A Remarkable Influence of a Trifluoromethyl Group on the Reactions of β-Mercaptoalcohols with Fluorinated α-Bromoenones

Article abstract of DOI:10.1002/ejoc.201701752

Isomeric fluorinated α-bromoenones react with dinucleophilic β-mercaptoalcohols in CH₂Cl₂ at room temperature in the presence of Et₃N in a multistep process. Depending on the position of the CF₃ group, different O,S-heterocycles or non-cyclic products were obtained. With 3-bromo-1,1,1-trifluorobut-3-en-2-ones derivatives of 1,4-oxathianes were formed, but isomeric 2-bromo-4,4,4-trifluorobut-2-en-1-ones yielded 1,3-oxathiolanes or non-cyclic sulfides. The thia-Michael addition is proposed as the initial step of the reaction, and the final heterocyclization is governed by the location of the CF₃ group.

Full text of DOI:10.1002/ejoc.201701752

A Journal of
Accepted Article
Title: A Remarkable Influence of the Trifluoromethyl Group on
the Reactions of ꢀ-Mercaptoalcohols with Fluorinated ꢀ
-Bromoenones
Authors: Grzegorz Mloston, Emilia Obijalska, Maria Pawelec, Antonella
Capperuzcci, Damiano Tanini, and Heinz Heimgartner
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701752
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701752
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10.1002/ejoc.201701752
European Journal of Organic Chemistry
A Remarkable Influence of the Trifluoromethyl Group on the Reactions of
-Mercaptoalcohols with Fluorinated -Bromoenones
Emilia Obijalska,[a] Maria Pawelec,[a] Grzegorz Mlostoń,*[a] Antonella
Capperucci,[b] Damiano Tanini,[b] and Heinz Heimgartner[c]
Abstract: Isomeric fluorinated -bromoenones react with dinucleophilic -
mercaptoalcohols in CH2Cl2 at room temperature in the presence of Et3N in a
multistep process. Depending on the position of the CF3 group, different O,S-
heterocycles or non-cyclic products were obtained. Whereas in the case of 3-
bromo-1,1,1-trifluorobut-3-en-2-ones derivatives of 1,4-oxathianes were formed,
the isomeric 2-bromo-4,4,4-trifluorobut-2-en-1-ones yielded 1,3-oxathiolanes or
non-cyclic sulfides. The thia-Michael addition is proposed as the initial step of the
reaction, and the final heterocyclization is governed by the location of the CF3
group.
[a] Department of Organic and Applied Chemistry, University of Łódź, Tamka 12,
PL-91-403 Łódź, Poland
E-mail: gmloston@uni.lodz.pl
[b] Chemistry Department ‘Ugo Schiff’, University of Florence, Via della
Lastruccia 3-13, I-50019 Sesto Fiorentino, Italy
[c] Department of Chemistry, University of Zurich, Winterthurerstrasse 190,
CH-8057 Zurich, Switzerland
KEYWORDS
Fluorinated enones, mercaptoalcohols, thia-Michael addition, heterocyclization,
trifluoromethylated S-heterocycles
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2
Graphical abstract:
Graphical abstract-text: β-Mercaptoalcohols react smoothly as binucleophilic
agents with fluorinated -bromoenones, and the type of the formed products
depends strongly on the location of the CF3 group in the enones. Whereas 2-bromo-
4,4,4-trifluorobut-2-en-1-ones yield the corresponding 5-membered 1,3-
oxathiolanes or, alternatively, open chain sulfides, reactions with isomeric 3-
bromo-1,1,1-trifluorobut-3-en-2-ones lead to 6-membered 1,4-oxathiane
derivatives, exclusively.
Introduction
Reactions generally known as Michael addition are widely applied for the synthesis
of both chiral and achiral organic compounds.[1] Depending on the structure of the
Michael acceptor and the nucleophilic Michael donor, the reaction leads to diverse
acyclic final products. Michael reactions with dinucleophiles open access to a
plethora of heterocycles with diverse ring size and heteroatoms via an
addition/heterocyclization sequence.
The development of methods for the synthesis of fluorinated heterocycles is
of current interest,[2] and reactions with fluorinated Michael acceptors, especially
with -unsaturated trifluoromethylketones, offers a straightforward approach to
this class of compounds.[3] In a series of recent publications, reactions of 3-bromo-
1,1,1-trifluorobut-3-en-2-ones with dinucleophiles such as 1,2-diamines and -
aminoalcohols have been studied in detail.[4] The formation of piperazine and
morpholine derivatives, respectively, was explained via a cascade of reaction steps,
initiated by the Michael-type addition. Moreover, in a recent study, α-
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bromo(trifluoromethyl)enones were described as prone heterodienes, which reacted
with α,β-unsaturated aldehydes in the presence of an organocatalyst to give highly
substituted fluoroalkylated 3,4-dihydro-2H-pyrans in an asymmetric hetero-Diels-
Alder reaction.[5a]
On the other hand, we reported that electron-rich thiocarbonyl S-methanides 1
react chemoselectively with isomeric 1,1,1-trifluorobut-3-en-2-ones (2) and 4,4,4-
trifluorobut-2-en-1-ones (3) yielding 1,3-oxathioles 4 or tetrahydrothiophene
derivatives 5, respectively, as products of the [3+2]-cycloaddition (Scheme 1).[5b]
Based on this observation, and prompted by results reported by Nenajdenko and
collaborators,[4] we decided to examine reactions of -mercaptoalcohols as
binucleophilic agents with -bromoenones derived from 2 and 3.
Scheme 1. Chemoselective [3+2]-cycloadditions of the in situ generated
thiocarbonyl S-methanides 1 with trifluoromethylated ,-unsaturated ketones 2
and 3.
Thiols are known as excellent nucleophiles in Michael addition reactions, and
thiol-Michael additions have been studied extensively. Two recent comprehensive
reviews summarize its importance in materials chemistry[6] and biological
chemistry.[7] In the latter case, the thia-Michael addition found application for the
detection of thiols in living cells.[8]
The reactions of non fluorinated -bromoenones 6 with aliphatic and
aromatic thiols, performed in the presence of a base, gave either -disulfanyl
ketones 7 or -sulfanylenones 8 resulting from a sequence of addition and
elimination reactions[9] (Scheme 2).
