Indium-promoted diastereoselective addition of fluorinated haloallylic derivatives to imines

Article abstract of DOI:10.1021/jo402810s

We report herein the first general access to fluorinated homoallylic amines by means of an addition of fluorinated organoindium reagent. The corresponding amines were obtained in good to excellent yield with excellent diastereoisomeric ratio. A plausible mechanism is proposed to explain the stereochemical outcome of the reaction based on the X-ray structure of the products.

Full text of DOI:10.1021/jo402810s

Article
pubs.acs.org/joc
Indium-Promoted Diastereoselective Addition of Fluorinated
Haloallylic Derivatives to Imines
Gerald Lemonnier, Nathalie Van Hijfte, Thomas Poisson,* Samuel Couve-Bonnaire,
́
and Xavier Pannecoucke*
Normandie Universite,
Saint-Aignan Cedex, France
́
COBRA, UMR 6014 et FR 3038, Universite
́
Rouen, INSA Rouen, CNRS, 1 rue Tesnier
̀
e, 76821 Mont
S
* Supporting Information
ABSTRACT: We report herein the first general access to fluorinated homoallylic amines by means of an addition of fluorinated
organoindium reagent. The corresponding amines were obtained in good to excellent yield with excellent diastereoisomeric ratio.
A plausible mechanism is proposed to explain the stereochemical outcome of the reaction based on the X-ray structure of the
products.
imidazolidinone (Figure 2a).9c,10 Thus, taking into account the
remarkable properties of indium to promote allylation reaction
INTRODUCTION
■
Molecules containing fluorine atom are of great interest on
account of the impressive features of fluorine atom to severely
affect the physical and biological properties of a molecule.1
Hence, fluorine became an unavoidable partner toward the
development of biologically active compounds, resulting in the
presence of at least one fluorine atom in about 20% of
pharmaceuticals and 40% of agrochemicals.2 Among all of these
fluorinated compounds, fluoroolefins represent an important
class of compounds3 used in material science,4 in medicinal
chemistry as peptide isosteres,5 or as versatile fluorinated
building blocks6 (Figure 1).
Figure 2. Past and present work.
Figure 1. Relevant fluoroolefins.
under neutral and mild conditions,11 we were wondering if an
indium-promoted addition of a fluorinated allylic derivative to
an imine would give a straightforward access to the highly
valuable fluorinated homoallylic amines (Figure 2b). Note-
worthy, indium is very appealing because it can be used without
activation prior to use under Barbier conditions along with a
broad functional group tolerance and a very low toxicity. As a
result, indium metal has been extensively used to promote
allylation, propargylation, allenylation, or Reformatsky reac-
tions, while organoindium reagents are becoming very popular
reagents in organic synthesis.12
In addition, chiral homoallylic amines are key compounds
from a synthetic point of view,7 offering a wide range of
possible postfunctionalizations to access to more elaborate
chiral compounds. As part of our ongoing research program
devoted to the synthesis and the development of relevant
fluorinated building blocks8 and our previous work dealing with
the synthesis of fluorinated homoallylic alcohols,8h we have
been surprised that a sole method dealing with the access to
chiral fluorinated homoallylic amines has been reported to date.
Haufe and co-workers described an elegant access to
homoallylic amine derived from glycine by means of a
diastereoselective alkylation of a camphor-based glycine
iminoesters,9a (R,R,R)-2-hydroxy-3-pinanone,9b or Seebach’s
Received: December 18, 2013
Published: March 12, 2014
© 2014 American Chemical Society
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a
Scheme 1. Diastereoselective Addition of Fluorinated Allyl Bromide Derivatives 2a−d to N-Tosylimine 1a−h
a
b
c
Conditions: 1 (0.3 mmol), 2 (1.5 equiv), In0 (1.5 equiv), THF (1 mL), 60 °C, 18 h. Isolated yield. Syn:anti ratio determined by 19F NMR on the
d
e
crude reaction mixture. Reaction was carried out at 75 °C. In0 and 2 were added portionwise; see the Experimental Section for further details.
resulting addition products3b,c were isolated in 64% and 76%
yield, respectively. Noteworthy, the reaction proceeded with a
At the beginning of the project, the N-tosylimine 1a derived
complete syn selectivity, and no trace of the anti adduct was
from 4-chlorobenzaldehyde was engaged in the reaction with
observed. The aliphatic-substituted allyl bromide derivative
RESULTS AND DISCUSSION
■
In(0) and the commercially available 3-chloro-2-fluoropropene
(Z)-2d was then used, and the corresponding adduct 3d was
obtained in 55% yield with a lower diastereoisomeric ratio,
65:35. The N-tosylimine-derived from p-trifluoromethyl
benzaldehyde 1b was tested in our reaction, and the products
resulting from the addition of (Z)-2b and (Z)-2c were isolated
in good yield with a complete syn-selectivity. The addition of
(Z)-2d to imine 1b gave the addition product 3g in 47% yield
with an 85:15 diastereoisomeric ratio. An ester moiety was
compatible under our reaction conditions, imines 1c reacted
2a in THF at 60 °C.13 Gratefully, the desired product 3a was
isolated in 98% yield after 16 h, showing the viability of the
proposed scenario (Figure 2). Using these conditions, we
extended the scope of the reaction to several imines and
fluorinated allyl reagents (Scheme 1).
First, the addition of several fluorinated allyl halides
derivatives 2 was performed on imine 1a. Substituted allyl
bromide derivatives (Z)-2b and (Z)-2c were used, and the
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Figure 3. Crystal structure of compounds 3b and 3n.
smoothly to afford 3h and 3i in moderate to good yield as a
sole syn-diastereoisomer. Then, an imine bearing an electron-
donating group was tested. Imine 1e derived from p-
anisaldehyde reacted with (Z)-2b to give the addition product
3k in good yield, as a syn-stereoisomer. Then, heteroaromatic
imines derived from pyridine and furan were successfully
engaged in the reaction, and homoallylic amines 3l and 3m
were isolated in 58% and 45% yield, respectively. Finally,
aliphatic imines 1h derived from hydrocinnamaldehyde reacted
smoothly, affording the syn adduct 3n in 80% yield as a single
diastereoisomer. Unfortunately, despite all our attempts, N-
tosylketimines remained unreactive under our conditions. One
should note that the N-Ts protecting group might be removed
under standard conditions.14 Interestingly, when the reaction
was carried out with the other diastereoisomer (E)-2b the same
syn addition product 3b than the one obtained with (Z)-2b was
isolated in 83% yield as a single diastereoisomer. This result
might arise from an isomerization of the latent allyl indium
species from the (E)-isomer to the thermodynamically more
stable (Z)-isomer.15,16
The complete γ-selectivity of the reaction as well as the syn-
selectivity of our process has been highlighted through an X-ray
analysis of compound 3b and 3n (Figure 3). The crystal
structure clearly shows the γ-addition of the allylic indium
species and the syn relationship between the two newly created
stereogenic centers. Based on this observed diastereoselectiv-
ities and the experiments between imines 1a and the (Z)- and
(E)-isomer of 2b, we propose the mechanistic pathway
depicted in Figure 4 to explain the stereochemical outcome
of the reaction.
According to the observations independently made by
Chan13 and Paquette,14 the (E)- and (Z)-allyl indium species
are in equilibrium and the thermodynamically more stable (Z)-
allyl isomer is predominant in the reaction media. Then the
allyl species reacts through an open-chain transition state II
giving predominantly the syn-addition product regardless of the
geometry of the starting fluoro allyl compound. It is noteworthy
that transition state III appeared less favorable than transition
state II due to several gauche interactions.17 This difference
might result in the displacement of equilibrium between the E
and Z allyl indium species toward the Z-species, thus explaining
the observed selectivity with (E)-2b (Scheme 1). Finally, the
previous experimental results preclude a coordination of the
nitrogen to the metal center forming of a six-membered
transition state I, which would afford the product with the anti-
relative configuration.
Figure 4. Proposed transition state.
Then, we turned our attention to the development of an
asymmetric approach of the allylation reaction. To access to
chiral fluorinated homoallylic amines by controlling the
addition of our allyl indium species we focused our strategy
on the use of the efficient Ellman auxiliary.18
Under our previous optimized conditions, although only 40%
of the 4-chlorobenzaldehyde-derived sulfinylimine 4a was
converted into the desired homoallylic amine 5a, the latter
was obtained with an excellent 98:2 diastereoselective ratio, and
the only other product detected in the crude mixture was the
starting imine (Table 1, entry 1). Encouraged by this promising
result, we decided to reoptimize the reaction parameters to
access chiral fluorinated homoallylic amines. Using water as a
solvent, no addition occurred and only hydrolysis of the starting
imine 4a was observed (entry 2). Among other organic solvents
tested, dichloroethane (DCE) gave the best result regarding
yields and diastereomeric ratios (entries 3−6). Indeed, the
corresponding amine 5a was obtained with 46% yield, 99:1 dr,
and the starting sulfinylimine 4a was the only side product
detected in the crude mixture at the end of the reaction.
