Photochemically induced intramolecular radical cyclization reactions with imines

Article abstract of DOI:10.1021/acs.joc.7b02810

The photochemically induced intramolecular hydrogen abstraction or hydrogen atom transfer in cyclic imines 8a,b followed by a cyclization is investigated. Two types of products are observed, one resulting from the formation of a C-C bond, the other from the formation of a C-N bond. A computational study reveals that hydrogen is exclusively transferred to the imine nitrogen leading to a triplet diradical intermediate. After intersystem crossing, the resulting zwitterionic intermediate undergoes cyclization leading to the final product.

Full text of DOI:10.1021/acs.joc.7b02810

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Article
Photochemically Induced Intramolecular
Radical Cyclization Reactions with Imines
Corentin Lefebvre, Clément Michelin, Thomas Martzel, Vaneck Djou’ou
Mvondo, Véronique Bulach, Manabu Abe, and Norbert Hoffmann
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02810 • Publication Date (Web): 15 Jan 2018
Downloaded from http://pubs.acs.org on January 15, 2018
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Photochemically Induced Intramolecular Radical Cyclization Reactions with
Imines
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Corentin Lefebvre a, Clément Michelin a, Thomas Martzel a, Vaneck Djou’ou Mvondo a, Véronique
Bulach b, Manabu Abe* c,d, Norbert Hoffmann* a
a CNRS, Université de Reims Champagne-Ardenne, ICMR, Equipe de Photochimie, UFR Sciences, B.P.
1039, 51687 Reims, France, Phone: + 33 3 26 91 33 10, e-mail: norbert.hoffmann@univ-reims.fr
b Université de Strasbourg, Laboratoire de Tectonique Moléculaire (UMR 7140), Institut Le Bel, 4, rue
Blaise Pascal, 67000 Strasbourg, France.
c Hiroshima University, Department of Chemistry, Graduate School of Science, 1-3-1 Kagamiyama,
Higashi-Hiroshima, Hiroshima 739-8526, Japan.
d Hiroshima Research Center for Photo-Drug-Delivery Systems (Hi-P-DDS), 1-3-1 Kagamiyama,
Higashi-Hiroshima, Hiroshima 739-8526, Japan.
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Graphical Abstract
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Abstract
The photochemically induced intramolecular hydrogen abstraction or hydrogen atom transfer (HAT)
in cyclic imines 8a,b followed by a cyclization is investigated. Two types of products are observed,
one resulting from the formation of a C-C bond, the other from the formation of a C-N bond. A
computational study reveals that hydrogen is exclusively transferred to the imine nitrogen leading to
a triplet diradical intermediate. After intersystem crossing the zwitterionic intermediate undergoes
cyclization leading to the final product.
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Introduction
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Currently, photochemical reactions are intensively investigated for application to organic
synthesis.1,2,3,4 Due to the change of electronic configuration at the electronically excited state in
comparison with that of the ground state, the chemical reactivity including the chemo-selectivity,
and regio-selectivity is considerably modified.5 Mechanistic investigations of such transformations
facilitates optimization and efficient application to synthesis. The Norrish-Yang (NA) cyclization6,7 is
one of these reactions which were often applied in this context. In the context of sustainable
chemistry, the photo-induced chemical transformation is also very important since C-C bonds are
formed without any chemical activation (the photon as traceless reagent).8 Furthermore, C-H
activation9 is possible in the absence of additional chemical reagents. In these reactions, a carbonyl
functional group is electronically excited. A hydrogen transfer then occurs which leads to the
formation of a diradical intermediate. The radical combination yields the final cyclization products.
Macrocyclizations are also possible under similar photochemical conditions.10 Other chromophores
such as imides also undergo similar transformations.11,12
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Recently, similar reactions of α,β-unsaturated lactones of furanones such as 1 have been studied
(Scheme 1).13,14,15 These reactions can be carried out in the presence of acetone as a triplet sensitizer.
After the triplet energy transfer onto the furanone 1, the ππ* triplet 2 possessing a high spin density
in the β position16 is generated. Due to the increased reactivity in this position, the hydrogen atom is
transferred to the β position of the furanone moiety and the diradical intermediate 3 is generated.
After the radical combination, the final spiro-cyclic products 4a,b are formed. Depending on the
structure variations, a hydrogen atom can also be transferred from other positions of the donor
moiety. In our previous investigation13, the stereo- and regioselectivity have been studied in detail.
Mechanistic details of the hydrogen transfer step17,18 and the consequences for the outcome of such
reactions has been discussed.13,19
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Most frequently, the hydrogen transfer from the donor moiety to the photochemical excited
chromophore may occur according to a one step mechanism in which the proton and the electron
are transferred in the same time. Or, in a two-step process, the electron is transferred first and the
proton follows. These mechanistic steps of hydrogen atom transfer (HAT) can also be discussed in
connection to proton coupled electron transfer (PCET) which is, for example, currently done for
photoredox catalytic reactions.20 We decided to replace the CH group in the β position of a furanone
moiety (structure A) by a nitrogen atom and we became interested in the photochemical reactivity of
cyclic imines (structure B) (Figure 1). In contrast to the corresponding carbonyl compounds,
photochemical reactions with electronically excited imines have been much less studied.21,22
Recently, systematic investigations have been carried out on intramolecular hydrogen abstraction of
aromatic electronically excited imines.23 In such cases, aminoazaxylene intermediates are
generated.24 Imines are valuable intermediates in organic synthesis.25 Photochemical reactions
further enlarge the fields of application to organic synthesis.
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3
h ,
= 300 nm
H
O
H
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H
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H
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CH3CN
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3
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*
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O
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+
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4a
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:
4b
43%
Scheme 1. Intramolecular hydrogen abstraction (hydrogen atom transfer, HAT) at the ππ* triplet
state of furanones
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Figure 1. Furanones and related imine compounds.
Results and Discussion
Cyclic imines possessing the core structure B as depicted in Figure 1 were synthesized starting with
the oxazolone derivative 5 (Scheme 2).26,27 The alkylation of such compounds is reported to occur
efficiently at the 4 position carrying the trifluoromethyl group.26,28,29 The Michael reactions with
acrolein and crotonaldehyde yielded the aducts 6 and 7 respectively. Acetalization with ethylene
glycol or 1,3-dhydroxypropanol gave the corresponding acetales 8a, 9a, 8b, and 9b, respectively.
Scheme 2. Synthesis of cyclic imines for photochemical transformations.