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Scheme 2. Addition-elimination reactions of -bromoenones 6 with thiols
performed in the presence of a base.
In a very recent publication we reported on reactions of diverse thiols and
selenols, including β-mercaptoalcohols, with electron deficient dialkyl
dicyanofumarates.[10] In these systems, instead of the expected thia-Michael
addition, a new redox reaction, resulting in the formation of the corresponding
disulfides or diselenides, respectively, was observed. The course of the reaction was
rationalized by a SET mechanism, which replaced the expected addition of the
reactive R–XH (X = S or Se) nucleophile to the C=C bond.
The goal of the present study was to examine whether the reaction of
fluorinated -bromoenones with -mercaptoalcohols is limited to the Michael
addition or heterocyclization within the initially formed adduct will lead to
fluorinated O,S-heterocycles. In addition, the influence of the position of the CF3
group on the reaction course and the type of the final products should be
investigated.
Results and Discussion
Earlier studies with fluorinated -bromoenones relate to 4-aryl-3-bromo-1,1,1-
trifluorobut-3-en-2-ones 9 exclusively.[4] The isomeric 1-aryl-2-bromo-4,4,4-
trifluorobut-2-en-1-ones 10 were prepared for the present study as a mixture of
(E/Z)-stereoisomers from enones 3[5b] via a bromination/dehydrobromination
procedure. An alternative method for its preparation was a multistep reaction
starting with 2-bromo-3,3,3-trifluoropropene leading to (E)-configured enones 3,
which subsequently were converted to (E)-10.
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In a test experiment, -bromoenone 9a was reacted with mercaptoethanol
(11a) in CH2Cl2 solution in the presence of an excess of Et3N at r.t. The TLC
control showed that the reaction was complete after 48 h. The chromatographic
separation led to a colorless solid. The 1H-NMR spectrum showed four
characteristic signals at 4.18, 4.02, 3.20 and 2.86 ppm, corresponding to a CH2O
13
and a CH2S group. In the C-NMR spectrum, these groups absorbed at 60.1 and
28.7 ppm, respectively. Two quartets found at 122.2 (1ЈC,F = 285.0 Hz) and 96.7
ppm (2ЈC,F = 31.5 Hz) were attributed to a CF3–C unit. Correlation analysis allowed
to identify an olefinic unit C=CH by the presence of two signals at 123.0 and 128.3
ppm. The strong IR absorption at 3379 cm–1 indicated the presence of an OH group.
Finally, the ESI-MS showed a peak at m/z 275.2 (100%), which corresponded to
[M+1]+ for C12H10F3O2S. Based on these data, the structure of the obtained
compound corresponded to a 1:1-adduct after elimination of HBr and could be
formulated as 1,4-oxathiane derivative 12a, most likely with (Z)-configuration of
the C=C bond (Scheme 3).
Scheme 3. Reactions of -bromoenones 9 with -mercaptoalcohols 11 to give 1,4-
oxathiane derivatives 12.
Using the same reaction conditions, -bromoenone 9a was reacted with -
mercaptoalcohols 11b–d, and in all cases the corresponding 1,4-oxathianes 12b–d
were isolated as sole products in variable yields (49–15%). In all three cases the
isolated material consisted of a mixture of two diastereoisomers for which the d.r.
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values were determined in a range of 96:4 to 90:10 based on the registered 19F
NMR spectra. All attempts to separate these mixtures, including semi-preparative
flash chromatography, were unsuccessful. In addition, enones 9b,c with a 4-
chlorophenyl and 4-methoxyphenyl group, respectively, and 11a gave the expected
products of type 12. In the case of 9c, the yield of the isolated product 12f was low
(17%). The chromatographic separation of the reaction mixture delivered, along
with the desired product 12f, a comparable amount of an oily material, which,
according to the registered spectra, consisted of a mixture of non-identified
compounds.
In order to compare the influence of the CF3 group, mercaptoethanol 11a was
tested in the reaction with -bromoenone 10a, which is an isomer of 9a, under the
same conditions (CH3Cl2, Et3N, r.t.). In that case, the product was obtained as an
1
oily material. The H NMR spectrum revealed the presence of three CH2 groups,
registered as two multiplets at 4.29–4.19 and 3.15–3.06 ppm and a singlet at 3.65
ppm. In the 13C NMR spectrum, an absorption at 194.1 ppm was attributed to a
ketone C=O group, evidenced by a strong absorption at 1698 cm–1 in the IR
spectrum. Again, two signals at 124.9 (1JC,F = 289.5 Hz) and 92.0 ppm (2JC,F = 30.0
Hz) were attributed to a CF3–C fragment. The ESI-MS showed the [M+1]-peak at
m/z 277.1 (85%). Also in that case, the structure of the product corresponded with
that of the initial 1:1-adduct after elimination of HBr and subsequent
heterocyclization. Thus, it can be formulated as the 1,3-oxathiolane derivative 13
(Scheme 4).
When the reaction of 11a was performed with 10b, bearing a 4-
methoxyphenyl substituent, another reaction course was observed, and the sulfide
14a was isolated in 76% yield. The structure of this compound was elucidated on
the basis of its spectroscopic data. In addition, the same type of sulfide, 14b, was
obtained in 34% yield when 10a was reacted with 11c. Also in this case, the
isolated product was identified as an inseparable mixture of two diastereoisomers in
a ratio ca.1:1 (19F NMR).
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Scheme 4. Reactions of -bromoenones 10 with β-mercaptoalcohols 11a,c
The obtained results demonstrate that the position of the CF3 group in the α-
bromoenones determines the reaction course and the type of the resulting product.
