Chemo- and stereoselective synthesis of fluorinated enamides from ynamides in HF/pyridine: Second-generation approach to potent ureas bioisosteres

Article abstract of DOI:10.1021/jo502699y

(E)- and (Z)-α-fluoroenamides could be easily prepared with high levels of chemo- and regioselectivities by hydrofluorination of readily available ynamides with HF/pyridine. The scope and limitations of this new process for the hydrofluorination of ynamides, as well as the stability of the resulting α-fluoroenamides, have been extensively studied. Theoretical calculations at the MP2 and B3LYP levels of theory showed that the resulting fluoroenamides exhibit geometrical and electronic properties that partially mirror those of ureas, therefore demonstrating that the hydrofluorination of ynamides provides a general, straightforward, and user-friendly approach to bioisosteres of ureas, potent building blocks for biological studies and medicinal chemistry.

Full text of DOI:10.1021/jo502699y

Article
pubs.acs.org/joc
Chemo- and Stereoselective Synthesis of Fluorinated Enamides from
Ynamides in HF/Pyridine: Second-Generation Approach to Potent
Ureas Bioisosteres
Benoît Metayer,† Guillaume Compain,† Kevin Jouvin,‡ Agnes Martin-Mingot,† Christian Bachmann,§
́
́
̀
Jerome Marrot,‡ Gwilherm Evano,*,∥ and Sebastien Thibaudeau*,†
́
̂
́
†Superacid Group in “Organic Synthesis” Team, Universite
́
de Poitiers, CNRS UMR 7285 IC2MP, Bat
̂
. B28, 4 rue Michel Brunet,
TSA 51106, 86073 Poitiers Cedex 09, France
‡Institut Lavoisier de Versailles, UMR CNRS 8180, Universite
78035 Versailles Cedex, France
́
de Versailles Saint-Quentin en Yvelines, 45, avenue des Etats-Unis,
§Computational Chemistry Group in “Catalysis and Renewable Carbon” Team, Universite
́
de Poitiers, CNRS UMR 7285 IC2MP,
Libre de Bruxelles, Avenue F. D.
TSA 51106, 86073 Poitiers Cedex 09, France
∥Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Universite
Roosevelt 50, CP160/06, 1050 Brussels, Belgium
́
S
* Supporting Information
ABSTRACT: (E)- and (Z)-α-fluoroenamides could be easily
prepared with high levels of chemo- and regioselectivities by
hydrofluorination of readily available ynamides with HF/pyridine.
The scope and limitations of this new process for the
hydrofluorination of ynamides, as well as the stability of the
resulting α-fluoroenamides, have been extensively studied.
Theoretical calculations at the MP2 and B3LYP levels of theory
showed that the resulting fluoroenamides exhibit geometrical and
electronic properties that partially mirror those of ureas, therefore
demonstrating that the hydrofluorination of ynamides provides a general, straightforward, and user-friendly approach to
bioisosteres of ureas, potent building blocks for biological studies and medicinal chemistry.
bioisosteres in SAR studies (Scheme 1).18−20 Based on the well-
INTRODUCTION
■
known bioisosterism between fluoroolefins and amides, which
has been extensively used in medicinal chemistry,21−24 we
envisioned that, in analogy, fluoroenamines C might be an
especially versatile class of ureas D isosteres (Scheme 1).
Over the past decade, the chemistry of urea has undergone
nothing short of a renaissance with remarkable applications in
many fields of chemistry. The unique structural properties of
ureas (planarity of the urea linkage, hydrogen-bonding ability,
coordination to metals, etc.)1 have indeed been elegantly used,
for example, in the preparation of noncovalent organo-
catalysts,2−4 in the development of selective anion chemo-
sensors,5,6 and, recently, in the design of imidazole quartet for
(water)proton-channel systems.7,8 In addition, and besides the
historical use of ureas (and more specifically sulfonyl ureas) as
antidiabetic agents,9,10 the recent development of urea-based
anticancer and antiinfective molecules11−13 unambiguously
demonstrated their strong potential as key structural elements
and/or pharmacophores in medicinal chemistry. Although the
modification of structural properties of ureas is now a common
strategy in the design of new bioactive molecules or lead
optimization, as recently shown for selective enzyme inhib-
itors,14,15 little attention has been paid to their replacement with
rigid, stable, and adjustable bioisosteres, which might represent
an interesting strategy in medicinal chemistry and chemical
biology as well.16,17 Indeed, and to the best of our knowledge,
only triazoles and aminopyrimidines have been evaluated as urea
Scheme 1. Previously Reported and Targeted Urea D
Bioisosteres and Synthesis of α-Fluoroenamines C
Received: November 27, 2014
© XXXX American Chemical Society
A
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Since this class of enamides is virtually unknown, we recently
reported the first general synthesis of α-fluoroenamides via a
superacid-catalyzed25 hydrofluorination26 of ynamides A27−31
through the intermediacy of a keteniminium ion B (Scheme 1).32
Although this method was shown to have a rather broad substrate
scope, some acid-sensitive and chiral ynamides were not well
tolerated under these conditions. In addition, the necessary
safety arrangements and procedure for handling pure liquid
hydrogen fluoride could be considered as a major limitation to
the use of this method. To address this drawback and develop a
more user-friendly second-generation procedure, we considered
using less volatile solutions of HF with an organic base33−35 or
other sources of fluoride ions in the hydrofluorination process.
Herein, we report a general and more practical process for the
stereo- and regioselective synthesis of α-fluoroenamides. This
second-generation hydrofluorination process enables the syn-
thesis of a wider range of fluorinated enamides and allows the
hydrofluorination of ynamides that could not be cleanly
fluorinated in liquid hydrogen fluoride. We therefore report in
this manuscript the results obtained with our second-generation
procedure as well as a full account on the hydrofluorination of
ynamides in neat hydrogen fluoride. A mechanistic investigation
and a study of the stability of the fluoroenamides allowed us to
propose a hypothesis to explain the substrate dependence of the
stereoselectivity. In addition, and in order to validate our
hypothesis on the potential use of fluoroenamides as new potent
isosteres of ureas, calculations at the theoretical level were
conducted on selected representative fluoroenamides and the
corresponding ureas.
fluorinated product could be detected in the crude reaction
mixture, the major product formed being amide 3a resulting from
the hydrolysis of the intermediate keteniminium ion (Table 1,
entry 1). No improvement was observed at higher temperature,
and the competitive formation of amide 3a, which was still
formed as the main product, could not be avoided (Table 1, entry
2). To evaluate whether superacidic conditions were needed to
perform the hydrofluorination reaction, the use of trifluorome-
thanesulfonic acid was tested. While the keteniminium ion must
definitely be formed under these conditions,36−39 the subsequent
addition of tetrabutylammonium fluoride did not, however, allow
trapping of this highly reactive intermediate. The amide 3a was
once again predominantly formed under these conditions, which
can be attributed to a competitive trapping of the intermediate N-
sulfonylketeniminium ion by the triflate counterion yielding an
unstable ketene N,O-acetal that would next decompose under
the reaction conditions (Table 1, entry 3).40
In order to avoid the presence of other counteranions for the
keteniminium that could competitively trap this highly reactive
intermediate and, therefore, increase the amount of fluoroena-
mide formed, we decided to switch to HF/base reagents.41,42 We
first evaluated the use of HF/Et3N but, whatever the conditions
used, this fluorinating agent was found not to be acidic enough to
generate a keteniminium ion or to allow the hydrofluorination
process, as only starting material was recovered with this reagent
(Table 1, entries 4 and 5). Then the use of HF/pyridine was
evaluated as the reaction media for the hydrofluorination of the
ynesulfonamide 1a. While no reaction occurred at −78 °C, due
to the mixture freezing under these conditions, the desired (E)-α-
fluoroenesulfonamide 2a was, gratifyingly, formed at −50 °C
(Table 1, entries 6 and 7). However, 95 h at −20 °C was needed
to fully convert the ynesulfonamide under these conditions, and
the formation of the undesired amide 3a could not be fully
avoided (Table 1, entry 8). Considering that the amide could
result from partial hydrolysis of the remaining ynamide when the
reaction time was too long, the reaction was next tested at higher
temperature. At 20 °C, the ynamide was almost fully converted
after 5 min, but amide formation could still not be avoided (Table
1, entry 9). Since pyridine concentration of Olah’s reagent is
known to influence the selectivity of addition reaction,43 we
therefore evaluated the influence of this parameter on the
hydrofluorination reaction. When the pyridine concentration
increased, no reaction occurred (Table1, entry 10), confirming
the necessity of sufficiently acidic conditions for the hydro-
fluorination reaction. It was finally found that when the reaction
was performed in HF/pyridine (70/30, w/w) for 15 min at −10
°C, the ynesulfonamide 1a was fully converted to the desired
(E)-α-fluoroenesulfonamide 2a, which was formed as a single
regio- and stereoisomer and could be isolated in 86% yield
(Table 1, entry 11).
RESULTS AND DISCUSSION
■
Screening of Reagents and Conditions for the Second-
Generation Hydrofluorination Process. In order to extend
the scope of the reaction and avoid the use of pure fluorhydric
acid, other fluorinating agents were tested using ynesulfonamide
1a as a model substrate (Table 1). BF3·OEt2 was first evaluated at
low temperature, but unfortunately, only traces of the desired
Table 1. Screening of Fluorinating Agents for the
Hydrofluorination of Model Ynamide 1a
b
products (%)
a
c
entry
conditions
BF3·OEt2
BF3·OEt2
temp (°C)
time
1a
2a
3a
d
1
−10
20
15 min
15 min
15 min
15 min
15 min
5 min
5 min
95 h
0
5
95
93
63
0
d
2
0
37
7
0
3
CF3SO3H/Bu4NF
−10
−10
20
Second-Generation Hydrofluorination of Ynamides.
