Asymmetric Allylation/RCM-Mediated Synthesis of Fluorinated Benzo-Fused Bicyclic Homoallylic Amines As Dihydronaphthalene Derivatives

Article abstract of DOI:10.1021/acs.joc.6b01590

Enantiomerically enriched fluorinated benzo-fused bicyclic homoallylic amines have been synthesized through an asymmetric allylation/ring closing metathesis (RCM) sequence. This sequence has been carried out using α-trifluoromethylstyrene derivatives as key intermediates, synthesized by microwave radiation. The great deactivating effect exerted by such substituents has been brought to light by a comparative study.

Full text of DOI:10.1021/acs.joc.6b01590

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Article
Asymmetric Allylation/RCM-Mediated Synthesis of Fluorinated Benzo-
fused Bicyclic Homoallylic Amines as Dihydronaphthalene Derivatives
Daniel M. Sedgwick, Pablo Barrio, Antonio Simon, Raquel Roman, and Santos Fustero
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01590 • Publication Date (Web): 30 Aug 2016
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Asymmetric Allylation/RCM-Mediated Synthesis of Fluorinated Benzo-fused
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Bicyclic Homoallylic Amines as Dihydronaphthalene Derivatives
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Daniel M. Sedgwick,† Pablo Barrio,† Antonio Simón,† Raquel Román,*‡ Santos
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Fustero*†‡
†Departamento de Química Orgánica, Universidad de Valencia, E-46100 Burjassot,
Spain.
‡Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, E-46012
Valencia, Spain.
santos.fustero@uv.es
raquel.roman@uv.es
ABSTRACT: Enantiomerically enriched fluorinated benzo-fused bicyclic homoallylic
amines have been synthesized through an asymmetric allylation/ring closing metathesis
(RCM) sequence. This sequence has been carried out using α-trifluoromethylstyrene
derivatives as key intermediates, synthesized by microwave radiation. The great
deactivating effect exerted by such substituents has been brought to light by a
comparative study.
INTRODUCTION
In recent years, the importance of organofluorine compounds in pharmacy and
agrochemistry has dramatically increased,1 due to the beneficial effects brought about
by the incorporation of fluorine or fluorine-containing groups in organic molecules,
such as increased metabolic stability or lipophilicity.2 For this reason, the interest in the
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development of new methodologies for the introduction of fluorinated units in organic
molecules has rapidly increased.
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In this context, chiral homoallylic amines are interesting building blocks in organic
synthesis, and one of the most important methods for their preparation is the
asymmetric allylation of imines.3 Specifically, the diastereoselective addition of
allylzinc bromide to Ellman’s tert-butylsulfinyl imines represents the most
advantageous method with a high degree of diastereocontrol and chemical yields,
reliability, and functional group compatibility.4 This methodology has recently been
combined with the ring closing metathesis reaction (RCM), one of the most versatile
methods for the construction of medium-sized rings,5 for the synthesis of cyclic amino
acid derivatives, pyrazolopyridines, pyrazoloazepines6a and, more recently, benzo-fused
systems.6b,c
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Therefore, continuing our work within the context of diversity oriented synthesis
(DOS)7,8 focused on the use of tert-butylsulfinyl imines derived from ortho-substituted
benzaldehydes,9,10 a small library of fluoroalkylated 1-amino-1,2-hydronaphthalene
derivatives is described herein (Scheme 1). It is worth mentioning that such derivatives
are unprecedented in the literature.
Scheme 1. Diversity Oriented Synthesis strategy
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Dihydronaphthalene, as a bicyclic molecular scaffold, has been used as model for the
design of many interesting pharmacophores.11 Some noteworthy examples include
sertraline (Figure 1a),
a
selective serotonin reuptake inhibiting (SSR1)
antidepressant,5d,12 or podophyllotoxin (Figure 1b), which has a wide range of medical
applications in purgative, vesicant, antirheumatic, antiviral, and antitumor agents.13 2-
ADN (Figure 1c), also a 1,2-dihydronaphthalene derivative, represents a new, potent
and conformationally restricted analog of amphetamine.14 It produces stimulation of
spontaneous motor activity in mice, and the racemate is approximately one-fourth as
potent as (+)-amphetamine on a molar basis.
Figure 1. Examples of natural products containing the hydronaphthalene substructure.
RESULTS AND DISCUSSION
In view of this background, and given our interest in fluorinated compounds, we
describe a practical method for the synthesis of various fluorinated benzo-fused
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homoallylic amines (Scheme 1, this work) using fluorinated building blocks 3 as key
intermediates (Scheme 2). The strategy described by Valdés et al. for the synthesis of α-
trifluoromethylstyrenes is a highly versatile technique permitting the addition of
fluorinated single-carbon units.15 This method proceeds through a Palladium-catalyzed
cross coupling reaction of 1,1,1-trifluoromethylacetone tosylhydrazone 2 with aryl
bromides 1 and represents an alternative to the coupling between boronic acids and 2-
bromo-3,3,3-trifluoropropene.16 However, the original reaction conditions failed when
applied to our model substrate 2-bromobenzaldehyde 1a. A small optimization allowed
the determination of the best reaction conditions for complete conversion, which for our
system involved microwave heating at 100 °C and an increase in palladium catalytic
loading with respect to the conditions already described, finally affording products 3a-f
in good yields. These compounds were used immediately after their purification in the
next reaction step due to their instability.
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Scheme 2. Synthesis of α-trifluoromethylstyrenes 3a-f
With aldehyde intermediates 3a-f in hand, and based on our recent research,6,9 the
strategy next required the synthesis of the corresponding Ellman’s (R)-N-(tert-
butanesulfinyl)imines 4a-f followed by the allylation reaction, giving rise to products
5a-f in moderate to good yields and excellent diastereoselectivities (Scheme 3).17 The
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obtained results show that electron-donating (3d,e), halogen substituents (3b,c), and
heteroaromatic imines (3f) are all compatible with the reactions conditions. Moreover,
the crotylation reaction made the formation of a new stereocenter possible, and
compound 5g was obtained in 82 % yield as a single diastereoisomer (Scheme 3).
Scheme 3. Asymmetric allylation of sulfinimines 4a-h
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According to our synthetic strategy, and once a varied library of substrates had been
obtained, we set out to apply the RCM reaction as a suitable approach to synthesize the
corresponding fluorinated dihydronaphthalene derivatives. Unfortunately, despite
several attempts under different reaction conditions, the outcome was not satisfactory
for the RCM of 5a, most likely due to the presence of the tert-butanesulfinyl group and
the lower reactivity of fluorinated olefins in metathesis processes.18 In view of this
result, we next evaluated the influence of the N-protecting group.6c To this end, N-Boc
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and N-Ac protected amines 6a-g, 6a’ and 6f’ were prepared and subjected to the RCM
reaction in the presence of 5 mol % of 2nd Generation Grubbs catalyst [Ru-II] in toluene
at 100 ºC, leading to the bicyclic derivatives 7a-g, 7a’ and 7f’ (Scheme 4).
Scheme 4. Protecting group exchange and RCM
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In view of the good results obtained with α-CF3-substituted 2-vinylbenzaldehyde
derivatives, we decided to extend our methodology to other α-fluoroalkylated 2-
vinylbenzaldehyde systems. In addition, we envisioned the preparation of two non-
fluorinated α-substituted 2-vinylbenzaldehyde derivatives in order to study the influence
of fluoroalkyl groups directly attached to a vinyl moiety on their reactivity in olefin
metathesis reactions. However, the strategy described above (see Scheme 2) proved
inefficient for the synthesis of other fluoroalkylated substrates by the cross-coupling
reaction of tosylhydrazones containing different RF (C2F5, CF2H, CF2SO2Ph and
CFHSO2Ph). Therefore, alternative synthetic sequences were set up for each substrate
(Scheme 5). The corresponding CH3- and C2F5-substituted substrates 3h,i were prepared
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by means of palladium-catalyzed Suzuki cross-coupling reactions (Scheme 5, Equation
1). It is worth noting that, regarding fluoroalkylated substrates, this methodology has
mainly been studied for the trifluoromethyl group and to a much lesser extent for other
fluorinated groupings.16b On the other hand, substrates bearing electron-withdrawing
groups at the α-position of the styrene, such as the ester or difluorosulfone,19 were
synthesized by a Wittig methylenation of the corresponding ketones 13a,b (Scheme 5,
Equation 2). Final deprotection of the ortho acetal group yielded the desired substrates
3j,k.
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Scheme 5. Synthesis of substrates 3h-k
Next, the condensation and allylation steps proceeded uneventfully affording substrates
5h-k in moderate to good yields with good to complete diastereoselectivities (Scheme
6). Due to their lack of reactivity (vide infra), fluoroalkylated sulfinamides 5h,k were
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converted into the corresponding tert-butyl carbamate 6h or acetamide 6k, respectively
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(Scheme 6).