A plausible mechanistic pathway leading to the 1,3-oxathianes 12 is presented in
Scheme 5. The initial step of the reaction sequence comprises the thia-Michael
addition to give 15, which easily undergoes the intramolecular nucleophilic
substitution leading to the thiiranium salt 16. The latter intermediate undergoes
deprotonation and simultaneous thiirane ring opening. The resulting capto-dative
olefin 17 forms the heterocyclic product 12 via an intramolecular acetalization. The
last step corresponds with the well-known tendency of fluorinated aldehydes and
ketones to form stable hydrates and hemiacetals. An alternative formation of 17 can
be proposed via addition of 11a to 16 to give 18, and subsequent elimination of
11a. No attempts were made to evidence the appearance of the thiiranium cation 16
but analogous intermediates are frequently postulated in reactions of β-halogen-
substituted sulfides or thiols[9] with nucleophiles (so called ‘neighbouring group
participation’). However, in a recent study, the attempted NMR detection of an
intermediate of that type was completely unsuccessful.[11]
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Scheme 5. Proposed reaction mechanism for the formation of 1,4-oxathianes 12.
The explanation of the reaction pathway leading to 1,3-oxathiolane 13 from
-bromoenone 10a and 11a via the Michael adduct 19 as key intermediate is based
on the assumption that after elimination of HBr the -unsaturated ketone 20 is
formed (Scheme 6). The latter undergoes preferably the heterocyclization leading to
the 1,3-oxathiolane 13. On the other hand, the formation of sulfides 14 can be
rationalized by intramolecular substitution of the Br atom (SNi(Hal))[12] in 19. This
step leads to the zwitterionic intermediate 21, which reacts with water to give 14.
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Scheme 6. Reaction mechanisms for the formation of 1,3-oxathiolane 13 and
sulfides 14.
Conclusions
The presented study shows that in addition to 1,2-diamines and -aminoalcohols, -
mercaptoalcohols are useful dinucleophiles for exploration in reactions with
fluorinated -bromoenones as superior Michael acceptors. The comparison of the
results obtained with isomeric fluorinated butenones demonstrates that the CF3
group governs the reaction course. In both systems studied, the initially formed
thia-Michael adducts undergo further transformations, and in both reaction
pathways, the final heterocyclization occurs via intramolecular nucleophilic attack
of the OH group at the electrophilic sp2-C-atom bearing the activating CF3 group.
In two of the studied cases, the initially formed Michael adducts undergo an
intramolecular halogen-substitution, which is a competitive process of the sequence
HBr-elimination/cyclization.
The presented results open straightforward ways for the synthesis of very little
known fluoroalkylated 1,4-oxathianes and 1,3-oxathiolanes. Diverse compounds
derived from both systems have extensively been studied as biologically active
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compounds [13a–e] and some applications of ligands derived from 1,3-oxathianes
in asymmetric synthesis are also reported [13f].
Experimental Section
General Remarks: All reactions were carried out in oven-dried glassware under
inert atmosphere (N2), CH2Cl2 was dried over CaH2 and distilled prior to use.
Column chromatography purifications were performed with silica gel 60 (230-400
mesh). Thin layer chromatography was carried out on TLC plates (silica gel 60
1
F254). H NMR (600 MHz) and 13C NMR spectra (150 MHz) were recorded in
19
CDCl3 using a Bruker Avance III 600 spectrometer. F NMR spectra (188 MHz)
were recorded on Varian Gemini 200 spectrometer. NMR signals were referenced
to residual non-deuterated solvent signals (7.26 ppm for 1H, 77.0 ppm for 13C). The
abbreviations used are: s (singlet), d (doublet), dd (doublet of doublet), m
(multiplet), b (broad). IR spectra were measured using a NEXUS FT-IR
spectrophotometer (as film or KBr pellets). The ESI-MS spectra were obtained
using a Varian 500 MS LS Ion Trap spectrometer. HRMS (ESI) were registered
using a GCT Premier Waters instrument.
Starting materials
Commercially available solvents and mercaptoethanol (11a) were used. β-
Mercaptoalcohols 11b–d were synthesized according to ref.[14] The fluorinated β-
bromoenones of type 9[15] and 10[16] were prepared based on the published
procedures.
Synthesis of 4-aryl-1,1,1-trifluorobut-3-en-2-ones 2
General procedure: Trifluoroacetone (2.0 g, 17.8 mmol) was added to the solution
of an appropriate aromatic aldehyde (4.40 mol), acetic acid (400 mg, 6.67 mmol)
and piperidine (300 mg, 3.53 mmol) in anhydrous toluene while cooling the
reaction flask in an ice-bath (0° C). The reaction mixture was left over night and
was then diluted with CH2Cl2 (~10 ml) and a saturated aqueous solution of NH4Cl.
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The organic layer was separated and the water phase was washed with CH2Cl2
(3x10 ml). The combined organic layers were dried over anhydrous Na2SO4,
filtrated, and finally the solvents were removed under reduced pressure. The crude
products were purified on an automatic flash chromatography system on SiO2
columns with mixtures of petroleum ether with increasing amounts of CH2Cl2 (0–
5%) as an eluent.
1
4-Phenyl-1,1,1-trifluorobut-3-en-2-on (2a).[5] Yield: 449 mg (51%); yellow oil. H
3
NMR (600 MHz, CDCl3): δ 7.97 (d, JH,H = 16.0 Hz, 1H, CH), 7.65–7.64 (m, 2
arom. CH), 7.50–7.44 (m, 3 arom. CH), 7.02 (d, 3JH,H = 16.0 Hz, 1H, CH) ppm.
4-(4-Chlorophenyl)-1,1,1-trifluorobut-3-en-2-on (2b).[17] Yield: 485 mg (47%);
yellow crystals, m.p. 62.4–63.5 ºC (without crystallization) (lit.[17a], m.p. 43−46
1
3
°C). H NMR (600 MHz, CDCl3): δ 7.92 (d, JH,H = 16.0 Hz, 1H, CH), 7.59–7.57
3
(m, 2 arom. CH), 7.44–7.43 (m, 2 arom. CH), 6.99 (d, JH,H = 16.0 Hz, 1H, CH)
ppm.
4-(4-Methoxyphenyl)-1,1,1-trifluorobut-3-en-2-on (2c).[5] Yield: 314 mg (31%);
yellow semi-solid, m.p. 54.3–55.5 ºC. 1H NMR (600 MHz, CDCl3): δ 7.94 (d, 3JH,H
= 15.8 Hz, 1H, CH), 7.61–7.60 (m, 2 arom, CH), 6.96–6.95 (m, 2 arom. CH), 6.89
(d, 3JH,H = 15.8 Hz, 1H, CH), 3.87 (s, 3H, CH3) ppm.