With these new optimized conditions in hand based on the use of
the classical fluorinating agent HF/pyridine, the effect of
pyridine−(poly) hydrogen fluoride complexes on the efficiency,
regioselectivity, and stereoselectivity of the hydrofluorination of
a set of representative ynamides was evaluated (Table 2).44 For
all substrates tested, including aryl- and alkyl- substituted
ynesulfonamides, ynecarbamates, and ynimides, the hydro-
fluorination reaction in HF/pyridine allowed the synthesis of
the desired nitrogen-substituted fluoroolefins. Aryl- and alkyl-
substituted ynesulfonamides 1a−i and ynecarbamate 1j led to
the corresponding fluorinated enamides with similar yields under
liquid HF (conditions B) and HF/pyridine (conditions A)
e
4
HF/Et3N
>95
>95
>95
78
0
e
5
HF/Et3N
0
0
f
6
HF/pyridine
−78
−50
−20
20
0
0
f
7
HF/pyridine
22
84
65
0
0
f
8
HF/pyridine
4
12
30
0
f
9
HF/pyridine
5 min
5 min
15 min
5
g
10
11
HF/pyridine
20
>95
0
f
HF/pyridine
−10
98
2
a
b
Reaction media. Ratio determined by 1H NMR analysis of the crude
c
reaction mixture. Only the (E)-α-fluoroenamide was detected and no
d
traces of the (Z)-isomer could be detected. Side product formation.
e
f
g
37/63, w/w. 70/30, w/w. 50/50, w/w.
B
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Table 2. Hydrofluorination of Ynamides: Scope and Limitations
a
b
c
1
Yields of pure, isolated fluoroenamides (E/Z) . E/Z ratio determined by H NMR analysis of crude reaction mixtures. E and Z isomers were
d
e
f
g
h
i
separated. 0 °C. 60 min. Addition of HF/pyridine to reaction media. Complex mixture. 20 °C. Not evaluated.
(Table 2, entries 1−10).45 In these cases, the possibility to access
to the same α-fluoroenamides in good yields using HF/pyridine,
a widely used and practical reagent, instead of neat hydrogen
fluoride reinforces the potential of the method which can now be
performed much more easily. In addition, when substrates 1k−o
only led to complex mixtures when hydrofluoric acid was used,
these ynamides could be converted to the corresponding desired
α-fluoroenamides 2k−o by using HF/pyridine (Table 2, entries
C
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Scheme 2. Possible Keteniminium Intermediates and Basis for Observed Stereoselectivity
11−15). When the hydrofluorination process could not be
achieved by using our previous procedure, our second-
generation conditions allowed the synthesis of the desired
heteroaromatic fluorinated products. Starting from these
substrates, the stereoselectivity of the reaction dramatically
decreased. To check whether the stereochemical outcome of the
reaction could also be influenced by a steric effect, the behavior of
xylyl-substituted ynamide 1o was evaluated (Table 2, entry 15).
To our surprise, the reaction turned out to be completely Z
selective in this case, and α-fluoroenesulfonamide 2o could be
isolated in 63% yield after 1 h of reaction at 0 °C. It has to be
noted that the tolyl analogue 1p selectively yielded the (E)-α-
fluoroenesulfonamide 2p after 5 min reaction at −10 °C (Table
2, entry 16).
promotes the Z isomer formation (Scheme 2).46,47 The dramatic
effect of methyl substitution of the aromatic ring on the
selectivity of the process led us to propose the following
rationalization (Table 2, entries 15 and 16). It first has to be
noted that substrate 1o possessing a xylyl group is by far less
reactive than its tolyl analogue 1p. By analogy to the elucidated
mechanism involving a [1,5] sigmatropic methyl hydrogen shift
from keteniminium ions,38 it could be postulated that a partial
stabilization of the keteniminium ion B3 through a hyper-
conjugation effect could account for the stereoselectivity of the
process. The partial stabilization of the charge must distort the
keteniminium ion (decrease of angle A°) favoring the
nucleophilic attack of HF/pyridine complex by the upper face
of the distorted ion B′3 and leading to the formation of the Z
isomer. In the case of the tolyl analogue, the strong reactivity of
the keteniminium ion toward the fluoride ions (immediate
reaction) would prevent such a process, resulting in a “classical”
stereoselectivity for the reaction. For substrate 1l, which also led
to the (Z) isomer, a similar behavior could be postulated.
Study of the Fluoroenamide Stability. The strong
substrate dependency of the stereochemical outcome of the
hydrofluorination reaction also could have been attributed to
thermodynamic control. An equilibrium between (E)- and (Z)-
α-fluoroenamides, through the intermediate formation of a
fluoroiminium ion E, could indeed account for the formation of
the Z isomers in some cases and therefore needed to be evaluated
(Scheme 3).
Finally, to evaluate whether these conditions could be
extended to the synthesis of α-fluoroenimides, ynimides 1q
and 1r were tested as substrates using our second-generation
optimized procedure. To our delight, the hydrofluorination also
occurred from these ynimides, allowing the synthesis of original
fluoroenimides such as 2q and 2r (Table 2, entries 17 and 18).
Stereochemical Outcome of the Keteniminium Ion
Fluorination. As previously mentioned, the nature of the
substituent of the ynamides strongly influences the stereo-
chemical outcome of their hydrofluorination. To rationalize the
observed differences in stereoselectivity, we proposed the
involvement of the following intermediates in the mechanism
(Scheme 2). After protonation, the aryl-substituted ynesulfona-
mides should lead to the formation of keteniminium ion
intermediates such as ion B1, with an upper face being sterically
hindered by the phenyl group, thus favoring the pyridinium
(poly)hydrogen fluoride complexes to approach syn to the H
atom (formation of the E isomer). For alkyl- and styryl-
substituted ynamides, the smaller steric hindrance would disfavor
the selectivity of the reaction. As expected, a similar impact of the
substituent is also observed for ynimide derivatives (Table 2,
entries 17 and 18). For heteroaryl-substituted ynamides, the
position of the heteroatom strongly influences the stereo-
chemical outcome of the reaction. When starting from 3-
pyridinyl-substituted ynesulfonamide 1h, the hydrofluorination
process led selectively to the formation of the (E)-α-
fluoroenesulfonamide 2h; under the same conditions, the 2-
pyridinyl substrate 1i led mainly to the formation of the Z
product 2i. Analogously, for thiofuranyl-substituted ynamides
1m and 1n, the reaction led selectively to the (Z)-fluoroenamide
products, the stereoselectivity being lower in these cases. To
explain the behavior of these substrates, it could be postulated
that an intermediate ion B2 could be formed through competitive
hydrogen bonds with the heteroatom of the aromatic ring of the
ynamide forcing the attack of the fluoride ions by the face that
Scheme 3. Possible Isomerization of α-Fluoroenamides under
Acidic Conditions
Although X-ray diffraction analyses of crystals of (E)-α-
fluoroenamide 2b and (Z)-α-fluoroenamide 2i showed a partial
pyramidalization of the sulfonamide nitrogen atom (Figure 1),32
which is not favorable for the formation of the fluoroiminium
ions due to nonoptimal conjugation between the nitrogen lone
pair and the double bond, the intermediacy of such
fluoroiminium species could, however, not be ruled out on this
basis. The conformation of the fluoroenamides being indeed
most certainly different in solution, the possibility of a
thermodynamic control through the formation of a fluoroimi-
nium ion needed to be assessed.
Toward this end, a set of fluoroalkenes were subjected to the
reaction conditions to check whether an isomerization could be
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made starting from both E and Z isomers of 2-pyridyl-substituted
fluoroenamide 2i. When the conditions were forced by
increasing the temperature, the E isomer 2i was also recovered
at the end of the reaction, while surprisingly, the corresponding Z
isomer 2i led to the exclusive formation of the difluorinated
product 4 after 20 min at 20 °C. In this case, the intermediate
formation of a highly reactive fluoroiminium ion intermediate
could favor the difluorination process but not the equilibration
between both double-bond isomers. All together, these experi-
ments are in strong agreement with a kinetic control instead of a
thermodynamic control of the hydrofluorination reaction in HF/
pyridine. As previously mentioned, α-fluoroenamides could be
potentially used as novel isosteres of ureas. Taking into account
the recently reported potential of N-sulfonyl-substituted ureas as
anticancer agents,14,15 the synthesis of potent α-fluoroenesulfo-
namide bioisosteres could offer further advances in this field,
provided that these compounds would be stable enough. With
this goal in mind, we briefly tested the chemical stability of (E)-α-
fluoroenamide 2b. To our delight, this fluorinated enamide was
found to be perfectly stable not only in water or methanol (Table
3, entries 7 and 8) but also under basic or acidic aqueous
conditions (Table 3, entries 9 and 10), with 2b being totally
recovered in all trials. This stability confirms that these potential
urea isosteres should definitely be stable under physiological
conditions, making them good candidates for further biological
studies.
Figure 1. X-ray crystal structures of fluoroenesulfonamides (E)-2b and
(Z)-2i.32
observed or not. Under our defined reaction conditions in HF/
pyridine, both (E) and (Z) isomers of the enimide 2q were found
to be perfectly stable and no isomerization could be detected
1
from H NMR analysis of crude reaction mixtures (Table 3,
entries 1 and 2).
These two substrates could be completely recovered, even
after 1 h under the reaction conditions, therefore confirming the
chemical and stereochemical stability of these fluoroenimides
under the reaction conditions. A similar observation could be
Table 3. Study of the Chemical and Stereochemical Stability of α-Fluoroenamides
a
b
c
d
e
Yields obtained after purification. HF/pyridine (70/30, w/w), 15 min, −20 °C. No reaction. HF/pyridine (70/30, w/w), 60 min, −10 °C. HF/
f
pyridine (70/30, w/w), 20 min, 20 °C. 24 h, rt.
E
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Evaluation of the Fluoroenamine Mimetic Character.