Surprisingly, when the reaction was performed at higher
temperature, the conversion remained almost the same (entry
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9). Thiophene aldimine 5j afforded the addition product in
good yield and very good diastereoselectivity (entry 10). α,β-
Unsaturated aldehydes reacted smoothly under our conditions,
and addition products 5k and 5l were isolated with a nice
diatereoselective ratio (97:3) in very good yield, 80% and 77%,
respectively (entries 11 and 12). Interestingly, the reaction with
chiral imine 4m derived from ferrocenyl aldehyde proceeded
nicely, giving the addition adduct 5m as a sole diastereomer
with 78% yield (entry 13). We then moved toward the
extension to valuable aliphatic aldimines, and pleasingly, both
imines 4n and 4o provide the addition products 5n and 5o in
good yield and very good diastereoisomeric ratio, 96:4 and
95:5, respectively (entries 14 and 15). Imines derived from
citronellal 4p and hydrocinnamaldehyde 4q were tested and
afforded the addition products 5p and 5q in excellent yield and
a 97:3 diastereoisomeric ratio (entries 16 and 17). Then,
reaction was performed using ketimine 4r derived from
acetophenone, and the addition product was isolated in 84%
yield with a 83:17 diastereoisomeric ratio (entry 18). Finally,
we sought to extend the reaction with γ-substituted fluorinated
allyl bromide 2b. Unfortunately, despite all our attempts to get
the corresponding addition product 5s we have not been able
to isolate the desired compound with synthetically useful yield
and selectivity.19 Noteworthy, the addition product 5a might be
easily deprotected under standard conditions17 to give the free
amine 6 without loss of optical purity.20
Table 1. Optimization of the Diastereoselective Addition of
Fluorinated Allyl Derivatives 2a
a
b
c
entry
solvent
T (°C)
x
y
conv
dr
1
THF
60
60
60
60
60
60
70
53
53
53
53
53
3
3
40
98:2
2
H2O
3
3
0
38
52
11
46
49
82
5
3
CH3CN
toluene
DCM
DCE
DCE
DCE
DCE
DCE
DCE
DCE
3
3
99:1
97:3
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
4
3
3
5
3
3
6
3
3
7
3
3
8
3
3
9
1.1
2
1.1
2
10
11
45
6
6
94
d
e
12
3
4
100 (96)
a
Conditions: 4a (0.1 mmol), 2a (x equiv), In0 (y equiv), solvent (1
b
1
mL), 14 h. Conversion of starting sulfinylimine, determined by H
c
NMR of the crude material. Determined by 19F NMR of the crude
d
material. In(0) and 2a were added portionwise, 48 h reaction time.
e
Isolated yield.
The absolute configuration of the addition product 5a has
been determined by an X-ray analysis (Figure 5). The crystal
7). However, lowering temperature to 53 °C gave 82%
conversion into 5a (entry 8). The low boiling point of the
starting allyl chloride 2a (55 °C) might explain the observed
result. Next, the stoichiometry of both In(0) and fluorinated
allyl chloride was modulated (entries 9−11). With a slight
excess of reactants relative to the starting imine 4a, only 5%
conversion into amine 5a was observed (entry 9). Using 2
equiv of In(0) and allyl chloride 2a, conversion reached 45%
(entry 10). Unfortunately, to get almost total conversion of the
imine 4a, the use of a large excess of reactants (6 equiv) was
required (entry 11). However, by adding the reactants in two
portions, 4 equiv of In(0) and 3 equiv of allyl chloride 2a were
sufficient to ensure a total conversion of imine 4a and to isolate
the homoallylic amine 5a in 96% yield (entry 12). Having
optimized the addition of 2a onto the model chiral imine we
sought to extend the scope of this transformation with other
chiral imines (Table 2).
First, imines derived from benzaldehyde and aromatic
aldehydes bearing an electron-donating group were engaged
under our reaction conditions. Imines derived from both p-
anisaldehyde and piperonal gave the desired adducts in very
good yield with excellent diastereoselectvities, 98:2 and 100:0,
respectively, while imine derived from benzaldehyde afforded
the addition product 5b in 95% yield and 98:2 diastereoiso-
meric ratio (entries 2−4). We then investigated the functional
group tolerance of our In-mediated addition reaction.
Interestingly, unprotected phenol and ester derivatives reacted
nicely to afford the corresponding fluorinated homoallylic
compounds 5e and 5f as a single diastereoisomer in good to
excellent yield (entries 5 and 6). Heteroaromatic derivatives
were also compatible and pyridine aldimine 4h provided the
allylation product 5h in pretty good yield with an excellent
diastereoisomeric ratio (97%, 99:1, entry 8), while the
chloroquinoline 4i gave 5i as a single diastereoisomer in
good yield without alteration of the chlorine substituent (entry
Figure 5. Crystal structure of compound 5a.
structure allowed us to determine a (R) configuration of the
newly created stereogenic center. Taking this result into
account, we are able to propose the following transition state
of the reaction (Figure 6).
To explain the observed stereochemistry, we proposed a six-
membered ring transition state, involving a coordination of the
indium metal center21 to the oxygen of the chiral auxiliary. This
coordination would rigidify the intermediate and would allow
an α-addition of the allyl residue giving the corresponding
homoallylic imines with a R configuration of the newly created
Figure 6. Proposed transition state.
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Table 2. Scope of the Reaction
a
b
c
Conditions: 1 (0.1 mmol), 2a (0.3 mmol), In0 (0.4 mmol), DCE (1 mL), 53 °C, 48 h. Isolated yield. Determined by 19F NMR on the crude
d
reaction mixture. 2b was used instead of 2a.
stereocenter. Noteworthy, an open transition state would have
led to the opposite diastereoisomer.
aromatic and aliphatic imines were suitable substrates giving a
straightforward access to chiral fluorinated building blocks. The
relative configuration of the resulting product determined by a
X-ray analysis led us to assume a plausible six-membered ring
intermediate of the reaction. In summary, we reported herein
the first general access to fluorinated homoallylic amines in
both racemic and diastereoselective fashion giving an easy
access to new valuable fluorinated olefins compounds.
CONCLUSION
■
In conclusion, we reported the access to fluorinated homoallylic
amines in good yields and excellent diastereoisomeric ratios.
The complete γ-selectivity of the reaction using γ-substituted
allylic derivative 2b−d was clearly proved by X-ray analysis of
the corresponding products 3b and 3n as well as the syn-
selectivity of the reaction. This methodology was applied to a
broad range of aromatic and aliphatic N-Ts imines in good
yields and excellent diastereoselectivities (up to 100:0). This
process represents the first general access to the syn- addition
products. Then, the use of the Ellman’s auxiliary provided an
efficient access to chiral fluorinated homoallylic amines. Both
EXPERIMENTAL SECTION
■
1
Residual CHCl3 served as internal standards (δ = 7.26) for H NMR,
CFCl3 served as internal standard (δ = 0.0) for 19F NMR and CDCl3
served as internal standard (δ = 77.16) for 13C NMR. Flash
chromatographies were performed with silica gel (0.063−0.200
mm). Analytical thin-layer chromatography (TLC) was performed
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on silica gel aluminum plates with F-254 indicator and visualized by
UV fluorescence and/or staining with KMnO4 or PMA. THF was
distilled over Na/benzophenone prior to use. HRMS analyses were
performed under (ESI) conditions with a micro TOF detector. All
experiments were conducted under nitrogen atmosphere in oven-dried
glassware with magnetic stirring using standard Schlenk techniques. N-
Tosylaldimines 1,22 fluorinated bromoallylic derivatives 2,23 and N-
sulfinylimines 524 were prepared according to literature methods.
General Procedure for the Addition of Fluorinated Bromo
Allylic Derivative 2 to N-Ts Imine 1. In a 1.5 mL vial, 1 (0.3
mmol), indium (0.45 mmol), 2 (0.45 mmol), and THF (1 mL) were
introduced, and the vial was sealed (screwed caps). The resulting
mixture was stirred at 60 °C for 18 h. The reaction mixture was
quenched with 5 drops of NH4Cl (saturated aqueous solution), and
DCM was added. The mixture was filtered through a pad of Celite and
evaporated. The residue was purified by flash chromatography (SiO2,
cyclohexane/EtOAc mixture) to afford the corresponding fluorinated
sulfonamide 3 (see Scheme 1).
N-(1-(4-Chlorophenyl)-3-fluorobut-3-enyl)-4-methylbenzenesul-
fonamide (3a). Compound 3a was obtained as a white solid (mp 88−
92 °C) in 98% yield (69 mg) after trituration in cyclohexane. 1H NMR
(300 MHz, CDCl3): δ 7.57 (d, J = 6.7 Hz, 2H), 7.26−6.90 (m, 6H),
5.95 (d, J = 5.9 Hz, 1H), 4.65−4.38 (m, 2H), 4.19 (d, J = 49.4 Hz,
1H), 2.80−2.43 (m, 2H), 2.40 (s, 3H). 13C NMR (75 MHz, CDCl3):
δ 161.45 (d, J = 257 Hz), 143.6, 138.2, 137.1, 133.4, 129.4 (2C), 128.6
(2C), 128.1 (2C), 127.2 (2C), 93.9 (d, J = 19 Hz), 54.7, 40.1 (d, J =
27 Hz), 21.5. 19F NMR (282 MHz, CDCl3): δ −96.4 (m). IR (cm−1):
3265, 1321, 1151, 809, 671, 534. Anal. Calcd for C17H17ClFNO2S: C,
57.70; H, 4.84; N, 3.96; S, 9.06. Found: C, 58.04; H, 4.96; N, 4.21; S,
9.07.
