
CDCl3): δ 52.8, 58.3 (t, J = 23.5 Hz), 123.7 (t, J = 308.9 Hz), 127.4,
128.1 (2×), 128.6 (2×), 139.3. 19F NMR (376.5 MHz, CDCl3, ref =
CFCl3): δ −51.34 (2F, t, J = 12.5 Hz). IR (ATR, cm−1): νNH = 3360,
νmax = 1117, 909, 889, 697. MS (ES+): m/z (%): 250/52 (M + H+,
20), 150 (100). HRMS (ES+): calcd for C9H11BrF2N+: 250.0037,
found 250.0036.
1542, 1130. MS (ES−): m/z (%): 214/16 (M − H+, 100).
Synthesis of Acetamides 27b and 27c and Bromodifluoro-
acetanilides 19a and 19b. The synthesis of N-(4-methoxybenzyl)-
2-bromo-2,2-difluoroacetamide 27c is given as a representative
example. To a solution of ethyl bromodifluoroacetate 18 (2.23 g, 11
mmol) in EtOAc (50 mL) were added 4-methoxybenzylamine (1.51 g,
11 mmol, 1 equiv) and Et3N (1.11 g, 11 mmol, 1 equiv), after which
the mixture was stirred at reflux for 4 h. Subsequently, H2O (30 mL)
was added and an extraction with EtOAc (3 × 30 mL) was performed.
After drying of the organic layer (MgSO4), filtration, and evaporation
of the solvent, yellow crystals were obtained, which were recrystallized
from Et2O, affording pure amide 27c as white crystals (2.43 g) in 75%
yield.
N-(4-Methoxybenzyl)-2-bromo-2,2-difluoroethylamine 6c.
Colorless oil. Rf 0.12 (petroleum ether/EtOAc 92/8). Yield: 73%
(1.41 g). 1H NMR (400 MHz, CDCl3): δ 1.78 (1H, br s), 3.34 (2H, t,
JH,F = 12.6 Hz), 3.81 (3H, s), 3.88 (2H, s), 6.88 (2H, d, J = 8.8 Hz),
7.25 (2H, d, J = 8.8 Hz). 13C NMR (100.6 MHz, ref = CDCl3): δ 52.2,
55.2, 58.1 (t, J = 23.5 Hz), 113.9 (2×), 123.8 (t, J = 308.8 Hz), 129.3
(2×), 131.3, 158.9. 19F NMR (376.5 MHz, CDCl3, ref = CFCl3): δ
N-(4-Methoxybenzyl)-2-bromo-2,2-difluoroacetamide 27c.
−51.23 (2F, t, JH,F = 12.7 Hz). IR (ATR, cm−1): νNH = 3362, νmax
=
White crystals. Melting point: 89−90 °C. Rf 0.05 (petroleum ether/
1
1512, 1246, 1033. MS (ES+): m/z (%): 121 (100).
EtOAc 9/1). Yield: 75% (2.43 g). H NMR (400 MHz, CDCl3): δ
3.78 (3H, s), 4.42 (2H, d, J = 5.8 Hz), 6.79 (1H, br s), 6.87 (2H, d, J =
8.7 Hz), 7.21 (2H, d, J = 8.7 Hz). 13C NMR (100.6 MHz, ref =
CDCl3): δ 43.7, 55.4, 111.9 (t, J = 316.1 Hz), 114.4 (2×), 128.3, 129.4
(2×), 159.6, 160.0 (t, J = 27.5 Hz). 19F NMR (376.5 MHz, CDCl3, ref
N-{2-[(tert-Butyldimethylsilyl)oxy]phenyl}-2-bromo-2,2-di-
fluoroethylamine 21a. Yellow oil. Rf 0.14 (petroleum ether/EtOAc
99/1). Yield: 90% (3.10 g). 1H NMR (300 MHz, CDCl3): δ 0.25 (6H,
s), 1.02 (9H, s), 3.95 (2H, td, JH,F = 11.8 Hz, J = 3.4 Hz), 4.65 (1H, br
s), 6.65 (1H, ddd, J = 7.8 Hz, 7.4 Hz, 1.5 Hz), 6.70 (1H, d, J = 7.9 Hz),
6.77 (1H, dd, J = 7.8 Hz, 1.4 Hz), 6.87 (1H, ddd, J = 7.9 Hz, 7.4 Hz,
1.4 Hz). 13C NMR (75 MHz, ref = CDCl3): δ −4.2 (2×), 18.3, 25.9,
54.3 (t, J = 25.4 Hz), 110.9, 118.0, 118.3, 122.0, 122.6 (t, J = 309.2
Hz), 138.0, 142.7. 19F NMR (282 MHz, CDCl3, ref = CFCl3): δ
−53.30 (t, JH,F = 11.8 Hz). IR (ATR, cm−1): νNH = 3446, νmax = 1514,
1254, 916, 781. MS (ES+): m/z (%): 366/68 (M + H+, 100). HRMS
(ES+): calcd for C14H23BrF2NOSi+: 366.0695, found 366.0702.
N-{4-Methoxy-2-[(tert-butyldimethylsilyl)oxy]phenyl}-2-
bromo-2,2-difluoroethylamine 21b. Yellow oil. Rf 0.57 (petro-
= CFCl3): δ −60.99 (2F, s). IR (ATR, cm−1): νNH = 3233, νCO
=
1695, νmax = 1514, 1169, 1125, 820. MS (ES+): m/z (%): 311/13 (M +
+
−
NH4 , 20), 221 (100). HRMS (ES−): calcd for C10H9BrF2NO2 :
291.9790, found 291.9790.
N-(2-Hydroxy-4-methoxyphenyl)-2-bromo-2,2-difluoroace-
tamide 19b. Brown crystals. Melting point: 159−160 °C. Yield: 40%
1
(0.067 g). H NMR (400 MHz, CD3CN): δ 3.79 (3H, s), 6.53 (1H,
dd, J = 8.6 Hz, 2.6 Hz), 6.56 (1H, d, J = 2.6 Hz), 7.52 (1H, d, J = 8.6
Hz), 7.60 (1H, br s), 8.62 (1H, br s). 13C NMR (100.6 MHz,
CD3COCD3): δ 55.6, 102.8, 105.6, 112.9 (t, J = 315.5 Hz), 117.6,
124.9, 150.9, 158.5 (t, J = 27.1 Hz), 159.7. 19F NMR (376.5 MHz,
CDCl3, ref = CFCl3): δ −60.53 (2F, s). IR (ATR, cm−1): νNH = 3386,
νOH = 3244, νCO = 1685, νmax = 1547, 1151, 1110. MS (ES+): m/z
1
leum ether/EtOAc 9/1). Yield: 95% (0.25 g). H NMR (400 MHz,
CDCl3): δ 0.26 (6H, s), 1.02 (9H, s), 3.73 (3H, s), 3.89 (2H, td, JH,F
=
12.1 Hz, J = 7.2 Hz), 4.33 (1H, t, J = 7.2 Hz), 6.42 (1H, d, J = 2.8 Hz),
6.44 (1H, dd, J = 8.4 Hz, 2.8 Hz), 6.62 (1H, d, J = 8.4 Hz). 13C NMR
(100.6 MHz, CDCl3): δ −4.3 (2×), 18.2, 25.8, 55.1 (t, J = 24.9 Hz),
55.6, 105.5, 106.2, 111.5, 122.6 (t, J = 309.2 Hz), 132.1, 143.6, 152.5.
+
(%): 296/98 (M + H+, 30), 313/15 (M + NH4 , 20). HRMS (ES−):
−
calcd for C9H7BrF2NO3 : 293.9583, found 293.9572. Anal. Calcd for
C9H8BrF2NO3: C 36.51, H 2.72, N 4.73. Found: C 36.86, H 2.68, N
19F NMR (376.5 MHz, CDCl3, ref = CFCl3): δ −53.13 (2F, t, JH,F
=
4.57.
12.1 Hz). IR (ATR, cm−1): νNH = 3442, νmax = 1518, 1163, 837, 780.
MS (ES+): m/z (%): 396/98 (M + H+, 100). HRMS (ES+): calcd for
C15H25BrF2NO2Si+: 396.0801, found 396.0813.
The spectral data of N-benzyl-2-bromo-2,2-difluoroacetamide 27b
and N-(2-hydroxyphenyl)-2-bromo-2,2-difluoroacetamide 19a were in
accordance with those reported in the literature.32
Synthesis of N-Propyl-2-bromo-2,2-difluoroethylamine 6a.
N-Propyl-2-bromo-2,2-difluoroethylamine 6a was synthesized follow-
ing a literature procedure.22
Synthesis of N-2-Bromo-2,2-difluoroethyl-N-propylbenza-
mide 7. To a mixture of N-propyl-2-bromo-2,2-difluoroethylamine
6a (0.33 g, 1.7 mmol) and Et3N (0.84 g, 8.3 mmol, 5 equiv) in
anhydrous CH2Cl2 (20 mL) was added a solution of benzoyl chloride
(0.23 g, 1.7 mmol, 1 equiv) in anhydrous CH2Cl2 (5 mL) slowly at 0
°C. After being stirred at room temperature for 20 h, the reaction
mixture was washed with an aqueous solution of HCl (5%, 10 mL)
and NaHCO3 (aq satd). After drying (MgSO4) and filtration, the
solvent was evaporated in vacuo. Column chromatography (SiO2, PE/
EtOAc 8/2) afforded pure benzamide 7 in 90% yield (0.41 g).
N-2-Bromo-2,2-difluoroethyl-N-propylbenzamide 7. Yellow
N-Propyl-2-bromo-2,2-difluoroethylamine 6a. Colorless oil.
1
Yield: 89% (5.33 g). H NMR (400 MHz, CDCl3): δ 0.93 (3H, t, J =
7.3 Hz), 1.47 (1H, br s), 1.50 (2H, sextet, J = 7.3 Hz), 2.72 (2H, t, J =
7.3 Hz), 3.36 (2H, t, JH,F = 12.6 Hz). 13C NMR (100.6 MHz, CDCl3):
δ 11.5, 23.4, 51.2, 59.4 (t, J = 23.3 Hz), 123.9 (t, J = 309.1 Hz). 19F
NMR (376.5 MHz, CDCl3): δ −51.15 (2F, t, JH,F = 12.6 Hz). IR
(ATR, cm−1): νNH = 3216, νmax = 1462, 1195, 1094, 904. MS (ES+):
m/z (%): 202/04 (M + H+, 100). HRMS (ES+): calcd for
C5H11BrF2N+: 202.0037, found 202.0033.
1
oil. Rf 0.34 (petroleum ether/EtOAc 8/2). Yield: 90% (0.41 g). H
Synthesis of Amines 6b, 6c, 21a, and 21b. Amines 6b, 6c, 21a,
and 21b were synthesized via a slightly modified literature
NMR (400 MHz, CDCl3, 50 °C): δ 0.79 (3H, t, J = 7.2 Hz), 1.52−
1.58 (2H, m), 3.45 (2H, t, J = 6.8 Hz), 4.33 (2H, t, JH,F = 11.2 Hz),
G
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The Journal of Organic Chemistry
Article
7.39−7.46 (5H, m). 13C NMR (100.6 MHz, ref = CDCl3): δ 10.8,
21.1, 51.3, 52.1, 121.2 (t, J = 308.8 Hz), 126.8 (2×), 128.6 (2×), 129.9,
135.6, 172.8. 19F NMR (376.5 MHz, CDCl3): δ −50.02 (2F, br s). IR
(ATR, cm−1): νCO = 1647, νmax = 1407, 1089, 1021, 935, 699. MS
(ES+): m/z (%): 306/08 (M + H+, 100). HRMS (ES+): calcd for
C12H15BrF2NO+: 306.0300, found 306.0295.