Besides their chemical stability, which clearly is a prerequisite for
the potential use of fluorinated enamides as urea bioisosteres, we
next focused our attention on getting further insights on the
analogy between these two functional groups. With this goal in
mind, theoretical calculations were carried out on selected and
representative substituted ureas (urea D1, N-methylurea D2, N-
tert-butylurea D3, and N-phenylurea D4) and their proposed
isosteres.48−50 As an initial evaluation of the ability for a
fluoroenamine to mimic a urea, the comparison between the
simplest existing models, urea D1 and its fluoroenamine
analogue C1, was first performed. Equilibrium structures and
transition structures for internal rotations are depicted in Figure
2. Selected geometrical parameters, NBO charges, and free
energies of solvation in water are reported in Table 4.
participate to the stabilization of the transition state C1TS1
through an electron-density donation to the antibonding σ*C−F
orbital.
Calculated geometrical parameters for the urea minima
conformers were also shown to correlate well with the reported
ones (Table 4), whatever the calculation methods used. For
further comparison, charges derived from Mulliken population
analyses and NBO charges have also been determined, the
former calculations correlating well with the second but showing
lower values.51 Solvation free energies of ureas and their potent
isosteres in aqueous phase were also determined by using an
implicit solvation method and compared.51 The comparison of
the geometrical parameters of the simplest ureido derivative and
its fluoroenamine hypothetical isostere was needed to evaluate
the steric characteristics of the two, a special attention being paid
to selected parameters, summarized in Table 4. For clarity, the
following discussion will be focused on the data extracted from
calculations at the MP2 level. Geometrical parameters and
charges of the global minimum structures D1 C2 and D1 Cs can
be compared to the fluoroenamine minimum C1a values (Figure
3). The results indicate that while the C−F bond (1.366 Å) is
longer than the CO bond (1.230 Å) and the CC bond
(1.347 Å) is shorter than the N1−C2 bond (1.394 Å), the N3−C2
bonds for urea and fluoroenamine are very close (1.394 and
1.392 Å). The angle C1C2−F (120.1°) is very close to the N1−
C2O one (123.3°). However, the N3−C2−F angle (109.7°) is
smaller than the N3−C2O angle (123.3°). The studied
geometric values seem to indicate an overall steric similarity
between urea D1 and its analogous fluoroenamine C1a.
We were also particularly interested in comparing the
electronic distribution between the atoms of the compared
functions and thus especially to evaluate the ability to use these
isosteres for synthetic purposes (H bond donor ability, original
dipoles). The set of charges all depict larger charge separations
between urea elements than for the fluoroenamine one.
However, it is really interesting to note that the same trends
are observed. Respective NBO charges are for example of −0.42
and −0.63 for the fluorine and carbon atom C1 of the
fluoroenamine, and the corresponding oxygen and nitrogen
atom charge values for the urea are −0.76 and −0.94. In addition,
the central carbon atom charge is positive in both cases (+1.06
for D1C2 and D1Cs and +0.75 for C1a), confirming an overall
identical variation of charges. It is also worth noting that the
substitution of the N−CO by the fluoroolefin CC−F did
not impact the negative charge on the second nitrogen atom, the
negative charge on N3 being almost identical in D1 (−0.94) and
C1 (−0.91). In addition, the vinylic hydrogen charge of +0.21 is
close to the H1 charge value in the urea (+0.39), and H3 values
were identical between fluoroenamine C1a (+0.39) and ureas
D1C2 (+0.39) and D1Cs (+0.38), results which suggest a similar
ability of the fluoroenamine to participate in hydrogen bonding.
To gain further insight into the evaluation of the ability of
fluoroenamines to act as hydrogen-bonding donors and
acceptors, the solvation free energies in the aqueous phase
were calculated (ΔGs, Table 4). As for urea D1, the solvation free
energy of fluoroenamine C1 was negative (−10.1 and −11.96
kcal mol−1 for D1C2 and D1Cs and −3.27 for C1), confirming the
strong interactions between the ureas and water molecules and a
similar, but lower, aptitude of fluoroenamine to be stabilized in a
water environment.
Figure 2. Equilibrium structures and internal rotation transition
structures for urea D1 and fluoroenamine C1. ZPE-corrected relative
energies (kcal·mol−1) are indicated in parentheses (MP2/cc-pVDZ)
and in square brackets [B3LYP/cc-pVDZ].51
Comparison of Urea D1 and Its Fluoroolefin Mimic C1. For
urea D1, in accordance with recently reported calculations,52−55
MP2 calculations led to the identification of two equilibrium
structures and two transition states corresponding to internal
rotations. The two minima of D1 correspond to conformations
in which the NH2 groups are pyramidalized on opposite sides
with C2 symmetry (D1 C2) and on the same sides with Cs
symmetry (D1 Cs). The rotation around the C2−N3 urea bond
breaks the conjugation, which must destabilize the resulting
transition state, a result that is in agreement with reported data.
Moreover, two transition structures were located owing to the
two possible orientations of the nitrogen lone pair. Assuming that
during rotation the inversion of the nitrogen atom occurs with a
lower barrier height than the rotation around the C−N bond, the
rotational barrier was calculated as the difference between the
lowest transition structure and the lowest equilibrium structure
(7.5 kcal mol−1 at the MP2/cc-pVDZ level). It has to be noted
that similar optimized geometries and values were obtained by
conducting calculations at the DFT level of theory.51 For
fluoroenamine C1, similar calculations led to the identification of
one minimum C1a and two transition states C1TS1 and C1TS2
.
Going from C1a to C1TS1 through a rotation around the N3−C2
bond requires 1.84 kcal mol−1. At this stage, it is noteworthy that
rotation around the N3−C2 bond affect the stabilities of the
conformers, this effect being smaller in the case of fluoroenamine
compared to the corresponding urea. This variation of stabilities
could be attributed to the absence of conjugation breaking in this
case. It could also be envisaged that the nitrogen lone pair could
This initial promising comparison between fluoroenamines
and ureas prompted us to extend this study to substituted ureido
analogues, especially considering the impact of the nitrogen
F
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Table 4. Selected Geometric Parameters, Charges, and Energies of Solvation in the Aqueous Phase for Optimized Minima
Figure 3. Comparison of geometrical parameters of urea D1C2 and
fluoroenamine C1a.
Figure 4. Compared optimized minima (MP2/cc-pVDZ) for ureas
D2−4 and fluoroenamine C2−4 and C′2−4.
substituents on the conformational preference of the ureido
derivatives.
Comparison of Substituted Ureas D2−4 and Fluorolefin
Proposed Isosteres C2−4. In this context, and by using the same
procedures than the ones described above, conformational
analyses, charges, and solvation free energies of methyl D2, tert-
butyl D3, and phenyl ureas D4 were compared to those of their
fluoroenamine analogues C2, C3, and C4 (Figure 4).
For the purpose of clarity, Figure 4 presents only the optimized
minima obtained from MP2 calculations. It is also important to
mention at this stage that equilibrium structures were identified
for all the calculated ureas, and all the parameters of these species
were found to be almost identical to the ones reported in the
literature, with the substituent group pointing in the direction of
the carbonyl group (s-cis derivative Dicis) or in the opposite
direction (s-trans derivative Ditrans). For substituted enamines
(Ci), two families of potent mimics were calculated, the ones
presenting the substituent located on the olefin (Ci) and the
ones with the R group located on the nitrogen atom (C′i). In all
cases, two minima were identified and called cis and trans (for
derivatives C′i, the cis and trans terms refer to the orientation of
the R group in the same direction than the C−F bond or opposite
to this bond). In addition to these minima, transitions structures
were also identified to connect to the minima.51
To focus on one significant derivative, the extrema of the MP2
rotational energy profile of the tert-butyl urea D3 and of its
fluoroenamine postulated isostere C′3 was evaluated (Figure 5).
For this urea derivative, the D3cis conformer was shown to be
more stable than its trans conformer by 2.93 kcal mol−1, a result
in accordance with the classically observed cis-preferred
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Figure 6. Polarization of urea Di and fluoroenamines Ci and C′i.
calculated and compared. First, solvation free energies show
strong negative values for urea derivatives confirming the strong
ability of ureas to interact with polarized molecules through
hydrogen bonding. Then, it is noteworthy that the impact of the
substitution of one hydrogen with an alkyl or aromatic group is
dramatic for the solvation properties of the molecule. For the cis
minima (with D1Cs as a reference), the ability to solvate water
molecules decreases in the following order H > Me > Ph > tBu
with a variation of solvation free energies going from 2.65 to 3.99
kcal mol−1 (similar variation were obtained when calculations
were performed at the DFT level).51 For the trans-optimized
geometries, the negative impact of the substituent is also
predominant with a variation of solvation free energies going
from 2.29 to 4.16 kcal mol−1. However, it has to be noted that the
impact of the phenyl and tert-butyl groups are similar for the trans
ureas. This variation probably comes from the increase of the
hydrophobicity of the molecule resulting of the addition of
lipophilic alkyl chains, even if it could also be due to the removal
of a hydrogen that could participate in a hydrogen bond. As
already observed when comparing electronic distribution, similar
trends can be highlighted by analyzing the solvation free energies
of substituted fluoroenamines. The energies were shown to be
lower than for ureas, a result which confirms that the proposed
isosteres are less prone to solvation than their corresponding
ureas. However, the observed substitution negative effect is
smaller for fluoroenamines than for ureas. For the C′i isosteres
the decrease of these energies goes from 0.81 to 1.27 kcal mol−1
for the cis derivatives and from 0.45 to 1.96 kcal mol−1 for the
trans ones. It also has to be noted that for C′icis derivatives
substituting a hydrogen with a phenyl group has the strongest
impact. An original behavior of the Ci isosteres was also
observed. When the negative impact of an additional substituent
on the water solvation was also shown, and thus for cis and trans
derivatives, for the phenyl substituted cis isomers, the
substitution was in favor of an increase of the solvation
enthalpies, a result which could probably come from electronic
delocalization of the π electrons. More interestingly, comparing
the solvation energies between Ci and C′i isosteres revealed a
stronger ability of the Ci isosteres than the C′i ones to interact
with water. The free NH bond available to act as hydrogen donor
could account for this difference of behavior.