128.3, 127.9 (2C), 127.1 (2C), 125.0 (q, J = 3 Hz, 2C), 124.0 (q, J =
272 Hz), 93.7 (d, J = 19 Hz), 58.3, 55.8 (d, J = 24 Hz), 21.3. 19F NMR
(282 MHz, CDCl3): δ −63.1 (s), −103.9 (ddd, J = 49, 25, 17 Hz). IR
(cm−1): 3256, 2926, 1677, 1437, 1321, 1152, 1065. HRMS (ESI+):
calcd for [M + H] C24H22F4NO2S 464.1307, found 464.1304 (−0.6
ppm).
syn-N-(2-(4-Bromophenyl)-3-fluoro-1-(4-(trifluoromethyl)-
phenyl)but-3-enyl)-4-methylbenzenesulfonamide (3f). Compound
3f was obtained as a white solid (mp 191−193 °C) in 62% yield (101
mg), after flash chromatography (SiO2, cyclohexane/EtOAc, 95:5 to
65:35, Rf = 0.35 cyclohexane/EtOAc 8:2). 1H NMR (300 MHz,
CDCl3): δ 7.41−7.30 (m, 4H), 7.24−7.15 (m, 4H), 7.08 (d, J = 8.1
Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 5.63 (d, J = 7.5 Hz, 1H), 4.85 (dd, J
= 10.3, 7.6 Hz, 1H), 4.32 (dd, J = 17.3, 3.5 Hz, 1H), 4.12 (dd, J = 49.4,
3.5 Hz, 1H), 3.54 (dd, J = 25.7, 10.4 Hz, 1H), 2.38 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 162.1 (d, J = 261 Hz), 143.5, 142.5, 136.4, 134.9,
131.9 (2C), 130.0 (2C), 129.8 (q, J = 32 Hz), 129.3 (2C), 127.7 (2C),
126.8 (2C), 125.2 (q, J = 4 Hz, 2C), 123.9 (q, J = 272 Hz), 122.1, 93.9
(d, J = 19 Hz), 58.3, 55.1 (d, J = 24 Hz), 21.3. 19F NMR (282 MHz,
CDCl3): δ −63.1 (s), −104.9 (ddd, J = 49, 26, 17 Hz). IR (cm−1):
3231, 1673, 1453, 1321, 11150, 1113, 1065. HRMS (ESI-): calcd for
[M−H] C24H19BrF4NO2S 540.0256, found 540.0234 (−4.1 ppm).
syn-Methyl 4-(3-Fluoro-1-(4-methylphenylsulfonamido)-2-phe-
nylbut-3-enyl)benzoate (3h). Compound 3h was obtained as a
yellow solid (mp 191−193 °C) in 55% yield (74.8 mg), after flash
chromatography (SiO2, cyclohexane/EtOAc, 95:5 to 65:35, Rf = 0.16
cyclohexane/EtOAc 8:2). 1H NMR (300 MHz, CDCl3): δ 7.76 (d, J =
7.5 Hz, 2H), 7.27−6.90 (m, 11H), 4.82 (d, J = 3.4 Hz, 1H), 4.75 (dd, J
= 8.8, 5.0 Hz, 1H), 4.26 (dd, J = 17.5, 3.1 Hz, 1H), 4.07 (dd, J = 49.5,
3.1 Hz, 1H), 3.83 (s, 3H), 3.48 (dd, J = 24.7, 9.4 Hz, 1H), 2.27 (s,
3H). 13C NMR (75 MHz, CDCl3): δ 166.7, 162.6 (d, J = 261 Hz),
143.8, 143.4, 136.2, 135.2, 129.5, 129.4 (2C), 129.3(2C), 129.2 (2C),
128.5 (2C), 128.3, 127.5 (2C), 127.2 (2C), 93.7 (d, J = 19 Hz), 58.4,
56.0 (d, J = 24 Hz), 52.1, 21.4. 19F NMR (282 MHz, CDCl3): δ
−103.6 (ddd, J = 49, 24, 17 Hz). IR (cm−1): 3237, 2859, 11674, 1435,
1322, 1152, 1080. HRMS (ESI+): calcd for [M + H] C25H25FNO4S
454.1488, found 454.1496 (1.8 ppm).
syn-Methyl 4-(2-(4-Bromophenyl)-3- fluoro-1- (4-
methylphenylsulfonamido)but-3-enyl)benzoate (3i). Compound 3i
was obtained as a white solid (mp 197−199 °C) in 60% yield (95.5
mg), after flash chromatography (SiO2, cyclohexane/EtOAc, 95:5 to
65:35, Rf = 0.19 cyclohexane/EtOAc 8:2). 1H NMR (300 MHz,
CDCl3): δ 7.78 (d, J = 8.4 Hz, 2H), 7.31−7.20 (m, 4H), 7.11 (d, J =
8.2 Hz, 2H), 7.02−6.89 (m, 4H), 4.82−4.68 (m, 2H), 4.29 (dd, J =
17.5, 3.5 Hz, 1H), 4.09 (dd, J = 49.5, 3.5 Hz, 1H), 3.84 (s, 3H), 3.45
(dd, J = 24.5, 9.6 Hz, 1H), 2.30 (s, 3H). 13C NMR (75 MHz, CDCl3):
δ 166.7, 162.2 (d, J = 261 Hz), 143.9, 143.5, 136.5, 135.0, 134.9, 131.9
(2C), 130.0, 130.0, 129.6, 129.5, 129.3 (2C), 127.3 (2C), 126.9 (2C),
122.1, 93.9 (d, J = 19 Hz), 58.5, 55.2 (d, J = 24 Hz), 52.2, 21.5. 19F
NMR (282 MHz, CDCl3): δ −104.5 to −104.9 (m). IR (cm−1): 3214,
1686, 1431, 1291, 1158, 1073. HRMS (ESI-): calcd for [M−H]
C25H22BrFNO4S 530.0437, found 530.0421 (−3.0 ppm).
syn-N-(1-(4-Chlorophenyl)-3-fluoro-2-phenylbut-3-enyl)-4-meth-
ylbenzenesulfonamide (3b). Compound 3b was obtained as a white
solid (mp 164−166 °C) in 64% yield (82.5 mg) after flash
chromatography (SiO2, cyclohexane/EtOAc, 95:5 to 70:30, Rf = 0.37
1
cyclohexane/EtOAc 8:2). H NMR (300 MHz, CDCl3): δ 7.43−6.96
(m, 13H), 5.08 (s, 1H), 4.77 (dd, J = 9.4, 5.6 Hz, 1H), 4.36 (dd, J =
17.5, 3.2 Hz, 1H), 4.17 (d, J = 49.6, 3.2 Hz, 1H), 3.54 (dd, J = 25.0, 9.9
Hz, 1H), 2.41 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 162.8 (d, J =
260 Hz), 143.3, 137.2, 136.4, 135.5, 133.5, 129.2 (3C), 129.1, 128.8
(2C), 128.4, 128.4, 128.3 (2C), 128.2, 127.2 (2C), 93.6 (d, J = 19 Hz),
58.2, 56.0 (d, J = 24 Hz), 21.5. 19F NMR (282 MHz, CDCl3): δ
−103.9 (ddd, J = 49, 25, 17 Hz). IR (cm−1): 3251, 1920, 1671, 1446,
1322, 1159, 1064. HRMS (ESI+): calcd for [M + NH4]
C23H25ClFN2O2S 447.1309, found 447.1300 (−2.0 ppm).
syn-N-(2-(4-Bromophenyl)-1-(4-chlorophenyl)-3-fluorobut-3-
enyl)-4-methylbenzenesulfonamide (3c). Compound 3c was ob-
tained as a white solid (mp 208−210 °C) in 76% yield (116 mg), after
flash chromatography (SiO2, cyclohexane/EtOAc, 95:5 to 65:35, Rf =
1
0.31 cyclohexane/EtOAc 8:2). H NMR (300 MHz, CDCl3): δ 7.35
(d, J = 8.4 Hz, 2H), 7.27 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H),
7.10−7.00 (m, 6H), 5.10 (d, J = 6.5 Hz, 1H), 4.74 (dd, J = 10.0, 6.8
Hz, 1H), 4.37 (dd, J = 17.5, 3.4 Hz, 1H), 4.16 (dd, J = 49.5, 3.4 Hz,
1H), 3.50 (dd, J = 25.1, 10.1 Hz, 1H), 2.43 (s, 3H). 13C NMR (75
MHz, acetone): δ 164.4 (d, J = 260 Hz), 143.3, 139.8, 139.3, 137.9 (d,
J = 2 Hz), 133.5, 132.2 (2C), 131.9 (2C), 130.1 (2C), 129.9 (2C),
128.9 (2C), 127.5 (2C), 121.8, 93.81 (d, J = 19 Hz), 59.1 (d, J = 8
Hz), 55.4 (d, J = 23 Hz), 21.4. 19F NMR (282 MHz, CDCl3): δ
−104.4 (ddd, J = 49, 25, 17 Hz). IR (cm−1): 3324, 1672, 1489, 1317,
1154, 1075. HRMS (ESI-): calcd for [M−H] C23H19BrClFNO2S
505.9992, found 505.9998 (1.2 ppm).