Synthesis of N-Propyl-N-tosyl-2-bromo-2,2-difluoroethyl-
amine 9. To a mixture of N-propyl-2-bromo-2,2-difluoroethylamine
6a (5.00 g, 25 mmol), Et3N (4.00 g, 21 mmol, 0.8 equiv), and DMAP
(0.26 g, 2.1 mmol, 0.08 equiv) in anhydrous CH2Cl2 (100 mL) was
added a solution of p-toluenesulfonyl chloride (2.12 g, 21 mmol, 0.8
equiv) in anhydrous CH2Cl2 (25 mL) at 0 °C. The reaction mixture
was stirred at reflux temperature for 47 h, poured in 1 N HCl (50 mL),
and extracted with CH2Cl2 (3 × 50 mL). After drying of the organic
phase (MgSO4), filtration of the drying agent, and evaporation of the
solvent in vacuo, N-propyl-N-tosyl-2-bromo-2,2-difluoroethylamine 16
was obtained in 78% yield (5.81 g).
removed in vacuo. After column chromatography (SiO2, PE/EtOAc
24/1), enamide 11a was isolated in 69% yield (0.20 g).
(Z)-N-[2-Fluoro-2-(phenylthio)vinyl]-N-propyl-4-methylben-
zenesulfonamide 11a. White crystals. Melting point: 85−86 °C. Rf
1
0.13 (petroleum ether/EtOAc 24/1). Yield: 69% (0.20 g). H NMR
(400 MHz, CDCl3): δ 0.96 (3H, t, J = 7.4 Hz), 1.58 (2H, sextet, J =
7.3 Hz), 2.43 (3H, s), 3.19 (2H, t, J = 7.2 Hz), 5.89 (1H, d, JH,F = 5.5
Hz), 7.30−7.33 (5H, m), 7.38−7.40 (2H, m), 7.69 (2H, d, J = 8.3 Hz).
13C NMR (100.6 MHz): δ 11.2, 21.6 (2×), 52.0, 115.1 (d, J = 52.2
Hz), 127.5 (2×), 128.2, 129.2 (2×), 129.77 (2×), 129.85, 131.5 (2×),
134.8, 143.9, 158.9 (d, J = 297.3 Hz). 19F NMR (282 MHz, CDCl3): δ
−98.83 (1F, d, JH,F = 5.5 Hz). IR (ATR, cm−1): νmax = 1344, 1161,
1145, 672. MS (ES+): m/z (%): 366 (M + H+, 100). Anal. Calcd for
C18H20FNO2S2: C 59.15, H 5.52, N 3.83. Found: C 59.35, H 5.72, N
+
3.73. HRMS (ES+): calcd for C18H21FNO2S2 : 366.0992, found
366.0989.
Enamides 11b (major) and 12b (minor) Were Obtained as
an Inseparable Mixture (ratio 11b:12b = 4:1). (E)-N-(2-Fluoro-
2-phenoxyvinyl)-N-propyl-4-methylbenzenesulfonamide 11b
and (Z)-N-(2-Fluoro-2-phenoxyvinyl)-N-propyl-4-methylbenze-
nesulfonamide 12b. Yellow oil. Rf 0.13 (petroleum ether/EtOAc
N-Propyl-N-tosyl-2-bromo-2,2-difluoroethylamine 9. White
crystals. Melting point: 56−57 °C. Yield: 78% (5.81 g). 1H NMR (400
MHz, CDCl3): δ 0.82 (3H, t, J = 7.4 Hz), 1.58 (2H, sextet, J = 7.6 Hz),
2.43 (3H, s), 3.18−3.22 (2H, m), 4.10 (2H, t, JH,F = 13.3 Hz), 7.31
(2H, d, J = 8.1 Hz), 7.71 (2H, d, J = 8.1 Hz). 13C NMR (100.6 MHz,
CDCl3): δ 10.9, 20.8, 21.5, 50.9, 56.0 (t, J = 24.2 Hz), 120.6 (t, J =
309.5 Hz), 127.3 (2×), 129.8 (2×), 136.6, 143.9. 19F NMR (376.5
MHz, CDCl3): δ −51.47 (2F, t, JH,F = 13.3 Hz). IR (ATR, cm−1): νm+ax
= 1345, 1154, 942, 732. MS (ES+): m/z (%): 373/75 (M + NH4 ,
1
95/5). Yield: 32% (0.13 g). H NMR (400 MHz, CDCl3): δ 0.87
(2.4H, t, J = 7.4 Hz (major)), 0.94 (0.6H, t, J = 7.4 Hz (minor)), 1.56
(2H, sextet, J = 7.3 Hz), 2.36 (2.4H, s (major)), 2.39 (0.6H, s
(minor)), 3.15 (0.4H, t, J = 7.1 Hz (minor)), 3.21 (1.6H, t, J = 7.0 Hz
(major)), 4.88 (0.2H, d, JH,F = 19.3 Hz (minor)), 5.33 (0.8H, d, JH,F
=
+
H+, 80). HRMS (ES+): calcd for
1.0 Hz (major)), 6.91−6.93 (1.6H, m (major)), 7.07−7.37 (4H, m
(major)), 7.07−7.37 (1.4H, m (minor)), 7.64−7.67 (1.6H, m
(major)), 7.69 (0.4H, d, J = 8.4 Hz (minor)). 13C NMR (100.6
MHz, ref = CDCl3): δ 11.0, 21.48 (major), 21.50 (minor), 21.53
(major), 21.6 (minor), 51.5, 91.9 (d, J = 20.7 Hz (minor)), 92.8 (d, J =
60.3 Hz (major)), 116.8 (2× (minor)), 116.9 (2× (major)), 124.5
(major), 124.8 (minor), 127.4 (2× (major) and 2× (minor)), 129.60
(2× (major)), 129.62 (2× (major)), 129.7 (2× (minor)), 130.0 (2×
(minor)), 135.1 (minor), 135.4 (major), 143.6 (major), 143.7
(minor), 153.5 (d, J = 1.2 Hz (major)), 154.6 (d, J = 1.5 Hz
(minor)), 156.5 (d, J = 283.9 Hz (major)), 157.5 (d, J = 290.0 Hz
(minor)). 19F NMR (376.5 MHz, CDCl3, ref = CFCl3): δ −84.57
(0.2F, d, JH,F = 19.3 Hz (minor)), −95.80 (0.8F, s (major)). IR (ATR,
cm−1): νmax = 1341, 1190, 1163, 748, 658. MS (ES+): m/z (%): 350
(M + H+, 100). HRMS (ES+): calcd for C18H21FNO3S+: 350.1221,
found 350.1224.
100), 356/58 (M
C12H17BrF2NO2S+: 356.0126, found 356.0125.
Synthesis of β,β-Difluoroenamides 8 and 10. The synthesis of
benzamide 8 is given as a representative example. To a solution of N-
2-bromo-2,2-difluoroethyl-N-propylbenzamide 7 (1.29 g, 4.2 mmol) in
anhydrous THF (40 mL) was added a solution of LiHMDS in THF (1
M, 4.4 mL, 1.05 equiv) at 0 °C. The reaction mixture was stirred at
room temperature for 3 h, after which it was quenched with NaHCO3
(aq satd) and extracted with EtOAc (3 × 50 mL). After drying of the
combined organic phases (MgSO4), filtration, and evaporation of the
solvent, crude benzamide 8 was obtained, which was purified via
column chromatography (SiO2, PE/EtOAc 9/1), affording pure amide
8 in 85% yield (0.80 g).
N-(2,2-Difluorovinyl)-N-propylbenzamide 8. Yellow oil. Rf 0.23
1
(petroleum ether/EtOAc 9/1). Yield: 85% (0.80 g). H NMR (400
MHz, CDCl3): δ 0.94 (3H, br s), 1.62−1.68 (2H, m), 3.57 (2H, br s),
5.42 (1H, br s), 7.36−7.46 (5H, m). 13C NMR (100.6 MHz, ref =
CDCl3): δ 11.2, 20.9, 49.4, 89.0−89.5 (m), 127.5 (2×), 128.3 (2×),
130.3, 135.7, 155.5 (t, J = 289.9 Hz), 171.1. 19F NMR (376.5 MHz,
CDCl3): δ −87.75 (1F, dd, J = 40.2 Hz, JH,F = 18.2 Hz), −100.56 (1F,
d, J = 37.6 Hz). IR (ATR, cm−1): νCO = 1647, νmax = 1407, 1089,
1021, 935, 699. MS (ES+): m/z (%): 226 (M + H+, 100). HRMS
(ES+): calcd for C12H14F2NO+: 226.1038, found 226.1038.
N-(2,2-Difluoro-2-phenoxyethyl)-N-propyl-4-methylbenze-
nesulfonamide 13b. White crystals. Melting point: 77−78 °C. Rf
1
0.08 (petroleum ether/EtOAc 95/5). Yield: 10% (0.051 g). H NMR
(400 MHz, CDCl3): δ 0.86 (3H, t, J = 7.4 Hz), 1.67 (2H, sextet, J =
7.5 Hz), 2.41 (3H, s), 3.27−3.31 (2H, m), 3.96 (2H, t, JH,F = 9.3 Hz),
7.03−7.06 (2H, m), 7.18−7.22 (1H, m), 7.27−7.33 (4H, m), 7.76
(2H, d, J = 8.3 Hz). 13C NMR (100.6 MHz): δ 11.0, 20.9, 21.5, 49.5 (t,
J = 34.5 Hz), 50.4, 121.7 (2×), 122.2 (t, J = 270.2 Hz), 125.8, 127.4
(2×), 129.4 (2×), 129.6 (2×), 137.3, 143.4, 149.7. 19F NMR (376.5
MHz, CDCl3, ref = CFCl3): δ −73.49 (2F, t, JH,F = 9.3 Hz). IR (ATR,
cm−1): νmax = 1336, 1264, 1146, 994. MS (ES+): m/z (%): 370 (M +
N-(2,2-Difluorovinyl)-N-tosylpropylamine 10. Yellow crystals.
Melting point: 51−52 °C. Rf 0.30 (petroleum ether/EtOAc 10/1).
1
Yield: 82% (4.27 g). H NMR (300 MHz, CDCl3): δ 0.92 (3H, t, J =
7.2 Hz), 1.54 (2H, sextet, J = 7.2 Hz), 2.44 (3H, s), 3.10 (2H, t, J = 7.2
Hz), 4.87 (1H, dd, JH,F = 18.3 Hz, 2.8 Hz), 7.33 (2H, d, J = 8.3 Hz),
7.68 (2H, d, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3) δ 10.9, 21.4,
21.6, 51.6, 84.9 (dd, J = 49.6 Hz, 13.9 Hz), 127.4 (2×), 129.8 (2×),
134.8, 143.9, 159.5 (dd, J = 300.0 Hz, 289.6 Hz). 19F NMR (282 MHz,
CDCl3): δ −83.20 (1F, dd, J = 28.3 Hz, JH,F = 18.3 Hz), −93.38 (1F,
d, J = 28.3 Hz). IR (ATR, cm−1): νmax = 1749, 1341, 1240, 1164. MS
+
H+, 100), 387 (M + NH4 , 12). HRMS (ES+): calcd for
C18H22F2NO3S+: 370.1283, found 370.1279. Anal. Calcd for
C18H21F2NO3S: C 58.52, H 5.73, N 3.79. Found: C 58.53, H 5.32,
N 3.66.