Figure 5. Equilibrium structures and internal rotation transition
structures for urea D3 and fluoroenamine C′3. ZPE corrected relative
energies (kcal mol−1) are indicated in brackets (MP2/cc-pVDZ).51
orientation of urea derivatives.54,55 Two different transition
states (D3TS1 and D3TS2) have also been identified to connect
the two minima by rotation around the N1−C2 bond. This
rotation from D3cis gives rise to D3TS1 (relative energy of +8.23
kcal. mol−1). A rotation from D3trans leading to the same
transition state requires 5.30 kcal mol−1 (Figure 5). It has to be
noted that the effect of the substitution of the urea with a tert-
butyl group is present but did only affect slightly the rotational
energy profile (destabilization of the trans isomer). For the
proposed fluoroenamine C′3 mimic, four stable geometries were
identified, two minima which are symmetrical and show similar
parameters (C′3cis and C′3trans) and two transition states C′3TS1
and C′3TS2. Going from C′3cis to C′3TS1 through a rotation
around the N1−C2 bond requires 1.91 kcal mol−1. As for urea, it is
interesting to note that rotation around the N1−C2 bond also
affect the stability of the fluoroenamine, but has a lower impact.
This can be attributed to the fact that compared to the urea, no
conjugation is broken, in addition to the fact that the C−F bond
is longer than the CO one, the small fluorine atom therefore
not sterically interacting with the alkyl group.
Calculated geometrical parameters for the urea minima
conformers reported in Table 4 were also compared to the
parameters of the proposed isosteres, and the following general
comments can be extracted from the selected data:
For all the calculated geometries, the results indicate that the
CC bond of the fluoroolefin is shorter than the corresponding
C−N bonds of the ureas and that the C−F bond is longer than
the CO bond. No effects of the substituents were observed.
The N−CO and CC−F bond angles were shown to be very
close for all of the calculated urea/fluoroenamine couples
(around 120°). However, the comparison of the N−CO to the
corresponding N−C−F bond in the mimetic revealed a shorter
angle regardless the relative stereochemistry of the fluoroalkene
or the nature of the substituent.
In light of these discussions, the following general remarks can
be made. Structurally speaking, the fluoroenamine unit is found
to be similar in terms of steric demand to an ureido unit. The
charge distribution, as evaluated by calculating the NBO and
Mulliken charges, in addition to the calculated solvation free
energies indicate that the fluoroenamine moiety imparts the
proper polarity to mimic that of a urea, with a lowest magnitude
of charge separation. Evaluating the electronic deficiency on the
hydrogen atoms also revealed interesting similarities between the
substituted ureas and their proposed isosteres, similarities that
could find interesting applications in term of hydrogen-bonding
interactions, and thus especially considering the partial rigidity of
the proposed isosteres.4 To further explore this assumption, the
Then, special attention was paid to the comparison of
electronic distribution between ureas elements and fluoroen-
amine ones. As for the unsubstituted derivatives, a larger charge
separation was observed for urea elements than for the proposed
isosteres, but a similar trend was observed with the expected
negative charges on fluorine atom and carbon C1, as for O and N1
in the ureas. Even more interesting was the similarity of the
positive charges located on the hydrogen atoms, revealing a
potential ability of the isosteres to act as hydrogen bond donor
(Figure 6).
To further explore this aspect, the solvation free energies in the
aqueous phase of the ureas and the fluoroenamines were
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Figure 7. Electrostatic potential of the ureas D1C2 and D3cis and their fluoroenamines isosteres C1a and C′3cis (color alteration from red to blue
describes the shift of the electronically rich to deficient circumstance).
comparison of the electrostatic potential profiles was performed
for ureas D1C2 and D3cis and fluoroenamines C1a and C′3cis
minima (Figure 7).
exploited in SAR studies and could be used as potent isosteres of
urea derivatives.
EXPERIMENTAL SECTION
As already anticipated, the ureas have a very negative oxygen, a
highly positive carbonyl carbon, and very positive NH hydro-
gens. The evaluated isosteres have an appropriately polarized
CC double bond, a negative fluorine atom in place of the
oxygen atom of the urea, and a positive CH in place of one NH
moiety of ureas, the enamide free NH2 group showing close
electronic distribution to the corresponding NH2 group of the
urea. Thus, the fluoroenamines indeed mimic the ureas
electronically, with analogous continuous charge distribution.
Finally, the question remains to the overall effectiveness of the
fluorenamines as ureido bioisosteres. It could be considered that
there are a lot of effects that determine or influence the effect of a
group to act as a bioisostere, and the ideal evaluation would come
from bioactivities comparison of fluoroenamine-containing
bioactive derivatives. However, in a pharmaceutical context
where new molecular frameworks are needed,56 this work sets
the stage for further evaluation in this field. In addition, taking
into account the similarity of charge distribution between the
proposed isosteres and their ureido analogues, these results
would find great interest in the field of homogeneous catalysis
and organic synthesis, with the proposed synthetic procedure for
the preparation of their analogues offering a straightforward
access to these derivatives.
■
Reactions performed in HF/pyridine media were carried out in a sealed
Teflon flask with a magnetic stirrer. No further precautions have to be
taken to keep the mixture from moisture (a test reaction performed in
anhydrous conditions leads to the same results, as expected). Yields refer
to isolated pure products. 1H, 13C, and 19F NMR were recorded on a 400
MHz spectrometer using CDCl3 as solvent. DEPT 135, COSY 1H−1H,
and 1H−13C experiments were used to confirm the NMR peaks
assignments. Melting points were determined in a capillary tube. All
separations were done under flash chromatography conditions on silica
gel (15−40 μm). High-resolution mass spectra were obtained on a Qtof
spectrometer. All reactions for ynamide synthesis were carried out in
oven-dried glassware under an argon atmosphere employing standard
techniques in handling air-sensitive materials. Copper-catalyzed
reactions were carried out in resealable pressure tubes. All solvents
were reagent grade. 1,4-Dioxane was freshly distilled from sodium/
benzophenone under argon and degassed immediately prior to use.
Copper(I) iodide (99.999% purity) was purchased from Aldrich and
used as supplied. Finely powdered cesium carbonate was used for
copper-mediated coupling reactions. All other reagents were used as
supplied. Unless otherwise noted, reactions were magnetically stirred
and monitored by thin-layer chromatography using Merck-Kiesegel
60F254 plates. Flash chromatography was performed with silica gel 60
(particle size 35−70 μm) supplied by SDS. Yields refer to chromato-
graphically and spectroscopically pure compounds, unless otherwise
noted. Data are presented as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, quint = quintuplet, sext =
sextuplet, sept = septuplet, m = multiplet, br = broad), integration, and
coupling constant (J/Hz).
CONCLUSION
■
In conclusion, a new, improved procedure for the synthesis of α-
fluoroenamides has been developed. This second-generation
procedure displays a broader scope than the previously reported
procedure on the basis of the use of neat HF, therefore
circumventing the problem of handling pure HF superacid, and
can be applied to the synthesis of E and Z isomers. These new
conditions also allowed a better understanding of the mechanism
of the hydrofluorination process and its substrate-dependent
stereoselectivity. Stability studies and calculations tend to
confirm that these new fluorinated building blocks could be
Procedure A: General Procedure for the Synthesis of
Ynamides from 1,1-Dibromo-1-alkenes. A 15 mL pressure tube
was charged with the sulfonamide, amide, or oxazolidinone (3.2 mmol, 1
equiv), the 1,1-dibromo-1-alkene (3.8 mmol, 1.2 equiv), Cs2CO3 (12.8
mmol, 4 equiv), and copper(I) iodide (0.4 mmol, 0.12 equiv). The tube
was fitted with a rubber septum, evacuated under high vacuum, and
backfilled with argon. Dry and degassed 1,4-dioxane or DMF (6 mL)
and N,N′-dimethylethylenediamine (60 μL, 0.6 mmol, 0.18 equiv) were
next added, the rubber septa was replaced by Teflon-coated screw cap,
and the light blue-green suspension was heated at 80 °C for 1 or 2 days.
The brownish suspension was cooled to rt. When the reaction was run in
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1,4-dioxane, the crude reaction mixture was filtered over a plug of silica
gel (washed with EtOAc) and concentrated. When the reaction was run
in DMF, the crude reaction mixture was diluted with water and extracted
with diethyl ether, and the combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated. The crude residue
was purified by flash chromatography over silica gel.
N-Benzyl-2-(thiophen-3-yl)-N-tosylethynamine (1n). This com-
pound was obtained from N-benzyl-N-tosylamine (846 mg, 3.2
mmol) and 3-(2,2-dibromovinyl)thiophene (1.04 g, 3.8 mmol)
following general procedure A. The crude reaction mixture was purified
over silica gel with petroleum ether/ethyl acetate 90/10 as the eluent,
thereby obtaining compound 1n (1.03 g, 87%). Orange solid. Mp:
97.5−99.0 °C. 1H NMR (CDCl3, 400 MHz, ppm) δ: 7.78 (d, 2 H, J = 8.3
Hz), 7.33−7.29 (m, 7 H), 7.27 (dd, 1 H, J = 3.0 Hz, J = 1.1 Hz), 7.27 (dd,
1 H, J = 3.0 Hz, J = 1.1 Hz), 7.20 (dd, 1 H, J = 5.0 Hz, J = 3.0 Hz), 6.95
(dd, 1 H, J = 5.0 Hz, J = 1.1 Hz), 4.57 (s, 2 H), 2.45 (s, 3 H). 13C NMR
(CDCl3, 100 MHz, ppm) δ: 144.7, 134.9, 134.6, 130.2 (CH), 129.8
(CH), 128.9 (CH), 128.6 (CH), 128.6 (CH), 128.4 (CH), 127.9 (CH),
125.2 (CH), 121.6, 82.1, 66.5, 55.8 (CH2), 21.8 (CH3). HRMS (Q-
TOF, ES+, CH3CN): m/z calcd for C20H17NO2S2 [M + H]+ 368.0779,
m/z found 368.0777.
ppm) δ: 7.84 (d, 2 H, J = 7.9 Hz), 7.34 (d, 2 H, J = 8.0 Hz), 7.28 (dd, 2 H,
J = 8.6 Hz, J = 5.4 Hz), 7.15 (m, 5 H), 6.92 (dd, 2 H, J = 8.8 Hz, J = 8.8
Hz), 6.13 (d, 1 H, J = 8.6 Hz), 4.38 (s, 2 H), 2.46 (s, 3 H). 13C NMR
(CDCl3, 100 MHz, ppm) δ: 162.4 (d, J = 248 Hz), 146.8 (d, J = 274 Hz),
144.7, 135.7, 133.5, 130.1 (dd, CH, J = 8 Hz, J = 4 Hz), 129.9 (CH),
129.5 (CH), 128.4 (5 CH), 127.2 (dd, J = 8 Hz, J = 3 Hz), 115.3 (d, CH,
J = 22 Hz), 110.9 (d, CH, J = 42 Hz), 52.1 (CH2), 21.7 (CH3). 19F {1H}
NMR (CDCl3, 376 MHz, ppm) δ: −113.51, −89.09. HRMS (ESI,
CH3OH): m/z calcd for C22H19NO2F2S [M + H]+ 400.1183, m/z found
400.1179.