syn-N-(3-Fluoro-2-phenyl-1-(4-(trifluoromethyl)phenyl)but-3-
enyl)-4-methylbenzenesulfonamide (3e). Compound 3e was ob-
tained as a white solid (mp 133−135 °C) in 68% yield (94.3 mg), after
flash chromatography (SiO2, cyclohexane/EtOAc, 95:5 to 65:35, Rf =
0.27 cyclohexane/EtOAc 8:2). 1H NMR (300 MHz, CDCl3): δ 7.30−
7.08 (m, 11H), 6.86 (d, J = 6.0 Hz, 2H), 5.38 (d, J = 5.7 Hz, 1H), 4.79
(dd, J = 9.9, 5.8 Hz, 1H), 4.22 (dd, J = 17.5, 3.2 Hz, 1H), 4.07 (dd, J =
49.5, 3.3 Hz, 1H), 3.48 (dd, J = 25.0, 9.9 Hz, 1H), 2.25 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 162.6 (d, J = 260 Hz), 143.4, 142.5, 136.3,
135.3, 129.4 (q, J = 30 Hz), 129.2 (2C), 129.1 (2C), 128.5 (2C),
syn-N-(1-(3,4-Dichlorophenyl)-3-fluoro-2-phenylbut-3-enyl)-4-
methylbenzenesulfonamide (3j). Compound 3j was obtained as a
white solid (mp 163−165 °C) in 57% yield (79 mg), after flash
chromatography (SiO2, cyclohexane/EtOAc, 95:5 to 65:35, Rf = 0.43
1
cyclohexane/EtOAc 8:2). H NMR (300 MHz, CDCl3): δ 7.29−6.88
(m, 12H), 5.04 (d, J = 5.4 Hz, 1H), 4.66 (dd, J = 10.0, 5.6 Hz, 1H),
4.28 (dd, J = 17.4, 3.2 Hz, 1H), 4.08 (dd, J = 49.4, 3.0 Hz, 1H), 3.42
(dd, J = 25.4, 10.1 Hz, 1H), 2.30 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 162.5 (d, J = 260 Hz), 143.6, 138.8, 136.2, 135.2, 132.2,
131.8, 130.1, 129.5, 129.3 (2C), 129.2 (2C), 128.4, 128.3, 128.3, 127.1
(3C), 93.8 (d, J = 19 Hz), 57.8, 55.7 (d, J = 24 Hz), 21.5.19F NMR
(282 MHz, CDCl3): δ −104.2 (ddd, J = 49, 25, 17 Hz). IR (cm−1):
3268, 2922, 1673, 1451, 1329, 1152, 1068. HRMS (ESI+): calcd for
[M + NH4] C23H24Cl2FN2O2S 481.0920, found 481.0915 (−1.0
ppm).
syn-N-(3-Fluoro-1-(4-methoxyphenyl)-2-phenylbut-3-enyl)-4-
methylbenzenesulfonamide (3k). Compound 3k was obtained as a
yellow solid (mp 131−133 °C) in 53% yield (68 mg), after flash
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chromatography (SiO2, cyclohexane/EtOAc, 97:3 to 65:35, Rf = 0.34
cyclohexane/EtOAc 8:2). H NMR (300 MHz, CDCl3): δ 7.21−7.15
N-(1-(4-Chlorophenyl)-3-fluoro-2-phenethylbut-3-enyl)-4-meth-
ylbenzenesulfonamide (3d). Compound 3d was obtained as a white
solid in 55% yield (25 mg), after flash chromatography as an
inseparable mixture of diastereoisomers (SiO2, cyclohexane/EtOAc,
1
(m, 5H),, 7.09 (d, J = 6.7 Hz, 2H), 6.94 (t, J = 7.3 Hz, 4H), 6.59 (d, J
= 8.2 Hz, 2H), 4.74 (d, J = 5.2 Hz, 1H), 4.71−4.60 (m, 1H), 4.27 (dd,
J = 17.4, 2.5 Hz, 1H), 4.10 (dd, J = 49.9, 2.5 Hz, 1H), 3.68 (s, 3H),
3.48 (dd, J = 24.6, 9.5 Hz, 1H), 2.28 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 163.3 (d, J = 260 Hz), 159.0, 142.9, 136.7, 135.9, 130.6,
129.1 (2C), 129.0 (3C), 128.5 (3C), 128.1, 127.2 (2C), 113.5 (2C),
93.3 (d, J = 19 Hz), 58.3, 56.3 (d, J = 23 Hz), 55.2, 21.4.19F NMR (282
MHz, CDCl3): δ −103.4 (ddd, J = 50, 24, 18 Hz). IR (cm−1): 3251,
2923, 1671, 1447, 1323, 1153, 1056. HRMS (ESI+): calcd for [M + K]
C24H24FKNO3S 464.1098, found 464.1099 (0.2 ppm).
1
95:5 to 70:30, Rf = 0.37 cyclohexane/EtOAc 8:2). H NMR (300
MHz, CDCl3): δ 7.36 (d, J = 8.3 Hz, 3.2H), 7.22−7.08 (m, 6.3H),
7.02−6.89 (m, 10H), 6.82−6.71 (m, 3.2H), 5.42 (d, J = 9.1 Hz, 1H,
syn), 5.30 (d, J = 6.7 Hz, 0.6H, anti), 4.63 (dd, J = 17.7, 2.9 Hz, 0.6H,
anti), 4.41 (dd, J = 17.8, 3.0 Hz, 1H, syn), 4.31−4.09 (m, 2.2H), 3.97
(dd, J = 50.3, 3.1 Hz, 1H, syn), 2.70−2.52 (m, 1.7H), 2.45−2.30 (m,
3.5H), 2.27 (s, 1.8H, anti), 2.26 (s, 3H, syn), 1.99−1.84 (m, 1.2H),
1.73−1.56 (m, 1.9H), 1.44−1.30 (m, 0.9H). 13C NMR (75 MHz,
CDCl3): δ 163.1 (d, J = 260 Hz), 143.4 (syn), 143.3 (anti), 141.0
(syn), 140.7 (anti), 137.2 (anti), 137.1 (anti), 137.0 (syn), 136.9 (syn),
133.40 (anti), 133.2 (syn), 129.3 (2C, syn), 129.2 (2C, anti), 128.6
(2C, anti), 128.5 (2C, syn), 128.4 (4C, syn), 128.3 (4C, anti), 128.3
(2C, anti), 128.2 (2C, syn), 127.1 (2C, anti), 127.0 (2C, syn), 126.1
(anti), 126.0 (syn), 95.5 (d, J = 20 Hz, anti), 94.8 (d, J = 20 Hz, syn),
59.1 (syn), 58.4 (anti), 48.9 (d, J = 24 Hz, syn), 48.6 (d, J = 25 Hz,
anti), 33.0 (syn), 32.8 (anti), 29.6 (anti), 29.4 syn), 21.4. 19F NMR
(282 MHz, CDCl3): δ −104.7 (ddd, J = 50, 26, 18 Hz, syn), −106.1
(ddd, J = 50, 29, 18 Hz, anti). IR (cm−1): 3239, 2919, 1673, 1452,
1318, 1162, 1088. HRMS (ESI-): calcd for [M − H] C25H24ClFNO2S
456.1200, found 456.1183 (−3.7 ppm).
syn-N-(3-Fluoro-2-phenyl-1-(pyridin-3-yl)but-3-enyl)-4-methyl-
benzenesulfonamide (3l). Compound 3l was obtained as a white solid
(mp 219−221 °C) in 58% yield (69 mg), after flash chromatography
(SiO2, cyclohexane/EtOAc, 85:15 to 60:40, Rf = 0.27 cyclohexane/
EtOAc 8:2). 1H NMR (300 MHz, CDCl3): δ 8.42−8.30 (m, 2H), 7.42
(d, J = 7.9 Hz, 1H), 7.30−7.21 (m, 5H), 7.11−7.00 (m, 5H), 4.74−
4.63 (m, 2H), 4.31 (dd, J = 17.5, 2.8 Hz, 1H), 4.10 (dd, J = 49.6, 3.1
Hz, 1H), 3.48 (dd, J = 24.8, 9.4 Hz, 1H), 2.32 (s, 3H). 13C NMR (75
MHz, CDCl3): δ 162.3 (d, J = 261 Hz), 149.1 (2C), 143.6 (2C),
135.8, 134.9, 134.3, 129.5 (2C), 129.3 (2C), 128.6, 128.4 (2C), 127.2
(2C), 123.1, 94.0 (d, J = 19 Hz), 56.5, 56.1 (d, J = 21 Hz), 21.5. 19F
NMR (282 MHz, CDCl3): δ −103.7 (ddd, J = 49, 25, 17 Hz). IR
(cm−1): 3257, 1858, 1674, 1435, 1323, 1153, 1078. HRMS (ESI+):
calcd for [M + H] C22H22FN2O2S 397.1386, found 397.1391 (1.3
ppm).