When compound 8b was irradiated at λ = 300 nm in acetonitrile, two products 10b and 11b were
isolated (Scheme 3). Compound 10b was formed in the photochemical reaction. When the reaction
mixture was heated to 65°C, compound 10b was completely converted into 11b. In this case, 11b
was isolated with a yield of 83% as a single product. At room temperature, the thermal
transformation was slow in acetonitrile. Thus, a crystalline sample of compound 10b was obtained
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and the structure was determined by X-ray diffraction analysis (See supporting information S35).
Using the Norrish type II reaction of valerophenone as actinometer30, a high quantum yield of φ = 0.7
was determined for the conversion of 8b.
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Scheme 3. Photochemical transformation of cyclic imines 8a and 8b.
When compound 8a was irradiated under the same conditions, compound 11a was formed and no
corresponding primary cyclization product 10a was detected. Obviously, the thermal decarboxylation
is more efficient than the case of 10b. To our surprise, compound 12a was detected resulting from
the formation of the C-N bond. The structure was determined by X-ray diffraction analysis (See
supporting information S35). We have performed the reaction of compound 8a also in
trifluoromethyl benzene as an apolar solvent. Interestingly, the portion of 12a is considerably
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reduced (1.4%, of isolated yield) under these conditions. Furthermore, the yield of 11a increased.
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The transformation is also faster.
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We assume that compounds 8a,b after photochemical excitation undergo intersystem crossing and
the first chemical reaction step will occur at the triplet state. Intramolecular hydrogen transfer from
the acetale moiety to the imine nitrogen atom leads to intermediate 13 (Scheme 4). It must be
pointed out that this hydrogen transfer occurs in one step in which the electron and the proton are
transferred simultaneously.19 A corresponding two-step process in which an electron is first
transferred and the proton then follow may be excluded. Single electron transfer from acetal
functions is very difficult.31 Radical combination in intermediate 13 leads to cylization products such
as 10a,b. In the case of 10a, fast decarboxylation occurs so that these compound could not be
isolated. Such a mechanism was previously suggested for the similar reactions with α,β-unsaturated
butyrolactones.13,14. The regioselectivity of the cyclization observed in this reaction also resembles to
that one observed for similar reactions with carbonyl compounds.6,7,10 The compound 12a might be
generated via hydrogen abstraction at the carbon atom of the imine function leading to intermediate
a corresponding intermediate 14. We argued however that the formation of such nitrogen centered
radicals is unfavorable. A computational study was performed to get quantitative data on such
hydrogen transfer steps.
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Scheme 4. Mechanistic discussion for the photochemical transformation of imines 8a and 8b.
First, the triplet states of compounds 8a and 8b were computed at the UB3LYP/6-31G(d)32 level of
theory with the Gaussian 09 suite of program33, respectively. The spin distribution in the triplet states
was summarized in Figure 2 In both of the triplet states 38a and 38b, one of the two spins is mainly
localized at the nitrogen atom, 0.78. Another spin is highly delocalized to the phenyl ring. As
expected, the spin-density distribution was not affected by the acetal moiety.
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Figure 2. Spin density distribution of the triplet states 38b and 38a.
The hydrogen abstraction reactions in 38b and 38a were computed at the same level of
theory (Scheme 5). As clearly shown in Scheme 5, the hydrogen abstraction reaction at the acetal
moiety by the nitrogen atom (path a (NH)) was calculated to be the most energetically favored
pathway to give the corresponding triplet diradical T-DRNH. Other hydrogen abstraction pathways,
path b (CH) and path c (OH), were found to be energetically less favored than the path a by ~15 and
~25 kcal mol-1, respectively, indicating that the path a should be the exclusive reaction from 38a and
38b to afford T-DRa,bNH. The higher spin density at the nitrogen atom in 38 than the α-carbonyl
methyl radical moiety is responsible for the lower energy barrier.
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Scheme 5. Calculations (UB3LYP/6-31G(d)) of different hydrogen transfer steps at the triplet excited
state of 8a,b, the energies are reported in kcal mol-1.
The triplet diradical intersystem crosses to produce the singlet state S-DRa,NH, which should
have a zwitterionic character as depicted in the resonance structure.34 The CC coupling reaction, i.e.
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C-attack, produces the bicyclo[3.2.1]octane derivative 10. The bicyclo[3.3.0]octane derivative 12 is
formed in the NC coupling reaction, i.e. N-attack, from the singlet state of the diradical species. A
computational study on the C-C and N-C bond formation in acetonitrile at M06-2x level of theory has
been performed. We could not find any transitions state structures, which means that the both of
the bond formation steps are barrier-less processes. Due to the zwitterionic character of S-DRNH, the
regioselectivity (described in Scheme 3 for the transformation of 8a) is affected by the solvent
polarity during the final cyclization. A very similar mechanism has recently been proposed for a
photochemically induced intramolecular hydrogen abstraction in naphthoquinone derivatives.35 As in
our case, diradical intermediates are formed. An intramolecular electron transfer has been discussed
yielding zwitterionic intermediates which leads to the formation of a C-O bond via charge
combination.
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As we have previously shown for similar reactions with α,β-unsaturated butyrolactones,
attaching a substituent on the linker may have influence on the regioselectivity of the cyclization
step.13 Conformational equilibria are affected by this substituent and thus have an influence on the
regioselectivity of hydrogen abstraction. We have transformed compounds 9a,b carrying a methyl
group at the linker under the same conditions (Scheme 6). In the case of the dioxolane derivative 9a,
the effect of the methyl substituent is only small. The yield of the product resulting from the
cyclization in the α position at the imine carbon is slightly improved. In the case of the dioxane
derivative 9b, the formation of compound 16b resulting from cyclization at the nitrogen atom of the
imine function is enabled while the yield of the corresponding compound 15b resulting from
cyclization at the carbon atom of the imine function is reduced (compare Scheme 3). In contrast to
the previously reported reactions of furanone derivatives13, hydrogen abstraction always occurs at
the same site (imine nitrogen) in the present case. Conformational equilibria affected by the methyl
substituent should therefore influence the regioselectivity in the final cyclization step and not in the
hydrogen abstraction step.
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O
N
O
Ph
Ph
O
Ph
O
O
h
N
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+
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O
( = 300 nm)
Acetonitril
O
O
CF3
CF3
CF3
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(7/3)
34% (3/1)
30% (1/1)
9a
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O
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Ph
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h
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( = 300 nm)
Acetonitril
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(7/3)
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16b
9b
15b
Scheme 6. Photochemical transformation of cyclic imines 8a and 8b. The influence of a methyl
substituent on the regioselectivity.