(E)-N-Benzyl-1-fluoro-N-tosylbut-1-en-1-amine (2c). This com-
pound was obtained from ynamide 1c (84 mg, 0.267 mmol) following
general procedure B at −10 °C during 15 min. The crude reaction
mixture was purified over silica gel with petroleum ether/ethyl acetate
92/8 as the eluent, thereby obtaining compound 2c (37 mg, 42%).
White solid. Mp: 74−75 °C. 1H NMR (C3D6O, 400 MHz, ppm) δ: 7.84
(d, 2 H, J = 8.3 Hz), 7.48 (d, 2 H, J = 8.0 Hz), 7.34 (m, 5 H), 5.13 (dd, 1
H, J = 7.7 Hz, J = 7.7 Hz), 4.40 (s, 2 H), 2.47 (s, 3 H), 1.78 (dqd, 2 H, J =
7.6 Hz, J = 7.6 Hz, J = 1.7 Hz), 0.61 (td, 3 H, J = 7.5 Hz, J = 0.9 Hz). 13C
NMR (C3D6O, 100 MHz, ppm) δ: 146.9 (d, J = 267 Hz), 145.3, 137.4,
135.9, 130.8 (CH), 130.1 (CH), 129.3 (CH), 129.0 (CH), 128.6 (CH),
113.6 (d, CH2, J = 32 Hz), 52.0 (CH2), 21.5 (CH3), 20.1 (d, CH2, J = 4
Hz), 13.4 (d, CH3, J = 3 Hz). 19F {1H} NMR (C3D6O, 376 MHz, ppm)
δ: −99.15. HRMS (ESI, CH3OH): m/z calcd for C18H20NO2FS [M +
Na]+ 356.1096, m/z found 356.1097.
(E)-N-Benzyl-1-fluoro-N-tosyldec-1-en-1-amine (2d). This com-
pound was obtained from ynamide 1d (52 mg, 0.130 mmol) following
general procedure B at −10 °C during 15 min. The crude reaction
mixture was purified over silica gel with petroleum ether/ethyl acetate
96/4 as the eluent, thereby obtaining compound 2d (25 mg, 46%).
White solid. Mp: 40−42 °C. 1H NMR (C3D6O, 400 MHz, ppm) δ: 7.84
(d, 2 H, J = 8.2 Hz), 7.48 (d, 2 H, J = 8.5 Hz), 7.34 (m, 5 H), 5.16 (dd, 1
H, J = 7.7 Hz, J = 7.7 Hz), 4.41 (s, 2 H), 2.47 (s, 3 H), 1.76 (dtd, 2 H, J =
7.9 Hz, J = 7.9 Hz, J = 1.7 Hz), 1.11−1.36 (m, 8 H), 1.05 (m, 2 H), 0.92
(m, 2 H), 0.89 (t, 3 H, J = 7.1 Hz). 13C NMR (C3D6O, 100 MHz, ppm)
δ: 147.1 (d, J = 267 Hz), 145.3, 137.4, 135.9, 130.8 (CH), 130.2 (CH),
129.3 (CH), 129.0 (CH), 128.6 (CH), 112.3 (d, CH, J = 32 Hz), 52.0
(CH2), 32.6 (CH2), 30.1 (CH2), 30.0 (CH2), 29.5 (d, CH2, J = 2 Hz),
26.8 (d, CH2, J = 3 Hz), 23.3 (2 CH2), 21.5 (CH3), 14.4 (CH3). 19F
{1H} NMR (C3D6O, 376 MHz, ppm) δ: −98.44. HRMS (ESI,
CH3OH): m/z calcd for C24H32NO2FS [M + Na]+ 440.2035, m/z found
440.2031.
N-((E)-1-Fluoro-2-phenylvinyl)-N-tosylprop-2-en-1-amine (2e).
This compound was obtained from ynamide 1e (80 mg, 0.257 mmol)
following general procedure B at −10 °C during 5 min. The crude
reaction mixture was purified over silica gel with petroleum ether/ethyl
acetate 95/5 as the eluent, thereby obtaining compound 2e (69 mg,
81%). White solid. Mp: 52−53 °C. 1H NMR (C3D6O, 400 MHz, ppm)
δ: 7.81 (d, 2 H, J = 7.9 Hz), 7.55 (d, 2 H, J = 7.1 Hz), 7.26−7.36 (m, 5 H),
6.29 (d, 1 H, J = 8.5 Hz), 5.63 (tdd, 1 H, J = 17.0 Hz, J = 10.1 Hz, J = 6.7
Hz), 5.12 (dd, 1 H, J = 16.6 Hz, J = 2.3 Hz), 5.08 (dd, 1 H, J = 10.1 Hz, J =
2.2 Hz), 3.91 (d, 2 H, J = 6.9 Hz), 2.44 (s, 3 H). 13C NMR (C3D6O, 100
MHz, ppm) δ: 147.2 (d, J = 275 Hz), 144.6, 135.9, 131.4 (d, J = 8 Hz),
130.8 (CH), 129.8 (CH), 128.7 (CH), 128.5 (d, 2CH, J = 4 Hz), 128.3
(CH), 128.2 (CH), 120.6 (CH2), 111.3 (d, CH, J = 42 Hz), 51.4 (d,
CH2, J = 2 Hz), 21.7 (CH3). 19F {1H} NMR (C3D6O, 376 MHz, ppm)
δ: −85.58. HRMS (ESI, CH3OH): m/z calcd for C18H18NO2FS [M +
Na]+ 354.0940, m/z found 354.0934.
All other ynamides synthesized using this method were previously
reported.57
Ynamide 1j was prepared by copper-catalyzed cross-coupling
between oxazolidinone and potassium (1-phenylethynyl) trifluorobo-
rate and previously reported.58
Ynamides 1q and 1r were prepared by copper-catalyzed coupling
reaction between alkynyl(triaryl)bismuthonium salts and five mem-
bered imides.59
Procedure B: General Procedure for the Synthesis of
Fluoroenamides from Ynamides. To a mixture of hydrofluoric
acid and pyridine (4 mL, 70/30 w/w) maintained at the required
temperature was added the starting ynamide. The mixture was
magnetically stirred at the same temperature during the required time.
The reaction mixture was then neutralized with water−ice−sodium
carbonate solution and extracted with dichloromethane (×3). The
combined organic phases were dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo. Products were isolated by column
chromatography over silica gel.
(E)-N-Benzyl-1-fluoro-2-phenyl-N-tosylethenamine (2a). This
compound was obtained from N-benzyl-2-phenyl-N-tosylethynamine
(1a) (80 mg, 0.221 mmol) following general procedure B at −10 °C
during 15 min. The crude reaction mixture was purified over silica gel
with petroleum ether/ethyl acetate 97/3 as the eluent, thereby obtaining
1
compound 2a (73 mg, 86%). White solid. Mp: 70−72 °C. H NMR
(CDCl3, 400 MHz, ppm) δ: 7.84 (d, 2 H, J = 8.1 Hz), 7.34 (m, 4 H), 7.27
(m, 3 H), 7.16 (m, 3 H), 7.08 (m, 2 H), 6.17 (d, 1 H, J = 8.7 Hz), 4.40 (s,
2 H), 2.48 (s, 3 H). 13C NMR (CDCl3, 100 MHz, ppm) δ: 147.0 (d, J =
273 Hz), 144.6, 136.0, 133.7, 131.2 (d, J = 8 Hz), 129.9 (2 CH), 129.5 (2
CH), 128.4 (9 CH), 128.0 (CH), 111.5 (d, CH, J = 42 Hz), 52.2 (CH2),
21.8 (CH3). 19F {1H} NMR (CDCl3, 376 MHz, ppm) δ: −87.13.
HRMS (Q-TOF, ES+, CH3OH): m/z calcd for C22H20FNO2S [M +
Na]+ 404.1097, m/z found 404.1098.
N-Benzyl-2-phenyl-N-tosylacetamide (3a). This compound is the
byproduct obtained when the reaction conditions are optimized. It was
purified over silica gel with petroleum ether/ethyl acetate 95/5 as the
eluent. White solid. Mp: 70−72 °C. 1H NMR (CDCl3, 400 MHz, ppm)
δ: 7.65 (d, 2 H, J = 8.4 Hz), 7.33 (m, 5 H), 7.25 (m, 5 H), 6.99 (dd, 2 H, J
= 7.0 Hz, J = 2.5 Hz), 5.08 (s, 2 H), 3.87 (s, 2 H), 2.43 (s, 3 H). 13C NMR
(CDCl3, 100 MHz, ppm) δ: 171.4, 145.1, 136.7, 136.7, 133.3, 129.8
(CH), 129.4 (CH), 128.8 (CH), 128.7 (CH), 128.1 (CH), 127.9 (CH),
127.9 (CH), 127.3 (CH), 49.8 (CH2), 43.0 (CH2), 21.8 (CH3). HRMS
(ESI, CH3OH): m/z calcd for C22H21NO3S [M + Na]+ 402.1140, m/z
found 402.1136.