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Scheme 6. Condensation/asymmetric allylation/protecting group exchange
sequence
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The final RCM step revealed the dramatic effect of the fluoroalkyl substituent at the
vinyl group on its performance in olefin metathesis processes (Scheme 7).18 More
specifically, although this step proceeded in high yields with sulfinamides 5i,j at room
temperature using the Hoveyda-Grubbs second generation catalyst [Ru-III] in DCM,
fluoroalkylated substrates 5h,k required a protecting group exchange to either Boc or
Ac in order to participate in the RCM step using [Ru-II] or [Ru-III], respectively
(Scheme 7). Moreover, the reaction temperature had to be increased to 100 ºC in
toluene, showcasing the deactivating effect of fluoroalkyl substituents directly attached
to vinyl group in olefin metathesis reactions (Scheme 7). It should be noted that, not
only the CH3-substituted substrate 5i but also the acrylate derivative 5j reacted at room
temperature, indicating that the deactivating effect of a fluoroalkyl group is higher than
that of an ester group. Besides this noticeable deactivating effect of fluoroalkyl groups,
we have also observed a trend in the influence of the several protecting groups used:
may only be used for the non-fluorine containing substituents while any fluoroalkyl
substitution requires the use of an acetyl or a carbamate protecting groups. This may
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indicate that the tert-butylsulfinyl group is somewhat deactivating for homoallylic
amines in metathesis processes.
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Scheme 7. RCM on fluorinated and non-fluorinated α-substituted 2-
vinylbenzaldehyde derivatives
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CONCLUSION
In summary, a new approach to the synthesis of 1-amino-4-fluoroalkyl-1,2-
dihydronaphthalene derivatives from readily available ortho-fluoroalkylvinyl
benzaldehydes has been developed, with a particular emphasis on those bearing
trifluoromethyl substituents. Additionally, we have studied the deactivating effect of
such fluoroalkyl substitution on RCM reactions. We can conclude that α-fluoroalkylated
styrenes are much less reactive than the corresponding non-fluorinated α-substituted
ones. This deactivation is much more pronounced than for common electron-
withdrawing groups, i.e. esters. Building on the principles of diversity-oriented
synthesis, a new family of fluorinated building-blocks suitable for the preparation of
more complex molecules has been described. Further applications for the, in our
opinion, understudied α-CF3-substituted 2-vinylbenzaldehyde scaffold are currently
underway in our laboratories.
EXPERIMENTAL SECTION
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General methods: Reactions were carried out under a nitrogen atmosphere unless
otherwise indicated. Solvents were purified prior to use: THF and PhMe were distilled
from sodium and CH2Cl2 from calcium hydride. The reactions were monitored with the
aid of TLC on 0.25 mm pre-coated silica-gel plates. Visualization was carried out with
UV light and aqueous ceric ammonium molybdate solution or potassium permanganate
stain. Flash column chromatography was performed with the indicated solvents on silica
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gel 60 (particle size: 0.040–0.063 mm). H and C NMR spectra were recorded on a
300 MHz spectrometer. Chemical shifts are given in ppm (δ), referenced to the residual
proton resonances of the solvents. Coupling constants (J) are given in Hertz (Hz). The
letters m, s, d, t, and q stand for multiplet, singlet, doublet, triplet, and quartet,
respectively. The letters br indicate that the signal is broad. The abbreviations DCM and
THF indicate dichloromethane and tetrahydrofuran.
Microwave reactions were carried out in a 2–5 mL or 15 mL vial with a Biotage
InitiatorTM 2.0 microwave synthesizer. The solutions were stirred before the irradiation
was started and the absorbance of the solvent was set as “normal”. The reaction time
was initiated as soon the system reached the input temperature, although it took
approximately 2 min to reach it.
QTOF mass analyzer system has been used for the HRMS measurements.
Enantiomeric excess was determined by means of HPLC using a chiral columns and
mixtures of hexane and isopropanol as mobile phase.
Synthesis of 3a-f. General procedure. A 5-mL microwave glass vial was charged with
Pd2(dba)3 (4 mol%, 0.07 mmol), Xphos (8 mol%, 0.09 mmol), Na2CO3 (2.2 equiv., 2.37
mmol) and N-tosylhydrazone 2 (1.40 mmol, 1.3 equiv.), which was previously prepared
from 1,1,1–trifluoroacetone (1 equiv., 22 mmol) and tosylhydrazide (1 equiv., 22
mmol) by heating at 70 ºC in EtOH (0.5 M) for 5 h and then filtering the precipitate
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solid at room temperature as a crystalline white solid. The solid reagents were dried
together under reduced pressure before being used. THF (0.3 M) and the corresponding
o-bromobenzaldehyde 1 (1.08 mmol) were added. The vial was sealed and the mixture
was heated by microwave irradiation at 100 ºC for 1.5 h. The reaction mixture was
cooled to room temperature, opened, filtered through celite and concentrated under
reduced pressure. The residue obtained was purified by flash chromatography and used
immediately for the next condensation reaction.20
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2-(3,3,3-trifluoro-1-propen-2-yl)benzaldehyde (3a). Flash chromatography of the crude
reaction product [n-hexane-Et2O (30:1)] afforded 3a as a yellow oil (73%, 200 mg). The
spectroscopic data of 3a are consistent with those described in the literature.21
5-Chloro-2-(3,3,3-trifluoro-1-propen-2-yl)benzaldehyde (3b). Flash chromatography of
the crude reaction product [n-hexane-Et2O (30:1)] afforded 3b as a yellow oil (69%, 250
mg). 1H NMR (CDCl3, 300 MHz) δ 5.64 (q, J= 3.0 Hz, 1H), 6.32 (q, J= 3.0 Hz, 1H),
7.36 (dd, J= 3.0, 1.5 Hz, 1H), 7.59 (dd, J= 8.4, 2.4 Hz, 1H), 7.97 (d, J= 3.0 Hz, 1H),
10.07 (s, 1H) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 122.3 (q, J1CF= 273.9 Hz; CF3),
125.6 (q, J3CF= 4.7 Hz; C), 128.2 (CH), 132.1 (CH), 133.6 (CH), 134.4 (q, J3CF= 30.2
Hz; C), 134.4 (q, J3CF= 30.2 Hz; C), 134.7 (C), 136.0 (C), 136.3 (C), 189.4 (CHO) ppm.
19F NMR (CDCl3, 282.4 MHz) δ -67.5 (s, 3F; CF3) ppm.
4-Fluoro-2-(3,3,3-trifluoro-1-propen-2-yl)benzaldehyde (3c). Flash chromatography of
the crude reaction product [n-hexane-Et2O (30:1)] afforded 3c as a colorless oil (59%,
220 mg). 1H NMR (CDCl3, 300 MHz) δ 5.67 (q, J= 2.7 Hz, 1H), 6.32 (q, J= 3.0 Hz,
1H), 7.12 (dd, J= 8.7, 2.4 Hz, 1H), 7.28-7.21 (m, 2H), 8.05 (dd, J= 8.7, 5.7 Hz, 1H),
10.05 (s, 1H) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 117.1 (d, J2CF= 21.7 Hz; CH), 117.8
(d, J2CF= 23.0 Hz; CH), 122.1 (q, J1CF=273.8 Hz; CF3), 125.7 (q, J3CF= 4.8 Hz; C), 131.2
(d, J3CF= 9.9 Hz; CH), 131.5 (d, J3CF= 2.8 Hz; CH), 134.4 (q, J2CF= 32.5 Hz; C), 139.1
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(d, J3CF= 9.4 Hz; CH), 165.2 (d, J1CF= 264.2 Hz; CF), 189.0 (CHO) ppm. 19F NMR
(CDCl3, 282.4 MHz) δ -103.2 to -103.1 (m, 1F; CF), -66.4 (s, 3F; CF3) ppm.
6-(3,3,3-Trifluoro-1-propen-2-yl)benzo[d][1,3]dioxole-5-carbaldehyde (3d). Flash
chromatography of the crude reaction product [n-hexane-Et2O (20:1)] afforded 3d as a
yellow solid (71%, 200 mg). Mp 74-76 °C. 1H NMR (CDCl3, 300 MHz) δ 4.74 (q, J=
1.2 Hz, 1H), 5.22 (s, 2H), 5.41 (q, J= 1.5 Hz, 1H), 5.94 (s, 1H), 6.56 (s, 1H), 9.06 (s,
1H) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 102.4 (CH2), 106.7 (CH), 110.6 (CH), 125.3
(q, J1CF= 273.8 Hz; CF3), 125.7 (q, J3CF= 4.8 Hz; C), 130.4 (C), 133.5 (C), 134.6 (q,
J2CF= 31.9 Hz; CH2), 149.0 (C), 152.1 (C), 189.0 (CHO) ppm. 19F NMR (CDCl3, 282.4
MHz) δ -67.6 (s, 3F; CF3) ppm. HRMS (EI) calcd. for C11H7F3O3 [M+H+]: 245.0420,
found: 245.0416.
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5-Methoxy-2-(3,3,3-trifluoro-1-propen-2-yl)benzaldehyde (3e). Flash chromatography
of the crude reaction product [n-hexane-Et2O (20:1)] afforded 3e as a yellow oil (73%,
300 mg). 1H NMR (CDCl3, 300 MHz) δ 3.88 (s, 3H), 5.58 (q, J= 1.2 Hz, 1H), 6.37 (q,
J= 1.5 Hz, 1H), 7.16 (dd, J= 8.7, 3.0 Hz, 1H), 7.32 (d, J= 8.7 Hz, 1H), 7.48 (d, J= 3.0
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Hz, 1H), 10.08 (s, 1H) ppm. C NMR (CDCl3, 75.5 MHz) δ 55.6 (CH3), 111.0 (CH),
120.9 (CH), 122.5 (q, J1CF= 273.9 Hz; CF3), 125.3 (q, J3CF= 4.8 Hz; CH2), 129.3 (CH),
131.9 (CH), 134.9 (q, J2= 32.1 Hz; C), 136.1 (C), 160.3 (C), 190.7 (CHO) ppm. 19F
NMR (CDCl3, 282.4 MHz) δ -67.6 (s, 3F; CF3) ppm.