Phenyl N-Propyl-N-tosylglycinate 14b. White crystals. Melting
point: 88−89 °C. Rf 0.03 (petroleum ether/EtOAc 95/5). Yield: 85%
(0.29 g). 1H NMR (400 MHz, CDCl3): δ 0.89 (3H, t, J = 7.4 Hz), 1.61
(2H, sextet, J = 7.4 Hz), 2.38 (3H, s), 3.24−3.28 (2H, m), 4.27 (2H,
s), 6.98−7.01 (2H, m), 7.18−7.22 (1H, m), 7.27 (2H, d, J = 8.1 Hz),
7.31−7.36 (2H, m), 7.77 (2H, d, J = 8.3 Hz). 13C NMR (100.6 MHz):
δ 11.1, 21.3, 21.5, 48.1, 50.2, 121.2 (2×), 126.1, 127.4 (2×), 129.4
+
(ES+): m/z (%): 276 (M + H+, 100), 293 (M + NH4 , 33). HRMS
(ES+): calcd for C12H16F2NO2S+: 276.0864, found 276.0863.
Synthesis of Enamides 11a, 11b, and 12b, amine 13b, and
glycinate 14b. The synthesis of enamide 11a is described as a
representative example. To a solution of N-(2,2-difluorovinyl)-N-
tosylpropylamine 10 (0.21 g, 0.78 mmol) in acetonitrile (5 mL) were
added thiophenol (0.103 g, 0.93 mmol, 1.2 equiv) and KOH (0.052 g,
0.93 mmol, 1.2 equiv). After the reaction mixture was stirred for 20 h
at reflux, an aqueous solution of HCl (1 N, 10 mL) was added and an
extraction with EtOAc (3 × 10 mL) was performed. The combined
organic layers were dried (MgSO4) and filtered, and the solvent was
(2×), 129.6 (2×), 136.6, 143.5, 150.2, 167.7. IR (ATR, cm−1): νCO
=
1769, νmax = 1334, 1148, 656. MS (ES+): m/z (%): 348 (M + H+,
+
100), 365 (M + NH4 , 58). HRMS (ES+): calcd for C18H22NO4S+:
348.1264, found 348.1273.
Synthesis of Enamides 11c and 12c. To a solution of enamide
10 (0.15 g, 0.55 mmol) in anhydrous THF (10 mL) was added a
H
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Article
solution of NaOMe in MeOH (1 M, 0.55 mL, 1 equiv). This mixture
was stirred for 3 h at room temperature. Subsequently, an aqueous
solution of NH4Cl (10 mL) was added, followed by an extraction with
EtOAc (3 × 10 mL). After drying of the combined organic phases
(MgSO4), filtration, and evaporation of the solvent under reduced
pressure, a mixture of two isomers 11c and 12c was obtained. After
column chromatography (SiO2, PE/EtOAc 9/1), enamides 11c and
12c were isolated in 57% (0.090 g) and 15% (0.024 g) yield,
respectively.
(E)-N-(2-Fluoro-2-methoxyvinyl)-N-propyl-4-methylbenze-
nesulfonamide 11c. Yellow oil. Rf 0.31 (petroleum ether/EtOAc 9/
1). Yield: 57% (0.090 g). 1H NMR (400 MHz, CDCl3): δ 0.91 (3H, t,
J = 7.4 Hz), 1.53 (2H, sextet, J = 7.3 Hz), 2.42 (3H, s), 3.10 (2H, td, J
= 7.2 Hz, 0.8 Hz), 3.71 (3H, d, J = 1.0 Hz), 4.63 (1H, d, JH,F = 0.7 Hz),
7.30 (2H, d, J = 8.1 Hz), 7.68 (2H, d, J = 8.1 Hz). 13C NMR (100.6
MHz, ref = CDCl3) δ 10.9, 21.3, 21.4, 51.9 (d, J = 1.2 Hz), 57.4 (d, J =
6.0 Hz), 86.5 (d, J = 64.1 Hz), 127.4 (2×), 129.4 (2×), 135.1, 143.4,
161.7 (d, J = 280.1 Hz). 19F NMR (282 MHz, CDCl3): δ −97.22 (1F,
s). IR (ATR, cm−1): νmax = 1721, 1339, 1161, 732. MS (ES+): m/z
(%): 288 (M + H+, 25). HRMS (ES+): calcd for C13H19FNO3S+:
288.1064, found 288.1068.
(0.2H, d, JH,F = 19.7 Hz (minor)), 5.76 (0.8H, br s (major)), 6.81−
6.91 (3H, m), 7.13−7.56 (7H, m). 13C NMR (100.6 MHz, ref =
CDCl3): δ 11.2, 20.8, 49.4, 96.8 (minor), 97.4 (d, J = 57.0 Hz
(major)), 115.4, 116.4, 120.0, 124.4, 127.6, 127.9, 128.1, 128.3, 129.4,
129.8, 129.9, 130.2, 130.3, 135.8, 152.8 (d, J = 281.0 Hz (minor)),
154.7 (d, J = 323.4 Hz (major)), 171.3. 19F NMR (282 MHz, CDCl3):
δ −87.11 (1F, d, JH,F = 20.0 Hz (minor)), −100.96 (1F, s (major)). IR
(ATR, cm−1): νmax = 1627, 1191, 1164, 751, 691. MS (ES+): m/z (%):
+
300 (M + H+, 100). HRMS (ES+): calcd for C18H19FNO2 : 300.1394,
found 300.1408.
Synthesis of Silyl Ethers 20a and 20b. The synthesis of silyl
ether 20a is given as representative example. To a mixture of amide
19a (2.00 g, 7.5 mmol) and imidazole (1.02 g, 15.0 mmol, 2 equiv) in
anhydrous CH2Cl2 (40 mL) under N2 atmosphere was added
TBDMSCl (1.19 g, 7.9 mmol, 1.05 equiv) at room temperature.
This mixture was stirred for 17 h at room temperature. Subsequently,
H2O (40 mL) was added and an extraction was performed with
CH2Cl2 (3 × 30 mL). After drying of the combined organic phases
(MgSO4), filtration, and evaporation of the solvent under reduced
pressure, acetamide 20a was obtained as orange crystals in 95% yield
(2.71 g).
(Z)-N-(2-Fluoro-2-methoxyvinyl)-N-propyl-4-methylbenze-
nesulfonamide 12c. Yellow oil. Rf 0.12 (petroleum ether/EtOAc 9/
1). Yield: 15% (0.024 g). 1H NMR (400 MHz, CDCl3): δ 0.92 (3H, t,
J = 7.4 Hz), 1.54 (2H, sextet, J = 7.4 Hz), 2.42 (3H, s), 3.14 (2H, t, J =
7.2 Hz), 3.69 (3H, s), 4.39 (1H, d, JH,F = 21.6 Hz), 7.29 (2H, d, J = 8.3
Hz), 7.69 (2H, d, J = 8.3 Hz). 13C NMR (100.6 MHz, ref = CDCl3): δ
11.0, 21.4, 21.5, 52.1 (d, J = 1.8 Hz), 57.0 (d, J = 3.6 Hz), 81.6 (d, J =
20.4 Hz), 127.4 (2×), 129.5 (2×), 135.4, 143.4, 162.5 (d, J = 268.9
Hz). 19F NMR (282 MHz, CDCl3): δ −85.13 (1F, d, JH,F = 21.6 Hz).
IR (ATR, cm−1): νmax = 1348, 1166, 998, 665. MS (ES+): m/z (%):
288 (M + H+, 25). HRMS (ES+): calcd for C13H19FNO3S+: 288.1064,
found 288.1059.
Synthesis of Enamide 11d. To a solution of enamide 10 (0.36 g,
1.3 mmol) in anhydrous THF (20 mL) was added a solution of
KOtBu in THF (1 M, 1.44 mL, 1.1 equiv) at 0 °C. After this reaction
mixture was stirred for 2 h at room temperature, a saturated solution of
NH4Cl in H2O (20 mL) was added. Upon subsequent extraction with
EtOAc (3 × 20 mL), drying of the organic layers (MgSO4), filtration,
and evaporation of the solvent in vacuo, a mixture of enamides 11d
and 12d was obtained (11d:12d = 8:2), from which enamide 11d
could be isolated in 46% yield (0.20 g) via column chromatography
(SiO2, PE/EtOAc 97/3).
N-{2-[(tert-Butyldimethylsilyl)oxy]phenyl}-2-bromo-2,2-di-
fluoroacetamide 20a. Orange crystals. Melting point: 56−57 °C.
1
Yield: 95% (2.71 g). H NMR (300 MHz, CDCl3): δ 0.30 (6H, s),
1.03 (9H, s), 6.88 (1H, dd, J = 7.7 Hz, 1.7 Hz), 7.01 (1H, ddd, J = 7.7
Hz, 7.7 Hz, 1.7 Hz), 7.71 (1H, ddd, J = 7.7 Hz, 7.7 Hz, 2.2 Hz), 8.30
(1H, dd, J = 7.7 Hz, 2.2 Hz), 8.55 (1H, br s). 13C NMR (75 MHz,
CDCl3): δ −4.4 (2×), 18.1, 25.6, 111.6 (t, J = 316.1 Hz), 117.5, 120.2,
121.9, 125.7, 127.3, 144.7, 156.8 (t, J = 27.7 Hz). 19F NMR (282 MHz,
CDCl3, ref = CFCl3): δ −60.87 (2F, s). IR (ATR, cm−1): νNH = 3398,
νCO = 1717, νmax = 1458, 1100, 783, 752. MS (ES+): m/z (%): 380/
82 (M + H+, 100). HRMS (ES+): calcd for C14H21BrF2NO2Si+:
380.0488, found 380.0478.
N-{4-Methoxy-2-[(tert-butyldimethylsilyl)oxy]phenyl}-2-
bromo-2,2-difluoroacetamide 20b. Brown crystals. Melting point:
69−70 °C. Rf 0.36 (petroleum ether/EtOAc 9/1). Yield: 74% (0.033
1
g). H NMR (400 MHz, CDCl3): δ 0.30 (6H, s), 1.03 (9H, s), 3.79
(3H, s), 6.45 (1H, d, J = 2.7 Hz), 6.55 (1H, dd, J = 9.0 Hz, 2.7 Hz),
8.30 (1H, d, J = 9.0 Hz), 8.36 (1H, br s). 13C NMR (100.6 MHz,
CDCl3): δ −4.4 (2×), 18.1, 25.6, 55.5, 105.1, 105.5, 111.7 (t, J = 316.8
Hz), 120.8, 120.9, 145.9, 156.5 (t, J = 27.2 Hz), 157.4. 19F NMR
(376.5 MHz, CDCl3, ref = CFCl3): δ −60.61 (2F, s). IR (ATR, cm−1):
νNH = 3404, νCO = 1717, νmax = 1530, 1109, 834. MS (ES+): m/z
(%): 410/12 (M + H+, 100). Anal. Calcd for C15H22BrF2NO3Si: C
43.91, H 5.40, N 3.41. Found: C 44.02, H 5.74, N 3.35.