(3E)-N-Benzyl-1-fluoro-4-phenyl-N-dien-1-amine (2f). This com-
pound was obtained from ynamide 1f (33 mg, 0.085 mmol) following
general procedure B at 0 °C during 2 h. The crude reaction mixture was
purified over silica gel with petroleum ether/ethyl acetate 95/5 as the
eluent, thereby obtaining compound 2f (16 mg, 46%). White solid. 1H
NMR (C3D6O, 400 MHz, ppm) δ: 7.88 (d, 2 H, J = 8.3 Hz), 7.85 (d, 2 H,
J = 8.4 Hz), 7.20−7.53 (m, 12 H), 6.83 (ddd, 1 H, J = 15.9 Hz, J = 10.9
Hz, J = 1,0 Hz), 6.62 (d, 1 H, J = 15.9 Hz), 6.50 (d, 1 H, J = 15.8 Hz), 6.32
(ddd, 1 H, J = 15.8 Hz, J = 10.8 Hz, J = 1.1 Hz), 6.04 (ddd, 1 H, J = 10.8
Hz, J = 5.1 Hz, J = 0.5 Hz), 5.64 (ddd, 1 H, J = 27.2 Hz, J = 10.9 Hz, J =
0.5 Hz), 4.60 (s, 2 H), 4.59 (s, 2 H), 2.48 (s, 3 H), 2.41 (s, 3 H). 13C
NMR (C3D6O, 100 MHz, ppm) δ: 149.1 (d, J = 276 Hz), 147.7 (d, J =
(E)-N-Benzyl-1-fluoro-2-(4-fluorophenyl)-N-tosylethenamine (2b).
This compound was obtained from ynamide 1b (70 mg, 0.184 mmol)
following the general procedure B at −10 °C during 15 min. The crude
reaction mixture was purified over silica gel with petroleum ether/ethyl
acetate 97/3 as the eluent, thereby obtaining compound 2b (63 mg,
1
85%). White solid. Mp: 107−109 °C. H NMR (CDCl3, 400 MHz,
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280 Hz), 145.7, 145.5, 137.8, 137.6, 137.3, 136.9, 136.2, 135.9, 134.8 (d,
CH, J = 4 Hz), 134.4 (d, CH, J = 11 Hz), 130.9 (CH), 130.9 (CH), 130.1
(CH), 129.5 (CH), 129.5 (CH), 129.4 (CH), 129.4 (CH), 129.3 (CH),
129.1 (CH), 129.0 (CH), 128.9 (CH), 128.7 (CH), 128.6 (CH), 127.4
(CH), 127.2 (CH), 122.2 (d, CH, J = 4 Hz), 120.3 (d, CH, J = 1 Hz),
113.0 (d, CH, J = 40 Hz), 111.4 (d, CH, J = 25 Hz), 53.0 (CH2), 52.6
(CH2), 21.5 (CH3), 21.5 (CH3). 19F {1H} NMR (C3D6O, 376 MHz,
ppm) δ: −94.53 (d, J = 27.3 Hz), −92.84 (d, J = 4.8 Hz). HRMS (ESI,
CH3OH): m/z calcd for C24H22NO2FS [M + H]+ 408.1428, m/z found
408.1436.
N-((E)-1-Fluoro-2-phenylvinyl)-N-tosylpropan-1-amine (2g). This
compound was obtained from ynamide 1g (105 mg, 0.336 mmol)
following general procedure B at −10 °C during 1 h. The crude reaction
mixture was purified over silica gel with the eluent petroleum ether/
ethyl acetate 96/4 as the eluent, thereby obtaining compound 2g (25
mg, 22%). Light yellow oil. 1H NMR (C3D6O, 400 MHz, ppm) δ: 7.83
(d, 2 H, J = 8.0 Hz), 7.64 (m, 2 H), 7.46 (d, 2 H, J = 8.6 Hz), 7.36 (m, 2
H), 7.30 (m, 1 H), 6.44 (d, 1 H, J = 8.9 Hz), 3.27 (td, 2 H, J = 7.6 Hz, J =
1.7 Hz), 2.45 (s, 3 H), 1.48 (tq, 2 H, J = 7.6 Hz, J = 7.4 Hz), 0.76 (t, 3 H, J
= 7.4 Hz). 13C NMR (C3D6O, 100 MHz, ppm) δ: 148.4 (d, J = 273 Hz),
145.5, 137.0, 132.5 (d, J = 8 Hz), 130.7 (CH), 129.3 (d, CH, J = 4 Hz),
129.3 (CH), 128.9 (3 CH), 111.8 (d, CH, J = 43 Hz), 50.9 (CH2), 21.9
(CH2), 21.5 (CH3), 11.4 (CH3). 19F {1H} NMR (C3D6O, 376 MHz,
ppm) δ: −86.35. HRMS (ESI, CH3OH): m/z calcd for C18H20NO2FS
[M + Na]+ 356.1097, m/z found 356.1092.
123.0 (CH), 112.1 (d, CH, J = 43 Hz), 53.5 (CH2), 21.5 (CH3). 19F
{1H} NMR (C3D6O, 376 MHz, ppm) δ: −78.64. HRMS (ESI,
CH3OH): m/z calcd for C21H19N2O2FS [M + H]+ 383.1230, m/z found
383.1233.
(Z)-N-Benzyl-1-fluoro-2-(pyridin-2-yl)-N-tosylethenamine (2i-Z).
1
Brown solid. Mp: 118−121 °C. H NMR (C3D6O, 400 MHz, ppm)
δ: 8.50 (dm, 1 H, J = 4.8 Hz), 7.88 (d, 2 H, J = 8.4 Hz), 7.71 (ddd, 1 H, J =
7.8 Hz, J = 7.8 Hz, J = 1.8 Hz), 7.54 (d, 1 H, J = 8.0 Hz), 7.50 (d, 2 H, J =
8.5 Hz), 7.39 (m, 2 H), 7.34 (m, 2 H), 7.28 (m, CH), 7.20 (dd, 1 H, J =
7.5 Hz, J = 4.8 Hz), 5.87 (d, 1 H, J = 29.9 Hz), 4.69 (s, 2 H), 2.47 (s, 3 H).
13C NMR (C3D6O, 100 MHz, ppm) δ: 152.5 (d, J = 8 Hz), 150.4 (CH),
149.8 (d, J = 285 Hz), 145.7, 137.2 (CH), 136.7, 136.1, 130.9 (CH),
129.5 (CH), 129.4 (CH), 128.9 (CH), 128.6 (CH), 124.3 (d, CH, J = 13
Hz), 123.3 (CH), 111,6 (d, CH, J = 20 Hz), 52.9 (CH2), 21.5 (CH3). 19
F
{1H} NMR (C3D6O, 376 MHz, ppm) δ: −84.70. HRMS (ESI,
CH3OH): m/z calcd for C21H19N2O2FS [M + H]+ 383.1230, m/z found
383.1232.
3-((E)-1-Fluoro-2-phenylvinyl)oxazolidin-2-one (2j). This com-
pound was obtained from ynamide 1j (100 mg, 0.534 mmol) following
general procedure B at −20 °C during 5 min. The crude reaction mixture
was purified over silica gel with petroleum ether/ethyl acetate 80/20 as
the eluent, thereby obtaining compound 2j (99 mg, 89%). White solid.
Mp: 57−59 °C. 1H NMR (C3D6O, 400 MHz, ppm) δ: 7.37 (m, 4 H),
7.27 (t, 1 H, J = 6.9 Hz), 6.34 (d, 1 H, J = 8.6 Hz), 4.57 (dd, 1 H, J = 8.6
Hz, J = 7.2 Hz), 3.97 (ddd, 2 H, J = 9.4 Hz, J = 7.2 Hz, J = 2.7 Hz). 13C
NMR (C3D6O, 100 MHz, ppm) δ: 155.5 (d, J = 3 Hz), 147.5 (d, J = 263
Hz), 132.6 (d, J = 8 Hz), 129.5 (CH), 128.8 (d, CH, J = 4 Hz), 128.5
Compounds 2h. These compounds were obtained from ynamide 1h
(108 mg, 0.298 mmol) following general procedure B at −20 °C during
20 min. The crude reaction mixture was purified over silica gel with
petroleum ether/ethyl acetate 85/15 as the eluent, thereby obtaining
compounds 2h (90 mg, 79%). The isomers can be separated through a
subsequent flash chromatography with eluent petroleum ether/
CH2Cl2/MeOH 50/48/2 as the eluent.
(CH), 107.5 (d, CH, J = 40 Hz), 64.1 (CH2), 44.7 (d, CH2, J = 2 Hz). 19
F
{1H} NMR (C3D6O, 376 MHz, ppm) δ: −92.38. HRMS (ESI,
CH3OH): m/z calcd for C11H10NO2F [M + H]+ 208.0774, m/z found
208.0779.
(E)-N-Benzyl-1-fluoro-2-(4-cyano)phenyl-N-tosylethenamine (2k).