3-(3,3,3-trifluoro-1-propen-2-yl)thiophene-2-carbaldehyde (3f). Flash chromatography
of the crude reaction product [n-hexane-Et2O (20:1)] afforded 3f as a yellow oil (94%,
500 mg). 1H NMR (CDCl3, 300 MHz) δ 5.74 (q, J= 1.5 Hz, 1H), 6.27 (q, J= 1.5 Hz,
1H), 7.16-7.19 (m, 1H), 7.72 (dd, J= 4.8, 1.2 Hz, 1H), 9.85 (d, J= 1.5 Hz, 1H) ppm. 13C
NMR (CDCl3, 75.5 MHz) δ 122.1 (q, J1CF= 273.8 Hz; CF3), 126.1 (q, J3CF= 5.1 Hz;
CH2), 129.5 (C), 131.9 (q, J2CF= 32.5 Hz; C), 134.1 (C), 141.4 (C), 142.2 (C), 182.9
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(CHO) ppm. 19F NMR (CDCl3, 282.4 MHz) δ -67.0 (s, 3F; CF3) ppm. HRMS (EI)
calcd. for C8H5F3OS [M+H+]: 207.0086, found: 207.0081.
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Synthesis of 3h. To a solution of 9 (1.3 equiv, 0.87 mmol) in DME–THF (1:1, 2 mL)
and aq. 2 M KOH (1.3 mL), the phenylboronic acid 8 (1 equiv., 0.67 mmol),
PdCl2(PPh3)2 (0.03 equiv., 0.02 mmol), and AsPh3 (0.15 equiv.; 0.1 mmol) were added
under an inert atmosphere in a sealed tube. The mixture was stirred at 74 °C for 12 h.
The mixture was cooled to room temperature, H2O (5 mL) was added, and the mixture
was extracted with Et2O (2 × 10 mL). The combined organic layers were washed with
brine and dried (MgSO4). The solvent was removed and the crude residue was used
immediately in the next condensation reaction.
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Synthesis of 3i. A solution of potassium isopropenyltrifluoroborate 10 (237 mg, 1.6
mmol), PdCl2(dppf).CH2Cl2 (21 mg, 0.03 mmol), o-bromobenzaldehyde 1a (237 mg,
1.28 mmol), and Et3N (0.2 mL, 1.4 mmol) in n-PrOH (20 mL) was heated at 98 °C
under a N2 atmosphere for 13 h. Then the mixture was cooled to room temperature, and
diluted with water (10 mL) followed by extraction with diethyl ether (20 mL). The
ethereal layer was washed with brine (10 mL) and dried over MgSO4. The solvent was
removed in vacuo, and the crude product was purified by silica gel chromatography
(eluting with hexane/DCM 30:1) affording 2-(1-propen-2-yl)benzaldehyde (130 mg, 0.9
mmol, 70%), whose spectroscopic data are consistent with those described in the
literature.22 This product was used immediately for the next condensation reaction.
Synthetic strategy for the synthesis of 3j. (a) Synthesis of ketone 13a: n-BuLi (2.5M
in n-hexane, 1.24 mmol, 0.5 mL) was added slowly to a solution of 2-
bromobenzaldehyde ethylene acetal 11 (1.12 mmol, 0.2 mL) in THF (10 mL) at -78 °C.
After stirring for 1h, diethyloxalate (1.24 mmol, 0.17 mL) was added to the mixture at -
78 °C. The mixture was stirred for 3h, and at this time, saturated aqueous NH4Cl was
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added. The mixture was extracted with Et2O and the combined organic layers were
washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The
residue was purified by flash chromatography [n-hexane: Et2O (7:1)] to afford 13a (188
mg, 70%). whose spectroscopic data are consistent with those described in the
literature.23 (b) Wittig methylenation: NaHMDS (1 M in toluene, 1.4 mL, 0.822 mmol)
was added dropwise to a suspension of methyl triphenylphosphonium chloride (294 mg,
0.822 mmol) in THF (4 mL) at 0 °C under nitrogen atmosphere. The resulting mixture
was stirred at this temperature for 45 min, after which a solution of 13a (525 mg, 0.685
mmol) in THF (4 mL) was slowly added. The reaction mixture was stirred at room
temperature until 13a was no longer detectable by TLC (12 h). The reaction mixture
was then hydrolyzed with a saturated solution of NH4Cl (3 mL) and extracted with
EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo to give a yellow oil, which was purified by means of column
chromatography on silica gel [n-hexane-EtOAc (10:1)] to afford ethyl 2-[2-(1,3-
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dioxolan-2-yl)phenyl]acrylate (Wittig product I) as a colorless oil (60%, 120 mg). H
NMR (CD3OD, 300 MHz) δ 1.24 (t, J= 7.2 Hz, 3H), 3.91-3.93 (m, 2H), 4.00-4.03 (m,
2H), 4.19 (q, J= 7.2, 2H), 5.70 (d, J= 2.0 Hz, 1H), 5.71 (s, 1H), 6.45 (d, J= 2.0 Hz, 1H),
7.15-7.18 (m, 1H), 7.35-7.38 (m, 2H), 7.53-7.56 (m, 1H) ppm. 13C NMR (CD3OD, 75.5
MHz) δ 14.5 (CH3), 62.2 (CH2), 64.4 (2CH2), 102.9 (CH), 127.7 (CH), 128.1 (CH2),
128.9 (CH), 129.4 (CH), 131.4 (CH), 137.4 (C), 138.0 (C), 143.1 (C), 168.2 (C) ppm.
HRMS (EI) calcd. for C14H16O4 [M+H+]: 249.1121, found: 249.1114. (c) Acetal group
deprotection: to a solution of the Wittig product (420 mg, 1.15 mmol) in acetone (6 mL)
at 0 °C, I2 (one bead) was added and the mixture was stirred at this temperature for 5 h.
After this time, the solvent was removed under reduced pressure and the residue was
purified by flash chromatography [n-hexane-EtOAc (7:1)] affording 3j as a colorless oil
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(54% two steps, 150 mg), whose spectroscopic data are consistent with those described
in the literature.24
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Synthetic strategy for the synthesis of 3k. (a) CF2HSO2Ph addition: In a round-
bottom flask, 2-bromobenzaldehyde ethylene acetal 11 (5 mmol, 1 equiv) was dissolved
in dry THF (25 mL) and cooled to -78 °C. Then a solution of n-BuLi (2.6 M in hexane,
7.5 mmol, 1.5 equiv) was added dropwise and stirred for 1 h at the same temperature.
Then, N,N-dimethyl formamide (7.5 mmol, 1.5 equiv.) was added dropwise and the
reaction mixture was allowed to warm up to 0 °C. The reaction was quenched with a
saturated solution of ammonium chloride and the mixture was extracted with diethyl
ether. The organic phase was subsequently washed with brine and dried over anhydrous
sodium sulfate. The solvent was evaporated in vacuo, and crude 12 (883 mg, 4.96
mmol) was dissolved in THF (24 mL). PhSO2CF2H (0.9 mL, 5.95 mmol) was added,
and the mixture was cooled at -78 ºC. At this temperature, LiHMDS (1M in THF, 6.5
mL, 6.5 mmol) was added dropwise and the mixture was stirred for 15 h. Saturated aq.
NH4Cl was then added at –78 °C and the residue was brought to room temperature and
extracted with diethyl ether. The combined organic layers were dried (MgSO4) and the
solvent was evaporated under reduced pressure. Flash chromatography of the crude
reaction mixture [n-hexane-EtOAc (4:1)] afforded 1-[2-(1,3-dioxolan-2-yl)phenyl]-2,2-
difluoro-2-(phenylsulfonyl)-1-ethanol (addition product II) as a colorless oil (70%, 1.2
g). 1H NMR (CDCl3, 300 MHz) δ 3.63 (br, 1H), 4.00-4.07 (m, 2H), 4.12-4.20 (m, 2H),
5.95 (s, 1H), 6.22 (d, J= 22.5 Hz, 1H), 7.35-7.42 (m, 2H), 7.55-7.62 (m, 3H), 7.71-7.76
(m, 2H), 8.02 (d, J= 7.5 Hz, 2H) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 65.1 (CH2), 65.2
(CH2), 66.2 (dd, J2CF= 27.2, 18.4; CH), 102.1 (CH), 120.7 (dd, J1CF= 299.9, 289.4; CF2),
126.9 (CH), 128.8 (CH), 128.9 (CH), 129.2 (CH), 129.5 (CH), 130.7 (CH), 132.9 (C),
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139.0 (C), 135.4 (CH), 135.8 (C) ppm. F NMR (CDCl3, 282.4 MHz) δ -119.1 (ddd,
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J= 238.3, 22.6, 1.9 Hz; 1F; CFF), -103.0 (d, J= 238.3 Hz, 1F; CFF). HRMS (EI) calcd.