Synthesis of 4-aryl-3-bromo-1,1,1-trifluorobut-3-en-2-ones 9
General procedure: A solution of Br2 (240 mg, 1.5 mmol) in CH2Cl2 (~2 ml) was
added dropwise to an enone 2 (1.5 mmol) dissolved in anhydrous CH2Cl2 (~10 ml).
Next, Et3N (227 mg, 2.25 mmol) was added, and the reaction mixture was stirred
1
over 12 h. The progress of the reaction was controlled via H NMR spectroscopy,
and if the elimination of HBr was not complete, an additional portion of Et3N (227
g, 2.25 mmol) was added. The reaction mixture was left over night, then a portion
of H2O (~20 ml), was added. The organic layer was separated, and the water phase
was washed with CH2Cl2 (3x10 ml). The combined organic layers were dried over
anhydrous Na2SO4, filtrated, and the solvent was evaporated under reduced
pressure. Pure products were isolated by column chromatography on SiO2 with
petroleum ether with an increasing amount of CH2Cl2 (0–25%) as an eluent.
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(Z)-3-Bromo-4-phenyl-1,1,1-trifluorobut-3-en-2-on (9a).[15b] Yield: 352 mg (84%);
yellow oil. 1H NMR (600 MHz, CDCl3): δ 8.21 (s, 1H, CH), 7.98–7.96 (m, 2 arom.
13
CH), 7.55–7.49 (m, 3 arom. CH) ppm. C NMR (150 MHz, CDCl3): δ 175.9 (q,
5
2JC,F = 34.5 Hz, C=O), 147.3 (q, JC,F = 4.5 Hz, CH), 132.9 (1 arom. C), 132.1,
1
19
131.3, 128.8 (5 arom. CH), 115.8 (q, JC,F = 289.5 Hz, CF3), 116.7 (CBr) ppm. F
NMR (188 MHz, CDCl3): δ –69.09 (s, CF3) ppm. IR (film): v 1714vs (C=O), 1207–
1147s (CF3) cm–1. ESI-(+)-MS: m/z [M + H]+: 278 (100%), 280 (100%).
(Z)-3-Bromo-4-(4-chlorophenyl)-1,1,1-trifluorobut-3-en-2-on (9b).[4c] Yield: 348
1
mg (74%); yellow crystals, m.p. 83.4–84.2 ºC (without crystallization). H NMR
(600 MHz, CDCl3): δ 7.49–7.47 (m, 2 arom. CH), 7.93–7.90 (m, 2 arom. CH), 8.14
(s, 1H, CH) ppm. 13C NMR (150 MHz, CDCl3): δ 175.8 (q, 2JC,F = 34.5 Hz, C=O),
145.7 (q, 5JC,F = 4.5 Hz, CH), 138.3, 131.2 (2 arom. C), 132.5 129.2 (4 arom. CH),
118.6 (CBr), 115.7 (q, 1JC,F = 289.5 Hz, CF3) ppm. 19F NMR (188 MHz, CDCl3): δ
–69.15 s, CF3) ppm. IR (KBr): v 1704vs (C=O), 1204–1157s (CF3) cm–1. ESI-(–)-
MS: m/z [M – H]–: 312 (70%), 314 (100%).
(Z)-3-Bromo-4-(4-methoxyphenyl)-1,1,1-trifluorobut-3-en-2-on (9c).[15b] Yield:
1
0.394 mg (85%); orange semi-solid. H NMR (600 MHz, CDCl3): δ 8.14 (s, 1H,
CH), 8.05–8.04 (m, 2 arom. CH), 7.01–7.00 (m, 2 arom. CH), 3.90 (s, 3H, CH3)
ppm. 13C NMR (150 MHz, CDCl3): δ 175.7 (q, 2JC,F = 34.5 Hz, C=O) 163.0, 146.9
1
(2 arom. C), 134.2, 114.4 (4 arom. CH), 125.4 (CH), 117.9 (q, JC,F = 289.5 Hz,
19
CF3), 113.9 (CBr), 55.5 (CH3O) ppm. F NMR (188 MHz, CDCl3): δ –68.72 (s,
CF3) ppm. IR (KBr): v 1701s (C=O), 1185–1150s (CF3) cm–1. ESI-(+)-MS: m/z [M
+ H]+: 309 (97%), 311 (100%).
Synthesis of 1-aryl-4,4,4-trifluorobut-2-en-1-ones 3
General procedure: 2-Bromo-3,3,3-trifluoropropene (4.7 g, 0.027 mol) was
o
dissolved in anhydrous THF (30 ml) and the reaction flask was cooled to –78 C.
Next, a solution of LDA, prepared from diisopropylamine (5.4 ml, 0.035 mol) in
THF (30 ml) and a 2.5M solution of n-BuLi in hexane (14 ml, 0.035 mol) at –78
oC, was added dropwise and the mixture was stirred over 15 min. Then, an
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10.1002/ejoc.201701752
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appropriate aromatic aldehyde (0.015 mol), dissolved in THF (~5 ml), was added.
The cooling bath was removed and the reaction flask was left to reach room
temperature. Next, a 1M solution of HCl (50 ml) and AcOEt (50 ml) were added.
The organic layer was separated and the water layer was washed with AcOEt (3x50
ml). The combined organic layer was dried over anhydrous Na2SO4, filtrated, and
the solvents were removed under reduced pressure. The crude 1-aryl-4,4,4-
trifluorobut-2-yn-1-oles were used for next step without purification.
A 1-aryl-4,4,4-trifluorobut-2-yn-1-ol was dissolved in THF (120 ml) and Et3N
(6.06 g, 0.060 mol) was added. The reaction mixture was heated to 60 °C over 12 h
in an Ar atmosphere. Next, the solvent was removed in rotary evaporator. The
products were purified by column chromatography on SiO2 with petroleum ether
with increasing amounts of CH2Cl2 (9:1) as the eluent. The diastereoisomers (E/Z)
were not separated.