This compound was obtained from ynamide 1k (96 mg, 0.248 mmol)
following general procedure B at 0 °C during 30 min. The crude reaction
mixture was purified over silica gel with petroleum ether/ethyl acetate
90/10 as the eluent, thereby obtaining compound 2k (28 mg, 28%). Pale
yellow visquous solid. 1H NMR (CDCl3, 400 MHz, ppm) δ: 7.82 (d, 2
H, J = 7.9 Hz), 7.48 (d, 2 H, J = 8.4 Hz), 7.36 (m, 4 H), 7.15 (m, 5 H),
6.15 (d, 1 H, J = 8.0 Hz), 4.36 (s, 2 H), 2.48 (s, 3 H). 13C NMR (CDCl3,
100 MHz, ppm) δ: 148.6 (d, J = 279 Hz), 145.1, 136.3 (d, J = 9 Hz),
135.4, 133.1, 132.0 (CH), 130.1 (CH), 129.7 (CH), 128.9 (d, CH, J = 4
Hz), 128.7 (CH), 128.6 (CH), 128.4 (CH), 118.9, 111.3, 110.9 (d, CH,
J = 43 Hz), 52.2 (CH2), 21.8 (CH3). 19F {1H} NMR (CDCl3, 376 MHz,
ppm) δ: −84.82. HRMS (ESI, CH3OH): m/z calcd for C23H19N2O2FS
[M + H]+ 407.1230, m/z found 407.1227.
(Z)-N-Benzyl-1-fluoro-2-(9-anthracyl)-N-tosylethenamine (2l).
This compound was obtained from ynamide 1l (81 mg, 0.176 mmol)
following general procedure B at 0 °C during 1h. The crude reaction
mixture was purified over silica gel with petroleum ether/ethyl acetate
92/8 as the eluent, thereby obtaining compound 2l (9 mg, 10%). White
viscous solid. 1H NMR (CDCl3, 400 MHz, ppm) δ: 8.37 (s, 1 H), 7.92
(d, 2 H, J = 8.5 Hz), 7.90 (d, 2 H, J = 8.3 Hz), 7.58 (dbroad, 2 H, J = 8.6
Hz), 7.50 (m, 5 H) 7.42 (tm, 2 H, J = 7.2 Hz), 7.34 (tm, 4 H, J = 8.1 Hz),
6.48 (d, 1 H, J = 29.2 Hz), 4.61 (s, 2 H), 2.42 (s, 3 H). 13C NMR (CDCl3,
100 MHz, ppm) δ: 146.7 (d, J = 280 Hz), 144.6, 135.8, 134.5, 131.3,
130.1 (CH), 129.9 (CH), 129.8, 129.1 (CH), 128.7 (CH), 128.6 (CH),
128.0 (CH), 127.4 (CH), 126.0 (CH), 125.9 (CH), 125.3 (CH), 108.5
(d, J = 28 Hz), 51.6 (CH2), 21.8 (CH3). 19F {1H} NMR (CDCl3, 376
MHz, ppm) δ: −92.23. HRMS (ESI, CH3OH): m/z calcd for
C30H24NO2FS [M + H]+ 482.1590, m/z found 482.1589.
(E)-N-Benzyl-1-fluoro-2-(pyridin-3-yl)-N-tosylethenamine (2h-E).
1
Light brown solid. Mp: 89−92 °C. H NMR (C3D6O, 400 MHz,
ppm) δ: 8.48 (d, 1 H, J = 2.1 Hz), 8.40 (dd, 1 H, J = 4.8 Hz, J = 1.6 Hz),
7.88 (d, 2 H, J = 8.0 Hz), 7.79 (ddd, 1 H, J = 8.0 Hz, J = 1.7 Hz, J = 0.5
Hz), 7.49 (d, 2 H, J = 8.6 Hz), 7.18 (m, 6 H), 6.31 (d, 1 H, J = 8.3 Hz),
4.48 (s, 2 H), 2.47 (s, 3 H). 13C NMR (C3D6O, 100 MHz, ppm) δ: 150.4
(d, CH, J = 4 Hz), 149.6 (CH), 148.9 (d, J = 276 Hz), 145.9, 136.6, 135.2
(d, CH, J = 3 Hz), 134.6, 130.9 (CH), 130.4 (CH), 129.2 (CH), 129.1
(CH), 129.0 (CH), 128.4 (d, J = 8 Hz), 123.8 (CH), 109.5 (d, CH, J =
44 Hz), 52.7 (CH2), 21.5 (CH3). 19F {1H} NMR (C3D6O, 376 MHz,
ppm) δ: −87.08. HRMS (ESI, CH3OH): m/z calcd for C21H19N2O2FS
[M + H]+ 383.1230, m/z found 383.1229.
(Z)-N-Benzyl-1-fluoro-2-(pyridin-3-yl)-N-tosylethenamine (2h-Z).
White solid. Mp: 135−137 °C. 1H NMR (C3D6O, 400 MHz, ppm) δ:
8.52 (d, 1 H, J = 2.0 Hz), 8.44 (dd, 1 H, J = 4.8 Hz, J = 1.5 Hz), 7.88 (d, 2
H, J = 8.3 Hz), 7.77 (dd, 1 H, J = 8.0 Hz, J = 1.8 Hz), 7.52 (d, 2 H, J = 8.6
Hz), 7.33 (m, 6 H), 5.82 (d, 1 H, J = 30.3 Hz), 4.64 (d, 2 H, J = 0.8 Hz),
2.49 (s, 3 H). 13C NMR (C3D6O, 100 MHz, ppm) δ: 150.5 (d, CH, J = 7
Hz), 149.7 (CH), 149.1 (d, J = 282 Hz), 145.7, 136.7, 136.1, 135.9 (d,
CH, J = 9 Hz), 131.0 (CH), 129.6 (CH), 129.4 (CH), 129.1 (d, J = 5
Hz), 129.0 (CH), 128.7 (2CH), 124.4 (CH), 107.6 (d, CH, J = 22 Hz),
52.9 (CH2), 21.5 (CH3). 19F {1H} NMR (C3D6O, 376 MHz, ppm) δ:
−87.08. HRMS (ESI, CH3OH): m/z calcd for C21H19N2O2FS [M +
H]+: 383.1230, m/z found 383.1229.
Compounds 2i. These compounds were obtained from ynamide 1i
(103 mg, 0.285 mmol) following general procedure B at −20 °C during
20 min. The crude reaction mixture was purified over silica gel with
petroleum ether/ethyl acetate 85/15 as the eluent, thereby obtaining
compounds 2i-E (17 mg, 16%) and 2i-Z (74 mg, 68%).
(Z)-N-Benzyl-1-fluoro-2-(2-thiofuranyl)-N-tosylethenamine (2m).
These compounds were obtained from ynamide 1m (100.4 mg, 0.274
mmol) following general procedure B at −20 °C during 1 h. The crude
reaction mixture was purified over silica gel with petroleum ether/
diethylamine 95/5 as the eluent, thereby obtaining compounds 2m
(55.9 mg, 53%). Only the main isomer Z is described. Colorless oil. 1H
NMR (CDCl3, 400 MHz, ppm) δ: 7.77 (d, 2 H, J = 8.3 Hz), 7.36−7.26
(m, 8 H), 7.01 (dbroad, 1 H, J = 3.5 Hz), 6.98−6.94 (m, 1 H), 5.96 (d, 1 H,
J = 29.4 Hz), 4.54 (s, 2 H), 2.46 (s, 3 H). For the E isomer, among
others: 6.38 (d, 1 H, J = 6.2 Hz). 19F {1H} NMR (CDCl3, 376 MHz,
(E)-N-Benzyl-1-fluoro-2-(pyridin-2-yl)-N-tosylethenamine (2i-E).
1
Beige solid. Mp: 73−76 °C. H NMR (C3D6O, 400 MHz, ppm) δ:
8.34 (dm, 1 H, J = 4.8 Hz), 7.83 (d, 2 H, J = 8.3 Hz), 7.64 (ddd, 1 H, J =
7.8 Hz, J = 7.8 Hz, J = 1.8 Hz), 7.53 (d, 2 H, J = 8.0 Hz), 7.40 (d, 2 H, J =
8.5 Hz), 7.23 (m, 5 H), 7.15 (ddd, 1 H, J = 7.4 Hz, J = 4.8 Hz, J = 0.9 Hz),
6.30 (d, 1 H, J = 8.4 Hz), 4.67 (d, 2 H, J = 1.9 Hz), 2.44 (s, 3 H). 13C
NMR (C3D6O, 100 MHz, ppm) δ: 152.1 (d, J = 12 Hz), 150.7 (d, J = 274
Hz), 150.0 (CH), 145.4, 137.4, 136.8 (CH), 135.6, 130.6 (CH), 130.1
(CH), 129.1 (CH), 129.0 (CH), 128.9 (CH), 124.0 (d, CH, J = 4 Hz),
K
DOI: 10.1021/jo502699y
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
ppm) δ: −91.37. For the E isomer, among others: −93.15. HRMS (Q-
TOF, ES+, CH3OH): m/z calcd for C20H18FNO2S2 [M + H]+ 388.0841,
m/z found 388.0847.
135.0 (CH), 131.6, 124.3 (CH), 111.2 (d, CH, J = 23 Hz), 31.1 (CH2),
24.1 (CH2), 22.3 (CH2), 13.9 (CH3). 19F {1H} NMR (C3D6O, 376
MHz, ppm) δ: −98.60. HRMS (Q-TOF, ES+, CH3OH): m/z calcd for
C14H14FNO2 [M + H]+ 248.1087, m/z found 248.1089.
N-Benzyl-1-fluoro-2-(3-thiofuranyl)-N-tosylethenamine (2n). This
compound was obtained from ynamide 1n (83.7 mg, 0.228 mmol)
following general procedure B at 0 °C during 1 h. The crude reaction
mixture was purified over silica gel with petroleum ether/ethyl acetate
90/10 as the eluent, thereby obtaining compound 2n (29.8 mg, 34%),
which is a mixture of E and Z isomers. Colorless oil. 1H NMR (CDCl3,
400 MHz, ppm) δ: 7.84 (d, 0.56 H, J = 8.1 Hz), 7.78 (d, 1.44 H, J = 8.3
Hz), 7.34 (d, 2 H, J = 8.1 Hz), 7.32−7.11 (m, 8 H), 6.20 (d, 0.28 H, J =
7.6 Hz), 5.74 (d, 0.72 H, J = 30.0 Hz), 4.53 (s, 1.44 H), 4.39 (s, 0.56 H),
2.46 (s, 3 H). 13C NMR (C3D6O, 100 MHz, ppm) δ: 144.3, 144.2, 136.9,
136.7, 134.7, 133.5, 132.7 (d, J = 7 Hz), 131.8 (d, J = 8 Hz), 130.1 (CH),
129.8 (CH), 129.7 (CH), 129.4 (CH), 128.8 (CH), 128.6 (CH), 128.5
(CH), 128.4 (CH), 128.3 (CH), 128.2 (CH), 128.1 (CH), 127.9 (CH),
127.9 (CH), 127.7 (CH), 127.2 (CH), 125.4 (CH), 125.3 (CH), 124.9
(CH), 124.5 (CH), 106.9 (d, CH, J = 43 Hz), 105.5 (d, CH, J = 24 Hz),
52.0 (CH2), 51.7 (CH2), 21.6 (CH3). 19F {1H} NMR (CDCl3, 376
MHz, ppm) δ: −92.69, −92.78. HRMS (Q-TOF, ES+, CH3OH): m/z
calcd for C20H18FNO2S2 [M + H]+ 388.0841, m/z found 388.0847.