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+
for C17H20F2NO5S [M+NH4 ]: 388.1025, found: 388.1025. (b) Oxidation to ketone 13b:
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To a solution of the alcohol obtained in the previous step (626 mg, 1.69 mmol) in DCM
(17 mL), NaHCO3 (20 mg) and Dess-Martin periodinane were added (907 mg, 2.03
mmol) at room temperature. The reaction mixture was stirred at room temperature for 2
h and was then filtered through celite and the filtrate was extracted with H2O and
saturated aq. NaHCO3. The combined organic layers were dried (MgSO4) and the
solvent was evaporated under reduced pressure. The crude product was purified by
column chromatography using as eluent hexane:EtOAc (4:1) to afford 1-[2-(1,3-
dioxolan-2-yl)phenyl]-2,2-difluoro-2-(phenylsulfonyl)-1-ethanone 13b as a colorless oil
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(80%, 520 mg). H NMR (CDCl3, 300 MHz) δ 3.74-3.82 (m, 2H), 3.85-3.93 (m, 2H),
6.12 (s, 1H), 7.50-7.55 (m, 3H), 7.60-7.69 (m, 3H), 7.76-7.81 (m, 1H), 7.99-8.02 (m,
2H) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 64.5 (2CH2), 101.5 (CH), 114.7 (t, J1
=
CF
303.4; CF2), 126.9 (CH), 127.9 (CH), 129.0 (CH), 129.3 (2CH), 130.9 (2CH), 131.5
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(CH), 132.8 (C), 133.1 (C), 135.8 (CH), 138.6 (C), 190.2 (t, J2CF=25.2; CO) ppm. F
NMR (CDCl3, 282.4 MHz) δ -105.5 (s, 2F; CF2) ppm. HRMS (EI) calcd. for
+
C17H18F2O5SN [M+NH4 ]: 386.0874, found: 386.0870. (c) Wittig reaction and acetal
deprotection: The Wittig reaction to afford 2-{2-[3,3-difluoro-3-(phenylsulfonyl)-1-
propen-2-yl]phenyl}-1,3-dioxolane and deprotection of the acetal group to afford 3k,
were carried out following the methodology described in the previous section. Flash
chromatography
[n-hexane-EtOAc
(6:1)]
afforded
2-{2-[3,3-difluoro-3-
(phenylsulfonyl)-1-propen-2-yl]phenyl}-1,3-dioxolane (Wittig product III), as a
colorless oil (78%, 235 mg). 1H NMR (CDCl3, 300 MHz) δ 3.97-4.16 (m, 4H), 5.88 (s,
1H), 5.96 (t, J= 0.9 Hz, 1H), 6.37 (t, J=1.5 Hz, 1H), 7.37-7.46 (m, 3H), 7.55-7.60 (m,
2H), 7.65-7.75 (m, 2H), 7.97 (d, J= 7.20 Hz, 2H) ppm. 13C NMR (CDCl3, 75.5 MHz) δ
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65.4 (2CH2), 101.5 (CH), 120.4 (t, J1CF= 288.3; CF2), 126.8 (CH), 128.7 (CH), 128.9
(CH), 129.1 (2CH), 129.95 (t, J3CF= 6.8; CH2), 130.3 (CH), 130.8 (2CH), 132.9 (C),
133.8 (C), 134.6 (t, J2CF= 22.1; C), 135.1 (CH), 136.7 (C) ppm. 19F NMR (CDCl3, 282.4
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MHz) δ -97.7 (br, 2F; CF2) ppm. HRMS (EI) calcd. for C18H20F2O4SN [M+NH4 ]:
384.1081, found: 384.1076. Deprotection of the acetal group and flash chromatography
purification [n-hexane-EtOAc (7:1)] afforded 2-[3,3-difluoro-3-(phenylsulfonyl)-1-
propen-2-yl]benzaldehyde 3k as a white solid (70%, 260 mg). Mp 120-122 °C. 1H NMR
(CDCl3, 300 MHz) δ 5.91 (t, J= 0.9 Hz, 1H), 6.42 (t, J= 1.5 Hz, 1H), 7.54-7.60 (m, 5H),
7.72-7.78 (m, 1H), 7.94-7.99 (m, 3H), 10.18 (s, 1H) ppm. 13C NMR (CDCl3, 75.5 MHz)
δ 120.1 (t, J1CF= 288.9; CF2), 129.1 (CH), 129.3 (2CH), 129.4 (CH), 130.2 (t, J3CF= 6.8;
CH2), 130.8 (2CH), 131.7 (CH), 132.6 (C), 133.5 (CH), 134.4 (t, J2CF= 22.3; C), 135.0
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(C), 135.4 (CH), 136.9 (C), 191.3 (CHO) ppm. F NMR (CDCl3, 282.4 MHz) δ -99.3
+
(s, 2F; CF2) ppm. HRMS (EI) calcd. for C16H16F2O3SN [M+NH4 ]: 340.0819, found:
340.0814.
General procedure for the condensation of aldehydes 3 to imines 4. A solution of
the corresponding aldehyde 3 (5 mmol, 1.0 equiv) and Ti(OEt)4 (5.0 equiv) in
dichloromethane (0.1 M) was stirred for 5 minutes at room temperature. To the resulting
solution, (R)-N-(tert-butanesulfinyl)amine was added, and the mixture was stirred at
room temperature for 12 hours. After this time, saturated aqueous NaHCO3 was added
until white titanium salts precipitated. The suspension was filtered through a short pad
of Celite® washing with small portions of dichloromethane. The filtrate was extracted
with ethyl acetate and the combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by flash
chromatography affording imines 4.
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(RS-E)-2-methyl-N-[2-(3,3,3-trifluoro-1-propen-2-yl)benzylidene]propane-2-
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sulfinamide (4a). Flash chromatography of the crude reaction product [n-hexane-Et2O
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(5:1)] afforded 4a as a yellow oil (95%, 525 mg). [α]D = -13.9 (c 1.0; CHCl3). H
NMR (CDCl3, 300 MHz) δ 1.25 (s, 9H), 5.56 (q, J= 1.2 Hz, 1H), 6.25 (q, J= 1.5 Hz,
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1H), 7.36-7.39 (m, 1H), 7.50-7.53 (m, 2H), 8.10-8.13 (m, 1H), 8.71 (s, 1H), ppm. C
NMR (CDCl3, 75.5 MHz) δ 22.6 (3CH3), 57.9 (C), 122.5 (q, CF3, J1CF= 274.3), 124.9
(q, CH2, J3CF= 5.0), 128.4 (CH), 129.3 (CH), 130.5 (CH), 131.6 (CH), 132.9 (C), 135.6
(C), 135.9 (q, C, J2CF= 31.7), 160.8 (CH) ppm. F NMR (CDCl3, 282.4 MHz) δ -67.3
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(s, 3F; CF3) ppm. HRMS (EI) calcd. for C14H17F3NOS [M+H+]: 304.0977, found:
304.0982.
(RS-E)-N-[5-chloro-2-(3,3,3-trifluoro-1-propen-2-yl)benzylidene]-2-methylpropane-2-
sulfinamide (4b). Flash chromatography of the crude reaction product [n-hexane-Et2O
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(5:1)] afforded 4b as a pale yellow solid (99%, 400 mg). [α]D = -85.1 (c 1.0; CHCl3).
Mp 49-51 °C. 1H NMR (CDCl3, 300 MHz) δ 1.25 (s, 9H), 5.57 (q, J= 3.0 Hz, 1H), 6.28
(q, J= 3.0 Hz, 1H), 7.33 (d, J= 9.0 Hz, 1H), 7.48 (dd, J= 8.4, 2.4 Hz, 1H), 8.08 (d, J=
13
3.0 Hz, 1H), 8.63 (s, 1H) ppm. C NMR (CDCl3, 75.5 MHz) δ 22.6 (3CH3), 58.2 (C),
122.3 (q, CF3, J1CF= 271.8), 125.7 (q, CH2, J3CF= 4.0), 125.7 (C), 128.1 (CH), 131.6
(CH), 131.8 (CH), 133.7 (C), 134.4 (C), 135.8 (C), 134.9 (q, C, J2CF =31.9), 159.6 (CH)
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ppm. F NMR (CDCl3, 282.4 MHz) δ -67.4 (s, 3F; CF3) ppm. HRMS (EI) calcd. for
C14H16F3NOSCl [M+H+]: 338.0588, found: 338.0582.
(RS-E)-N-[4-fluoro-2-(3,3,3-trifluoro-1-propen-2-yl)benzylidene]-2-methylpropane-2-
sulfinamide (4c). Flash chromatography of the crude reaction product [n-hexane-Et2O
(5:1)] afforded 4c as a white solid (94%, 425 mg). [α]D25 = -116.94 (c 1.0; CHCl3). Mp
46-48 ºC. 1H NMR (CDCl3, 300 MHz) δ 1.24 (s, 9H), 5.60 (q, J= 1.20 Hz, 1H), 6.29 (q,
J= 1.5 Hz, 1H), 7.09 (dd, J= 8.7, 2.4 Hz, 1H), 7.18-7.25 (m, 1H), 8.14 (dd, J= 9.0, 6.0
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Hz, 1H), 8.64 (s, 1H) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 22.4 (3CH3), 57.8 (C),
117.0 (d, CH, J2CF= 21.7), 117.8 (d, CH, J2CF= 20.7), 122.2 (q, CF3, J1CF= 273.8), 125.6
(q, CH2, J3CF= 5.1), 129.4 (q, C, J3CF= 5.0), 131.3 (d, CH, J2CF= 9.9), 131.5 (d, CH,
J3CF= 2.8), 134.6 (q, C, J2CF= 31.9), 137.6 (d, C, J3CF= 8.9), 159.5 (CH), 164.1 (d, CF,
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J1CF= 256.7) ppm. F NMR (CDCl3, 282.4 MHz) δ -67.3 (s, 3F; CF3), -106.7 (s, 1F;
CF) ppm. HRMS (EI) calcd. for C14H15F4NOS [M+H+]: 322.0883, found: 322.0875.