Conclusion
Under photochemical reaction conditions, cyclic imines (oxazolones) undergo intramolecular
hydrogen abstraction followed by cyclization. In contrast to similar reactions with carbonyl or α,β-
unsaturated lactones, two different regioisomers are obtained. The formation of a C-N bond in of
these isomers is unusual. A computational study suggest that after intersystem crossing of the triplet
hydrogen is transferred exclusively to the imine nitrogen atom. The resulting diradical intermediate
undergoes intersystem crossing and the resulting singlet state possesses a zwitterionic character. The
final step is therefore strongly characterized by the charge combination. It determines the
regioselectivity of the reaction and thus the competition between the formation of a C-C and the C-N
bond. The regioselectivity in the cyclization step is further affected by the presence or absence of a
methyl substituent at the side chain tether.
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Experimental section
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General Information. NMR spectra were recorded with a Bruker AC 250 (250 MHz for 1H and 62 MHz
for 13C) or a Bruker DRX 500 (500 MHz for 1H and 125 MHz for 13C). Chemical shifts are given in ppm
relatively to TMS using residual solvent signals as secondary references. IR spectra were recorded on
a Nicolet AVATAR 320 FT-IR. UV spectra were recorded with a UVKON 941 PLUS (KONTRON
Instruments). GCMS and MS analysis were performed with Termoquest CE Instruments (Trace GC:
2000 series, Finnigan Trace MS). UV Irradiations have been performed with Rayonet® reactors (The
Southern New England Ultraviolet Company, Branford, Connecticut) at λ = 350 nm. The reaction
mixture was irradiated in pyrex tubes (Ø = 0.9cm). Preparative chromatography was carried out with
silica gel 60A from Carlo Erba Reactifs-SDS. TLC was carried out with Kieselgel 60F254 plates form
Merck.
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X-ray diffraction: data were collected at 173(2) K on a Bruker APEX8 CCD Diffractometer equipped
with an Oxford Cryosystem liquid N2 device, using a molybdenum microfocus sealed tube generator
with mirror-monochromated Mo-Kα radiation (λ = 0.71073 Å), operated at 50 kV/600 mA. The
diffraction data were corrected for absorption. Structures were solved using SHELXS-97 and refined
by full matrix least-squares on F2 using SHELXL-97. The hydrogen atoms were introduced at
calculated positions and not refined (riding model)36 . They can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/datarequest/cif. CCDC N° 1583694
(16a), N° 1583695 (10b), N° 1583696 (12a)
Synthesis of 4-phenyl-2-(trifluoromethyl)oxazol-5(2H)-one 5.37
2-amino-2-phenylacetic acid (22.0 g, 146 mmol, 1.0 eq) was dissolved in 2,2,2-trifluoroacetic
anhydride (122.4 g, 81 mL, 583 mmol, 4.0 eq) at 0 °C. The reaction mixture was stirred at 70 °C during
3 h, cooled to room temperature, then remaining 2,2,2-trifluoroacetic anhydride was removed under
reduced pressure. The crude product was dissolved in DCM and washed with sat. NaHCO3 until pH
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was neutral. A last washing with sat. NaCl was done and the organic layers were dried over MgSO4,
filtered and removed under reduced pressure to give a white/yellow crystalline solid.
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Recrystallization in n-hexane gave compound 5 as a white crystalline solid in 92 % yield (30.7 g, 134
mmol). Rf = 0.51 (n-hexane : Ethylacetate, 90 : 10). Melting range = 89-90 °C. UV/vis (acetonitrile): ε
= 13500 (λmax = 271 nm), 4400 (λ = 300 nm) L·cm-1·mol-1. 1H NMR (500 MHz, CDCl3 , ppm): δ = 6.26 (q,
J = 6.26 Hz, 1 H), 7.54 (m, 2 H), 7.65 (tt, J = 1.5, 8 Hz, 1 H), 8.44 (dd, J = 1.5, 8.5 Hz, 2 H). 13C (125 MHz,
CDCl3, ppm): δ = 92.5 (q, J = 35.5 Hz), 120.5 (q, J = 282 Hz), 127.4, 129.2, 129.3, 134.1, 160.8, 162.9.
19F (250 MHz, CDCl3, ppm): δ = −79.04 (d, J = 4 Hz). IR (ν): 1800, 1614, 1341, 1304, 1202, 1156, 968,
867 cm−1. LRMS (ESI-TOF) m/z: [M + H]+ Calcd for C10H7F3NO2 230; Found 230.
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Synthesis of 3-(5-oxo-4-phenyl-2-(trifluoromethyl)-2,5-dihydrooxazol-2-yl)propanal 6.
4-phenyl-2-(trifluoromethyl)oxazol-5(2H)-one 5 (10.0 g, 43.6 mmol, 1.0 eq) and triethylamine (4.42 g,
6.08 mL, 43.6 mmol, 1.0 eq) were added in 400 mL of DCM. Acrylaldehyde (2.45 g, 2.92 mL, 43.6
mmol, 1.0 eq) was then added drop wise. The reaction mixture was vigorously stirred during 30 min.
DCM was removed under reduced pressure and the crude product was purified via flash
chromatography (Petroleum ether : Ethylacetate, 90 : 10) to give 3-(5-oxo-4-phenyl-2-
(trifluoromethyl)-2,5-dihydrooxazol-2-yl)propanal 6 as a yellow viscous oil in 90 % yield (11.20 g, 393
mmol). Rf = 0.47 (Petroleum ether : Ethylacetate, 80 : 20). 1H NMR (600 MHz, CDCl3 ppm): δ = 2.44
(ddd, J = 5.5, 9.5, 18.5 Hz, 1 H), 2.53 (ddd, J = 5.5, 9.5, 18.5 Hz, 1 H), 2.64 (ddd, J = 5.5, 9.5, 15 Hz, 1 H),
2.69 (ddd, J = 5.5, 9.5, 15 Hz, 1 H), 7.53 (m, 2 H), 7.66 (tt, J = 1.5, 7.5 Hz, 1 H), 8.41 (dd, J = 1.5, 8.5 Hz,
2 H), 9.73 (t, J = 1 Hz, 1 H). 13C NMR (150 MHz, CDCl3, ppm): δ = 24.3, 36.0, 100.5 (q, J = 31 Hz), 121.7
(q, J = 285 Hz), 127.2, 129.2, 129.4, 134.2, 160.7, 162.6, 198.5. 19F NMR (250 MHz, CDCl3, ppm): δ =
−80.18. IR (ν): 2837, 2734, 1575, 1386, 1302, 1269 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C13H11F3NO3 286.0691; Found 286.0699.