Synthesis of Benzamides 23a−d. The synthesis of N-(2-bromo-
2,2-difluoroethyl)-N-{2-[(tert-butyldimethylsilyl)oxy]phenyl}-
benzamide 23a is given as a representative example. To a mixture of
amine 21a (0.27 g, 0.74 mmol) and benzoyl chloride (0.10 g, 0.74
mmol, 1 equiv) in anhydrous CH2Cl2 (20 mL) was added
triethylamine (0.37 g, 3.7 mmol, 5 equiv) slowly. Subsequently, this
reaction mixture was stirred at reflux temperature for 5 h. After the
addition of an aqueous solution of HCl (1 M, 20 mL) and extraction
with CH2Cl2 (3 × 15 mL), the combined organic phases were dried
(MgSO4) and filtered and the solvent was removed under reduced
pressure. Purification of the crude mixture via column chromatography
(SiO2, PE/EtOAc 9/1) afforded pure benzamide 23a in 98% yield
(0.34 g).
(E)-N-(2-Fluoro-2-(tert-butoxy)vinyl)-N-propyl-4-methylben-
zenesulfonamide 11d. White crystals. Melting point: 91−92 °C. Rf
1
0.24 (petroleum ether/EtOAc 97/3). Yield: 46% (0.20 g). H NMR
(400 MHz, CDCl3): δ 0.89 (3H, t, J = 7.4 Hz), 1.34 (9H, d, J = 0.8
Hz), 1.52 (2H, sextet, J = 7.3 Hz), 2.42 (3H, s), 3.14 (2H, td, J = 7.2
Hz, 0.8 Hz), 4.88 (1H, d, JH,F = 1.2 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.69
(2H, d, J = 8.1 Hz). 13C NMR (100.6 MHz): δ 11.2, 21.3, 21.5, 28.6,
51.8, 84.7, 90.2 (d, J = 69.9 Hz), 127.5 (2×), 129.5 (2×), 135.8, 143.3,
159.3 (d, J = 284.9 Hz). 19F NMR (282 MHz, CDCl3): δ −85.62 (1F,
s). IR (ATR, cm−1): νmax = 1343, 1165, 1151, 1137, 660. MS (ES+):
m/z (%): 352 (M + Na+, 10). HRMS (ES+): calcd for C16H25FNO3S+:
330.1534, found 330.1542.
Synthesis of Enamides 15 and 16. To a solution of enamide 8
(0.045 g, 0.20 mmol) in acetonitrile (5 mL) were added phenol (0.023
g, 0.24 mmol, 1.2 equiv) and KOH (0.013 g, 0.24 mmol, 1.2 equiv).
After this reaction mixture was stirred for 4 h at reflux, a saturated
solution of NH4Cl in H2O (5 mL) was added. Upon subsequent
extraction with EtOAc (3 × 10 mL), drying of the organic layers
(MgSO4), filtration, and evaporation of the solvent in vacuo, enamides
15 and 16 were isolated as a mixture (ratio 15:16 = 4:1) in 80% yield
(0.048 g) after preparative TLC (SiO2, PE/EtOAc 9/1).
N - ( 2 - B r o m o - 2 , 2 - d i fl u o r o e t h y l ) - N - { 2 - [ ( t e r t -
butyldimethylsilyl)oxy]phenyl}benzamide 23a. White crystals.
Melting point: 89−90 °C. Rf 0.23 (petroleum ether/EtOAc 9/1).
1
Yield: 98% (0.34 g). H NMR (400 MHz, CDCl3): δ 0.26 (3H, s),
0.32 (3H, s), 1.02 (9H, s), 4.00 (1H, ddd, JH,F = 18.5 Hz, J = 14.9 Hz,
JH,F = 4.2 Hz), 5.44 (1H, ddd, JH,F = 18.9 Hz, J = 14.9 Hz, JH,F = 10.3
Hz), 6.74−6.77 (2H, m), 7.06−7.15 (4H, m), 7.21−7.22 (1H, m),
7.28−7.30 (2H, m). 13C NMR (100.6 MHz, CDCl3): δ −4.4, −3.9,
18.2, 25.7, 56.4 (dd, J = 25.0 Hz, 22.4 Hz), 118.6, 120.7 (dd, J = 311.4
Hz, 308.4 Hz), 121.0, 127.5 (2×), 128.0 (2×), 129.3, 129.9, 131.7,
132.9, 134.9, 150.7, 171.3. 19F NMR (376.5 MHz, CDCl3, ref =
CFCl3): δ −49.08 (1F, ddd, J = 154.5 Hz, JH,F = 18.9 Hz, 4.2 Hz),
Enamides 15 (major) and 16 (minor) Were Obtained as an
Inseparable Mixture (ratio 15:16 = 4:1). (E)-N-(2-Fluoro-2-
phenoxyvinyl)-N-propylbenzamide 15 and (Z)-N-(2-Fluoro-2-
phenoxyvinyl)-N-propylbenzamide 16. Yellow oil. Rf 0.18
1
(petroleum ether/EtOAc 9/1). Yield: 80% (0.048 g). H NMR (400
MHz, CDCl3): δ 0.94 (3H, br s), 1.70 (2H, br s), 3.63 (2H, br s), 5.43
I
DOI: 10.1021/acs.joc.5b00507
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
−50.75 (1F, ddd, J = 154.5 Hz, JH,F = 18.5 Hz, 10.3 Hz). IR (ATR,
cm−1): νCO = 1658, νmax = 1285, 909, 783. MS (ES+): m/z (%): 470/
72 (M + H+, 100). HRMS (ES+): calcd for C21H27BrF2NO2Si+:
470.0957, found 470.0957. Anal. Calcd for C21H26BrF2NO2Si: C
53.62, H 5.57, N 2.98. Found: C 53.53, H 5.90, N 2.91.
(2×), 129.2, 130.0, 130.2, 132.0, 134.7, 151.2, 154.6 (dd, J = 297.3 Hz,
280.2 Hz), 169.9. 19F NMR (376.5 MHz, CDCl3, ref = CFCl3): δ
−89.07 (1F, dd, J = 52.2 Hz, JH,F = 18.2 Hz), −103.03 (1F, d, J = 52.2
Hz). IR (ATR, cm−1): νCO = 1663, νmax = 1327, 1284, 913, 781, 714,
695. MS (ES+): m/z (%): 390 (M + H+, 100). HRMS (ES+): calcd for
C21H26F2NO2Si+: 390.1695, found 390.1693.
Synthesis of Ynamides 25. The synthesis of N-{2-[(tert-
butyldimethylsilyl)oxy]phenyl}-N-(2-fluoroethynyl)benzamide 25a is
given as representative example. To a solution of benzamide 23a (0.30
g, 0.64 mmol) in anhydrous THF (30 mL) was added a solution of
LiHMDS in THF (1 M, 1.40 mL, 2.2 equiv) at 0 °C. The reaction
mixture was allowed to warm to room temperature and was stirred at
that temperature for 2.5 h. Subsequently, an aqueous solution of
NH4Cl (30 mL) was added and this mixture was extracted with EtOAc
(3 × 20 mL). Drying of the combined organic layers (MgSO4),
filtration, and evaporation of the solvent under reduced pressure
afforded ynamide 19a, which was purified via column chromatography
(SiO2, PE/EtOAc 95/5) (97% yield, 0.23 g).
N-{2-[(tert-Butyldimethylsilyl)oxy]phenyl}-N-(2-
fluoroethynyl)benzamide 25a. Pale yellow crystals. Melting point:
72−73 °C. Rf 0.21 (petroleum ether/EtOAc 95/5). Yield: 97% (0.23
g). 1H NMR (300 MHz, CDCl3): δ 0.18 (6H, s), 0.94 (9H, s), 6.68−
6.80 (1H, m), 6.83−6.92 (1H, m), 7.11−7.13 (2H, m), 7.24−7.41
(5H, m). 13C NMR (75 MHz, ref = CDCl3): δ −4.6 (2×), 18.4, 27.5,
98.5 (d, J = 55.4 Hz), 116.4, 124.5, 125.0, 126.6, 128.1 (2×), 128.4
(2×), 129.8, 130.3, 135.3, 150.8, 162.5 (d, J = 274.6 Hz), 169.5. 19F
NMR (282 MHz, CDCl3, ref = CFCl3): δ −89.78 (1F, s). IR (ATR,
cm−1): νCO = 1657, νmax = 1491, 1347, 1244. MS (ES+): m/z (%):
370 (M + H+, 100). HRMS (ES+): calcd for C21H25FNO2Si+:
370.1633, found 370.1643.
N-{2-[(tert-Butyldimethylsilyl)oxy]phenyl}-N-(2-fluoroethyn-
yl)-4-methoxybenzamide 25c. Yellow oil. Rf 0.63 (petroleum
ether/EtOAc 9/1). Yield: 94% (0.160 g). 1H NMR (400 MHz,
CDCl3): δ 0.14 (6H, s), 0.92 (9H, s), 3.77 (3H, s), 6.77 (2H, d, J = 8.5
Hz), 6.90−6.94 (2H, m), 7.09−7.12 (2H, m), 7.32 (2H, d, J = 8.5 Hz).
13C NMR (100.6 MHz, ref = CDCl3): δ −4.70, −4.67, 18.3, 27.3, 55.2,
N-(2-Bromo-2,2-difluoroethyl)-N-{[4-methoxy-2-(tert-
butyldimethylsilyl)oxy]phenyl}benzamide 23b. White crystals.
Melting point: 119−120 °C. Rf 0.13 (petroleum ether/EtOAc 9/1).
1
Yield: 52% (0.16 g). H NMR (400 MHz, CDCl3): δ 0.26 (3H, s),
0.31 (3H, s), 1.02 (9H, s), 3.70 (3H, s), 4.91 (1H, ddd, JH,F = 18.4 Hz,
J = 14.9 Hz, JH,F = 4.3 Hz), 5.43 (1H, ddd, JH,F = 18.7 Hz, J = 14.9 Hz,
JH,F = 10.5 Hz), 6.28−6.31 (2H, m), 6.99−7.01 (1H, m), 7.13−7.17
(2H, m), 7.21−7.24 (1H, m), 7.29−7.31 (2H, m). 13C NMR (100.6
MHz, CDCl3): δ −4.4, −3.9, 18.2, 25.7, 55.3, 56.6 (dd, J = 24.9 Hz,
22.4 Hz), 105.1, 105.3, 120.9 (dd, J = 311.3 Hz, 308.3 Hz), 126.2,
127.5 (2×), 127.9 (2×), 129.8, 132.0, 135.1, 151.6, 160.0, 171.6. 19F
NMR (376.5 MHz, CDCl3, ref = CFCl3): δ −49.12 (1F, ddd, J = 154.5
Hz, JH,F = 18.7 Hz, 4.3 Hz), −50.71 (1F, ddd, J = 154.5 Hz, JH,F = 18.4
Hz, 10.5 Hz). IR (ATR, cm−1): νCO = 1652, νmax = 1509, 1171, 833.