1-Phenyl-4,4,4-trifluorobut-2-en-1-on (3a).[16b] Yield (for 2 steps): 1.59 g (53%);
1
3
yellow oil. H NMR (600 MHz, CDCl3): δ E-isomer: 7.98 (d, JH,H = 7.1 Hz, 1H,
3
3
3
CH), 6.82 (dq, JH,F = 13.3 Hz, JH,H = 7.1 Hz, 1H, CH); Z-isomer: 7.93 (d, JH,H
=
3
3
7.6 Hz, 1H, CH), 6.09 (dq, JH,F = 15.8 Hz, JH,H = 7.6 Hz, 1H, CH); both
diastereoisomers 7.66–7.64 (m, 2 arom. CH), 7.55–7.52 (m, 3 arom. CH) ppm.
1-(4-Methoxyphenyl)-4,4,4-trifluorobut-2-en-1-on (3b).[16b] Yield (for 2 steps): 1.41
1
g (41%); yellow oil. H NMR (600 MHz, CDCl3): δ E-isomer: 7.99–7.96 (m, 2
4
3
arom. CH), 7.53 (dq, JH,F = 2.0 Hz, JH,H = 14.4 Hz, 1H, CH), 7.01–6.89 (m, 2
arom. CH), 6.79 (dq, 3JH,F = 6.7 Hz, 3JH,H = 14.4 Hz, 1H, CH), 3.90 (s, 3H, CH3O);
3
Z-isomer: 7.91–7.89 (m, 2 arom. CH), 6.98–6.96 (m, 2 arom. CH), 6.82 (d, JH,H
=
3
3
12.8 Hz, 1H, CH), 6.04 (dq, JH,F = 7.9 Hz, JH,H = 12.8 Hz, 1H, CH), 3.89 (s, 3H,
CH3O) ppm.
Syntheses of 1-aryl-2-bromo-4,4,4-trifluorobut-2-en-1-ones 10
General procedure: A solution of Br2 (930 mg, 5.8 mmol) in dry n-hexane (~2 ml)
was added dropwise to the solution of a fluoroenone 3 (5.8 mmol) in dry n-hexane
(30 ml). The solution was stirred until disappearance of the red color. Next, a
portion of water (50 ml) was added, and the mixture was extracted with Et2O (3x25
ml). The organic layers were combined and dried over anhydrous Na2SO4, filtered,
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and the solvents were removed under reduced pressure. The crude
dibromoderivative was dissolved in Et2O (30 ml), Et3N (0.81 g, 8.0 mmol) was
added, and the solution was stirred for 24 h. The precipitated triethylammonium
bromide was filtrated off and the solvent was removed under reduced pressure. The
product was purified by column chromatography on SiO2 with petroleum ether with
increased amounts of CH2Cl2 (0–25%) as the eluent.
2-Bromo-1-phenyl-4,4,4-trifluorobut-2-en-1-on (10a).[18] Yield: 1.15 g (72%)
1
(single diastereoisomer); yellow oil. H NMR (600 MHz, CDCl3): δ 7.87–7.86 (m,
2 arom. CH), 7.67–7.65 (m, 1 arom. CH), 7.54–7.51 (m, 2 arom. CH), 6.76 (q, 3JH,F
= 6.8 Hz, 1H, CH) ppm. 13C NMR (150 MHz, CDCl3): δ 188.7 (C=O), 134.4,
2
130.3, 128.9 (5 arom. CH), 133.4 (1 arom. C), 130.4 (CBr), 126.9 (q, JC,F = 36.6
Hz, CHCF3), 121.4 (q, 1JC,F = 267.4 Hz, CF3) ppm. 19F NMR (188 MHz, CDCl3): δ
3
–69.93 (d, JF,H = 7.2 Hz, CF3) ppm. IR (film): v 1685s (C=O), 1242–1150s (CF3)
cm–1. ESI-(+)-MS: m/z [M + H]+: 279 (100%), 281 (92%).
2-Bromo-1-(4-methoxyphenyl)-4,4,4-trifluorobut-2-en-1-on (10b). Yield: 1.31 g
(73%) (both diastereoisomers, ratio 7:3); yellow oil. 1H NMR (600 MHz, CDCl3): δ
3
major isomer: 7.89–7.87 (m, 2 arom. CH), 6.67 (q, JH,F = 6.8 Hz, 1H, CH); minor
isomer: 7.92–7.90 (m, 2 arom. CH), 6.64 (q, 3JH,F = 7.3 Hz, 1H, CH); both isomers
7.00–6.98 (m, 2 arom. CH), 3.91 (s, 3H, CH3O)ppm. 13C NMR (150 MHz, CDCl3):
δ major isomer: 187.3 (C=O), 164.8, 125.8 (2 arom. C), 132.4, 114.3 (4 arom. CH),
3
2
1
130.1 (q, JC,F = 6.0 Hz, CBr), 125.3 (q, JC,F = 36.0 Hz, CHCF3), 121.5 (q, JC,F
=
271.5 Hz, CF3), 55.7 (CH3O); minor isomer: 186.5 (C=O), 165.0, 125.2 (2 arom.
C), 132.3, 114.4 (4 arom. CH), 129.7 (q, 3JC,F = 6.0 Hz, CBr), 122.4 (q, 2JC,F = 36.0
1
19
Hz, CHCF3), 121.1 (q, JC,F = 271.5 Hz, CF3), 55.6 (CH3O) ppm. F NMR (188
MHz, CDCl3): δ major isomer –65.86 (d, 3JF,H = 5.6 Hz, CF3), minor isomer –61.70
3
(d, JF,H = 5.6 Hz, CF3) ppm. IR (film): v 1682s (C=O), 1312–1138vs (CF3) cm–1.
ESI-(+)-MS: m/z [M + H]+: 309 (100%), 311 (97%).
Synthesis of -mercaptoalcohols 11c,d
1-(Benzyloxy)-3-mercaptopropan-2-ol (11c)
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Obtained following the reported procedure.[14] Yield: 562 mg (89%); yellowish oil.