Synthesis of 3-(5-oxo-4-phenyl-2-(trifluoromethyl)-2,5-dihydrooxazol-2-yl)butanal 7.
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4-phenyl-2-(trifluoromethyl)oxazol-5(2H)-one 5 (10.0 g, 43.6 mmol, 1.0 eq) and triethylamine (4.42 g,
6.08 mL, 43.6 mmol, 1.0 eq) were added in 400 mL of DCM. Crotonaldehyde (3.06 g, 3.62 mL, 43.6
mmol, 1.0 eq) was then added drop wise. The reaction mixture was vigorously stirred during 30 min.
DCM was removed under reduced pressure and the crude product was purified via flash
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chromatography (Petroleum ether : Ethylacetate, 90 : 10) to give 3-(5-oxo-4-phenyl-2-
(trifluoromethyl)-2,5-dihydrooxazol-2-yl)propanal 7 as a yellow liquid in 87 % yield (11.36 g, 393
mmol). Rf = 0.42 (Petroleum ether : Ethylacetate, 90 : 10). 1H NMR (600 MHz, CDCl3, ppm): δ = 1.17
(d, J = 7 Hz, 3 H), 2.44 (dd, J = 9, 18 Hz, 1 H; dia 1), 2.51 (dd, J = 9, 18 Hz, 1 H; dia 2), 2.77 (dd, J = 4, 18
Hz, 1 H; dia 2), 2.83 (dd, J = 3.5, 18 Hz, 1 H; dia 1), 3.14 (m, 1 H; dia 1), 3.18 (m, 1H; dia 2), 7.53 (t, J =
7.5Hz, 2H), 7.65 (tt, J =1.5,7.5 Hz, 1H), 8.41 (m, 2H), 9.74 (s,1H; dia 2), 9.75 (s, 1 H; dia 1). 13C NMR
(150 MHz, CDCl3, ppm): δ = 14.4 (dia 2), 14.8 (dia 1), 32.0 (dia 2), 44.8 (dia 2), 45.0 (dia 1), 102.15 (d, J
= 30 Hz, dia 2), 102.23 (q, J = 30 Hz, dia 1), 122 (q, J = 286.5 Hz), 127.25 (dia 2), 127.32 (dia 1), 129.2,
129.3 (dia 1), 129.4 (dia 2), 134.1 (dia 1), 134.2 (dia 2), 160.3 (dia 1), 160.5 (dia 2), 162.7, 198.8 (dia
1), 198.9 (dia 2). 19F NMR (250 MHz, CDCl3, ppm) : δ = −75.97, −75.80. IR (ν) : 2833, 2731, 1465, 1318
cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H13NO3F3 300.0848; Found 300.0857.
Synthesis of 2-(2-(1,3-dioxolan-2-yl)ethyl)-4-phenyl-2-(trifluoromethyl)oxazol-5(2H)-one 8a
In a 100 mL flask equipped with an inverse Dean-Stark trap was dissolved 3-(5-oxo-4-phenyl-2-
(trifluoromethyl)-2,5-dihydrooxazol-2-yl)propanal 6 (1.3 g, 4.6 mmol, 1.0 eq) in 30 mL of CHCl3.
Ethylene glycol was then added drop wise (2.11 g, 1.9 mL, 34 mmol, 7.0 eq) with PTSA (0.05 g, 0.285
mmol, 0.1 eq). The reaction mixture was vigorously stirred and refluxed during 1 h 30. Without
cooling, the reaction mixture was treated with 30 mL of NaHCO3. Organic layer was then dried over
MgSO4, filtered and removed under reduced pressure to give a yellow and viscous oil. The crude
product was purified via flash chromatography (Petroleum ether : diethyl ether, 90 : 10) to give 2-(2-
(1,3-dioxolan-2-yl)ethyl)-4-phenyl-2-(trifluoromethyl)oxazol-5(2H)-one 8a as a yellow and viscous oil
in 82 % yield (1.24 g, 3.8 mmol). Rf = 0.25 (Petroleum ether : Diethyl ether, 90 : 10). 1H NMR (600
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MHz, CDCl3, ppm): δ = 1.53 – 1.72 (m, 2 H), 2.45 – 2.56 (m, 2 H), 3.92 – 4.04 (m, 2 H), 4.92 (t, J = 4.2
Hz, 1 H), 7.55 (t, J = 7.8 Hz, 2 H), 7.66 (t, J = 7.5 Hz, 1 H), 8.40 – 8.50 (m, 2 H). 13C NMR (150 MHz,
CDCl3, ppm): δ = 25.4, 25.6, 65.07, 65.09, 101.0 (q, J = 31.0 Hz), 102.8, 121.7 (q, J = 285.2 Hz), 127.4,
128.99, 129.17, 133.8, 160.4, 162.8. 19F NMR (235 MHz, CDCl3, ppm): δ = −80.42. IR (ν): 1576, 1380,
1304, 1271, 1260 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H15NO4F3 330.0953; Found
330.0960.
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Synthesis of 2-(1-(1,3-dioxolan-2-yl)propan-2-yl)-4-phenyl-2-(trifluoromethyl)oxazol-5(2H)-one 9a
In a 100 mL flask equipped with an inverse Dean-Stark trap was dissolved 3-(5-oxo-4-phenyl-2-
(trifluoromethyl)-2,5-dihydrooxazol-2-yl)butanal 7 (2.4 g, 8.02 mmol, 1.0 eq) in 50 mL of CHCl3.
