Asymmetric induction in thia-Diels-Alder reactions of chiral polyfluoroalkylthionocarboxylates

Article abstract of DOI:10.1016/j.jfluchem.2009.11.011

A series of chiral S- or O-alkyl thionoesters have been synthesized by treatment of trifluorothioacetyl- or 2,2,3,3-tetrafluorothiopropionyl chloride with corresponding thiols or alcohols. The thia-Diels-Alder reaction of the thionoesters with symmetrical 1,3-dienes proceeds with diastereoselectivity up to 60%. Structures of cycloaddition products and corresponding transition states have been studied at the DFT level of approximation. The experimentally observed diastereomeric excess has been referred to differences in activation energies of transition states, preceding formation of the diastereomeric cycloaducts.

Full text of DOI:10.1016/j.jfluchem.2009.11.011

Journal of Fluorine Chemistry 131 (2010) 172–183
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Asymmetric induction in thia-Diels-Alder reactions of chiral
polyfluoroalkylthionocarboxylates
a
Vadim M. Timoshenko a, , Sergiy A. Siry , Alexander B. Rozhenko a,b, Yuriy G. Shermolovich a
*
a Institute of Organic Chemistry NAS of Ukraine, Murmanska str. 5, 02660 Kyiv, Ukraine
b University of Bielefeld, Universita¨tstr. 25, 33615 Bielefeld, Germany
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of chiral S- or O-alkyl thionoesters have been synthesized by treatment of trifluorothioacetyl- or
2,2,3,3-tetrafluorothiopropionyl chloride with corresponding thiols or alcohols. The thia-Diels-Alder
reaction of the thionoesters with symmetrical 1,3-dienes proceeds with diastereoselectivity up to 60%.
Structures of cycloaddition products and corresponding transition states have been studied at the DFT
level of approximation. The experimentally observed diastereomeric excess has been referred to
differences in activation energies of transition states, preceding formation of the diastereomeric
cycloaducts.
Received 22 July 2009
Received in revised form 16 November 2009
Accepted 18 November 2009
Available online 24 November 2009
Keywords:
Thioesters
ß 2009 Elsevier B.V. All rights reserved.
Fluorine
Thia-Diels-Alder reaction
Dihydrothiopyrans
Asymmetric induction
DFT
Transition state
1. Introduction
containing compounds, we were interested to study an asymmet-
ric variant of the thia-Diels-Alder reaction of alkyl polyfluoro
Synthetic methodologies based on the Diels-Alder reaction are
widely employed in organic chemistry and have an enormous
spectrum of application. Using heterodienes or heterodienophiles
in the [4 + 2] cycloaddition reaction makes it possible to construct
complex natural products or their analogues containing a six-
membered heterocyclic framework [1]. Thiocarbonyl compounds
are well known representatives of heterodienophiles which have
found applications in total syntheses [2,3], for preparation of
thioglycoside derivatives [4] and thiashikimic acid [5]. Electron-
dithioesters with dienes. For this purpose suitable dithioesters
bearing chiral groups were necessary. In this paper we describe a
preparation of such chiral substrates, a study of their cycloaddition
reactions and a comparison of the diastereoselectivity in these
reactions. Additionally, O-alkyl polyfluorothionoates have been
synthesized for comparison, dienophilic properties of which have
not been described to date.
2. Results and discussion
withdrawing groups in a-position to the thiocarbonyl group lower
the LUMO energy of the heterodienophile and significantly
facilitate the cycloaddition. Therefore, polyfluroalkyl thioalde-
hydes [6], thioketones [7], dithioesters [6–9] are excellent
dienophiles and can be used for syntheses of diverse sulfur-
containing heterocycles. For symmetrical dienes, at least one new
stereogenic centre is generated by Diels-Alder reaction. Therefore,
the application of a proper chiral dienophiles could influence the
stereochemical outcome of the cycloaddition and can be used in
the construction of optically active compounds.
Several synthetic methods are known for the preparation of
perfluoroalkyldithiocarboxylates, developed in our laboratory [8–
10] and by others groups [11–14]. In order to obtain a series of
dithioesters involving a chiral group we have developed another,
new and simple method which consists in nucleophilic displace-
ment of chlorine in polyfluorothioalkanoyl chlorides 1 by sulfur in
reactions with optically active mercaptanes. Trifluorothioacetyl
chloride 1a and 2,2,3,3-tetrafluorothiopropionyl chloride 1b were
prepared according to the known procedure [15] from correspond-
ing benzyl 1,1-dichloropolyfluoroalkyl sulfides [16] (Fig. 1).
The following chiral thiols prepared according to the described
procedure we have chosen as nucleophiles for reactions with
chlorides 1: (1S)-10-mercaptocamphor 2a [17], (1S)-thioisobor-
neol 2b [18], (1S)-thioborneol 2c [19], (1S,2S,5R)-thioneomenthol
Continuing our studies on applications of polyfluoroalkylthi-
nocarboxylic acids derivatives in syntheses of new fluorine–sulfur-
* Corresponding author. Tel.: +380 44 499 4938; fax: +380 44 573 2643.
E-mail address: vadim@ioch.kiev.ua (V.M. Timoshenko).
2d [20] and racemic
a-phenethylthiol 2e [21].
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.11.011