syn-N-(3-Fluoro-1-(furan-3-yl)-2-phenylbut-3-enyl)-4-methylben-
zenesulfonamide (3m). Compound 3m was obtained as a white solid
(mp 153−155 °C) in 45% yield (51.7 mg), after flash chromatography
(SiO2, cyclohexane/EtOAc, 95:5 to 65:35, Rf = 0.28 cyclohexane/
EtOAc 8:2). 1H NMR (300 MHz, CDCl3): δ 7.42 (d, J = 7.9 Hz, 2H),
7.31−7.15 (m, 6H), 7.14−7.10 (m, 3H), 6.12 (s, 1H), 5.03 (d, J = 7.3
Hz, 1H), 4.86 (t, J = 8.2 Hz, 1H), 4.50 (dd, J = 17.8, 2.2 Hz, 1H), 4.33
(dd, J = 50.0, 2.3 Hz, 1H), 3.64 (dd, J = 23.0, 9.0 Hz, 1H), 2.40 (s,
3H). 13C NMR (75 MHz, CDCl3): δ 163.5 (d, J = 260 Hz), 143.2,
142.9, 140.5, 136.9, 135.9, 129.3 (2C), 128.9 (2C), 128.6 (2C), 128.0,
127.1 (2C), 123.4, 108.6, 93.5 (d, J = 19 Hz), 55.1 (d, J = 24 Hz), 50.9,
21.5. 19F NMR (282 MHz, CDCl3): δ −102.84 (ddd, J = 50, 23, 18
Hz). IR (cm−1): 3251, 2922, 1671, 1447, 1323, 1154, 1055. HRMS
(ESI-): calcd for [M − H] C21H19FNO3S 384.1070, found 384.1074
(1.0 ppm).
syn-N-(5-Fluoro-1,4-diphenylhex-5-en-3-yl)-4-methylbenzenesul-
fonamide (3n). Compound 3n was obtained as a white solid (mp
177−179 °C) in 80% yield (69 mg), after flash chromatography (SiO2,
cyclohexane/EtOAc, 95:5 to 65:35, Rf = 0.43 cyclohexane/EtOAc
8:2). 1H NMR (300 MHz, CDCl3): δ 7.53 (d, J = 8.2 Hz, 2H), 7.25−
6.86 (m, 12H), 4.62 (dd, J = 17.9, 3.1 Hz, 1H), 4.36 (d, J = 8.0 Hz,
1H), 4.33 (dd, J = 49.9, 3.1 Hz, 1H), 3.79−3.61 (m, 1H), 3.50 (dd, J =
25.1, 6.9 Hz, 1H), 2.64−2.39 (m, 2H), 2.36 (s, 3H), 1.99−1.83 (m,
1H), 1.75−1.57 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 164.0 (d, J =
261 Hz), 143.4, 141.1, 137.5, 136.6, 129.7 (2C), 128.8 (2C), 128.4
(2C), 128.3(2C), 128.26, 128.23, 127.6, 127.1 (2C), 125.9, 94.4 (d, J =
19 Hz), 55.1, 52.6 (d, J = 23 Hz), 33.9, 31.3, 21.5. 19F NMR (282
MHz, CDCl3): δ −100.2 (ddd, J = 50, 25, 18 Hz). IR (cm−1): 3289,
2931, 1670, 1450, 1313, 1148, 1091. HRMS (ESI+): calcd for [M +
H] C25H27FNO2S 424.1747, found 424.1740 (−1.7 ppm).
Addition of Fluorinated Bromo Allylic Derivative 2d to N-Ts
Imine 1. In a vial, 1 (0.3 mmol), indium (0.15 mmol), 2d (0.2 mmol),
and THF (1 mL) were introduced the vial was sealed (screwed caps)
and heated at 75 °C under vigorous stirring for 18 h. The vial was
opened, extra portions of 2d (0.15 mmol) and indium (0.2 mmol)
were added, and the resulting mixture was stirred at 75 °C for 18 h.
The solution was quenched with 5 drops NH4Cl (saturated aqueous
solution) and stirred vigorously for 10 min. The mixture was filtered
through a pad of Celite (washed with DCM) and evaporated. The
residue was purified by flash chromatography (SiO2, cyclohexane/
EtOAc mixture) to afford the corresponding fluorinated amine 3 (see
Scheme 1).
N-(3-Fluoro-2-phenethyl-1-(4-(trifluoromethyl)phenyl)but-3-
enyl)-4-methylbenzenesulfonamide (3g). Compound 3g was ob-
tained as a white solid in 47% yield (23 mg), after flash
chromatography as an inseparable mixture of diastereoisomers (SiO2,
cyclohexane/EtOAc, 95:5 to 70:30, Rf = 0.27 cyclohexane/EtOAc
1
8:2). H NMR (300 MHz, CDCl3): δ 7.32 (d, J = 8.2 Hz, 2.72H),
7.25−7.08 (m, 6.8H), 7.03−6.86 (m, 8.2H), 5.54 (d, J = 9.2 Hz, 1H,
syn), 5.40 (d, J = 7.0 Hz, 0.36H), 4.65 (dd, J = 17.6, 3.1 Hz, 0.36H),
4.47−4.09 (m, 2.72H), 3.98 (dd, J = 50.2, 3.1 Hz, 1H), 2.73−2.53 (m,
1.36H), 2.49−2.30 (m, 2.72H), 2.22 (s, 1.07H), 2.20 (s, 3H), 2.03−
1.85 (m, 1.28H), 1.79−1.59 (m, 1.72H), 1.47−1.31 (m, 0.62H). 13C
NMR (75 MHz, CDCl3): δ 162.8 (d, J = 260 Hz, anti), 162.7 (d, J =
260 Hz, syn), 143.5 (syn), 143.4 (anti), 142.5 (syn), 142.3 (syn), 140.9
(syn), 140.6 (anti), 137.0 (anti), 136.9 (syn), 129.3 (q, J = 32 Hz, anti),
129.2 (2C, syn), 129.2 (2C, anti), 129.1 (q, J = 32 Hz, syn), 128.5 (2C,
syn), 128.4 (2C, anti), 128.4 (2C, syn), 128.3 (2C, anti), 127.6 (2C,
anti), 127.4 (2C, syn), 127.0 (2C, anti), 126.9 (2C, syn), 126.2 (anti),
126.1 (syn), 125.1 (q, J = 4 Hz, 2C, anti), 124.9 (q, J = 4 Hz, 2C, syn),
123.9 (q, J = 272 Hz), 95.7 (d, J = 19 Hz, anti), 95.0 (d, J = 20 Hz,
syn), 59.3 (syn), 58.6 (anti), 48.8 (d, J = 25 Hz, syn), 48.4 (d, J = 24
Hz, anti), 32.9 (syn), 32.8 (anti), 29.6 (anti), 29.4 (syn), 21.3. 19F
NMR (282 MHz, CDCl3): δ −63.1 (s), −105.1 (ddd, J = 50, 26, 18
Hz, syn), −106.1 (ddd, J = 50, 28, 17 Hz, anti). IR (cm−1): 3256, 2932,
1677, 1442, 1322, 1161, 1116, 1067, 1017. HRMS (ESI+): calcd for
[M + K] C26H25F4KNO2S 530.1179, found 530.1196 (3.2 ppm).
General Procedure for the Addition of 3-Chloro-2-fluoro-
prop-1-ene 2a to Chiral Imine 4. In a 1.5 mL vial, chiral imine 4
(0.1 mmol), indium (0.2 mmol), 2a (0.15 mmol), and DCE (1 mL)
were introduced, and the vial was sealed and heated at 53 °C under
vigorous stirring for 16 h. The vial was opened, extra portions of
indium (0.2 mmol) and 2a (0.15 mmol) were added, and the resulting
mixture was stirred at 53 °C for 16 h. The solution was quenched with
5 drops of NH4Cl (saturated aqueous solution), stirred vigorously for
5 min, and filtered over Celite (washed with DCM). The residue was
purified by flash chromatography (SiO2, petroleum ether/EtOAc
90:10 to 50:50) to afford the corresponding fluorinated chiral amine 5.
(S)-N-((R)-1-(4-Chlorophenyl)-3-fluorobut-3-enyl)-2-methylpro-
pane-2-sulfinamide (5a). Compound 5a was obtained as a white solid
(mp 106−110 °C) in 96% yield (29.2 mg), after flash chromatography
(Rf = 0.24 petroleum ether/EtOAc 5:5). [α]20D: +107 (c 0.40, CHCl3).
1H NMR (300 MHz, CDCl3): δ 7.35−7.29 (m, 2H), 7.29−7.23 (m,
2H), 4.70−4.59 (m, 1H), 4.65 (dd, J = 17.1, 3.1 Hz, 1H), 4.31 (dd, J =
49.4, 3.0 Hz, 1H), 3.78 (s, 1H), 2.63 (dd, J = 18.4, 6.9 Hz, 2H), 1.19
(s, 9H). 13C NMR (75 MHz, CDCl3): δ 162.2 (d, J = 258 Hz), 139.2,
133.9, 128.99 (2C), 128.96 (2C), 94.0 (d, J = 19 Hz), 55.9, 54.9, 41.5
(d, J = 26 Hz), 22.6 (3C). 19F NMR (282 MHz, CDCl3): δ −94.1 (dq,
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J = 50, 18 Hz). IR (cm−1): 3196, 2957, 1674, 1045, 823. Anal. Calcd
for C14H19ClFNOS: C, 55.34; H, 6.30; N, 4.61; S, 10.55. Found: C,
55.51; H, 6.33; N, 4.57; S, 10.33.