Ethylene glycol was then added drop wise (2.45 g, 2.2 mL, 40.1 mmol, 5.0 eq) with PTSA (0.14 g, 0.8
mmol, 0.1 eq). The reaction mixture was vigorously stirred and refluxed during 1 h 30. Without
cooling, the reaction mixture was treated with 50 mL of NaHCO3. Organic layer was then dried over
MgSO4, filtered and removed under reduced pressure to give a colorless and viscous oil. The crude
product was purified via flash chromatography (Petroleum ether : Ethylacetate, 95 : 5) to give 2-(1-
(1,3-dioxolan-2-yl)propan-2-yl)-4-phenyl-2-(trifluoromethyl)oxazol-5(2H)-one 9a as a colorless and
viscous oil in 80 % yield (2.24 g, 6.42 mmol). Rf = 0.24 (Petroleum ether : Ethylacetate, 95 : 5). 1H
NMR (500 MHz, CDCl3, ppm): δ = 1.25 (d, J = 7 Hz, 3 H), 1.54 (ddd, J = 4, 10, 14 Hz, 1 H), 1.90 (dt, J =
3.5, 5.5, 14 Hz, 1 H), 2.74 (dqd, J = 305, 7, 10 Hz, 1 H), 3.83 (m, 2 H), 3.94 (m, 2 H), 4.94 (dd, J = 4, 5.5
Hz, 1 H), 7.52 (t, J = 7.5, 8.5 Hz, 2 H), 7.62 (tt, J = 1.5, 7.5 Hz, 1 H), 8.41 (dd, J = 1.5, 8.5 Hz, 2 H). 13
C
NMR (125 MHz, CDCl3, ppm): δ = 13.8 (dia 1), 14.4 (dia 2), 33.8 (dia 2), 34.3 (dia 2), 34.5 (dia 1), 64.77
(dia 1), 64.79 (dia 2), 65.1, 102.7 (dia 1), 102.8 (dia 2), 102.9 (q, J = 30 Hz), 122.1 (q, J = 287 Hz), 127.6
(dia 2), 129.08, 129.05, 133.8, 160.2 (dia 1), 160.4 (dia 2), 162.9 (dia 2), 163.0 (dia 1). 19F NMR (150
MHz, CDCl3, ppm): δ = −75.63,−75.61. IR (ν): 1801, 1617, 1390, 1292, 1200, 1169 cm-1. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C16H17NO4F3 344.1110; Found 344.1111.
Synthesis of 2-(2-(1,3-dioxan-2-yl)ethyl)-4-phenyl-2-(trifluoromethyl)oxazol-5(2H)-one 8b
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In a 250 mL flask equipped with an inverse Dean-Stark trap was dissolved 3-(5-oxo-4-phenyl-2-
(trifluoromethyl)-2,5-dihydrooxazol-2-yl)propanal 6 (7.47 g, 26.2 mmol, 1.0 eq) in 100 mL of CHCl3.
Propane-1,3-diol was then added drop wise (16.01 g, 15.2 mL, 209.5 mmol, 8.0 eq) with PTSA (0.5 g,
2.62 mmol, 0.1 eq). The reaction mixture was vigorously stirred and refluxed during 1 h 30. Without
cooling, the reaction mixture was treated with 30 mL of NaHCO3. Organic layer was then dried over
MgSO4, filtered and removed under reduced pressure to give a colorless oil. The crude product was
purified via flash chromatography (Petroleum ether : Ethylacetate, 90 : 10) to give (12) as a white
powder in 83 % yield. Melting range = 48-48.5 °C. (7.50 g, 21.83 mmol). Rf = 0.43 (Petroleum ether :
Ethylacetate, 90 : 10). UV/vis (acetonitrile): ε = 12200 (λmax = 272 nm), 4400 (λ = 300 nm) L·cm-1·mol-1.
1H NMR (600 MHz, CDCl3, ppm): δ = 1.31 (m, 1 H), 1.48 (ddt, J = 5, 10.5, 14 Hz, 1 H), 1.55 (ddt, J = 5,
10.5, 14 Hz, 1 H), 2.02 (qt, J = 5, 13 Hz, 1 H), 2.47 (qdd, J = 5.5, 10, 14.5 Hz, 2 H), 3.72 (m, 2 H), 4.05
(ddd, J = 1.5, 5, 12 Hz, 2 H), 4.54 (t, J = 5 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.63 (t, J = 7.5 Hz, 1 H), 8.41
(d, J = 7.5 Hz). 13C NMR (150 MHz, CDCl3, ppm): δ = 25.7, 25.8, 27.1, 67.0, 100.6, 101.2 (q, J = 31 Hz),
121.9 (q, J = 285 Hz), 127.6, 129.1, 129.3, 133.9, 160.5, 163.00. 19F NMR (250 MHz, CDCl3, ppm): δ =
−80.44. IR (ν): 1802, 1613, 1390, 1267, 1197 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C16H17NO4F3 344.1110; Found 344.1109.
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Synthesis of 2-(1-(1,3-dioxan-2-yl)propan-2-yl)-4-phenyl-2-(trifluoromethyl)oxazol-5(2H)-one 9b
In a 250 mL flask equipped with an inverse Dean-Stark trap was dissolved 3-(5-oxo-4-phenyl-2-
(trifluoromethyl)-2,5-dihydrooxazol-2-yl)butanal 7 (5.0 g, 16.7 mmol, 1.0 eq) in 100 mL of CHCl3.
Propane-1,3-diol was then added drop wise (6.32 g, 6.0 mL, 83.5 mmol, 5.0 eq) with PTSA (0.16 g,
0.84 mmol, 0.05 eq). The reaction mixture was vigorously stirred and refluxed during 1 h 30. Without
cooling, the reaction mixture was treated with 100 mL of NaHCO3. Organic layer was then dried over
MgSO4, filtered and removed under reduced pressure to give a yellow oil. The crude product was
purified via flash chromatography (Petroleum ether : Ethylacetate, 95 : 5) to give 9b as a colorless
liquid in 90 % yield (5.34 g, 15.03 mmol). Rf = 0.3 (Petroleum ether : Ethylacetate, 95 : 5). 1H NMR
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(600 MHz, CDCl3, ppm): δ = 1.17 (d, J = 7 Hz, 3 Hdia;1), 1.22 (d, J = 7 Hz, 3 Hdia;2), 1.32 (dtt, J = 1.5,
2.5, 13.5 Hz, 1 H), 1.45 (ddd, J = 4, 9.5, 14 Hz, 1 H; dia 2), 1.56 (ddd, J = 4, 9.5, 14 Hz, 1 H; dia 1), 1.85
(ddd, J = 4, 6.5, 14 Hz, 1 H), 2.04 (m, 1 H), 2.72 (dqd, J = 4, 7, 10.5 Hz, 1 H; dia 2), 2.79 (m, 1 H; dia 1),
3.72 (m, 2 H), 4.05 (m, 2H), 4.61(m, 1H), 7.51 (t, J = 8Hz, 2H), 7.62 (tt, J = 1.5, 8 Hz, 1H), 8.41 (dd, J =
1.5, 8 Hz, 2 H). 13C NMR (150 MHz, CDCl3, ppm): δ = 13.8 (dia 1), 14.5 (dia 2), 25.7, 33.2 (dia 1), 33.4
(dia 2), 35.5 (dia 2), 35.6 (dia 1), 66.99, 67.03, 67.1, 100.2 (dia 1), 100.3 (dia 2), 103.0 (q, J = 29.5 Hz),
103.1 (q, J = 29.5 Hz), 122.2 (q, J = 287 Hz), 127.7, 129.1, 129.3, 133.8, 160.0 (dia 1), 160.4 (dia 2),
162.9 (dia 2), 163.1 (dia 1). 19F NMR (250 MHz, CDCl3, ppm): δ = −75.67, −75.6. IR (ν): 1798, 1614,
1379, 1289, 1252, 1235, 1198, 1170 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
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C17H19NO4F3 358.1266; Found 358.1259.