1H NMR (400 MHz, CDCl3): δ 7.38–7.31 (m, 5H), 4.56 (brs, 2H, CH2Ph), 3.88–
3.82 (m, 1H, CHOH), 3.57 (dd, J = 4.5, 9.6 Hz, 1H, CHaHbO), 3.53 (dd, J = 6.1,
9.6 Hz, 1H, CHaHbO), 2.75–2.62 (m, 2H, CH2S), 1.44 (t, J = 8.7 Hz, 1H, SH) ppm.
13C NMR (100 MHz, CDCl3): δ 137.9, 128.4, 127.9, 127.4, 73.3, 72.2, 71.2, 28.1
·
(CH2S) ppm. EI-MS: m/z: 198 (37) [M+ ], 122 (45), 107 (73), 91 (100). C10H14O2S
(198.28): calcd. C 60.58, H 7.12; found: C 60.51, H 7.17.
1-(Allyloxy)-3-mercaptopropan-2-ol (11d)
1
Obtained following reported procedure.[14] Yield: 527 mg (71%); yellowish oil. H
NMR (400 MHz, CDCl3): δ 5.95–5.85 (m, 1H), 5.30–5.19 (m, 2H), 4.04–4.02 (m,
2H, CH2OCH=CH2), 3.87–3.81 (m, 1H, CHOH), 3.53 (dd, J = 4.3, 9.5 Hz, 1H,
CHaHbO), 3.49 (dd, J = 6.2, 9.5 Hz, 1H, CHaHbO), 2.74–2.61 (m, 2H, CH2S), 2.39
13
(brs, 1H, OH), 1.48 (t, J = 8.7 Hz, 1H, SH) ppm. C NMR (100 MHz, CDCl3): δ
134.7, 117.6, 72.6, 71.1, 70.6, 28.4 (CH2S) ppm. ESI-(+)-MS: m/z [M+Na]+: 171
(100). C6H12O2S (148.22): calcd. C 48.62, H 8.16; found: C 48.50, H 8.21.
Reactions of bromoenones 9 and 10 with β-mercaptoalcohols
General procedure: A β-mercaptoalcohol 11a–d (1 mmol) and Et3N (0.152 g, 1.5
mmol) were added to a solution of an α-bromoenone 9a–c or 10a,b (1 mmol) in
anhydrous CH2Cl2 (10 ml). The solution was stirred in an Ar atmosphere for 48 h.
Then, the solvent was removed under reduced pressure and the product was
purified by column chromatography on SiO2 with petroleum ether with increased
amounts of CH2Cl2 (0–100%) as an eluent.
3-Benzylidene-2-(trifluoromethyl)-1,4-oxathian-2-ol (12a). Yield: 136 mg (49%);
1
colorless crystals, m.p. 135.8–137.4 ºC (hexane/CH2Cl2). H NMR (600 MHz,
CDCl3): δ 7.56–7.54 (m, 2 arom. CH), 7.41–7.39 (m, 2 arom. CH), 7.34–7.31 (m,
2H, 1 arom. CH + CH=C), 4.20–4.17 (m, 1H, CH2), 4.04–4.00 (m, 1H, CH2), 3.26–
3.22 (m, 1H, CH2), 3.15 (s, 1H, OH), 2.87–2.84 (m, 1H, CH2) ppm. 13C NMR (150
MHz, CDCl3): δ 135.4 (CH=C), 134.9 (1 arom. C), 129.9, 128.3, 128.1 (5 arom.
1
2
CH), 123.0 (CH=C), 122.2 (q, JC,F = 285.0 Hz, CF3), 96.7 (q, JC,F = 31.5 Hz,
CCF3), 60.1 (CH2O), 28.7 (CH2S) ppm. 19F NMR (188 MHz, CDCl3): δ –84.00 (s,
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CF3) ppm. IR (KBr): v 3379br.s (OH), 1188–1141vs (CF3) cm–1. ESI-(–)-MS: m/z:
275 (25%, [M – H]–), 276 (100%, [M]–). HR-ESI-(–)-MS: 275.0352 (275.0354
calcd. for C12H10F3O2S, [M – H]–).
3-Benzylidene-6-methyl-2-(trifluoromethyl)-1,4-oxathian-2-ol (12b). Yield: 43 mg
1
(15%); yellow oil (two diastereoisomers, ratio 96:4). H NMR (600 MHz, CDCl3):
δ 7.54–7.53 (m, 2 arom. CH), 7.40–7.39 (m, 2 arom. CH), 7.33–7.30 (m, 2H, 1
2
arom. CH + CH=C), 4.19–4.14 (m, 1H, CHCH3), 3.10 (s, 1H, OH), 2.95 (dd, JH,H
= 3JH,H = 11.2 Hz, 1H, CH2S), 2.83 (dd, 2JH,H = 11.2 Hz, 3JH,H = 6.4 Hz, 1H, CH2S),
3
13
1.36 (d, JH,H = 6.2 Hz , 3H, CH3) ppm. C NMR (150 MHz, CDCl3): δ 135.1 (1
arom. C), 134.7 (CH=C), 129.9, 128.2, 128.1 (5 arom. CH), 123.2 (CH=C), 122.1
1
2
(q, JC,F = 286.1 Hz, CF3), 96.9 (q, JC,F = 31.7 Hz, CCF3), 67.0 (CHCH3), 34.6
19
(CH3), 21.0 (CH2S) ppm. F NMR (188 MHz, CDCl3): δ major isomer –84.45 (s,
CF3); minor isomer –80.32 (s, CF3) ppm. IR (film): v 3443br.s (OH), 1188–1097vs
(CF3) cm–1. ESI-(+)-MS: m/z 273 (100%, [M–OH]+). HR-ESI-(–)-MS: 289.0506
(289.0510 calcd. for C13H12F3O2S, [M – H]–).
3-Benzylidene-6-(benzyloxymethyl)-2-(trifluoromethyl)-1,4-oxathian-2-ol
(12c).