MS (ES+): m/z (%): 500/02 (M + H+, 100). HRMS (ES+): calcd for
C22H29BrF2NO3Si+: 500.1063, found 500.1067.
N - ( 2 - B r o m o - 2 , 2 - d i fl u o r o e t h y l ) - N - ( 2 - ( ( t e r t -
butyldimethylsilyl)oxy)phenyl)-4-methoxybenzamide 23c.
Colorless oil. Rf 0.29 (petroleum ether/EtOAc 95/5). Yield: 76%
1
(0.74 g). H NMR (400 MHz, CDCl3): δ 0.19 (3H, s), 0.27 (3H, s),
0.97 (9H, s), 3.60 (3H, s), 4.00 (1H, ddd, JH,F = 19.0 Hz, J = 15.0 Hz,
JH,F = 3.8 Hz), 5.40 (1H, ddd, JH,F = 19.3 Hz, J = 15.0 Hz, JH,F = 9.6
Hz), 6.58 (2H, d, J = 8.7 Hz), 6.72−6.76 (1H, m), 6.76 (1H, d, J = 8.2
Hz), 7.05 (1H, ddd, J = 8.2 Hz, 7.6 Hz, 1.6 Hz), 7.11 (1H, d, J = 7.6
Hz), 7.26 (2H, d, J = 8.7 Hz). 13C NMR (100.6 MHz, ref = CDCl3): δ
−4.6, −4.1, 18.0, 25.5, 54.9, 56.6 (dd, J = 23.7 Hz, 23.1 Hz), 112.6
(2×), 118.7, 120.8 (dd, J = 311.1 Hz, 308.9 Hz), 121.1, 126.6, 129.1,
130.3 (2×), 131.2, 133.3, 150.5, 160.8, 170.4. 19F NMR (376.5 MHz,
CDCl3, ref = CFCl3): δ −48.91 (1F, ddd, J = 153.2 Hz, JH,F = 19.3 Hz,
3.8 Hz), −50.74 (1F, ddd, J = 153.2 Hz, JH,F = 19.0 Hz, 9.6 Hz). IR
(ATR, cm−1): νCO = 1657, νmax = 1497, 1253, 909, 782. MS (ES+):
m/z (%): 500/02 (M + H+, 100). HRMS (ES+): calcd for
C22H29BrF2NO3Si+: 500.1063, found 500.1070.
N - ( 2 - B r o m o - 2 , 2 - d i fl u o r o e t h y l ) - N - { 2 - [ ( t e r t -
butyldimethylsilyl)oxy]phenyl}-4-bromobenzamide 23d. White
crystals. Melting point: 83−84 °C. Rf 0.57 (petroleum ether/EtOAc 9/
1). Yield: 75% (0.69 g). 1H NMR (400 MHz, CDCl3): δ 0.24 (3H, s),
0.31 (3H, s), 1.01 (9H, s), 4.00 (1H, ddd, JH,F = 18.7 Hz, J = 15.0 Hz,
JH,F = 4.2 Hz), 5.43 (1H, ddd, JH,F = 19.0 Hz, J = 15.0 Hz, JH,F = 10.1
Hz), 6.75−6.79 (2H, m), 7.07−7.14 (2H, m), 7.20 (2H, d, J = 8.5 Hz),
7.26 (2H, d, J = 8.5 Hz). 13C NMR (100.6 MHz, ref = CDCl3): δ
−4.4, −4.0, 18.0, 25.6, 56.5 (dd, J = 24.8 Hz, 22.6 Hz), 118.7, 120.5
(dd, J = 311.2 Hz, 308.4 Hz), 121.2, 124.4, 129.5, 129.7 (2×), 130.6
(2×), 131.3, 132.6, 133.6, 150.6, 171.1. 19F NMR (376.5 MHz, CDCl3,
ref = CFCl3): δ −49.27 (1F, ddd, J = 154.4 Hz, JH,F = 19.0 Hz, 4.2 Hz),
−50.85 (1F, ddd, J = 154.4 Hz, JH,F = 18.7 Hz, 10.1 Hz). IR (ATR,
cm−1): νCO = 1664, νmax = 1479, 1282, 1100, 908, 732. MS (ES+):
m/z (%): 548/50/52 (M + H+, 100). HRMS (ES+): calcd for
C21H26Br2F2NO2Si+: 548.0062, found 548.0063.
Synthesis of Enamide 24a. To a solution of benzamide 23a (0.11
g, 0.24 mmol) in anhydrous THF (10 mL) was added a solution of
LiOtBu in THF (1 M, 0.24 mL, 1 equiv). After this reaction mixture
was stirred at room temperature for 1.5 h, a saturated solution of
NH4Cl in H2O (10 mL) was added. After extraction with EtOAc (3 ×
10 mL), drying (MgSO4), filtration, and evaporation of the solvent in
vacuo, crude enamide 24a was obtained. Purification via preparative
TLC (SiO2, PE/EtOAc 95/5) afforded pure enamide 24a in 73% yield
(0.067 g).
N-{2-[(tert-Butyldimethylsilyl)oxy]phenyl}-N-(2,2-
difluorovinyl)benzamide 24a. Colorless oil. Rf 0.43 (petroleum
ether/EtOAc 9/1). Yield: 73% (0.067 g). 1H NMR (400 MHz, CDCl3,
50 °C): δ 0.23 (6H, s), 0.99 (9H, s), 6.22 (1H, br s), 6.75 (1H, d, J =
7.4 Hz), 6.83 (1H, t, J = 7.5 Hz), 7.08−7.18 (4H, m), 7.24−7.28 (1H,
m), 7.34−7.42 (2H, m). 13C NMR (100.6 MHz, CDCl3): δ −4.3
(2×), 18.2, 25.7, 89.3 (d, J = 53.8 Hz), 119.1, 121.2, 127.5 (2×), 128.3
98.7 (d, J = 54.3 Hz), 113.2 (2×), 116.2, 124.5, 125.0, 126.3, 127.4,
130.2, 130.6 (2×), 150.8, 161.1, 162.4 (d, J = 274.3 Hz), 168.7. 19F
NMR (376.5 MHz, CDCl3, ref = CFCl3): δ −89.92 (1F, s). IR (ATR,
cm−1): νCC = 2244, νCO = 1649, νmax = 1245, 732. MS (ES+): m/z
(%): 400 (M + H+, 100). HRMS (ES+): calcd for C22H27FNO3Si+:
400.1739, found 400.1748.
N-{2-[(tert-Butyldimethylsilyl)oxy]phenyl}-N-(2-fluoroethyn-
yl)-4-bromobenzamide 25d. Yellow crystals. Melting point: 87−88
1
°C. Rf 0.63 (petroleum ether/EtOAc 9/1). Yield: 83% (0.14 g). H
NMR (400 MHz, CDCl3): δ 0.18 (6H, s), 0.93 (9H, s), 6.73 (1H, br
s), 6.91 (1H, ddd, J = 8.0 Hz, 6.5 Hz, 2.1 Hz), 7.11−7.17 (4H, m),
7.41 (2H, d, J = 8.5 Hz). 13C NMR (100.6 MHz, ref = CDCl3): δ
−4.6, −4.5, 18.4, 27.4, 89.5 (d, J = 54.9 Hz), 116.6, 124.7, 124.8, 124.9,
126.8, 129.5, 130.1 (2×), 131.3 (2×), 134.1, 150.7, 162.5 (d, J = 274.1
Hz), 168.2. 19F NMR (376.5 MHz, CDCl3, ref = CFCl3): δ −89.49
(1F, s). IR (ATR, cm−1): νCC = 2247, νCO = 1651, νmax = 1247,
730. MS (ES+): m/z (%): 448/50 (M + H+, 100). Anal. Calcd for
C21H23BrFNO2Si: C 56.25, H 5.17, N 3.12. Found: C 56.30, H 4.73, N
3.02. HRMS (ES+): calcd for C21H24BrFNO2Si+: 448.0738, found
448.0734.
Synthesis of Benzoxazines 26a−c. The synthesis of benzoxazine
26a is described as a representative example. To a solution of
benzamide 23a (0.10 g, 0.21 mmol) in anhydrous THF (10 mL) was
added a solution of KOtBu in THF (1 M, 0.21 mL, 1 equiv). After this
reaction mixture was stirred at room temperature for 2 h, a saturated
solution of NH4Cl in H2O (10 mL) was added. After extraction with
EtOAc (3 × 10 mL), drying (MgSO4), filtration, and evaporation of
the solvent in vacuo, crude benzoxazine 26a was obtained. Purification
via preparative TLC (SiO2, PE/EtOAc 95/5) afforded pure
benzoxazine 26a in 80% yield (0.043 g).
4-Benzoyl-2-fluorobenzo[b][1,4]oxazine 26a. Yellow oil. Rf
1
0.33 (petroleum ether/EtOAc 9/1). Yield: 80% (0.043 g). H NMR
(300 MHz, CDCl3): δ 6.16 (1H, br s), 6.98−7.14 (3H, m), 7.40−7.56
(6H, m). 13C NMR (75 MHz, CDCl3): δ 89.4 (d, J = 48.5 Hz), 117.1,
J
DOI: 10.1021/acs.joc.5b00507
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The Journal of Organic Chemistry
Article
123.2, 125.0, 126.7, 127.7, 128.1 (2×), 128.8 (2×), 131.1, 134.7, 147.2,
153.1 (d, J = 259.6 Hz), 167.5. 19F NMR (282 MHz, CDCl3, ref =
130.6 (4× (minor)), 128.7 (minor), 128.8 (major), 146.6, 168.6,
168.7, 168.9. 19F NMR (376.5 MHz, CDCl3, ref = CFCl3): δ −50.86
(2F, br s). IR (ATR, cm−1): νCO = 1767, νCO = 1651, νmax = 1192,
1177, 1078. MS (ES+): m/z (%): 364/66 (M + H+, 100). HRMS
CFCl3): δ −112.33 (1F, br s). IR (ATR, cm−1): νCO = 1657, νmax
=
1490, 1340, 1243, 748, 697. MS (ES+): m/z (%): 256 (M + H+, 30).
+
HRMS (ES+): calcd for C15H11FNO2 : 256.0768, found 256.0780.
+
(ES+): calcd for C14H17BrF2NO3 : 364.0354, found 364.0355.
4-Benzoyl-2-fluoro-7-methoxybenzo[b][1,4]oxazine 26b.