46% yield (19.6 mg), after flash chromatography (Rf = 0.54 petroleum
1
ether/EtOAc 6:4). [α]20D: −3 (c 0.37, CHCl3). H NMR (300 MHz,
CDCl3): δ 7.57 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 6.98 (t, J
= 8.0 Hz, 1H), 5.61 (q, J = 8.0 Hz, 1H), 4.57 (dd, J = 16.7, 2.9 Hz,
1H), 4.46−4.21 (m, 1H) 4.40 (s, 1H), 3.21−2.97 (m, 2H), 1.13 (s,
9H). 13C NMR (75 MHz, CDCl3): δ 162.1 (d, J = 258 Hz), 138.1,
134.4, 133.0, 130.1, 126.5, 122.6, 93.6 (d, J = 19 Hz), 58.8 (d, J = 1
Hz), 56.5, 37.9 (d, J = 27 Hz), 22.5 (3C). 19F NMR (282 MHz,
CDCl3): δ −94.6 (dddd, J = 49, 20, 19, 17 Hz). IR (cm−1): 2922,
2853, 1062, 774, 713. Anal. Calcd for C14H18Br2FNOS: C, 39.36; H,
4.25; N, 3.28; S, 7.51. Found: C, 39.13; H, 4.61; N, 3.38; S, 6.91.
(S)-N-((R)-3-Fluoro-1-(pyridin-3-yl)but-3-enyl)-2-methylpropane-
2-sulfinamide (5h). Compound 5h was obtained as a gum in 97%
yield (26.0 mg), after flash chromatography (Rf = 0.10 petroleum
ether/EtOAc 2:8). [α]20D: +96 (c 0.30, CHCl3). 1H NMR (300 MHz,
CDCl3): δ 8.67−8.42 (m, 2H), 7.63 (d, J = 7.9 Hz, 1H), 7.33−7.20
(m, 1H), 4.73−4.57 (m, 2H), 4.30 (dd, J = 49.3, 3.1 Hz, 1H), 3.84 (s,
1H), 2.80−2.57 (m, 2H), 1.18 (s, 9H). 13C NMR (75 MHz, CDCl3):
δ 161.6 (d, J = 258 Hz), 149.3, 149.0, 136.2, 135.3, 123.5, 94.2 (d, J =
19 Hz), 56.0, 53.5, 41.1 (d, J = 26 Hz), 22.5 (3C). 19F NMR (282
MHz, CDCl3): δ −94.1 (dq, J = 49, 18 Hz). IR (cm−1): 3194, 2963,
1044, 850, 714. Anal. Calcd for C13H19FN2OS: C, 57.75; H, 7.08; N,
10.36; S, 11.86. Found: C, 57.74; H, 7.08; N, 10.65; S, 11.27.
(S)-N-((R)-3-Fluoro-1-phenylbut-3-enyl)-2-methylpropane-2-sulfi-
namide (5b). Compound 5b was obtained as a yellowish oil in 95%
yield (25.6 mg), after flash chromatography (Rf = 0.34 petroleum
ether/EtOAc 6:4). [α]20D: +84 (c 0.56, CHCl3). 1H NMR (300 MHz,
CDCl3): δ 7.39−7.27 (m, 5H), 4.70−4.59 (m, 1H), 4.65 (dd, J = 16.8,
2.7 Hz, 1H), 4.32 (dd, J = 49.5, 2.7 Hz, 1H), 3.77 (s, 1H), 2.66 (dd, J
= 18.3, 6.8 Hz, 2H), 1.19 (s, 9H). 13C NMR (75 MHz, CDCl3): δ
162.8 (d, J = 258 Hz), 144.4, 128.2 (2C), 127.4, 126.4 (2C), 95.3 (d, J
= 20 Hz), 59.6 (d, J = 3 Hz), 56.3, 47.5 (d, J = 24 Hz), 22.8 (3C). 19F
NMR (282 MHz, CDCl3): δ −93.9 (dq, J = 50, 18 Hz). IR (cm−1):
3208, 1677, 1043, 856, 701. Anal. Calcd for C14H20FNOS: C, 62.42;
H, 7.48; N, 5.20; S, 11.90. Found: C, 62.68; H, 7.60; N, 5.03; S, 11.62.
(S)-N-((R)-3-Fluoro-1-(4-methoxyphenyl)but-3-enyl)-2-methyl-
propane-2-sulfinamide (5c). Compound 5c was obtained as a pale
yellow solid (mp 86−90 °C) in 99% yield (29.6 mg), after flash
chromatography (Rf = 0.39 petroleum ether/EtOAc 6:4). [α]20
:
D
1
−107 (c 0.35, CHCl3). H NMR (300 MHz, CDCl3): δ 7.24 (d, J =
8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.70−4.53 (m, 2H), 4.31 (dd, J
= 49.5, 2.8 Hz, 1H), 3.79 (s, 3H), 3.74 (s, 1H), 2.62 (dd, J = 18.4, 6.9
Hz, 2H), 1.18 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 162.7 (d, J =
258 Hz), 159.4, 132.5, 128.8 (2C), 114.0 (2C), 93.5 (d, J = 19.2 Hz),
55.7, 55.3, 54.9, 41.6 (d, J = 26.3 Hz), 22.6 (3C). 19F NMR (282 MHz,
CDCl3): δ −94.0 (dq, J = 50, 18 Hz). IR (cm−1): 3290, 2953, 1511,
1246, 1060, 876. Anal. Calcd for C15H22FNO2S: C, 60.17; H, 7.41; N,
4.68; S, 10.71. Found: C, 59.90; H, 7.66; N, 4.88; S, 10.71.
(S)-N-((R)-1-(2-Chloroquinolin-3-yl)-3-fluorobut-3-enyl)-2-meth-
ylpropane-2-sulfinamide (5i). Compound 5i was obtained as a gum
in 86% yield (30.5 mg), after flash chromatography (Rf = 0.24
1
petroleum ether/EtOAc 6:4). [α]20D: −93 (c 0.67, CHCl3). H NMR
(300 MHz, CDCl3): δ 8.20 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.80 (d, J
= 8.1 Hz, 1H), 7.73 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.56 (t, J = 7.5 Hz,
1H), 5.20 (dt, J = 7.1, 5.1 Hz, 1H), 4.66 (dd, J = 17.2, 3.1 Hz, 1H),
4.36 (dd, J = 49.5, 3.1 Hz, 1H), 4.03 (d, J = 3.7 Hz, 1H), 3.09−2.75
(m, 2H), 1.26 (d, J = 5.4 Hz, 9H). 13C NMR (75 MHz, CDCl3): δ
161.9 (d, J = 258 Hz), 149.4, 147.1, 137.7, 132.5, 130.8, 128.4, 127.7,
127.5, 127.1, 94.5 (d, J = 19 Hz), 56.4, 53.5, 39.1 (d, J = 26 Hz), 22.7
(3C). 19F NMR (282 MHz, CDCl3): δ −93.4 (bm). IR (cm−1): 2922,
1674, 1024, 858, 753. Anal. Calcd for C17H20ClFN2OS: C, 57.54; H,
5.68; N, 7.89; S, 9.04. Found: C, 57.93; H, 5.70; N, 8.14; S, 8.81.
(S)-N-((R)-3-Fluoro-1-(thiophene-2-yl)but-3-enyl)-2-methylpro-
pane-2-sulfinamide (5j). Compound 5j was obtained as a yellow solid
(mp 58−60 °C) in 74% yield (20.4 mg), after flash chromatography
(Rf = 0.36 petroleum ether/EtOAc 6:4). [α]20D: +93 (c 0.36, CHCl3).
1H NMR (300 MHz, CDCl3): δ 7.27 (dd, J = 3.8, 0.9 Hz, 1H), 7.05
(S)-N-((R)-1-(Benzo[d][1,3]dioxol-5-yl)-3-fluorobut-3-enyl)-2-
methylpropane-2-sulfinamide (5d). Compound 5d was obtained as
an orange gum in 80% yield (25.1 mg), after flash chromatography (Rf
= 0.30 petroleum ether/EtOAc 6:4). [α]20D: −122 (c 0.62, CHCl3).
1H NMR (300 MHz, CDCl3): δ 6.84−6.72 (m, 3H), 5.95 (m, 2H),
4.64 (dd, J = 17.1, 3.0 Hz, 1H), 4.56 (td, J = 7.2, 2.0 Hz, 1H), 4.32 (dd,
J = 49.5, 3.0 Hz, 1H), 3.71 (s, 1H), 2.67−2.52 (m, 2H), 1.19 (s, 9H).
13C NMR (75 MHz, CDCl3): δ 162.6 (d, J = 258 Hz), 148.1, 147.5,
134.5, 121.4, 108.3, 107.5, 101.3, 93.6 (d, J = 19.2 Hz), 55.8, 55.2, 41.7
(d, J = 26.2 Hz), 22.69 (3C). 19F NMR (282 MHz, CDCl3): δ −93.9
(dq, J = 50, 18 Hz). IR (cm−1): 3199, 2912, 1489, 1444, 1239, 1034.
Anal. Calcd for C15H20FNO3S: C, 57.49; H, 6.43; N, 4.47; S, 10.23.
Found: C, 57.39; H, 6.58; N, 4.61; S, 9.70.
(S)-N-((R)-3-Fluoro-1-(3-hydroxyphenyl)but-3-enyl)-2-methylpro-
pane-2-sulfinamide (5e). Compound 5e was obtained as a white solid
(mp 156−160 °C) in 62% yield (17.1 mg), after flash chromatography
(Rf = 0.21 petroleum ether/EtOAc 6:4). [α]20D: +80 (c 0.32, CHCl3).