(RS-E)-2-methyl-N-{[6-(3,3,3-trifluoro-1-propen-2-yl)benzo[d][1,3]dioxol-5-yl]
methylene}propane-2-sulfinamide (4d). Flash chromatography of the crude reaction
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product [n-hexane-Et2O (5:1)] afforded 4d as a white solid (89%, 300 mg). [α]D = -
50.3 (c 1.0; CHCl3). Mp 58-60ºC. 1H NMR (CDCl3, 300 MHz) δ 1.23 (s, 9H), 5.55 (q,
J= 1.5 Hz, 1H), 6.07 (d, J= 1.2 Hz, 1H), 6.08 (d, J= 1.2 Hz, 1H), 6.25 (q, J= 1.2 Hz,
13
1H), 6.81 (s, 1H), 7.58 (s, 1H), 8.57 (s, 1H) ppm. C NMR (CDCl3, 75.5 MHz) δ 22.5
(3CH3), 57.7 (C), 102.1 (CH2), 107.0 (CH), 109.7 (CH), 122.4 (q, CF3, J1CF= 274.0),
125.5 (q, CH2 J3CF= 4.7), 128.0 (C), 131.4 (C), 134.9 (q, C, J2CF= 31.5), 148.8 (C),
150.6 (C), 159.8 (CHO) ppm. 19F NMR (CDCl3, 282.4 MHz) δ -67.4 (s, 3F; CF3) ppm.
HRMS (EI) calcd. for C15H17F3NO3S [M+H+]: 348.0876, found: 348.0876.
(RS-E)-N-[5-methoxy-2-(3,3,3-trifluoro-1-propen-2-yl)benzylidene]-2-methyl propane-
2-sulfinamide (4e). Flash chromatography of the crude reaction product [n-hexane-Et2O
(5:1)] afforded 4e as a colorless oil (92%, 350 mg). [α]D = -80.1 (c 1.0; CHCl3). 1H
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NMR (CDCl3, 300 MHz) δ 1.21 (s, 9H), 3.83 (s, 3H), 5.48 (d, J= 1.5 Hz, 1H), 6.19 (d,
J= 1.5 Hz, 1H), 7.02 (dd, J= 8.4, 2.7 Hz, 1H), 7.26 (d, J= 8.7 Hz, 1H), 7.58 (d, J= 2.7
Hz, 1H), 8.64 (s, 1H) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 22.4 (3CH3), 55.3 (OCH3),
57.8 (C), 112.0 (CH), 118.1 (CH), 122.5 (q, CF3, J1CF= 274.0), 120.7 (C), 125.0 (q,
CH2, J3CF= 4.7), 131.5 (CH), 134.0 (C), 134.0 (q, C, J2CF= 31.5), 135.4 (q, C, J2
=
CF
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31.5), 159.5 (C), 160.0 (C), 160.7 (C) ppm. F NMR (CDCl3, 282.4 MHz) δ -67.0 (s,
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3F; CF3) ppm. HRMS (EI) calcd. for C15H19F3NO2S [M+H+]: 334.1108, found:
334.1093.
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(RS-E)-2-methyl-N-{[5-(3,3,3-trifluoro-1-propen-2-yl)benzo[b]thiophen-6-
yl]methylene}propane-2-sulfinamide (4f). Flash chromatography of the crude reaction
product [n-hexane-Et2O (5:1)] afforded 4f as a yellow oil (58%, 315 mg). [α]D25 = -55.0
(c 1.0; CHCl3). 1H NMR (CDCl3, 300 MHz) δ 1.24 (s, 9H), 5.64 (q, J= 1.5 Hz, 1H),
6.22 (q, J= 1.5 Hz, 1H), 7.13-7.16 (m, 1H), 7.55 (dd, J= 5.4, 1.2 Hz, 1H), 8.63 (s, 1H)
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ppm. C NMR (CDCl3, 75.5 MHz) δ 22.5 (3CH3), 58.2 (C), 120.4 (C), 125.7 (q, CH2,
J3CF= 5.05), 129.1 (CH), 131.4 (CH), 131.9 (q, C, J2CF=32.16), 138.5 (C), 139.2 (C),
154.2 (CH) ppm. 19F NMR (CDCl3, 282.4 MHz) δ -66.9 (s, 3F; CF3) ppm. HRMS (EI)
calcd. for C12H15F3NOS2 [M+H+]: 310.0542, found: 310.0545.
(RS-E)-2-methyl-N-[2-(3,3,4,4,4-pentafluoro-1-buten-2-yl)benzylidene]propane-2-
sulfinamide (4h). Flash chromatography of the crude reaction product [n-hexane-Et2O
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(5:1)] afforded 4h as colorless oil (66%, 100 mg). [α]D = - 60.2 (c 1.0; CHCl3). 1H
NMR (CDCl3, 300 MHz) δ 1.23 (s, 9H), 5.71 (br, 1H), 6.28 (br, 1H), 7.30-7.33 (m, 1H),
7.47-7.50 (m, 2H), 8.09-8.12 (m, 1H) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 22.5
(3CH3), 57.8 (C), 113.1 (tq, J1CF= 255.4, J2CF= 38.1; CF2F3), 119.1 (qt, J1CF= 286.9,
J2CF= 38.1; CF2CF3), 127.9 (t, J3CF= 7.6; CH2), 128.4 (CH), 129.3 (CH), 130.8 (CH),
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131.5 (CH), 132.9 (C), 135.4 (t, J2CF= 23.1; C), 139.9 (C), 160.8 (CH) ppm. F NMR
(CDCl3, 282.4 MHz) δ -114.4 (q, J= 57.8 Hz, 2F; CF2), -83.0 (t, J= 2.0 Hz, 3F; CF3)
ppm. HRMS (EI) calcd. for C15H17F5NOS [M+H+]: 354.0946, found: 354.0948.
(RS-E)-N-[2-(3,3-difluoro-3-phenylsulfonyl-1-propen-2-yl)benzylidene]-2-
methylpropane-2-sulfinamide (4k). Flash chromatography of the crude reaction product
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[n-hexane-EtOAc (5:1)] afforded 4k as colorless oil (52%, 120 mg). [α]D = - 16.3 (c
1.0; CHCl3). 1H NMR (CDCl3, 300 MHz) δ 1.21 (s, 9H), 5.86 (t, J= 0.9 Hz, 1H), 6.32 (t,
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J= 1.5 Hz, 1H), 7.47-7.61 (m, 5H), 7.70-7.76 (m, 1H), 7.95-8.06 (m, 3H), 8.71 (s, 1H)
ppm. 13C NMR (CDCl3, 75.5 MHz) δ 22.5 (3CH3), 57.8 (C), 120.18 (t, J1CF= 289.1;
CF2), 128.7 (CH), 129.2 (2CH), 129.3 (CH), 129.9 (t, J3CF= 6.7; CH2), 130.8 (2CH),
131.7 (2CH), 132.7 (C), 133.0 (C), 135.2 (t, J2CF=22.3; C), 135.3 (CH), 136.1 (C), 161.3
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(CH) ppm. F NMR (CDCl3, 282.4 MHz) δ -99.8 (br, 1F; CFF), -98.3 (br, 1F; CFF)
ppm. HRMS (EI) calcd. For C20H22F2NO3S2 [M+H+]: 426.1005, found: 426.1000.
General procedure for the allylation/crotylation of imines 4. A 1M solution of
allylzinc/crotylzinc bromide in THF was prepared by stirring, allyl/crotyl bromide (1.0
equiv) and activated Zn (3.0 equiv) in anhydrous THF (1 M) at 55 ºC. This freshly
prepared solution (1.1 equiv, 0.55 mmol) was then added to a solution of imine 4 (1.0
equiv, 0.5 mmol) in THF (0.1 M) at -60 ºC. After stirring for 3h at -60 ºC the reaction
mixture was quenched with saturated aqueous NH4Cl and extracted three times with
AcOEt. Flash chromatography afforded compounds 5.
(RS)-2-methyl-N-{(S)-1-[2-(3,3,3-trifluoro-1-propen-2-yl)phenyl]-3-buten-1-yl}
propane-2-sulfinamide (5a). Flash chromatography of the crude reaction product [n-
hexane-EtOAc (5:1)] afforded 5a as colorless oil (95%, 250 mg). [α]D25 = - 225.8 (c 1.0;
CHCl3). 1H NMR (CDCl3, 300 MHz) δ 1.09 (s, 9H), 2.24-2.50 (m, 2H), 3.69 (br, 1H),
4.54-4.59 (m, 1H), 5.10-5.16 (m, 2H), 5.66 (d, J= 3.0 Hz, 1H), 5.62-5.76 (m, 1H), 6.14
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(q, J= 3.0 Hz, 1H), 7.17-7.22 (m, 2H), 7.33-7.41 (m, 2H) ppm. C NMR (CDCl3, 75.5
MHz) δ 22.6 (3CH3), 43.1 (CH2), 52.4 (CH), 55.6 (C), 119.4 (CH2), 122.8 (q, CF3,
J1CF= 271.8), 124.2 (q, CH2, J3CF= 4.9), 127.2 (CH), 127.7 (CH), 129.1 (CH), 129.9
(CH), 133.3 (C), 134.5 (CH), 136.6 (q, C, J2CF= 31.1), 140.8 (C) ppm. 19F NMR
(CDCl3, 282.4 MHz) δ -67.5 (s, 3F; CF3) ppm. HRMS (EI) calcd. for C17H22F3NOS
[M+H+]: 346.1447, found: 346.1437.