3’-Phenyl-7a’-(trifluoromethyl)tetrahydro-2’H-spiro[[1,3]dioxolane-2,5’-pyrrolo[2,1-b]oxazol]-2’-one
12a and 6-phenyl-8-(trifluoromethyl)-1,4-dioxa-7-azaspiro[4.5]dec-6-ene 11a. A solution of 8a (300
mg, 0.91 mmol) was diluted in 91 mL of dry acetonitrile. The reaction mixture was then transferred
into quartz tubes and bubbled during 20 min with argon and then irradiated during 4 h 30 at λ = 300
nm. The solution was evaporated under vacuum and the crude product was purified via flash
chromatography (Petroleum Ether : Dichloromethane, 50 : 50) to give 3’-phenyl-7a’-
(trifluoromethyl)tetrahydro-2’H-spiro[[1,3]dioxolane-2,5’-pyrrolo[2,1-b]oxazol]-2’-one 12a as a white
powder in 33 % yield (100 mg, 0.30 mmol) and 6-phenyl-8-(trifluoromethyl)-1,4-dioxa-7-
azaspiro[4.5]dec-6-ene 11a as a white crystalline powder in 22 % yield (57 mg, 0.20 mmol).
Compound 12a. R = 0.58 (Petroleum ether : Dichloromethane, 50 : 50). Melting range = 79-81 °C. 1H
f
NMR (600 MHz, CDCl3, ppm): δ=2.22–2.44(m,3H),2.59–2.69(m,1 H), 3.78 – 4.03 (m, 4 H), 5.27 (s, 1 H),
7.31 – 7.36 (m, 1 H), 7.40 (t, J = 7.6 Hz, 2 H), 7.67 (d,J=8.1Hz,2H). 13C NMR (151 MHz, CDCl3, ppm): δ =
29.5, 33.3, 57.8, 64.2, 65.9, 98.0 (q, J = 34.3 Hz), 122.0, 122.5 (q, J = 285,2 Hz), 125.9, 127.9, 128.4,
134.4, 172.3. 19F NMR (235 MHz, CDCl3, ppm): δ = −83.88. IR (ν): 1961, 1809, 1655, 1333, 1282, 1204,
1179 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H15NO4F3 330.0954; Found 330.0955.
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Compound 11a. R = 0.33 (Petroleum ether : Dichloromethane, 50 : 50). Melting range = 90-91 °C. 1H
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NMR (600 MHz, CDCl3, ppm): δ = 1.94 (td, J = 13.2, 3.6 Hz, 1 H), 2.01 – 2.20 (m, 3 H), 3.68 (q, J = 7.2
Hz, 1 H), 3.84 – 4.02 (m, 3 H), 4.11 (dtd, J = 11.0, 7.7, 4.4 Hz, 1 H), 7.34 – 7.41 (m, 3 H), 7.57 – 7.63 (m,
2 H). 13C NMR (151 MHz, CDCl3, ppm): δ = 20.2, 31.1, 60.6 (q, J = 29.3 Hz), 64.9, 65.8, 102.3, 125.3 (q,
J = 279.3 Hz), 127.2, 127.9, 128.5, 129.2, 138.0, 171.1. 19F NMR (235 MHz, CDCl3, ppm): δ = −76.83 (d,
J = 7.7 Hz). IR (ν): 1654, 1367, 1275, 1184, 1128 cm-1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C14H14NO2F3Na 308.0874; Found 308.0880.
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7-Phenyl-9-(trifluoromethyl)-1,5-dioxa-8-azaspiro[5.5]undec-7-ene 11b via the intermediary of 5-
(trifluoromethyl)-6-oxa-8-azaspiro[bicyclo[3.2.1]octane-2,2’-[1,3]dioxan]-7-one 10b. A solution of 8b
(1.1 g, 3.22 mmol) was diluted in 150 mL of dry acetonitrile. The reaction mixture was then
transferred into quartz tubes and bubbled with argon during 20 min and then irradiated during 1 h at
λ = 300 nm. The solution was then heated at 65 °C during 2 h and solvent was evaporated under
reduced pressure. The crude product was purified via flash chromatography (Petroleum ether :
Ethylacetate, 60 : 40) to give 7-phenyl-9-(trifluoromethyl)-1,5-dioxa-8-azaspiro[5.5]undec-7-ene 11b
as a white crystalline powder in 83 % yield (802 mg, 2.67 mmol). A supplementary procedure enabled
the detection of the intermediate 10b. Compound 8b (40 mg, 0.12 mmol) was diluted in 12 mL of dry
acetonitrile. The solution was transferred in a quartz tube, bubbled with argon during 20 min and
irradiated during 30 min. The solvent was then evaporated and the crude product was diluted in n-
hexane to achieve a recrystallization. The precipitated compound 10b was retrieved by filtration as a
white crystalline powder in 38 % yield (15 mg, 0.046 mmol). The recrystallization solvent was
evaporated under reduced pressure and the crude product was purified via flash chromatography
(Petroleum ether : Ethylacetate, 90 : 10) to give 11b as a white crystalline solid in 32 % yield (12.7
mg, 0.038 mmol).
Compound 10b. R = 0.20 (Petroleum ether : Ethylacetate, 90 : 10). Decomposition range = 112-
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113 °C. 1H NMR (600 MHz, CDCl3, ppm) : δ = 1.26 – 1.34 (m, 1 H), 1.61 (ddt, J = 13.3, 11.7, 6.2 Hz, 1
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H), 1.92 (ddd, J = 14.8, 12.3, 6.5 Hz, 1 H), 2.18 (td, J=13.0,6.1Hz,1H),2.25–2.32(m,1H), 3.04–
3.10(m,1H), 3.32(s,1H),3.77–3.83 (m, 2 H), 3.93 (dtd, J = 15.0, 11.8, 3.2 Hz, 2 H), 7.36 (d, J = 2.3 Hz, 3
H), 7.76 – 7.85 (m, 2 H). 13C NMR (151 MHz, CDCl3, ppm): δ = 23.7, 24.6, 25.9, 59.8, 60.7, 70.6, 91.8
(q, J = 34.3 Hz), 94.2, 121.8 (d, J = 281.0 Hz), 127.2, 128.2, 128.5, 132.1, 170.7. 19F NMR (235 MHz,
CDCl3): δ = −76.60 (d, J = 7.8 Hz). IR (ν): 3312, 1948, 1811, 1710, 1604, 1349, 1271, 1245 cm-1. HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C16H16F3NO4Na 366.0929; Found 366.0931.