2-Acetoxy-N-(2-bromo-2,2-difluoroethyl)-N-(benzyl)-
benzamide 29b. Yellow oil. Rf 0.15 (petroleum ether/EtOAc 85/
15). Yield: 95% (5.66 g). 1H NMR (400 MHz, CDCl3): δ 2.03 (0.7H,
s (minor)), 2.32 (2.3H, s (major)), 3.57−4.43 (2H, br s), 4.57 (2H, s),
7.12 (2H, d, J = 6.8 Hz), 7.21−7.46 (7H, m). 13C NMR (100.6 MHz,
ref = CDCl3): δ 20.6 (minor), 20.8 (major), 47.9 (minor), 51.5 (t, J =
23.6 Hz (major)), 53.0 (major), 56.0 (t, J = 23.9 Hz (minor)), 120.4
(t, J = 309.5 Hz), 123.0 (minor), 123.3 (major), 126.2, 127.3 (2×),
127.5, 128.2, 128.4 (minor), 128.5 (major), 128.9 (2× (minor)), 129.1
(2× (major)), 130.8, 135.2 (major), 147.0 (major), 135.8 (minor),
146.5 (minor), 168.81, 168.85, 168.9, and 169.1 (2× major and 2×
minor). 19F NMR (376.5 MHz, CDCl3, ref = CFCl3): δ −49.11−52.76
(2F, m). IR (ATR, cm−1): νCO = 1767, νCO = 1656, νmax = 1190,
1076, 910, 730. MS (ES+): m/z (%): 412/14 (M + H+, 100). HRMS
Yellow oil. Rf 0.22 (petroleum ether/EtOAc 9/1). Yield: 82% (0.048
1
g). H NMR (400 MHz, CDCl3): δ 3.78 (3H, s), 6.12 (1H, br s),
6.57−6.58 (2H, m), 7.40−7.54 (6H, m). 13C NMR (100.6 MHz,
CDCl3): δ 55.8, 89.5 (d, J = 47.2 Hz), 103.0, 110.1, 120.7, 123.7, 128.0
(2×), 128.7 (2×), 130.8, 135.1, 147.9, 152.8 (d, J = 258.7 Hz), 158.2,
167.2. 19F NMR (376.5 MHz, CDCl3, ref = CFCl3): δ −113.34 (1F, br
s). IR (ATR, cm−1): νCO = 1651, νmax = 1503, 1307, 1246, 699. MS
(ES+): m/z (%): 286 (M + H+, 100). HRMS (ES+): calcd for
+
C16H13FNO3 : 286.0874, found 286.0879.
4-(4-Methoxybenzoyl)-2-fluorobenzo[b][1,4]oxazine 26c.
Yellow crystals. Melting point: 68−69 °C. Rf 0.06 (petroleum ether/
1
EtOAc 9/1). Yield: 70% (0.077 g). H NMR (400 MHz, CDCl3): δ
3.84 (3H, s), 6.22 (1H, d, J = 2.8 Hz), 6.90 (2H, d, J = 8.9 Hz), 6.98
(1H, ddd, J = 9.6 Hz, 7.1 Hz, 1.6 Hz), 6.98−7.00 (1H, m), 7.08 (1H,
ddd, J = 8.4 Hz, 7.1 Hz, 1.4 Hz), 7.51−7.55 (3H, m). 13C NMR (100.6
MHz, CDCl3): δ 55.4, 89.5 (d, J = 47.6 Hz), 113.8 (2×), 117.0, 123.0,
124.8, 126.3, 126.5, 128.1, 130.3 (2×), 147.1, 153.0 (d, J = 261.6 Hz),
161.8, 169.9. 19F NMR (376.5 MHz, CDCl3, ref = CFCl3): δ −113.01
(1F, d, JH,F = 2.5 Hz). IR (ATR, cm−1): νCO = 1652, νmax = 1605,
1238, 1180, 756. MS (ES+): m/z (%): 286 (M + H+, 100). HRMS
+
(ES+): calcd for C18H17BrF2NO3 : 412.0354, found 412.0361.
2-Acetoxy-N-(2-bromo-2,2-difluoroethyl)-N-(4-
methoxybenzyl)benzamide 29c. White crystals. Melting point:
109−110 °C. Rf 0.11 (petroleum ether/EtOAc 9/2). Yield: 78% (1.21
1
g). H NMR (400 MHz, CDCl3, 50 °C): δ 2.04 (0.6H, s (minor)),
2.30 (2.4H, s (major)), 3.80 (3H, s), 3.89 (0.4H, br s (minor)), 4.30
(1.6H, br s (major)), 4.49 (2H, s), 6.86−6.88 (2H, m), 7.02−7.04
(2H, m), 7.20−7.27 (2H, m), 7.38−7.45 (2H, m). 13C NMR (100.6
MHz, ref = CDCl3): δ 20.6 (minor), 20.8 (major), 47.2 (minor), 51.0
(t, J = 23.7 Hz (major)), 52.4 (major), 55.2, 55.8 (t, J = 23.5 Hz
(minor)), 114.2 (2× (minor)), 114.4 (2× (major)), 120.5 (t, J = 309.5
Hz), 123.0 (minor), 123.2 (major), 126.2, 126.8, 127.6 (major), 127.8
(minor), 128.26 (minor), 128.33 (2× (minor)), 128.5 (major), 128.8
(2× (major)), 130.4 (minor)), 130.8 (major), 146.4 (minor), 146.9
(major), 159.5, 168.7, 168.8, 168.9. 19F NMR (376.5 MHz, CDCl3, ref
+
(ES+): calcd for C16H13FNO3 : 286.0874, found 286.0880.
Synthesis of Benzoxazine 26d. To a solution of N-{2-[(tert-
butyldimethylsilyl)oxy]phenyl}-N-(2-fluoroethynyl)-4-bromobenza-
mide 25d (0.11 g, 0.23 mmol) in anhydrous THF (10 mL) at 0 °C
was added a solution of TBAF in THF (1 M, 0.23 mL, 1 equiv).
Stirring was continued for 1 h at the same temperature. Subsequently,
the reaction mixture was quenched with H2O (10 mL) and extracted
with EtOAc (3 × 10 mL). After drying of the organic layers (MgSO4),
filtration, and evaporation of the solvent, crude benzoxazine 26d was
obtained. Purification by means of preparative TLC (SiO2, PE/EtOAc
9/1) afforded benzoxazine 26d in 86% yield (0.067 g)
= CFCl3): δ −48.54 to −52.33 (2F, m). IR (ATR, cm−1): νCO
=
1765, νCO = 1654, νmax = 1188, 1080, 925, 790. MS (ES+): m/z (%):
+
442/44 (M + H+, 100). HRMS (ES+): calcd for C19H19BrF2NO4 :
442.0460, found 442.0458.
4-(4-Bromobenzoyl)-2-fluorobenzo[b][1,4]oxazine 26d. Yel-
low oil. Rf 0.40 (petroleum ether/EtOAc 9/1). Yield: 86% (0.067 g).
1H NMR (400 MHz, CDCl3): δ 6.14 (1H, br s), 7.00−7.03 (2H, m),
7.13 (1H, ddd, J = 8.1 Hz, 7.4 Hz, 1.4 Hz), 7.41−7.58 (5H, m). 13C
NMR (100.6 MHz): δ 89.1 (d, J = 47.7 Hz), 117.1, 123.0, 124.9,
125.6, 126.8, 127.4, 129.7 (2×), 131.9 (2×), 133.4, 147.1, 153.2 (d, J =
263.2 Hz), 166.1. 19F NMR (376.5 MHz, CDCl3, ref = CFCl3): δ
Synthesis of Benzamides 29d,e. The synthesis of benzamide
29d is described as representative example. A solution of 2,5-
diacetoxybenzoic acid (0.22 g, 0.94 mmol) in SOCl2 (distilled, 1 mL)
was stirred at reflux temperature for 15 min. Subsequently, the residual
SOCl2 was evaporated under reduced pressure. The resulting acid
chloride was used without purification and redissolved in anhydrous
THF (20 mL), and N-(4-methoxybenzyl)-2-bromo-2,2-difluoroethyl-
amine 6c (0.26 g, 1 equiv) and Et3N (0.19 g, 2 equiv) were added at 0
°C. Subsequently, the reaction mixture was stirred at room
temperature for 22 h, after which H2O (20 mL) was added and an
extraction was performed with EtOAc (3 × 20 mL). The combined
organic layers were dried (MgSO4) and filtered, and the solvent was
removed in vacuo. Purification via flash chromatography (SiO2, PE/
EtOAc 7/3) afforded benzamide 29d in 72% yield (0.34 g).
−111.80 (1F, d, JH,F = 2.6 Hz). IR (ATR, cm−1): νCO = 1654, νmax
=
1489, 1345, 1242, 750. MS (ES+): m/z (%): 334/36 (M + H+, 100).
+
HRMS (ES+): calcd for C15H10BrFNO2 : 333.9873, found 333.9875.
Synthesis of Benzamides 29a−c. The synthesis of benzamide
29a is described as representative example. To a mixture of N-propyl-
2-bromo-2,2-difluoroethylamine 6a (0.54 g, 2.7 mmol) and O-
acetylsalicyloyl chloride 28a (0.53 g, 2.7 mmol, 1 equiv) in THF
(30 mL) was slowly added triethylamine (1.35 g, 13 mmol, 5 equiv) at
room temperature. After this reaction mixture was stirred at the same
temperature for 2 h, an aqueous solution of HCl (1 N, 30 mL) was
added and an extraction with Et2O (3 × 20 mL) was performed. After
drying (MgSO4), filtration, and evaporation of the solvent, benzamide
29a was purified via column chromatography (SiO2, PE/EtOAc 85/
15) and obtained in 55% yield (0.53 g).
2-Acetoxy-N-(2-bromo-2,2-difluoroethyl)-N-(propyl)-
benzamide 29a. Colorless oil. Rf 0.29 (petroleum ether/EtOAc 85/
15). Yield: 55% (0.53 g). 1H NMR (400 MHz, CDCl3): δ 0.74 (2.3H,
t, J = 7.4 Hz (major)), 0.98 (0.7H, t, J = 7.3 Hz (minor)), 1.50 (1.5H,
sextet, J = 7.4 Hz (major)), 1.68 (0.5H, sextet, J = 7.3 Hz (minor)),
2.26 (3H, s), 3.28 (2H, t, J = 7.6 Hz), 3.83−4.62 (2H, m), 7.20 (1H, d,
J = 8.1 Hz), 7.30 (1H, d, J = 6.7 Hz), 7.33 (1H, ddd, J = 7.3 Hz, 7.3
Hz, 1.7 Hz), 7.45 (1H, ddd, J = 8.2 Hz, 7.3 Hz, 1.9 Hz). 13C NMR
(100.6 MHz, ref = CDCl3, 50 °C): δ 10.6 (major), 11.2 (minor), 19.8
(minor), 20.7, 20.9 (major), 47.7 (minor), 50.6 (major), 51.8 (t, J =
23.7 Hz (major)), 57.7 (t, J = 23.3 Hz (minor)), 120.5 (t, J = 309.6
Hz), 123.1, 125.9, 127.4, 130.4 (4× (major)), 122.9, 126.0, 128.0,
2,5-Diacetoxy-N-(2-bromo-2,2-difluoroethyl)-N-(4-
methoxybenzyl)benzamide 29d. Yellow oil. Rf 0.17 (petroleum
ether/EtOAc 7/3). Yield: 72% (0.34 g). 1H NMR (400 MHz, CDCl3,
50 °C): δ 2.03 (0.9H, br s (minor)), 2.27 (3H, s), 2.29 (2.1H, br s
(major)), 3.80 (3H, s), 3.89 (0.6H, br s (minor)), 4.27 (1.4H, br s
(major)), 4.50 (2H, br s), 6.86−6.88 (2H, m), 7.03−7.05 (2H, m),
7.15−7.25 (3H, m). 13C NMR (100.6 MHz): δ 20.6 (minor), 20.8
(major), 21.0, 47.4 (minor), 51.0 (t, J = 23.6 Hz (major)), 52.6
(major), 55.3, 55.8 (t, J = 24.0 Hz (minor)), 114.3 (2× (minor)),
114.5 (2× (major)), 120.5 (t, J = 309.3 Hz), 120.9 (major), 121.6
(minor), 123.9, 124.0 (minor), 124.2 (major), 126.6, 129.17 (2×
(major)), 129.24 (2× (minor)), 130.5, 143.8 (minor), 144.2 (major),
148.0, 159.5 (minor), 159.6 (major), 167.6 (minor), 167.8 (major),
168.8 (2×). 19F NMR (376.5 MHz, CDCl3, ref = CFCl3): δ −48.49 to
−51.32 (2F, m). IR (ATR, cm−1): νCO = 1763, νCO = 1655, νmax
=
1201, 1163. MS (ES+): m/z (%): 517/19 (M + NH4 , 100), 500/02
+
+
(M + H+, 98). HRMS (ES+): calcd for C21H21BrF2NO6 : 500.0515,
found 500.0496.