1H NMR (300 MHz, CDCl3): δ 7.77 (m, 1H), 7.19 (t, J = 7.8 Hz,
1H), 6.88 (s, 1H), 6.85−6.73 (m, 2H), 4.66 (dd, J = 17.1, 3.0 Hz, 1H),
4.56 (m, 1H), 4.34 (dd, J = 49.5, 3.0 Hz, 1H), 3.90 (s, 1H), 2.62 (m,
2H), 1.23 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 162.5 (d, J = 258
Hz), 157.0, 141.5, 129.9, 118.3, 115.4, 115.1, 93.7 (d, J = 19 Hz), 56.0,
55.7, 41.3 (d, J = 26 Hz), 22.6 (3C). 19F NMR (282 MHz, CDCl3): δ
−94.3 (ddt, J = 50, 20, 17 Hz). IR (cm−1): 3209, 2957, 1249, 1059.
Anal. Calcd for C14H20FNO2S: C, 58.92; H, 7.06; N, 4.91; S, 11.24.
Found: C, 59.27; H, 7.23; N, 5.06; S, 10.90.
Ethyl 4-((R)-1-((S)-1,1-Dimethylethylsulfinamido)-3-fluorobut-3-
enyl)benzoate (5f). Compound 5f was obtained as a yellow solid
(mp 68−70 °C) in 96% yield (32.8 mg), after flash chromatography
(Rf = 0.30 petroleum ether/EtOAc 6:4). [α]20D: +96 (c 0.37, CHCl3).
1H NMR (300 MHz, CDCl3): δ 8.02 (d, J = 8.2 Hz, 2H), 7.39 (d, J =
8.2 Hz, 2H), 4.76−4.66 (m, 1H), 4.64 (dd, J = 17.1, 3.1 Hz, 1H),
4.41−4.19 (m, 3H), 3.78 (s, 1H), 2.66 (dd, J = 18.4, 6.9 Hz, 2H), 1.38
(t, J = 7.1 Hz, 3H), 1.19 (s, 9H). 13C NMR (75 MHz, CDCl3): δ
166.4, 162.0 (d, J = 258 Hz), 145.8, 130.4, 130.0 (2C), 127.6 (2C),
94.1 (d, J = 19 Hz), 61.1, 56.0, 55.3, 41.4 (d, J = 26 Hz), 22.6 (3C),
14.4. 19F NMR (282 MHz, CDCl3): δ −94.0 (dq, J = 18, 49 Hz). IR
(cm−1): 3290, 3209, 2958, 1248, 1059. Anal. Calcd for C17H24FNO3S:
C, 59.80; H, 7.08; N, 4.10; S, 9.39. Found: C, 59.53; H, 7.41; N, 4.13;
S, 8.95.
(d, J = 3.3 Hz, 1H), 6.97 (dd, J = 5.0, 3.6 Hz, 1H), 4.98 (td, J = 6.7, 3.3
Hz, 1H), 4.69 (dd, J = 17.1, 3.0 Hz, 1H), 4.39 (dd, J = 49.4, 3.0 Hz,
1H), 3.83 (s, 1H), 2.89−2.65 (m, 2H), 1.23 (s, 9H). 13C NMR (75
MHz, CDCl3): δ 162.1 (d, J = 258 Hz), 144.8, 126.8, 126.0, 125.5,
94.1 (d, J = 19 Hz), 56.1, 52.0, 42.2 (d, J = 26 Hz), 22.7 (3C). 19F
NMR (282 MHz, CDCl3): δ −94.2 (dq, J = 50, 18 Hz). IR (cm−1):
2877, 1684, 1053, 830, 701. Anal. Calcd for C12H18FNOS2: C, 52.33;
H, 6.59; N, 5.09; S, 23.29. Found: C, 52.59; H, 6.75; N, 5.11; S, 23.32.
(S)-N-((R,E)-5-Fluoro-2-methyl-1-phenylhexa-1,5-dien-3-yl)-2-
methylpropane-2-sulfinamide (5k). Compound 5k was obtained as a
white solid (mp 114−116 °C) in 80% yield (24.7 mg), after flash
chromatography (Rf = 0.47 petroleum ether/EtOAc 6:4). [α]20D: +55
(c 0.53, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.29−7.03 (m, 5H),
6.49 (s, 1H), 4.56 (dd, J = 17.1, 2.9 Hz, 1H), 4.28 (dd, J = 49.4, 2.9
Hz, 1H), 4.09 (t, J = 6.9 Hz, 1H), 3.50 (s, 1H), 2.62−2.30 (m, 2H),
1.70 (s, 3H), 1.11 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 162.8 (d, J
= 258 Hz), 137.2, 135.3, 130.1, 129.1 (2C), 128.2 (2C), 126.9, 93.3 (d,
J = 19 Hz), 59.5, 55.7, 37.8 (d, J = 26 Hz), 22.7 (3C), 13.2. 19F NMR
(282 MHz, CDCl3): δ −93.9 (dq, J = 49, 18 Hz). IR (cm−1): 3290,
3209, 2958, 1679, 1247, 1059, 824. Anal. Calcd for C17H24FNOS: C,
65.98; H, 7.82; N, 4.53; S, 10.36. Found: C, 65.51; H, 7.68; N, 4.51; S,
9.93.
(S)-N-((R,Z)-2,5-Difluoro-1-(4-methoxyphenyl)hexa-1,5-dien-3-
yl)-2-methylpropane-2-sulfinamide (5l). Compound 5l was obtained
as a white solid (mp 88−90 °C) in 77% yield (26.4 mg), after flash
chromatography (Rf = 0.28 petroleum ether/EtOAc 6:4). [α]20D: +2 (c
1
0.62, CHCl3). H NMR (300 MHz, CDCl3): δ 7.43 (d, J = 8.8 Hz,
(S)-N-((R)-1-(2,6-Dibromophenyl)-3-fluorobut-3-enyl)-2-methyl-
propane-2-sulfinamide (5g). Compound 5g was obtained as a gum in
2H), 6.86 (d, J = 8.8 Hz, 2H), 5.75 (d, J = 39.1 Hz, 1H), 4.70 (dd, J =
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16.9, 3.0 Hz, 1H), 4.44 (dd, J = 49.2, 3.0 Hz, 1H), 4.24 (dtd, J = 19.6,
6.8, 4.5 Hz, 1H), 3.80 (s, 3H), 3.55 (d, J = 4.0 Hz, 1H), 2.77 (ddd, J =
21.0, 14.8, 6.6 Hz, 1H), 2.71 (ddd, J = 21.7, 14.8, 7.2 Hz, 1H), 1.23 (s,
9H). 13C NMR (75 MHz, CDCl3): δ 161.8 (d, J = 257 Hz), 159.1 (d, J
= 3 Hz), 154.9 (d, J = 267 Hz), 130.3 (d, J = 7 Hz, 2C), 125.2 (d, J = 3
Hz), 114.0 (2C), 109.0 (d, J = 7 Hz), 94.1 (d, J = 19 Hz), 56.1, 55.4,
54.7 (d, J = 27 Hz), 36.8 (d, J = 27 Hz), 22.6 (3C). 19F NMR (282
MHz, CDCl3): δ −95.1 (dddd, J = 55, 36, 19, 2 Hz), −122.6 (ddd, J =
39, 20, 2 Hz). IR (cm−1): 3210, 2962, 1274, 1045, 857. Anal. Calcd for
C17H23F2NO2S: C, 59.45; H, 6.75; N, 4.08; S, 9.34. Found: C, 59.43;
H, 6.78; N, 4.13; S, 9.07.
CDCl3): δ 7.26−7.04 (m, 5H), 4.61 (dd, J = 17.4, 2.8 Hz, 1H), 4.32
(dd, J = 50.1, 2.8 Hz, 1H), 3.51−3.30 (m, 2H), 2.78−2.52 (m, 3H),
2.49 (t, J = 5.5 Hz, 1H), 1.87−1.71 (m, 2H), 1.17 (s, 9H). 13C NMR
(75 MHz, CDCl3): δ 163.1 (d, J = 258 Hz), 141.5, 128.6 (2C), 128.5
(2C), 126.1, 93.9 (d, J = 19 Hz), 56.2, 53.6 (d, J = 1 Hz), 39.0 (d, J =
26 Hz), 37.0, 32.1, 22.8 (3C). 19F NMR (282 MHz, CDCl3): δ −92.3
(ddt, J = 50, 21, 18 Hz). IR (cm−1): 3214, 2922, 1672, 1048, 847, 698.
Anal. Calcd for C16H24FNOS: C, 64.61; H, 8.13; N, 4.71; S, 10.78.
Found: C, 64.83; H, 8.44; N, 4.68; S, 10.57.