(Z)-N-Benzyl-1-fluoro-2-(2,6-dimethylphenyl)-N-tosylethenamine
(2o). This compound was obtained from ynamide 1o (80 mg, 0.226
mmol) following general procedure B at 0 °C during 2 h. The crude
reaction mixture was purified over silica gel with petroleum ether/ethyl
acetate 95/5 as the eluent, thereby obtaining compound 2o (53 mg,
63%). White viscous solid. 1H NMR (CDCl3, 400 MHz, ppm) δ: 7.83
(d, 2 H, J = 8.3 Hz), 7.34 (m, 7 H) 7.04 (t, 1 H, J = 7,5 Hz), 6.94 (d, 2 H, J
= 7.5 Hz), 5.70 (d, 1 H, J = 30.5 Hz), 4.52 (s, 2 H), 2.46 (s, 3 H), 1.97 (s,
6 H). 13C NMR (C3D6O, 100 MHz, ppm) δ: 146.7 (d, J = 276 Hz),
145.5, 137.5, 137.0, 136.0, 131.0 (d, J = 3 Hz), 130.9 (CH), 129.9 (CH),
129.5 (CH), 129.0 (CH), 128.7 (CH), 128.5 (CH), 128.0 (CH), 109.9
(d, CH, J = 29 Hz), 52.5 (CH2), 21.5 (CH3), 20.2 (CH3). 19F {1H}
NMR (CDCl3, 376 MHz, ppm) δ: −93.34. HRMS (ESI, CH3OH): m/z
calcd for C24H24NO2FS [M + H]+ 410.1590, m/z found 410.1587.
(E)-N-Benzyl-1-fluoro-2-(2-methylphenyl)-N-tosylethenamine
(2p). This compound was obtained from ynamide 1p (100 mg, 0.266
mmol) following general procedure B at −10 °C during 10 min. The
crude reaction mixture was purified over silica gel with petroleum ether/
ethyl acetate 95/5 as the eluent, thereby obtaining compound 2p (86
mg, 82%). White viscous solid. 1H NMR (CDCl3, 400 MHz, ppm) δ:
7.80 (d, 2 H, J = 8.0 Hz), 7.42 (m, 1 H) 7.32 (d, 2 H, J = 8.0 Hz), 7.15 (m,
5 H), 7.03 (m, 1 H), 6.90 (m, 2 H), 6.21 (d, 1 H, J = 8.3 Hz), 4.28 (s, 2
H), 2.46 (s, 3 H), 1.93 (s, 3 H). 13C NMR (CDCl3, 100 MHz, ppm) δ:
147.4 (d, J = 272 Hz), 144.5, 136.6 (d, J = 4 Hz), 135.9, 133.7, 130.2 (d, J
= 8 Hz), 129.8 (CH), 129.6 (CH), 129.2 (CH), 128.5 (CH), 128.4 (2
CH), 128.3 (CH), 128.2 (CH), 126.0 (CH), 109.2 (d, CH, J = 40 Hz),
52.1 (CH2), 21.8 (CH3), 19.9 (CH3). 19F {1H} NMR (CDCl3, 376
MHz, ppm) δ: −86.69. HRMS (ESI, CH3OH): m/z calcd for
C23H22NO2FS [M + H]+ 396.1428, m/z found 396.1428.
2-((E)-1-Fluoro-2-phenylvinyl)isoindoline-1,3-dione (2r). This
compound was obtained from ynamide 1r (22.2 mg, 0.090 mmol)
following general procedure B at −10 °C during 1 h. The crude reaction
mixture was purified over silica gel with petroleum ether/ethyl acetate
80/20 as the eluent, thereby obtaining compound 2r (7 mg, 30%).
White solid. 1H NMR (C3D6O, 400 MHz, ppm) δ: 7.96−7.93 (m, 2 H),
7.84−7.81 (m, 2 H), 7.24−7.16 (m, 5 H), 7.73 (d, 1 H, J = 8.1 Hz). 13C
NMR (C3D6O, 100 MHz, ppm) δ: 165.3, 165.2, 140.6 (d, J = 265 Hz),
135.2 (CH), 131.6, 131.1 (d, J = 7 Hz), 128.9 (CH), 128.3 (CH), 127.7
(d, CH, J = 4 Hz), 124.7 (CH), 112.3 (d, CH, J = 34.0 Hz). 19F {1H}
NMR (C3D6O, 376 MHz, ppm) δ: −87.61. HRMS (Q-TOF, ES+,
CH3OH): m/z calcd for C16H10FNO2 [M + H]+ 268.0774, m/z found
268.0768.
N-Benzyl-1,1-difluoro-2-(pyridin-2-yl)-N-tosylethanamine (4).
This compound was obtained from (Z)-N-benzyl-1-fluoro-2-(pyridin-
2-yl)-N-tosylethenamine (2i-Z) (7.5 mg, 0.020 mmol) following general
procedure B, at +20 °C during 20 min. The crude reaction mixture was
purified over silica gel with petroleum ether/ethyl acetate 80/20 as the
eluent, thereby obtaining compound 4 (7.3 mg, 93%). White viscous
solid. 1H NMR (CDCl3, 400 MHz, ppm) δ: 8.50 (d, 1 H, J = 4.1 Hz),
7.64−7.58 (m, 3 H), 7.33 (d, 1 H, J = 7.7 Hz), 7.23−7.15 (m, 8 H), 4.51
(s, 2 H) 3.85 (t, 2 H, J = 15.3 Hz), 2.40 (s, 3 H). 13C NMR (CDCl3, 100
MHz, ppm) δ: 152.4 (t, J = 3 Hz), 149.4 (CH), 144.0, 137.5, 137.5,
136.4 (CH), 129.5 (CH), 128.3 (CH), 128.0 (CH), 127.7 (CH), 127.5
(CH), 125.4 (CH), 122.5 (CH), 49.5 (CH2), 46.5 (t, CH2, J = 30 Hz),
21.5 (CH3). Due to low stability of the compound 4, long time carbon
NMR acquisition could not have been performed, and so the carbons of
CF2 group did not appear. 19F {1H} NMR (CDCl3, 376 MHz, ppm) δ:
−71.41. HRMS (Q-TOF, ESI, CH3CN): m/z calcd for C21H20F2N2O2S
[M + H]+ 403.1286, m/z found 403.1286.
ASSOCIATED CONTENT
■
S
* Supporting Information
Cartesian coordinates and energies (hartrees) for the MP2/cc-
pVDZ- and B3LYP/cc-pVDZ-optimized geometries and 1H and
13C NMR data. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: gevano@ulb.ac.be.
*E-mail: sebastien.thibaudeau@univ-poitiers.fr. Fax: (+) 33-
549453501. Tel: (+) 33-549454588.
Compounds 2q. These compounds were obtained from ynamide 1q
(33.8 mg, 0.149 mmol) following general procedure B at −10 °C during
1 h. The crude reaction mixture was purified over silica gel with
petroleum ether/ethyl acetate 92/8 as the eluent, thereby obtaining
compounds 2q-E (24 mg, 66%) and 2q-Z (12 mg, 34%).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
2-((E)-1-Fluorohex-1-enyl)isoindoline-1,3-dione (2q-E). White
We thank the Universite
Poitiers, the Universite
́
Libre de Bruxelles, the Universite
de Versailles, the CNRS, and the ANR
́
de
1
solid. H NMR (C3D6O, 400 MHz, ppm) δ: 7.97−7.94 (m, 2 H),
́
7.84−7.80 (m, 2 H), 5.62 (d, 1 H, J = 7.9 Hz), 1.90 (qd, 2 H, J = 7.6 Hz, J
= 1.9 Hz), 1.43−1.35 (m, 2 H), 1.32−1.24 (m, 2 H), 0.84 (t, 3 H, J = 7.2
Hz). 13C NMR (C3D6O, 100 MHz, ppm) δ: 165.5, 165.4, 139.9 (d, J =
260 Hz), 135.1 (CH), 131.7, 124.5 (CH), 110.9 (d, CH, J = 26 Hz), 31.2
(CH2), 25.3 (d, CH2, J = 3 Hz), 22.3 (CH2), 13.9 (CH3). 19F {1H}
NMR (C3D6O, 376 MHz, ppm) δ: −93.67. HRMS (Q-TOF, ES+,
CH3OH): m/z calcd for C14H14FNO2 [M + H]+ 248.1087, m/z found
248.1087.
(project VINFLUSUP ANR-11-JS07-003-01) for financial
support. B.M., G.C., and K.J., respectively, acknowledge the
ANR, the Region Poitou-Charentes, and the University of
́
Versailles for graduate fellowships. We also deeply thank Prof.
Sueda for a generous gift of ynimides.
REFERENCES
■
2-((Z)-1-Fluorohex-1-enyl)isoindoline-1,3-dione (2q-Z). White
1
solid. H NMR (C3D6O, 400 MHz, ppm) δ: 7.95−7.92 (m, 2 H),
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DOI: 10.1021/jo502699y
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Article
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