K
DOI: 10.1021/acs.joc.5b00507
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
+
2-Acetoxy-5-methoxy-N-(2-bromo-2,2-difluoroethyl)-N-(4-
methoxybenzyl)benzamide 29e. White crystals. Melting point:
94−95 °C. Rf 0.12 (petroleum ether/EtOAc 9/2). Yield: 67% (0.19 g).
1H NMR (400 MHz, CDCl3): δ 2.02 (0.7H, s (minor)), 2.29 (2.3H,
(%): 222 (M + H+, 100). HRMS (ES+): calcd for C12H13FNO2 :
222.0925, found 222.0930.
Synthesis of Benzo[f ][1,4]oxazepin-5-ones 32a−e. As a
representative example, the synthesis of 2-fluoro-4-(4-methoxybenzyl)-
benzo[f ][1,4]oxazepin-5-one 32c is described here. To a solution of
benzamide 29c (1.15 g, 2.6 mmol) in anhydrous THF (30 mL) was
added a solution of KOtBu in THF (1 M, 5.2 mL, 2 equiv) at room
temperature. After the reaction mixture was stirred at reflux
temperature for 3 h, a saturated aqueous solution of NH4Cl (30
mL) was added. After extraction (3 × 30 mL EtOAc), drying with
MgSO4, filtration of the drying agent, and evaporation of the solvent,
crude oxazepin-5-one 32c was obtained. Purification by means of
column chromatography (SiO2, PE/EtOAc 9/1) afforded pure
oxazepin-5-one 32c in 77% yield (0.60 g).
4-Benzyl-2-fluorobenzo[f ][1,4]oxazepin-5-one 32b. White
crystals. Melting point: 65−66 °C. Rf 0.19 (petroleum ether/EtOAc
9/1). Yield: 62% (0.40 g). 1H NMR (400 MHz, CDCl3): δ 4.85 (2H,
s), 5.49 (1H, d, JH,F = 3.7 Hz), 7.11 (1H, dd, J = 8.2 Hz, 1.1 Hz),
7.28−7.38 (5H, m), 7.49 (1H, ddd, J = 8.2 Hz, 7.4 Hz, 1.8 Hz), 7.99
(1H, dd, J = 7.8 Hz, 1.8 Hz). 13C NMR (100.6 MHz, CDCl3): δ 51.5,
95.3 (d, J = 58.1 Hz), 119.5, 125.6 (d, J = 2.1 Hz), 126.1, 127.8, 128.0
(2×), 128.8 (2×), 132.8, 133.6, 136.0, 156.9 (d, J = 280.1 Hz), 159.7
(d, J = 4.4 Hz), 165.3. 19F NMR (376.5 MHz, CDCl3, ref = CFCl3): δ
s), 3.75 (3H, s), 3.80 (3H, s), 3.81 (2H, br s), 4.51 (2H, br s), 6.86−
6.88 (3H, m), 6.95 (1H, dd, J = 9.0 Hz, 2.9 Hz), 7.04 (2H, d, J = 8.6
Hz), 7.12 (1H, d, J = 9.0 Hz). 13C NMR (100.6 MHz, CDCl3): δ 18.8
(minor), 19.0 (major), 49.4 (t, J = 23.1 Hz), 50.7, 53.5, 53.9, 110.5
(major), 110.9 (minor), 112.4 (2× (minor)), 112.6 (2× (major)),
114.4 (major), 114.8 (minor), 118.6 (t, J = 309.6 Hz), 122.2 (minor),
122.4 (major), 125.1 (major), 125.9 (minor), 127.0 (2× (major)),
127.4 (2× (minor)), 128.7, 137.9 (minor), 138.4 (major), 155.4,
157.7, 166.7 (minor), 166.9 (major), 167.4 (minor), 167.5 (major).
19F NMR (376.5 MHz, CDCl3, ref = CFCl3): δ −48.56 to −52.09 (2F,
m). IR (ATR, cm−1): νCO = 1762, νCO = 1650, νmax = 1188, 1110,
1029. MS (ES+): m/z (%): 472/74 (M + H+, 100). HRMS (ES+):
+
calcd for C20H21BrF2NO5 : 472.0566, found 472.0557. Anal. Calcd for
C20H20BrF2NO5: C 50.86, H 4.27, N 2.97. Found: C 50.73, H 4.21, N
2.92.
Synthesis of Benzamide 30a, Enamide 31a, and 2-Fluoro-
1,4-benzoxazepin-5-one 32a. To an ice-cooled solution of
benzamide 29a (0.086 g, 0.24 mmol) in anhydrous THF (5 mL)
was added a solution of LiHMDS in THF (1 M, 0.52 mL, 2.2 equiv),
and the resulting mixture was stirred at room temperature for 5 h.
Subsequently, the reaction mixture was poured into a saturated
solution of NH4Cl in H2O (5 mL) and extracted with EtOAc (3 × 10
mL). Drying (MgSO4), filtration of the drying agent, and removal of
the solvent afforded benzamide 30a, enamide 31a, and 2-fluoro-1,4-
benzoxazepin-5-one 32a, which were further purified in 30% (0.024 g),
17% (0.010 g), and 31% (0.0.16 g) yield, respectively, by preparative
TLC (PE/EtOAc 9/1).
−98.64 (1F, d, JH,F = 3.7 Hz). IR (ATR, cm−1): νCO = 1627, νmax
=
1451, 1420, 1196, 692. MS (ES+): m/z (%): 270 (M + H+, 100).
+
HRMS (ES+): calcd for C16H13FNO2 : 270.0925, found 270.0921.
2-Fluoro-4-(4-methoxybenzyl)benzo[f ][1,4]oxazepin-5-one
32c. Yellow oil. Rf 0.12 (petroleum ether/EtOAc 9/1). Yield: 77%
(0.60 g). H NMR (400 MHz, CDCl3): δ 3.80 (3H, s), 4.78 (2H, s),
5.48 (1H, d, JH,F = 3.7 Hz), 6.88 (2H, d, J = 8.6 Hz), 7.11 (1H, dd, J =
8.2 Hz, 1.0 Hz), 7.27 (2H, d, J = 8.6 Hz), 7.31 (1H, ddd, J = 7.8 Hz,
7.4 Hz, 1.0 Hz), 7.49 (1H, ddd, J = 8.2 Hz, 7.4 Hz, 1.8 Hz), 7.98 (1H,
dd, J = 7.8 Hz, 1.8 Hz). 13C NMR (100.6 MHz, ref = CDCl3): δ 50.8,
55.0, 95.2 (d, J = 58.1 Hz), 114.0 (2×), 119.3, 125.5 (d, J = 2.1 Hz),
125.9, 128.0, 129.3 (2×), 132.6, 133.4, 156.6 (d, J = 279.9 Hz), 159.2,
159.5 (d, J = 4.3 Hz), 165.0. 19F NMR (376.5 MHz, CDCl3, ref =
1
N-2-Bromo-2,2-difluoroethyl-N-propyl-(2-hydroxy)-
benzamide 30a. Yellow oil. Rf 0.04 (petroleum ether/EtOAc 9/1).
Yield: 30% (0.024 g). 1H NMR (400 MHz, CDCl3): δ 0.82 (3H, t, J =
7.4 Hz), 1.60 (2H, sextet, J = 7.4 Hz), 3.64 (2H, t, J = 7.4 Hz), 4.40
(2H, t, JH,F = 12.3 Hz), 6.91 (1H, ddd, J = 7.8 Hz, 7.3 Hz, 0.9 Hz),
7.03 (1H, dd, J = 8.3 Hz, 0.9 Hz), 7.33 (1H, dd, J = 7.8 Hz, 1.6 Hz),
7.37 (1H, ddd, J = 8.3 Hz, 7.3 Hz, 1.6 Hz), 8.76 (1H, br s). 13C NMR
(100.6 MHz, ref = CDCl3): δ 10.9, 21.1, 51.6, 53.9, 117.8, 118.7,
119.4, 120.9 (t, J = 309.5 Hz), 128.1, 132.6, 157.0, 173.4. 19F NMR
(376.5 MHz, CDCl3, ref = CFCl3): δ −50.47 (2H, t, JH,F = 12.3 Hz).
IR (ATR, cm−1): νOH = 3174, νCO = 1620, νmax = 1595, 1083, 751.
MS (ES+): m/z (%): 322/24 (M + H+, 100). HRMS (ES+): calcd for
CFCl3): δ −98.67 (1F, d, JH,F = 3.7 Hz). IR (ATR, cm−1): νCO
=
1640, νmax = 1246, 1218, 1200, 1137, 760. MS (ES+): m/z (%): 300
+
(M + H+, 100). HRMS (ES+): calcd for C17H15FNO3 : 300.1030,
found 300.1023.
2-Fluoro-7-hydroxy-4-(4-methoxybenzyl)benzo[f ][1,4]-
oxazepin-5-one 32d. Brown crystals. Melting point: 108−109 °C.
1
Yield: 86% (0.10 g). H NMR (400 MHz, CDCl3): δ 3.80 (3H, s),
+
C12H15BrF2NO2 : 322.0249, found 322.0247.
4.77 (2H, s), 5.39 (1H, br s), 5.44 (1H, d, JH,F = 3.8 Hz), 6.88 (2H, d, J
= 8.7 Hz), 6.94−7.00 (2H, m), 7.24−7.26 (2H, m), 7.44 (1H, d, J =
2.9 Hz). 13C NMR (100.6 MHz, ref = CDCl3): δ 51.5, 55.4, 94.9 (d, J
= 60.2 Hz), 114.3 (2×), 118.2, 120.7, 121.4, 125.5, 127.6, 129.5 (2×),
153.1 (d, J = 4.4 Hz), 154.8, 157.4 (d, J = 282.4 Hz), 159.4, 166.1. 19F
NMR (376.5 MHz, CDCl3, ref = CFCl3): δ −97.96 (1F, s). IR (ATR,
cm−1): νOH = 3336, νCO = 1634, νmax = 1454, 1219, 1174, 813. MS
(ES+): m/z (%): 316 (M + H+, 100). HRMS (ES+): calcd for
N-2,2-Difluorovinyl-N-propyl-(2-hydroxy)benzamide 31a.