(S)-N-((R)-4-Fluoro-2-phenylpent-4-en-2-yl)-2-methylpropane-2-
sulfinamide (5r). Compound 5r was obtained as a colorless oil in 84%
yield (23.8 mg), after flash chromatography (Rf = 0.50 petroleum
ether/EtOAc 7:3). [α]20D: +210 (c 0.02, CHCl3). 1H NMR (300
MHz, CDCl3): δ 7.45 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.3 Hz, 2H),
7.31−7.24 (m, 1H), 4.65 (dd, J = 17.4, 2.7 Hz, 1H), 4.29 (dd, J = 50.0,
2.7 Hz, 1H), 4.03 (bs, 1H), 2.80 (dd, J = 44.1, 14.6 Hz, 1H), 2.73 (dd,
J = 49.4, 14.6 Hz, 1H), 1.86 (s, 3H), 1.23 (s, 9H). 13C NMR (75 MHz,
CDCl3): δ 162.4 (d, J = 258 Hz), 140.6, 128.6 (2C), 128.0, 127.5
(2C), 93.6 (d, J = 19 Hz), 55.7, 55.4, 41.5 (d, J = 26 Hz), 22.6, 22.5
(3C). 19F NMR (282 MHz, CDCl3): −89.0 (dq, J = 50, 18 Hz). IR
(cm−1): 3343, 1671, 997, 776, 704. Anal. Calcd for C15H22FNOS: C,
63.57; H, 7.82; N, 4.94; S, 11.31. Found: C, 63.42; H, 7.90; N, 4.56; S,
11.13.
(R)-1-(4-Chlorophenyl)-3-fluorobut-3-en-1-amine 6. To com-
pound 3a (69 mg, 0.227 mmol) solubilized in MeOH (5 mL) was
added HCl 12 N (0.2 mL), and the resulting solution was stirred at
room temperature for 12 h. After concentration under vacuum, the
residue was taken up in H2O, washed with Et2O, basified with
NaHCO3 saturated solution, and extracted twice with DCM. Organic
phases were assembled, dried over MgSO4, and concentrated to
furnish the pure amine 6 as a yellow oil (43 mg, 95%) with a 99:1 er.
[α]20D: −40 (c 1.2, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ 7.30 (s,
4H), 4.60 (dd, J = 17.3, 2.8 Hz, 1H), 4.40−4.13 (m, 2H), 2.58−2.29
(m, 2H), 1.69 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 163.6 (d, J =
257 Hz), 143.3, 133.0, 128.8 (2C), 127.8 (2C), 92.8 (d, J = 20 Hz),
52.2, 42.7 (d, J = 26 Hz). 19F NMR (282 MHz, CDCl3): −96.4 (m).
IR (cm−1): 1673, 1492, 1090, 819, 534. Anal. Calcd for C10H11ClFN:
C, 60.16; H, 5.55; N, 7.02. Found: C, 60.46; H, 5.48; N, 6.86. The
enantiomeric excess of 6 could be determined by chiral gas
chromatography (Chiraldex CB 25 m × 0.25), 50−190 °C, 20 °C.
min−1. tR (min): 39.12 (major), 44.63 (minor).
(S)-N-((R)-1-Ferrocenyl-3-fluorobut-3-enyl)-2-methylpropane-2-
sulfinamide (5m). Compound 5m was obtained as a brown gum in
78% yield (29.4 mg), after flash chromatography (Rf = 0.48 petroleum
1
ether/EtOAc 6:4). [α]20D: −116 (c 0.135, CHCl3). H NMR (300
MHz, CDCl3): δ 4.69 (dd, J = 17.3, 2.9 Hz, 1H), 4.53−4.31 (m, 2H),
4.29 (s, 1H), 4.16 (s, 7H), 4.11 (s, 1H), 3.71 (d, J = 5.5 Hz, 1H), 2.96
(td, J = 14.9, 4.6 Hz, 1H), 2.71 (ddd, J = 22.6, 14.9, 8.0 Hz, 1H), 1.21
(s, 9H). 13C NMR (75 MHz, CDCl3): δ 162.9 (d, J = 257 Hz), 93.5
(d, J = 19 Hz), 89.6, 68.7 (5C), 68.3, 68.1, 67.8, 65.9, 55.9, 51.8, 40.2
(d, J = 26 Hz), 22.68 (3C). 19F NMR (282 MHz, CDCl3): δ −93.9
(dddd, J = 50, 22, 17, 15 Hz). IR (cm−1): 3517, 2928, 1679, 1024, 815,
478. Anal. Calcd for C18H24FFeNOS: C, 57.30; H, 6.41; N, 3.71; S,
8.50. Found: C, 57.56; H, 6.42; N, 3.70; S, 8.29.
(S)-N-((S)-2-Fluoronon-1-en-4-yl)-2-methylpropane-2-sulfina-
mide (5n). Compound 5n was obtained as a colorless liquid in 93%
yield (24.5 mg), after flash chromatography (Rf = 0.40 petroleum
ether/EtOAc 6:4). [α]20D: +33 (c 0.57, CHCl3). 1H NMR (300 MHz,
CDCl3): δ 4.66 (dd, J = 17.4, 2.7 Hz, 1H), 4.38 (dd, J = 50.1, 2.7 Hz,
1H), 3.52−3.38 (m, 1H), 3.34 (d, J = 7.5 Hz, 1H), 2.66−2.42 (m,
2H), 1.60−1.48 (m, 2H), 1.34−1.25 (m, 6H), 1.21 (s, 9H), 0.88 (t, J =
6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 163.3 (d, J = 258 Hz),
93.4 (d, J = 19 Hz), 56.0, 53.8 (d, J = 1 Hz), 38.9 (d, J = 26 Hz), 34.9,
31.4, 25.3, 22.6 (3C), 22.5, 14.0. 19F NMR (282 MHz, CDCl3): δ
−92.5 (dq, J = 50, 20 Hz). IR (cm−1): 2928, 1668, 1132, 846. Anal.
Calcd for C13H26FNOS: C, 59.27; H, 9.95; N, 5.32; S, 12.17. Found:
C, 59.31; H, 9.92; N, 5.21; S, 12.01.
(S)-N-((S)-2-Fluorododec-1-en-4-yl)-2-methylpropane-2-sulfina-
mide (5o). Compound 5o was obtained as a colorless liquid in 91%
yield (27.8 mg), after flash chromatography (Rf = 0.63 petroleum
ether/EtOAc 6:4). [α]20D: −36 (c 0.29, CHCl3). 1H NMR (300 MHz,
CDCl3): δ 4.64 (dd, J = 17.4, 2.7 Hz, 1H), 4.37 (dd, J = 50.1, 2.7 Hz,
1H), 3.50−3.35 (m, 1H), 3.31 (d, J = 7.5 Hz, 1H), 2.64−2.41 (m,
2H), 1.66−1.44 (m, 2H), 1.24 (bs, 12H), 1.19 (s, 9H), 0.86 (t, J = 6.6
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 163.4 (d, J = 258 Hz), 93.6
(d, J = 19 Hz), 56.1, 53.9 (d, J = 1 Hz), 39.0 (d, J = 26 Hz), 35.1, 31.9,
29.6, 29.4, 29.3, 25.8, 22.76, 22.73 (3C), 14.21. 19F NMR (282 MHz,
CDCl3): 19F NMR (282 MHz, CDCl3): δ −92.5 (dq, J = 50, 20 Hz).
IR (cm−1): 3210, 2924, 2856, 1671, 1047, 845. Anal. Calcd for
C16H32FNOS: C, 62.90; H, 10.56; N, 4.58; S, 10.50. Found: C, 62.83;
H, 10.58; N, 4.62; S, 10.60.
(S)-N-((4S,6S)-2-Fluoro-6,10-dimethylundeca-1,9-dien-4-yl)-2-
methylpropane-2-sulfinamide (5p). Compound 5p was obtained as a
colorless liquid in 91% yield (28.9 mg), after flash chromatography (Rf
= 0.54 petroleum ether/EtOAc 6:4). [α]20D: −11 (c 0.40, CHCl3). 1H
NMR (300 MHz, CDCl3): δ 5.05 (t, J = 7.1 Hz, 1H), 4.64 (dd, J =
17.4, 2.7 Hz, 1H), 4.37 (dd, J = 50.2, 2.7 Hz, 1H), 3.59−3.42 (m, 1H),
3.23 (d, J = 9.2 Hz, 1H), 2.67−2.45 (m, 2H), 2.06−1.90 (m, 2H), 1.66
(s, 3H), 1.58 (s, 3H), 1.56−1.39 (m, 1H), 1.35−1.11 (m, 4H), 1.19 (s,
9H), 0.86 (d, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 163.3
(d, J = 258 Hz), 131.4, 124.7, 93.7 (d, J = 19 Hz), 56.3, 52.6 (d, J = 1
Hz), 42.7, 40.1 (d, J = 25 Hz), 37.5, 28.7, 25.8, 25.4, 22.7 (3C), 18.9,
17.8. 19F NMR (282 MHz, CDCl3): δ −92.1 (ddt, J = 50, 22, 18 Hz).
IR (cm−1): 2923, 1672, 1046, 848. Anal. Calcd for C17H32FNOS: C,
64.31; H, 10.16; N, 4.41; S, 10.10. Found: C, 64.28; H, 9.77; N, 4.36;
S, 9.87.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Authors
*E-mail: thomas.poisson@insa-rouen.fr.
*E-mail: xavier.pannecoucke@insa-rouen.fr.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work has been partially supported by INSA Rouen, Rouen
University, CNRS, EFRD, Labex SynOrg (ANR-11-LABX-
■
́
0029), and Region Haute-Normandie (CRUNCh network).
G.L. and N.V.H. thank the EFRD for a postdoctoral fellowship
(EFRD 32819 and EFRD 43209).
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2924
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