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Compound 11b. R = 0.21 (Petroleum ether : Ethylacetate, 90 : 10). Melting range = 124-125 °C. 1H
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NMR (600 MHz, CDCl3, ppm) : δ = 1.48 (dp, J = 2.0, 2.5, 13.5 Hz, 1 H), 1.77 (td, J = 3.5, 13.5 Hz, 1 H),
1.90 (tdd, J = 3.5, 10.5, 13.5 Hz, 1 H), 2.07 (dq, J = 3.5, 5, 13.5 Hz, 1 H), 2.27 (qt, J = 5.5, 12.5, 13.5 Hz,
1 H), 2.94 (dt, J = 5.0, 13.5 Hz, 1 H), 3.91 (ddt, J = 2.0, 5.5, 12 Hz, 1 H), 3.99 (ddt, J = 2.0, 5.5, 12 Hz, 1
H), 4.09 (m, 3 H), 7.37 (m, 3 H), 8.01 (dd, J = 2.0, 8.0 Hz, 2 H). 13C NMR (125 MHz, CDCl3, ppm): δ =
18.7 (m), 24.4, 25.0, 59.7, 59.8, 60.8 (q, J = 29.0 Hz), 93.9, 125.5 (q, J = 279 Hz), 127.7, 129.4, 129.6,
137.2, 168.8. 19F NMR (235 MHz, CDCl3, ppm): δ = −76.59 (d, J = 8.0 Hz). IR (ν): 1644, 1385, 1346,
1312, 1274, 1186 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H17NO2F3 300.1211; Found
300.1212.
6-Methyl-3-phenyl-6a-(trifluoromethyl)tetrahydrospiro[cyclopenta[b]furan-4,2’- [1,3]dioxolan]-2(5H)-
one 16a and 9-methyl-6-phenyl-8-(trifluoromethyl)-1,4-dioxa-7-azaspiro [4.5]dec-6-ene 15a. A
solution of 9a (1.03 g, 3.0 mmol) was diluted in 150 mL of dry acetonitrile. The reaction mixture was
then transferred into quartz tubes and bubbled with argon during 20 min and then irradiated during
1 h at λ = 300 nm. The solution was then heated at 65 °C during 2 h and solvent was evaporated
under reduced pressure. The crude product was purified via flash chromatography (Petroleum ether :
Dichloromethane, 60 : 40) to give the 6-methyl-3-phenyl-6a-(trifluoromethyl)tetrahydrospiro
[cyclopenta[b]furan- 4,2’-[1,3]dioxolan]-2(5H)-one 16a as a white powder in 34 % yield (355 mg, 1.02
mmol) and 9-methyl-6-phenyl-8-(trifluoromethyl)-1,4-dioxa-7-azaspiro[4.5]dec-6-ene 15a as a white
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powder in 25 % yield (263 mg,0.42mmol), (dia1: 14%, 48mg, 0.42mmol; dia2: 11%, 115mg,
0.33mmol).
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Compound 16a. R = 0.51 (Petroleum ether : Dichloromethane, 60 : 40), R (dia 1) = 0.84 (Petroleum
f
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ether : Ethylacetate, 80 : 20), R (dia 2) = 0.7 (Petroleum ether : Ethylacetate, 80 : 20). Melting range
f
= 93-95 °C. 1H (500 MHz, CDCl3, dia 1, ppm): δ = 1.24 (d, J = 7.5 Hz, 3 H), 1.96 (dd, J = 6.5, 13.5 Hz, 1
H), 2.51 (dd, J = 7.5, 13.5 Hz, 1 H), 2.91 (h, J = 6.5, 7.5 Hz, 1 H), 3.73 (td,J=6.5,8.0Hz,1H), 3.78(td,J=3.5,
7.0 Hz, 1 H), 3.86 (q, J = 7.0, 8.0 Hz, 1 H), 3.94 (ddd, J = 3.5, 6.5, 8.0 Hz, 1 H), 5.29 (s, 1 H), 7.31 (t, J =
7.5 Hz, 1 H), 7.38 (t, J = 7.5, 8.0 Hz, 2 H), 7.62 (d, J = 8.0 Hz, 2 H). 1H NMR (500 MHz, CDCl3, dia 2,
ppm): δ = 1.32 (dq, J = 2.0, 7.0 Hz, 3 H), 2.28 (d, J = 11.0 Hz, 2H), 2.68 (m,1H), 3.69 (td, J = 7.0, 11.0
Hz, 1H), 3.91 (m, 2H), 4.04 (td, J = 2.5, 6.0, 5.5 Hz, 1H), 5.31 (s, 1 H), 7.30 (t, J = 7.5 Hz, 1 H), 7.37 (t, J =
7.5 Hz, 2 H), 7.68 (d, J = 7.5 Hz, 2 H). 13C NMR (125 MHz, CDCl3, dia 1, ppm): δ = 14.2, 34.3, 40.7, 58.9,
63.6, 66.2, 99.6 (q, J = 33.0 Hz), 121.0, 123.1 (q, J = 286.5 Hz), 126.5, 129.1, 128.6, 134.9, 172.5. 13
C
NMR (125 MHz, CDCl3, dia 2, ppm): δ = 12.9, 40.6, 42.2, 57.2, 64.5, 66.0, 98.6 (q, J = 32.0 Hz), 120.1,
122.8 (q, J = 287.0 Hz), 126.1, 127.9, 128.5, 134.6, 172.2. 19F NMR (235 MHz, CDCl3, dia 1, ppm): δ =
−83.36. 19F NMR (235 MHz, CDCl3, dia 2, ppm): δ = −79.10. IR (ν): 1959, 1812, 1383, 1274, 1213, 1021
cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H17NO4F3 344.1110; Found 344.1110.