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(RS)-N-{(S)-1-[5-chloro-2-(3,3,3-trifluoro-1-propen-2-yl)phenyl]-3-buten-1-yl}-2-
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methylpropane-2-sulfinamide (5b). Flash chromatography of the crude reaction product
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[n-hexane-EtOAc (5:1)] afforded 5b as colorless oil (99%, 230 mg). [α]D = - 57.5 (c
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1.0; CHCl3). H NMR (CDCl3, 300 MHz) δ 1.18 (s, 9H), 2.27-2.36 (m, 1H), 2.49-
2.57(m, 1H), 3.76 (s, 1H), 4.60 (ddd, J= 6.0, 3.0, 0.5 Hz, 1H), 5.19-5.25 (m, 2H), 5.68-
5.81 (m, 2H), 6.23 (dd, J= 3.0, 3.0 Hz, 1H), 7.18 (d, J= 9.0 Hz, 1H), 7.26-7.29 (m, 1H),
7.45 (d, J= 3.0 Hz, 1H) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 22.5 (3CH3), 42.9 (CH2),
52.2 (CH), 55.8 (C), 119.8 (CH2), 122.5 (q, CF3, J1CF= 203.8), 124.8 (q, CH2, J3
4.8), 127.5 (CH), 128.1 (CH), 131.3 (CH), 131.6 (C), 133.9 (CH), 135.7 (q, C, J2
=
=
CF
CF
31.5), 142.9 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ -67.5 (s, 3F; CF3) ppm. HRMS
(EI) calcd. for C17H22ClF3NOS [M+H+]: 380.1057, found: 380.1053.
(RS)-N-{(S)-1-[4-fluoro-2-(3,3,3-trifluoro-1-propen-2-yl)phenyl]-3-buten-1-yl}-2-
methylpropane-2-sulfinamide (5c). Flash chromatography of the crude reaction product
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[n-hexane-EtOAc (4:1)] afforded 5c as colorless oil (94%, 265 mg). [α]D = - 103.4 (c
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1.0; CHCl3). H NMR (CDCl3, 300 MHz) δ 1.15 (s, 9H; 3CH3), 2.27-2.38 (m, 1H),
2.46-2.52 (m, 1H), 3.75 (s, 1H), 4.57 (ddd, J= 5.7, 3.9, 1.5 Hz, 1H), 5.16-5.21 (m, 2H),
5.66-5.80 (m, 2H), 6.22 (q, J= 1.2 Hz, 1H), 6.93 (dd, J= 9.3, 2.7 Hz, 1H), 7.09 (dt, J=
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8.4, 3.0 Hz, 1H), 7.43 (dd, J= 5.7, 2.2 Hz, 1H) ppm. C NMR (CDCl3, 75.5 MHz) δ
22.5 (3CH3), 43.1 (CH2), 51.8 (CH), 55.6 (C), 116.4 (d, CH, J2CF= 10.1), 116.7 (d, CH,
J2CF= 11.0), 119.5 (CH2), 122.6 (q, CF3, J1CF= 273.6), 124.7 (q, CH2, J3CF= 4.8), 129.7
(q, CH, J3CF= 8.4), 134.16 (CH), 135.0 (d, C, J3CF= 8.0), 135.4 (q, C, J2CF= 31.3), 136.6
(d, C, J3CF= 3.1), 161.1 (d, CF, J1CF= 249.1) ppm. F NMR (CDCl3, 282.4 MHz) δ -
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114.8 (ddd, JFH= 9.0, 8.2, 5.6 Hz, F; CF), -67.5 (s, 3F; CF3) ppm. HRMS (EI) calcd. for
C17H22F4NOS [M+H+]: 364.1353, found: 364.1345.
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buten-1-yl}propane-2-sulfinamide (5d). Flash chromatography of the crude reaction
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product [n-hexane-EtOAc (4:1)] afforded 5d as colorless oil (89%, 225 mg). [α]D = -
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61.6 (c 1.0; CHCl3). 1H NMR (CDCl3, 300 MHz) δ 1.17 (s, 9H), 2.24-2.38 (m, 1H),
2.44-2.51 (m, 3H), 3.72 (s, 1H), 4.54 (ddd, J= 9.6, 3.9, 1.5 Hz, 1H), 5.15-5.21 (m, 2H),
5.67-5.77 (m, 2H), 5.98 (dd, J= 6.0, 1.2 Hz, 2H), 6.18 (q, J= 1.2 Hz, 1H), 6.67 (s, 1H),
6.88 (s, 1H) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 22.5 (3CH3), 43.1 (CH2), 52.3 (CH),
55.5 (C), 101.4 (CH2), 107.2 (CH), 109.4 (CH), 119.3 (CH2), 122.8 (q, CF3, J1
=
CF
273.3), 124.6 (q, CH2, J3CF= 4.6), 134.4 (C), 134.6 (CH), 135.0 (q, C, J2CF= 31.2), 136.6
(C), 145.6 (C), 148.5 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ -67.6 (s, 3F; CF3) ppm.
HRMS (EI) calcd. for C18H23F3NO3S [M+H+]: 390.1345, found: 390.1356.
(RS)-N-{(S)-1-[5-methoxy-2-(3,3,3-trifluoro-1-propen-2-yl)phenyl]-3-buten-1-yl}-2-
methylpropane-2-sulfinamide (5e). Flash chromatography of the crude reaction product
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[n-hexane-EtOAc (4:1)] afforded 5e as a white solid (92%, 280 mg). [α]D = - 91.7 (c
1.0; CHCl3). Mp 60-62 ºC. 1H NMR (CDCl3, 300 MHz) δ 1.18 (s, 9H), 2.28-2.40 (m,
1H), 2.50-2.57 (m, 1H), 3.73 (br, 1H), 3.81 (s, 3H), 4.60 (ddd, J= 9.6, 3.9, 1.8 Hz, 1H),
5.17-5.23 (m, 2H), 5.69 (q, J= 1.5 Hz, 1H), 5.71-5.83 (m, 1H), 6.19 (q, J= 1.2 Hz, 1H),
6.84 (dd, J= 8.4, 2.7 Hz, 1H), 6.98 (d, J= 2.7 Hz, 1H), 7.16 (d, J= 9.0 Hz, 1H) ppm. 13C
NMR (CDCl3, 75.5 MHz) δ 22.5 (3CH3), 43.1 (CH), 52.5 (CH2), 55.1 (OCH3), 55.6 (C),
112.9 (CH), 112.8 (CH), 119.4 (CH2), 122.9 (q, CF3, J1CF= 273.8 Hz), 124.4 (q, CH2,
J3CF= 4.0 Hz), 125.5 (C), 131.1 (CH), 134.4 (CH), 135.9 (q, C, J2CF= 31.1 Hz), 142.4
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(C), 160.0 (C) ppm. F NMR (CDCl3, 282.4 MHz) δ -67.7 (s, 3F; CF3) ppm. HRMS
(EI) calcd. for C18H25F3NO2S [M+H+]: 376.1553, found: 376.1560.
(RS)-2-methyl-N-{(S)-1-[5-(3,3,3-trifluoro-1-propen-2-yl)benzo[b]thiophen-6-yl]-3-
buten-1-yl}propane-2-sulfinamide (5f). Flash chromatography of the crude reaction
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product [n-hexane-EtOAc (4:1)] afforded 5f as colorless oil (58%, 450 mg). [α]D = -
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75.7(c 1.0; CHCl3). H NMR (CDCl3, 300 MHz) δ 1.20 (s, 9H), 2.42-2.53 (m, 1H),
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1H), 5.64-5.77 (m, 1H), 6.12 (q, J= 1.5 Hz, 1H), 6.93 (dd, J= 5.4, 1.2 Hz, 1H), 7.28 (d,
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J= 4.8 Hz, 1H) ppm. C NMR (CDCl3, 75.5 MHz) δ 22.9 (3CH3), 44.9 (CH2), 50.9
(CH), 55.8 (C), 117.2 (C), 119.8 (C), 120.2 (CH2), 124.3 (q, J3CF= 5.13 Hz, CH2), 125.2
(CH), 128.2 (CH), 132.5 (q, J2CF= 31.63 Hz; C), 133.9 (CH), 145.2 (C) ppm. 19F NMR
(CDCl3, 282.4 MHz) δ -67.3 (s, 3F; CF3) ppm. HRMS (EI) calcd. for C15H20F3NOS2
[M+H+]: 352.1011, found: 352.1008.
(RS)-2-methyl-N-{(1S,2S)-2-methyl-1-[6-(3,3,3-trifluoro-1-propen-2-yl)benzo[d]
[1,3]dioxol-5-yl]-3-buten-1-yl}propane-2-sulfinamide (5g). Flash chromatography of
the crude reaction product [n-hexane-EtOAc (3:1)] afforded 5g as colorless oil (82%,
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133 mg). [α]D = - 71.1 (c 1.0; CHCl3). 1H NMR (CDCl3, 300 MHz) δ 0.75 (d, J= 6.9
Hz, 3H), 1.15 (s, 9H), 2.28-2.41 (m, 1H), 3.98 (s, 1H), 4.21 (dd, J= 9.3, 0.9 Hz, 1H),
5.17-5.25 (m, 2H), 5.63-5.75 (m, 1H), 5.93 (d, J=1.2 Hz, 1H), 5.99 (dd, J= 4.5, 1.5 Hz,
2H), 6.21 (q, J= 1.5 Hz, 1H), 6.72 (d, J= 0.9 Hz, 1H), 6.82 (s, 1H) ppm. 13C NMR
(CDCl3, 75.5 MHz) δ 16.9(CH3), 22.6 (3CH3), 47.5 (CH), 55.6 (C), 56.4 (CH), 101.5
(CH2), 107.4 (CH), 108.9 (CH), 117.7 (CH2), 121.1 (q, J1CF= 273.3 Hz; CF3), 124.6 (C),
125.6 (q, J3CF= 4.9 Hz; CH2), 132.9 (C), 135.6 (q, J2CF= 30.7 Hz; C), 146.7 (C), 141.6
(CH), 148.5 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ -65.5 (s, 3F; CF3) ppm. HRMS
(EI) calcd. for C19H24F3NO3S [M+H+]: 404.1502, found: 404.1523.