Yield: 149 mg (38%); yellow oil (two diastereoisomers, ratio 90:10). 1H NMR (600
MHz, CDCl3): δ 7.55–7.54 (m, 2 arom. CH), 7.40–7.29 (m, 9H, 8 arom. CH +
CH=C), 4.58 (s, 1H, OH), 4.59–4.54 (m, 2H, CH2Ph), 4.25–4.23 (m, 1H,
2
3
CHCH2OBn), 3.66 (dd, JH,H = 10.5 Hz, JH,H = 6.1 Hz, 1H, CHCH2OBn), 3.53
2
3
2
3
(dd, JH,H = 10.5 Hz, JH,H = 4.6 Hz, 1H, CHCH2O), 3.01 (dd, JH,H = JH,H = 11.3
2
3
Hz, 1H, CH2S), 2.89 (dd, JH,H = 11.3 Hz, JH,H = 2.9 Hz, 1H, CH2S) ppm. 13C
NMR (150 MHz, CDCl3): δ 137.7 (CH=C) , 135.3, 135.0 (2 arom. C), 129.9, 128.5,
1
128.3, 128.0, 127.9, 127.7 (10 arom. CH), 123.3 (CH=C), 122.1 (q, JC,F = 285.0
2
Hz, CF3), 97.0 (q, JC,F = 31.6 Hz, CCF3), 73.5, 71.5, 69.6 (2CH2 + CH), 30.6
19
(CH2S) ppm. F NMR (188 MHz, CDCl3): δ major isomer –83.55 (s, CF3); minor
isomer –80.47 (s, CF3) ppm. IR (film): v 3357br.s (OH), 1198–1112vs (CF3) cm–1.
ESI-(+)-MS: m/z 419.1 (100%, [M + Na]+), 435 (49%, [M + K]+). HR-ESI-(+)-MS:
419.0898 (419.0905 calcd. for C20H19F3O3SNa, [M + Na]+).
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6-(Allyloxymethyl)-3-benzylidene-2-(trifluoromethyl)-1,4-oxathian-2-ol
(12d).
1
Yield: 92 mg (27%); yellow oil (two diastereoisomers, ratio 91:9). H NMR (600
MHz, CDCl3): δ 7.55–7.53 (m, 2 arom. CH), 7.41–7.38 (m, 2 arom. CH), 7.33–7.32
(m, 2H, 1 arom. CH + CH=C), 5.92–585 (m, 1H, CH=CH2), 5.30–5.27 (m, 1H,
CH=CH2); 5.22–5.20 (m, 1H, CH=CH2), 4.21–4.17 (m, 1H, CHCH2O), 4.05–4.04
(m, 2H, OCH2CH=CH2), 3.64 (dd, 2JH,H = 10.6 Hz, 3JH,H = 6.2 Hz, 1H, CHCH2O),
2
3
3.10 (dd, JH,H = 10.6 Hz, JH,H = 4.6 Hz, 1H, CHCH2O), 3.49 (s, 1H, OH), 3.00
2
3
2
3
(dd, JH,H = JH,H = 11.2 Hz, 1H, CH2S), 2.89 (dd, JH,H = 11.2 Hz, JH,H = 3.0 Hz,
13
1H, CH2S) ppm. C NMR (150 MHz, CDCl3): δ 135.4, 135.0 (2CH=C), 134.3 (1
1
arom. C), 129.9, 128.3, 128.1 (5 arom. CH), 123.3 (CH=C-S), 120.1 (q, JC,F
=
285.0 Hz, CF3), 117.5 (CH=CH2), 97.0 (q, 2JC,F = 31.9 Hz, CCF3), 72.5, 71.5, 69.6
19
(2CH2 + CH), 30.6 (CH2S) ppm. F NMR (188 MHz, CDCl3): δ major isomer –
83.57 (s, CF3); minor isomer –80.46 (s, CF3) ppm. IR (film): v 3341br.s (OH),
1198–1100vs (CF3) cm–1. ESI-(–)-MS: m/z: 345.3 (100%, [M – H]–); 346 (97%,
[M]–). HR-ESI-(+)-MS: 369.0737 (369.0748 calcd. for C16H17F3O3SNa, [M+Na]+)
3-(4-Chlorobenzylidene)-2-(trifluoromethyl)-1,4-oxathian-2-ol (12e). Yield: 146
1
mg (47%); colorless crystals, m.p. = 143.1–145.8 ºC (hexane/CH2Cl2). H NMR
(600 MHz, CDCl3): δ 7.50–7.48 (m, 2 arom. CH), 7.37–7.35 (m, 2 arom. CH), 7.27
(s, 1H, CH), 4.21–4.18 (m, 1H, CH2), 4.03–3.98 (m, 1H, CH2), 3.27–3.23 (m, 1H,
CH2), 3.15 (s, 1H, OH), 2.88–2.85 (m, 1H, CH2) ppm. 13C NMR (150 MHz,
CDCl3): δ 134.1, 134.0 (CH=C + 1 arom. C), 133.4 (1 arom. C), 131.1, 128.3 (4
1
2
arom. CH), 123.8 (CH=C), 122.1 (q, JC,F = 286.2 Hz, CF3), 96.6 (q, JC,F = 31.8
Hz, CCF3), 60.1 (CH2O), 28.7 (CH2S) ppm. 19F NMR (188 MHz, CDCl3): δ –
84.06 (s, CF3) ppm. IR (KBr): v 3405br.s (OH), 1192–1144vs (CF3) cm–1. ESI-(–)-
MS: m/z 309 (100%, [M – H]–), 310 (80%, [M]–). HR-ESI-(–)-MS: 308.9961
(308.9964 calcd. for C12H9F3O2SCl, [M – H]–).
3-(4-Methoxybenzylidene)-2-(trifluoromethyl)-1,4-oxathian-2-ol (12f). Yield: 52
mg (17%); colorless crystals, m.p. 102.7–104.2 ºC (hexane/CH2Cl2). 1H NMR (600
MHz, CDCl3): δ 7.54–7.52 (m, 2 arom. CH), 7.27 (s, 1H, CH), 6.93–6.92 (m, 2
arom. CH), 4.19–4.16 (m, 1H, CH2), 4.03–3.99 (m, 1H, CH2), 3.84 (s, 3H, CH3O),
3.24–3.22 (m, 1H, CH2), 3.11 (br.s, 1H, OH), 2.87–2.85 (m, 1H, CH2) ppm. 13C
NMR (150 MHz, CDCl3): δ 159.6 (1 arom. C), 135.1 (CH=C), 131.5, 113.5 (4
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arom. CH), 127.7 (1 arom. C), 122.2 (q, 1JC,F = 286.5 Hz, CF3), 120.4 (CH=C), 96.8
(q, 2JC,F = 31.5 Hz, CCF3), 60.0 (CH2O), 55.3 (CH3O), 28.7 (CH2S). 19F NMR (188
MHz, CDCl3): δ –84.02 (s, CF3) ppm. IR (KBr): v 3383br.s (OH), 1195–1144vs
(CF3) cm–1. ESI-(+)-MS: m/z: 307.1 (100%, [M + H]+). HR-ESI-(–)-MS: 305.0454
(305.0459 calcd. for C13H12F3O3S, [M – H]–).