Compound 15a. R = 0.36 (Petroleum ether : Dichloromethane, 60 : 40). Melting range = 65-67 °C. 1H
f
NMR (600 MHz, CDCl3, ppm): δ = 1.21 (dd, J = 1.5, 6.5 Hz, 3 H), 1.73 (t, J = 13.5 Hz, 1 H), 1.96 (dd, J =
3.5, 13.5 Hz, 1 H), 2.29 (ddqd, J = 3.5, 6.5, 10.0, 13.5 Hz, 1 H), 3.67 (q, J = 6.5, 7.5 Hz, 1 H), 3.81 (dq, J =
8.0, 10.0 Hz, 1 H), 3.85 (ddd, J = 5.0, 6.5, 8.0 Hz, 1 H), 3.90 (q, J = 6.5, 7.5, 8.0 Hz, 1 H), 3.97 (td, J = 5.0,
6.5, 7.5 Hz, 1 H), 7.35 (m, 3 H), 7.58 (m, 2 H). 13C NMR (150 MHz, CDCl3, ppm): δ = 19.5, 27.4, 40.5,
65.1, 65.9, 67.1 (q, J = 27.0 Hz), 103.4, 125.8 (q, J = 281.0 Hz), 128.1, 128.7, 129.3, 138.0, 170.5. 19
F
NMR (235 MHz, CDCl3, ppm): δ = −72.37 (d, J = 7.5 Hz), −72.04 (d, J = 9 Hz). IR (ν): 1805, 1316, 1171
cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H17NO2F3 300.1211; Found 300.1212.
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6-Methyl-3-phenyl-6a-(trifluoromethyl)tetrahydrospiro[cyclopenta[b]furan-4,2’- [1,3]dioxan]-2(5H)-
one 16b and 10-methyl-7-phenyl-9-(trifluoromethyl)-1,5-dioxa-8-azaspiro [5.5]undec-7-ene 15b. A
solution of 9b (1.1 g, 3.22 mmol) was diluted in 150 mL of dry acetonitrile. The reaction mixture was
then transferred into quartz tubes and bubbled with argon during 20 min and then irradiated during
1 h at 300 nm. The solution was then heated at 65 °C during 2 h and solvent was evaporated under
reduced pressure. The crude product was purified via flash chromatography (Petroleum ether :
Dichloromethane, 70 : 30 → 60 : 40) to give 6-methyl-3-phenyl-6a-(trifluoromethyl)tetrahydrospiro
[cyclopenta[b]furan-4,2’-[1,3]dioxan]-2(5H)-one 16b as a white powder in 14 % yield (150 mg, 0.46
mmol) and 10-methyl-7-phenyl-9-(trifluoromethyl)-1,5-dioxa-8-azaspiro[5.5]undec-7-ene 15b as a
white powder in 60 % yield (560 mg, 1.93 mmol).
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Compound 16b. R = 0.74 (Petroleum ether : Dichloromethane, 60 : 40). Melting range = 126-128 °C.
f
1H NMR (500 MHz, CDCl3, ppm): δ = 1.23 (d, J = 7.0 Hz, 3 H), 1.37 (dp, J = 3.5, 13.5 Hz, 1 H), 1.78 (dd, J
= 11.0, 13.0 Hz, 1 H), 1.87 (m, 1 H), 2.26 (dd, J = 7.0, 13.0 Hz, 1 H), 2.92 (dp, J = 7.0, 11.0 Hz, 1 H), 3.47
(td, J = 3.5, 11.0 Hz, 1 H), 3.70 (dtd, J = 1.5, 4.5, 11.0 Hz, 1 H), 3.80 (dtd, J = 1.5, 4.5, 11.0 Hz, 1 H), 4.17
(td, J = 3.5, 11.0 Hz, 1 H), 5.23 (s, 1 H), 7.33 (t, J = 7.5 Hz, 1 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.65 (d, J = 7.5
Hz, 2 H). 13C NMR (125 MHz, CDCl3, ppm): δ = 13.7, 24.2, 34.4, 41.4, 59.9, 60.0, 63.5, 100.5 (q, J = 33
Hz), 122.1, 123.3 (q, J = 285.5 Hz), 126.6, 128.3, 128.8, 135.5, 172.5. 19F NMR (235 MHz, CDCl3, ppm):
δ = −82.29. IR (ν): 1798, 1368, 1284, 1252, 1215, 1178, 1143 cm-1. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C17H19NO4F3 358.1266; Found 358.1270.
Compound 15b. R = 0.31 (Petroleum ether : Dichloromethane, 60 : 40). Melting range = 148-151 °C.
f
1H NMR (500 MHz, CDCl3, ppm): δ = 1.23 (dd, J = 1.5, 6.5 Hz, 3 H), 1.47 (t, J = 12.5, 14.0 Hz, 1 H), 1.47
(dt, J = 2.0, 13.0 Hz, 1 H), 2.16 (ddtd, J = 3.5, 6.5, 13.0, 16.5 Hz, 1 H), 2.28 (qt, J = 5.5, 13.0 Hz, 1 H),
2.89 (dd, J = 4.0, 14.0 Hz, 1 H), 3.79 (dq, J = 8.0, 10.0 Hz, 1 H), 3.90 (ddt, J = 2.0, 5.5, 12.0 Hz, 1 H),
3.99 (ddt, J = 2.0, 2.5, 12.0 Hz, 1 H), 4.07 (td, J = 3.0, 12.0, 13.0 Hz, 1 H), 4.11 (td, J = 3.0, 12.0, 13.0 Hz,
1 H), 7.36 (m, 3 H), 8.01 (dd, J = 2.0, 8.0 Hz, 2 H). 13C NMR (125 MHz, CDCl3, ppm): δ = 19.7 (q, J = 2.5
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Hz), 25.1, 25.7, 34.0, 59.8, 59.9, 67.4 (q, J = 27.0 Hz), 94.8, 126.0 (q, J = 280.5 Hz), 127.7, 127.8, 129.5,
129.6, 136.9, 168.0. 19F NMR (235 MHz, CDCl3, ppm): δ = −72.55 (d, J = 8.0 Hz, dia 1), −71.75 (d, J =
9.0 Hz, dia 2). IR (ν) : 1966, 1911, 1646, 1373, 1260, 1192 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C16H19NO2F3 314.1368; Found 314.1363.
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Supporting Information
The Supporting Information is available free of charge on the ACS Publication website at DOI:
Spectra (1H-NMR, 13C-NMR, 19F-NMR, HRMS, UV), X-ray structure analysis reports and CIF files,
computational details for the reaction of 8a and 8b.
Acknowledgments
We are grateful for financial support from the Université de Reims Champagne-Ardenne and the
French Ministry of Higher Education Research and Innovation. We thank Dr. Dominique Harakat for
particular help with the recording of HRMS spectra.
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