(RS)-2-methyl-N-{(S)-1-[2-(3,3,4,4,4-pentafluoro-1-buten-2-yl)phenyl]-3-buten-1-
yl}propane-2-sulfinamide (5h). Flash chromatography of the crude reaction product [n-
hexane-EtOAc (5:1)] afforded 5h as a white solid (91%, 180 mg). [α]D25 = - 90.2 (c 1.0;
CHCl3). Mp 59-61 °C. 1H NMR (CDCl3, 300 MHz) δ 1.15 (s, 9H), 2.32-2.40 (m, 1H),
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2.51-2.58 (m, 1H), 3.78 (br, 1H), 4.56-4.61 (m, 1H), 5.17-5.24 (m, 2H), 5.50-5.83 (m,
1H), 5.88 (s, 1H), 6.23 (s, 1H), 7.17-7.19 (m, 1H), 7.24-7.30 (m, 1H), 7.36-7.47 (m, 2H)
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ppm. C NMR (CDCl3, 75.5 MHz) δ 22.5 (3CH3), 42.9 (CH2), 52.6 (CH), 55.6 (C),
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108.8-125.0 (C2F5), 119.4 (CH2), 127.1 (CH), 127.6 (t, J3CF= 7.7, CH2), 127.7 (CH),
129.1 (CH), 130.1 (CH), 133.8 (C), 134.5 (CH), 140.9 (C) ppm. 19F NMR (CDCl3,
282.4 MHz) δ -112.8 (d, J= 181.3 Hz, 2F; CF2), -82.7 (s, 3; CF3) ppm. HRMS (EI)
calcd. for C18H22F5OSN [M+H+]: 396.1415, found: 396.1422.
(RS)-2-methyl-N-{(S)-1-[2-(1-propen-2-yl)phenyl] -3-buten-1-yl}propane-2-sulfinamide
(5i). Flash chromatography of the crude reaction product [n-hexane-EtOAc (8:1)]
afforded 5i as a colorless oil (64% two steps, 100 mg). [α]D25 = - 88.8 (c 1.0; CHCl3). 1H
NMR (CDCl3, 300 MHz) δ 1.11 (s, 9H), 2.04 (s, 3H), 2.27-2.55 (m, 2H), 3.59 (br, 1H),
4.66 (br, 1H), 4.81 (s, 1H), 5.08-5.12 (m, 2H), 5.18 (s, 1H), 5.59-5.74 (m, 1H), 7.04 (d,
J= 7.0 Hz, 1H), 7.16-7.19 (m, 2H), 7.30 (d, J= 7.1 Hz, 1H) ppm. 13C NMR (CDCl3, 75.5
MHz) δ 22.5 (3CH3), 25.7 (CH3), 43.8 (CH2), 52.5 (CH), 55.5 (C), 115.8 (CH2), 118.9
(CH2), 127.0 (CH), 127.1 (CH), 128.1 (C), 134.6 (CH), 138.2 (C), 143.9 (C), 144.7 (C)
ppm. HRMS (EI) calcd. for C17H25NOS [M+H+]: 292.1730, found: 292.1722.
(RS)-ethyl 2-{2-[(1S)-1-[(tert-butylsulfinyl)amino]-3-buten-1-yl]phenyl}acrylate (5j).
Flash chromatography of the crude reaction product [n-hexane-EtOAc (3:1)] afforded 5j
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as colorless oil (62% two steps, 39 mg). [α]D = - 99.8 (c 1.0; CHCl3). H NMR
(CDCl3, 300 MHz) δ 1.16 (s, 9H), 1.27 (t, J= 8.5 Hz, 3H), 2.29-2.40 (m, 1H), 2.56-2.63
(m, 1H), 3.70 (br, 1H), 4.18-4.29 (m, 2H), 4.47-4.52 (m, 1H), 5.13-5.18 (m, 2H), 5.63-
5.77 (m, 1H), 5.81 (d, J= 1.5 Hz, 1H), 6.61 (d, J= 1.5 Hz, 1H), 7.12 (dd, J= 7.5, 1.7 Hz,
1H), 7.27-7.28 (m, 1H), 7.31-7.37 (m, 1H), 7.44 (dd, J= 8.0, 1.7 Hz, 1H) ppm. 13C
NMR (CDCl3, 75.5 MHz) δ 14.1 (CH3), 22.6 (3CH3), 42.8 (CH2), 52.9 (CH), 55.6 (C),
61.3 (CH2), 119.1 (CH2), 126.9 (CH), 127.1 (CH), 128.2 (CH), 129.8 (CH), 129.9
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(CH2), 134.5 (CH), 137.0 (C), 139.9 (C), 140.4 (C), 166.4 (C) ppm. HRMS (EI) calcd.
for C19H28NO3S [M+H+]: 350.1784, found: 350.1793.
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2-methylpropane-2-sulfinamide (5k). Flash chromatography of the crude reaction
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product [n-hexane-EtOAc (2:1)] afforded 5k as colorless oil (95%, 100 mg). [α]D = -
66.1 (c 1.0; CHCl3). 1H NMR (CDCl3, 300 MHz) δ 1.16 (s, 9H), 2.30-2.41 (m, 1H),
2.61-2.65 (m, 1H), 3.79 (br, 1H), 4.64-4.68 (m, 1H), 5.14-5.21 (m, 2H), 5.69-5.83 (m,
1H), 6.06 (br, 1H), 6.42 (t, J= 1.5 Hz, 1H), 7.18-7.47 (m, 4H), 7.57-7.62 (m, 2H), 7.72-
7.77 (m, 1H), 7.99 (d, J= 7.5 Hz, 2H) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 22.6
(3CH3), 42.9 (CH2), 52.8 (CH), 55.6 (C), 119.2 (CH2), 120.5 (t, J1CF= 287.7 Hz; CF2),
125.3 (C), 127.1 (CH), 127.5 (CH), 128.2 (CH), 129.0 (CH), 129.2 (2CH), 130.5 (t,
J3CF= 6.2 Hz; CH2), 130.6 (CH), 130.9 (2CH), 132.9 (C), 134.8 (CH), 135.2 (CH),
140.8 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ -99.9 (d, J= 219.1 Hz, 1F; CFF), -94.8
(d, J= 205.6 Hz, 1F; CFF) ppm. HRMS (EI) calcd. for C23H28F2NO3S2 [M+H+]:
468.1469, found: 468.1468.
General procedure for the protecting group exchange. Hydrogen chloride (2.9
mmol, 4.0 equiv, 4M solution in 1,4-dioxane) was added at room temperature to a
solution of the corresponding sulfinyl amine (0.73 mmol, 1.0 equiv) in MeOH (1 M).
After 30 minutes the deprotection was complete and the solution was concentrated to
dryness. The residue was re-dissolved in CH2Cl2 (5 mL) and 2M NaOH was added and
extracted three times with dichloromethane. The combined organic layers were dried
over anhydrous Na2SO4. Solvents were removed under reduced pressure and the crude
reaction mixture was used in the next protection step without further purification.
(a) N-Boc-protection: The resulting crude product was dissolved in anhydrous 1,4-
dioxane (0.2 M) and treated with K2CO3 (1.8 mmol, 2.5 equiv) and di-tert-butyl
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dicarbonate (Boc2O) (0.9 mmol, 1.1 equiv). The mixture was stirred at 50 ºC overnight,
until TLC revealed the disappearance of the free amine. The suspension was then
filtered through a short pad of Celite® and washed with small portions of ethyl acetate.
Solvents were removed under reduced pressure and the residue was purified by means
of flash chromatography on silica gel affording the desired product.
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Tert-Butyl
(S)-{1-[2-(3,3,3-trifluoro-1-propen-2-yl)phenyl]-3-buten-1-yl}carbamate
(6a). Flash chromatography of the crude reaction product [n-hexane-Et2O (30:1)]
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afforded 6a as a white solid (83%, 100 mg). [α]D = - 18.5 (c 1.0; CHCl3). Mp 30-32
°C . 1H NMR (CDCl3, 300 MHz) δ 1.39 (s, 9H), 2.41-2.47 (m, 2H), 4.78 (br, 1H), 4.92
(br, 1H), 5.04- 5.12 (m, 2H), 5.60-5.74 (m, 2H), 6.20 (d, J= 3.0 Hz, 1H), 7.25-7.38 (m,
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2H) ppm. C NMR (CDCl3, 75.5 MHz) δ 28.3 (3CH3), 41.0 (CH2), 50.4 (CH), 50.5
(CH), 79.4 (C), 118.8 (CH2), 122.9 (q, J1CF= 271.8, CF3), 124.4 (q, J3CF= 2.2, CH2),
125.9 (CH), 126.8 (CH), 129.2 (CH), 130.1 (CH), 132.5 (C), 134.0 (CH), 141.5 (C),
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154.7 (C), ppm. F NMR (CDCl3, 282.4 MHz) δ -67.0 (s, 3F; CF3) ppm. HRMS (EI)
calcd. for C18H22F3NO2 [M+H+]: 342.1675, found: 342.1673. HPLC (Chiralcel OD-H,
98:2 hexane/iPrOH, 1 mL min-1, 240 nm) tR(major) = 5.00 min, tR(minor) = 4.56 min.