1-Phenyl-2-[(2-trifluoromethyl)-1,3-oxathiolan-2-yl]ethan-1-on (13). Yield: 164
1
mg (59%); yellow oil. H NMR (600 MHz, CDCl3): δ 7.96–7.95 (m, 2 arom. CH),
7.60–7.57 (m, 1 arom. CH), 7.49–7.46 (m, 2 arom. CH), 4.29–4.19 (m, 2H, CH2O),
2
3.66, 3.63 (AB, JH,H = 16.3 Hz, 2H, CH2), 3.15–3.06 (m, 2H, CH2S) ppm. 13C
NMR (150 MHz, CDCl3): δ 194.1 (C=O), 137.3 (1 arom. C), 133.4, 128.6 (5 arom
CH), 124.9 (q, 1JC,F = 283.5 Hz, CF3), 92.0 (q, 2JC,F = 30.0 Hz, CCF3), 73.9 (CH2O),
42.2 (CH2), 33.8 (CH2S) ppm. 19F NMR (188 MHz, CDCl3): δ –79.77 (s, CF3)
ppm. IR (film): v 1698s (C=O), 1220–1119s (CF3) cm–1. ESI-(+)-MS: m/z 277
(85%, [M + H]+). HR-ESI-(–)-MS: 308.9961 (308.9964 calcd. for C12H9F3O2SCl,
[M – H]–).
3-[(2-Hydroxyethyl)sulfanyl)]-1-(4-methoxyphenyl)-4,4,4-trifluorobutan-1-on
1
(14a). Yield: 233 mg (76%); orange oil. H NMR (600 MHz, CDCl3): δ 7.97–7.94
(m, 2 arom. CH), 6.97–6.95 (m, 2 arom. CH), 4.08–4.04 (m, 1H, CHS), 4.00–3.95
(m, 1H, CH2O), 3.89 (s, 3H, CH3O), 3.88–3.83 (m, 1H, CH2O), 3.91–3.30 (m, 3H,
13
CH2 + OH), 3.06–3.02 (m, 1H, CH2S), 2.82–2.77 (m, 1H, CH2S) ppm. C NMR
1
(150 MHz, CDCl3): δ 193.9 (C=O), 164.3, 129.1 (2 arom. C), 127.2 (q, JC,F
=
276.2 Hz, CF3), 130.7, 114.0 (4 arom. CH), 61.3 (CH2O), 55.6 (CH3O), 41.8 (q,
2JC,F = 29.6 Hz, CHCF3), 37.5 (CH2), 36.5 (CH2S) ppm. 19F NMR (188 MHz,
CDCl3): δ –72.28 (d, 3JF,H = 8.3 Hz, CF3) ppm. IR (film): v 3458br.s (OH), 1676vs
(C=O), 1263–1174vs (CF3) cm–1. ESI-(+)-MS: m/z: 309 (100%, [M + H]+). HR-
ESI-(+)-MS: 331.0583 (331.0592 calcd. for C13H15F3O3SNa, [M + Na]+).
3-[(3-Benzyloxy-2-hydroxypropyl)sulfanyl]-1-phenyl-4,4,4-trifluorobutan-1-on
1
(14b). Yield: 135 mg (34%) (two diastereoisomers, ratio 1:1); orange oil. H NMR
(600 MHz, CDCl3): δ 7.97–7.88 (m, arom. CH), 7.64–7.61 (m, arom. CH), 7.52–
7.49 (m), 7.37–7.33 (m, arom. CH), 7.31–7.28 (m, arom. CH), 4.60–4.55 (m),
4.18–4.12 (m), 4.09–4.02 (m), 3.62–3.55 (m), 3.45–3.38 (m), 3.22 (d, J = 6.0 Hz),
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3.07 (dd, J(1) = 13.8 Hz, J(2) = 4.2 Hz), 2.90 (d, J = 6.6 Hz), 2.83 (dd, J(1) = 13.8 Hz,
J(2) = 6.6 Hz) ppm (a complex set of signals, it was impossible to attribute them to
particular diastereoisomer). 13C NMR (150 MHz, CDCl3): δ 195.3, 195.2 (C=O),
138.0, 137.9, 136.1, 136.0 (2 arom. C), 134.0, 133.9, 128.8, 128.4, 128.3, 128.2,
127.8, 127.75, 127.7 (10 arom. CH), 127.2, 127.1 (2q, 1JC,F = 276.0 Hz, CF3), 73.5,
2
72.7, 72.3, 71.2, 68.7 (HOCH, CH2O, CH2Ph), 43.1, 42.3 (q, JC,F = 28.5 Hz,
CHCF3), 38.2, 38.0 (CH2), 37.2, 37.0 (CH2S) ppm. 19F NMR (188 MHz, CDCl3): δ
3
–71.39 and –71.16 (2d, ratio 1:1, JF,H = 8.3 Hz for both doublets, CF3 for two
diastereoisomers) ppm. IR (film): v 3455br.s (OH), 1692vs (C=O), 1252–1154vs
(CF3) cm–1. ESI-(+)-MS: m/z: 421 (100%, [M + Na]+). HR-ESI-(+)-MS: 421.1049
(421.1061 calcd. for C20H21F3O3SNa, [M + Na]+).
Acknowledgements
The authors (GM, EO, HH) thank the National Science Center (Cracow, Poland)
for a generous financial support within the Opus-7 Project (Grant #
2014/13/B/ST5/04004).
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