White powder. Melting point: 59−60 °C. Rf 0.11 (petroleum ether/
1
EtOAc 9/1). Yield: 17% (0.010 g). H NMR (400 MHz, CDCl3): δ
0.96 (3H, t, J = 7.5 Hz), 1.69 (2H, sextet, J = 7.5 Hz), 3.60 (2H, t, J =
7.5 Hz), 5.61 (1H, dd, JH,F = 19.3 Hz, 2.1 Hz), 6.83 (1H, ddd, J = 7.9
Hz, 7.3 Hz, 1.0 Hz), 7.00 (1H, dd, J = 8.3 Hz, 1.0 Hz), 7.35 (1H, ddd,
J = 8.3 Hz, 7.3 Hz, 1.5 Hz), 7.43 (1H, dd, J = 7.9 Hz, 1.5 Hz), 9.95
(1H, br s). 13C NMR (100.6 MHz, CDCl3): δ 11.2, 20.6, 50.3, 89.6
(dd, J = 49.4 Hz, 13.3 Hz), 116.3, 118.1, 118.3, 128.7, 133.5, 155.4
(dd, J = 295.9 Hz, 287.7 Hz), 159.8, 171.6. 19F NMR (376.5 MHz,
CDCl3, ref = CFCl3): δ −87.33 (1F, dd, J = 40.8 Hz, JH,F = 19.3 Hz),
+
C17H15FNO4 : 316.0980, found 316.0975.
2-Fluoro-7-methoxy-4-(4-methoxybenzyl)benzo[f ][1,4]-
oxazepin-5-one 32e. Yellow oil. Rf 0.17 (petroleum ether/EtOAc 8/
2). Yield: 88% (0.059 g). H NMR (400 MHz, CDCl3): δ 3.80 (3H,
1
−99.90 (1F, d, J = 40.8 Hz). IR (ATR, cm−1): νOH = 3159, νCO
=
s), 3.83 (3H, s), 4.78 (2H, s), 5.44 (1H, d, JH,F = 3.8 Hz), 6.88 (2H, d,
J = 8.8 Hz), 7.00−7.01 (2H, m), 7.27 (2H, d, J = 8.8 Hz), 7.44 (1H,
dd, J = 2.4 Hz, 1.0 Hz). 13C NMR (100.6 MHz, ref = CDCl3): δ 51.2,
55.3, 55.9, 95.0 (d, J = 58.5 Hz), 114.3 (2×), 115.4, 120.3, 120.5, 126.2
(d, J = 2.2 Hz), 128.1, 129.5 (2×), 153.6 (d, J = 4.4 Hz), 157.26,
157.28 (d, J = 281.1 Hz), 159.4, 165.2. 19F NMR (376.5 MHz, CDCl3,
ref = CFCl3): δ −98.49 (1F, d, JH,F = 3.8 Hz). IR (ATR, cm−1): νCO
= 1640, νmax = 1429, 1244, 1214, 1174, 1032. MS (ES+): m/z (%): 330
1616, νmax = 1233, 760. MS (ES+): m/z (%): 242 (M + H+, 100).
+
HRMS (ES+): calcd for C12H14F2NO2 : 242.0987, found 242.0987.
2-Fluoro-4-propylbenzo[f][1,4]oxazepin-5-one 32a. Pale yel-
low oil. Rf 0.17 (petroleum ether/EtOAc 9/1). Yield: 31% (0.016 g)
(67% (0.076 g) yield was obtained following the procedure described
below). 1H NMR (400 MHz, CDCl3): δ 0.97 (3H, t, J = 7.4 Hz), 1.70
(2H, sextet, J = 7.4 Hz), 3.57−3.61 (2H, m), 5.50 (1H, d, JH,F = 3.7
Hz), 7.11 (1H, dd, J = 8.2 Hz, 1.1 Hz), 7.29 (1H, ddd, J = 7.8 Hz, 7.4
Hz, 1.1 Hz), 7.48 (1H, ddd, J = 8.2 Hz, 7.4 Hz, 1.8 Hz), 7.92 (1H, dd,
J = 7.8 Hz, 1.8 Hz). 13C NMR (100.6 MHz, CDCl3): δ 11.1, 21.1,
49.9, 95.8 (d, J = 57.7 Hz), 119.4, 125.98, 126.02, 132.6, 133.3, 156.8
(d, J = 279.7 Hz), 159.7 (d, J = 4.3 Hz), 165.1. 19F NMR (376.5 MHz,
CDCl3, ref = CFCl3): δ −99.24 (1F, d, JH,F = 3.7 Hz). IR (ATR,
cm−1): νCO = 1639, νmax = 1453, 1411, 1192, 759. MS (ES+): m/z
+
(M + H+, 100). HRMS (ES+): calcd for C18H17FNO4 : 330.1136,
found 330.1137.
Synthesis of Benzo[f ][1,4]oxazepin-5-ones 33a,b. The syn-
thesis of 2-fluorobenzo[f ][1,4]oxazepin-5-one 33a is described as
representative example. A solution of 2-fluoro-4-(4-methoxybenzyl)-
benzo[f ][1,4]oxazepin-5-one 32c (0.12 g, 0.38 mmol) in BF3·OEt2
(0.27 g, 5 equiv, 0.24 mL) was stirred at 128 °C for 6 h. Subsequently,
L
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Et2O (10 mL) and NaHCO3 (10 mL) were added and an extraction
was performed with EtOAc (3 × 10 mL). After drying (MgSO4),
filtration, and evaporation of the organic phase in vacuo, Et2O (10
mL) was added and the precipitate was filtered off. After evaporation,
crude benzoxazepinone 33a was obtained and recrystallized from
Et2O, affording pure benzoxazepinone 33a in 51% yield (0.035 g).
2-Fluorobenzo[f ][1,4]oxazepin-5-one 33a. White crystals.
(4) (a) Guo, Y.; Fujiwara, K.; Uneyama, K. Org. Lett. 2006, 8, 827.
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1
Melting point: 173−174 °C. Yield: 51% (0.035 g). H NMR (400
MHz, CDCl3): δ 5.60 (1H, t, JH,F = 4.0 Hz), 6.46 (1H, br s), 7.15 (1H,
d, J = 8.1 Hz), 7.32 (1H, ddd, J = 7.8 Hz, 7.4 Hz, 0.7 Hz), 7.55 (1H,
ddd, J = 8.1 Hz, 7.4 Hz, 1.7 Hz), 7.95 (1H, dd, J = 7.8 Hz, 1.7 Hz). 13C
NMR (100.6 MHz): δ 90.6 (d, J = 58.9 Hz), 120.2, 124.6 (d, J = 2.2
Hz), 126.1, 132.4, 134.4, 156.0 (d, J = 275.8 Hz), 158.7, 166.3. 19F
NMR (376.5 MHz, CDCl3, ref = CFCl3): δ −100.91 (1F, br s). IR
(ATR, cm−1): νCO = 1675, νmax = 1223, 1180, 786, 752. MS (ES+):
2492.
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2013, 24, 57. (d) Ichikawa, J.; Wada, Y.; Miyazaki, H.; Mori, T.;
Kuroki, H. Org. Lett. 2003, 5, 1455.
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O.; Miyoshi, T.; Ueda, M. ARKIVOC (Gainesville, FL, U. S.) 2013, 60.
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Synlett 2004, 2449. (b) Melkonyan, F.; Topolyan, A.; Karchava, A.;
Yurovskaya, M. Tetrahedron 2011, 67, 6826. (c) Buon, C.; Chacun-
+
m/z (%): 180 (M + H+, 100). HRMS (ES+): calcd for C9H7FNO2 :
180.0455, found 180.0454.
2-Fluoro-7-methoxybenzo[f ][1,4]oxazepin-5-one 33b. White
1
crystals. Melting point: 105−106 °C. Yield: 54% (0.044 g). H NMR
(400 MHz, CDCl3): δ 3.83 (3H, s), 5.56 (1H, t, JH,F = 4.1 Hz), 6.50
(1H, br s), 7.05−7.06 (2H, m), 7.39−7.40 (1H, m). 13C NMR (100.6
MHz, ref = CDCl3): δ 56.0, 90.6 (d, J = 58.9 Hz), 115.0, 121.2, 121.3,
125.3 (d, J = 2.3 Hz), 152.7 (d, J = 3.7 Hz), 156.4 (d, J = 277.7 Hz),
157.3, 167.1. 19F NMR (376.5 MHz, CDCl3, ref = CFCl3): δ −100.65
(1F, d, JH,F = 4.1 Hz). IR (ATR, cm−1): νCO = 1673, νmax = 1487,
1432, 1216, 1186, 768. MS (ES+): m/z (%): 210 (M + H+, 100).
̀
Lefevre, L.; Rabot, R.; Bouyssou, P.; Coudert, G. Tetrahedron 2000, 56,
605. (d) Morgans, G. L.; Ngidi, E. L.; Madeley, L. G.; Khanye, S. D.;
Michael, J. P.; de Koning, C. B.; van Otterlo, W. A. L. Tetrahedron
2009, 65, 10650.
+
HRMS (ES+): calcd for C10H9FNO3 : 210.0561, found 210.0558.
ASSOCIATED CONTENT
(14) Wu, J.-H.; Chang, F.-R.; Hayashi, K.-i.; Shiraki, H.; Liaw, C.-C.;
Nakanishi, Y.; Bastow, K. F.; Yu, D.; Chen, I.-S.; Lee, K.-H. Bioorg.
Med. Chem. Lett. 2003, 13, 2223.
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Ogino, R.; Koyama, M.; Nakajima, M.; Inoue, T.; Ohno, T.; Tatsuoka,
T. Bioorg. Med. Chem. 2006, 14, 1978.
■
S
* Supporting Information
1H NMR and 13C NMR spectra of all new compounds. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.joc.5b00507.
(16) Bioorganic and Medicinal Chemistry of Fluorine; John Wiley &
Sons: Hoboken, 2008.
(17) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: norbert.dekimpe@UGent.be.
*E-mail: sven.mangelinckx@UGent.be.
Thi, T. A.; The, C. P.; Pham, T. T.; Tornroos, K. W.; Van Tuyen, N.;
̈
Present Address
De Kimpe, N. Chem.Eur. J. 2013, 19, 5966. (b) Bodipati, N.;
Peddinti, R. K. Org. Biomol. Chem. 2012, 10, 1958. (c) Cocuzza, A. J.;
Chidester, D. R.; Cordova, B. C.; Klabe, R. M.; Jeffrey, S.; Diamond,
S.; Weigelt, C. A.; Ko, S. S.; Bacheler, L. T.; Erickson-Viitanen, S. K.;
Rodgers, J. D. Bioorg. Med. Chem. Lett. 2001, 11, 1389.
(20) Nosova, E. V.; Lipunova, G. N.; Charushin, V. N.; Chupakhin,
O. N. J. Fluorine Chem. 2010, 131, 1267.
‡(G.V.) Department of Chemistry, Faculty of Science and
Bioengineering Sciences, Free University Brussels, Pleinlaan 2,
B-1050 Brussels, Belgium.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors are indebted to Ghent University (GOA) and the
Fund for Scientific Research-Flanders (FWO-Vlaanderen) for
financial support.
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