Tert-Butyl
(S)-{1-[5-chloro-2-(3,3,3-trifluoro-1-propen-2-yl)phenyl]-3-buten-1-yl}
carbamate (6b). Flash chromatography of the crude reaction product [n-hexane-Et2O
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(30:1)] afforded 6b as a colorless oil (55%, 90 mg). [α]D = - 38.2 (c 1.0; CHCl3). 1H
NMR (CDCl3, 300 MHz) δ 1.40 (s, 9H), 2.30-2.48 (m, 2H), 4.83-4.89 (m, 2H), 5.09-
5.14 (m, 2H), 5.60-5.71 (m, 1H), 5.74 (br, 1H), 6.23 (d, J= 1.5 Hz, 1H), 7.18 (d, J= 9.0
Hz, 1H), 7.23 (dd, J= 9.0, 3.0 Hz, 1H), 7.35 (d, J= 3.0 Hz, 1H) ppm. 13C NMR (CDCl3,
75.5 MHz) δ 28.3 (3CH3), 40.9 (CH2), 50.5 (d, J4CF= 1.4; CH), 79.7 (C), 118.6 (CH2),
122.7 (q, J1CF= 273.8; CF3), 125.2 (q, CH2, J3CF= 4.7), 126.3 (CH), 127.0 (CH), 130.7
(C), 131.3 (CH), 133.5 (CH), 135.2 (C), 135.7 (C), 143.9 (C), 154.7 (C) ppm. 19F NMR
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(CDCl3, 282.4 MHz) δ -66.9 (s, 3F; CF3) ppm. HRMS (EI) calcd. for C14H13ClF3NO2
[M+H+]: 320.0660, found: 320.0658. HPLC (Chiralcel OD-H, 98:2 hexane/iPrOH, 1
mL min-1, 240 nm) tR(major) = 4.01 min, tR(minor) = 4.24 min.
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Tert-Butyl
(S)-{1-[4-fluoro-2-(3,3,3-trifluoro-1-propen-2-yl)phenyl]-3-buten-1-yl}
carbamate (6c). Flash chromatography of the crude reaction product [n-hexane-Et2O
(20:1)] afforded 6c as a yellow solid (68%, 105 mg). [α]D = - 12.2 (c 1.0; CHCl3). 1H
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NMR (CDCl3, 300 MHz) δ 1.38 (s, 9H), 2.37-2.46 (m, 2H), 4.81-4.89 (m, 2H), 5.04-
5.11 (m, 2H), 5.58-5.22 (m, 1H), 5.78 (br, 1H), 6.23 (d, J= 1.5 Hz, 1H), 6.95 (dd, J=
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9.3, 2.7 Hz, 1H), 7.07 (dd, J= 8.1, 2.7 Hz, 1H), 7.33 (dd, J= 8.7, 3.4 Hz, 1H) ppm. C
NMR (CDCl3, 75.5 MHz) δ 28.3 (3CH3), 41.0 (CH2), 50.1 (CH), 75.5 (C), 116.2 (d,
J2CF= 21.0; CH), 116.7 (d, J2CF= 22.1; CH), 118.3 (CH2), 122.7 (q, J1CF= 273.9; CF3),
125.0 (d, J3CF= 2.0; CH), 127.7 (d, J2CF= 83.3; CH), 133.7 (CH), 134.2 (C), 135.5 (d,
J3CF= 31.5; C), 137.6 (d, J4CF= 3.1; C), 154.7 (C), 160.9 (d, J1CF= 271.8; CH) ppm. 19F
NMR (CDCl3, 282.4 MHz) δ -115.7 (ddd, J= 14.4, 8.5, 5.6 Hz, 1F; CF), -66.9 (s, 3F;
CF3) ppm. HRMS (EI) calcd. for C18H21F4NO2 [M+H+]: 360.1581, found: 360.1573.
HPLC (Chiralcel OD-H, 99.5:0.5 hexane/iPrOH, 1 mL min-1, 240 nm) tR(major) =
8.96 min, tR(minor) = 9.82 min.
Tert-Butyl (S)-{1-[6-(3,3,3-trifluoro-1-propen-2-yl)benzo[d][1,3]dioxol-5-yl]-3-buten-
1-yl}carbamate (6d). Flash chromatography of the crude reaction product [n-hexane-
Et2O (10:1)] afforded 6d as colorless oil (67%, 120 mg). [α]D25 = - 19.2 (c 1.0; CHCl3).
1H NMR (CDCl3, 300 MHz) δ 1.25 (s, 9H), 2.25 (t, J= 6.9 Hz, 2H), 4.63-4.70 (m, 2H),
4.89-4.97 (m, 2H), 5.45-5.57 (m, 2H), 5.83 (s, 2H), 6.04 (d, J= 1.5 Hz, 1H), 6.55 (s,
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1H), 6.68 (s, 1H) ppm. C NMR (CDCl3, 75.5 MHz) δ 28.3 (3CH3), 41.1 (CH2), 50.7
(CH), 79.4 (C), 101.4 (CH2), 105.9 (CH), 109.7 (CH), 118.0 (CH2), 122.9 (q, J1
=
CF
279.3 Hz, CF3), 124.7 (q, J3CF= 2.3 Hz; CH2), 124.7 (C), 125.6 (C), 133.9 (CH), 135.8
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(C), 136.3 (C), 146.7 (C), 148.4 (C), 154.7 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ -
66.1 (s, 3F; CF3) ppm. HRMS (EI) calcd. for C19H22F3NO4 [M+H+]: 386.1574, found:
386.1580. HPLC (Chiralpak IC, 98:2 hexane/iPrOH, 1 mL min-1, 240 nm) tR(major) =
7.46 min, tR(minor) = 6.65 min.
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Tert-Butyl
(S)-{1-[5-methoxy-2-(3,3,3-trifluoro-1-propen-2-yl)phenyl]-3-buten-1-yl}
carbamate (6e). Flash chromatography of the crude reaction product [n-hexane-Et2O
(10:1)] afforded 6e as a colorless oil (84%, 105 mg). [α]D = - 26.3 (c 1.0; CHCl3). 1H
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NMR (CDCl3, 300 MHz) δ 1.39 (s, 9H), 2.34- 2.50 (m, 2H), 3.81 (s, 3H), 4.81-4.90 (m,
2H), 5.04-5.12 (m, 2H), 5.60-5.74 (m, 2H), 6.17 (d, J= 1.5 Hz, 1H), 6.79 (dd, J= 8.4,
2.7 Hz, 1H), 6.88 (d, J= 2.7 Hz, 1H), 7.16 (d, J= 8.1 Hz, 1H), ppm. 13C NMR (CDCl3,
75.5 MHz) δ 28.3 (3CH3), 40.9 (CH2), 50.7 (CH), 55.2 (OCH3), 79.4 (C), 111.8 (2CH),
118.0 (CH2), 122.9 (q, CF3, J1CF= 268.8 Hz), 124.5 (q, CH2, J3CF= 3.5 Hz), 124.7 (C),
131.2 (CH), 134.0 (CH), 136.2 (d, C, J3CF= 28.8 Hz), 143.1 (C), 154.7 (C), 160.1 (C)
ppm. 19F NMR (CDCl3, 282.4 MHz) δ -66.1 (s, 3F; CF3) ppm. HRMS (EI) calcd. for
C19H24F3NO3 [M+H+]: 372.1781, found: 372.1783. HPLC (Chiralpak IC, 98:2
hexane/iPrOH, 1 mL min-1, 240 nm) tR(major) = 6.67 min, tR(minor) = 5.74 min.
Tert-Butyl
(S)-{1-[3-(3,3,3-trifluoro-1-propen-2-yl)thiophen-2-yl]-3-but-3-en-1-yl}
carbamate (6f). Flash chromatography of the crude reaction product [n-hexane-Et2O
(20:1)] afforded 6f as a colorless oil (64%, 160 mg). [α]D = - 4.5 (c 1.0; CHCl3). 1H
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NMR (CDCl3, 300 MHz) δ 1.41 (s, 3H), 2.47-2.58 (m, 2H), 4.82 (s, 1H), 5.07-5.13 (m,
3H), 5.63-5.72 (m, 1H), 5.76 (s, 1H), 6.12 (d, J= 1.2 Hz, 1H), 6.96 (dd, J=5.1, 0.9 Hz,
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1H), 7.20 (d, J=5.4 Hz, 1H) ppm. C NMR (CDCl3, 75.5 MHz) δ 28.3 (3CH3), 42.0
(CH2), 48.6 (CH), 79.8 (C), 118.6 (CH2), 122.1 (q, J1CF= 267.0 Hz; CF3), 123.1 (CH),
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123.8 (CH2), 128.2 (CH), 130.7 (C), 133.2 (CH), 146.1 (C), 154.6 (C) ppm. F NMR
(CDCl3, 282.4 MHz) δ -66.7 (s, 3F; CF3) ppm. HRMS (EI) calcd. for C16H20F3NO2S
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