V.M. Timoshenko et al. / Journal of Fluorine Chemistry 131 (2010) 172–183
173
Table 2
Synthesis of thionoesters 4a–f.
Fig. 1. Synthesis of polyfluorothioalkanoyl chlorides 1 [15,16].
Thiols 2 smoothly react with chlorides 1 in inert solvents at
room temperature with evolution of hydrogen chloride yielding
dithioesters 3 (Table 1). Progress of reactions was monitored by the
19F NMR spectroscopy. Addition of bases (e.g., triethylamine, NaH)
leads to a substantial contamination of reaction mixture, probably
due to a thiophilic attack, typical for reactions of fluoroalkyl
thiocarbonyl compounds with nucleophiles [22]. Dithioesters 3
have been easily purified by column chromatography and isolated
in good yields as red liquids stable at storage.
.
Ester
Rf
Alcohol (R*OH)
Reaction conditions
Yield (%)
4a
H(CF2)2
Method A, i-PrOH, 10 min
78
We have tried to extend this synthetic protocol to reactions of
chloride 1 with optically active alcohols for preparing chiral O-
alkyl polyfluorothionocarboxylates (Method A, Table 2). In
literature the preparation of O-methyl ester is described by
treatment of 1b with an excess of methanol [15]. We have found
that chloride 1b readily reacts under similar conditions with
isopropanol as a model secondary alcohol to give the correspond-
ing thionoester (4a) in 78% of yield. The reactions of chlorides 1a,b
4b
4c
CF3
Method A, benzene, 4 days
Method A, benzene, 4 days
50
40
H(CF2)2
4d
4e
CF3
Method B
Method B
73
70
H(CF2)2
Table 1
Synthesis of dithioesters 3a–i.
4f
H(CF2)2
Method B
22
.
Ester
Rf
Mercaptane 2
Reaction
conditionsa
Yield (%)
(R*SH)
3a
3b
CF3
CHCl3, 2 h
82
75
H(CF2)2
CHCl3, 7 days
with (1R,2S,5R)-menthol have proceeded in benzene solution for 4
days, after purification by chromatography the target O-menthyl
esters (4b,c) were isolated in 40–50% yields. But our efforts to carry
out the reaction of (1S)-borneol with chloride 1b were unsuccess-
ful. At room temperature no reaction has been observed in benzene
or chloroform after 1 week; heating the reaction mixture was
accompanied by decomposition, what follows from 19F NMR
monitoring of the reaction. Attempts to replace borneol with the
corresponding trimethylsilyl derivative were also unsuccessful:
the reaction has not practically proceeded at room temperature
and provided a very low yield of the target product at heating,
probably, due to the numerous side processes. Our attempt to use a
racemic 2-methylbenzyl alcohol has failed, too. Therefore we apply
another approach to the synthesis of thionoesters, which consists
in thiolysis of iminoesters. Similar strategy was developed for the
preparation of perfluoroalkyl dithioesters [11] and trichlorothio-
noacetates [23]. Treatment of the corresponding alcohol with
trifluoroacetonitrile or tetrafluoropropionitrile (obtained by dehy-
dration of trifluoroacetamide or tetrafluoropropionamide with
P2O5, respectively) afforded iminoesters. Thiolysis of the latter
with gaseous hydrogen sulfide in presence of acetic acid has
yielded O-alkyl thionoesters 4d–f (Method B) (Table 2).
3c
CF3
CHCl3, 2 h
80
70
3d
H(CF2)2
Hexane, 2 days
3e
CF3
Hexane, 48 h
70
3f
CF3
Hexane, 7 days
Hexane, 10 days
62
60
3g
H(CF2)2
Esters 4a–e are stable yellow liquids, compound 4f decomposes
slowly even at storage in freezer.
Similarly to others known fluoroalkyl S-alkyl(aryl)thiocarbox-
ylates [7–10], dithioesters 3 readily react with symmetrical
conjugated dienes, such as 1,3-butadiene, 2,3-dimethyl-1,3-
butadiene (DMB) or cyclopentadiene giving corresponding
[2 + 4]-cycloadducts 5a–m (Table 3) as colourless or slightly
yellow oils in good to excellent yields (75–98%). Depending on
nature of the substrate and diene the cycloaddition can take a time
3h
3i
CF3
Hexane–ether, 16 h
Hexane–ether, 16 h
85
90
H(CF2)2
a
Reactions proceeded at room temperature.

174
V.M. Timoshenko et al. / Journal of Fluorine Chemistry 131 (2010) 172–183
Table 3
Diels-Alder reactions of thionoesters 3,4.
.
b
Entry
Compounds
Rf
Cycloadduct
Reaction conditionsa
Total yield (%)
Diastereomeric excess (de), %
1
2
3
5a
CF3
24 h, 20 8C
6 days, ꢀ208C
4 days, 20 8C
80
83
75
12
14
16
5b
H(CF2)2
4
5
6
7
5c
CF3
16 h, 20 8C
92
94
94
90
56
56
60
50
24 h, 20 8Cc
6 days, ꢀ208C
20 days, 20 8C
5d
H(CF2)2
8
5e
CF3
3 days, 20 8Cc
90
56
9
10
11
5f
CF3
1 h, 20 8C
16 h, ꢀ20 8C
1 min, 110 8C
95
94
90
22
34
16
12
13
5g
5h
H(CF2)2
CF3
24 h, 20 8C
24 h, 20 8Cc
98
98
8
32
14
15
5i
5j
CF3
0.5 min, 20 8C
5 min, 20 8C
90
85
38:5:52:5d
39:3:2:56d
H(CF2)2
16
17
18
5k
5l
CF3
3 days, 20 8C
6 days, ꢀ20 8C
5 days, 20 8C
98
98
85
18
16
20
H(CF2)2
19
5m
CF3
2 days, 20 8C
90
10
20
21
5n
5o
CF3
5 h, 130 8Ce
5 h, 130 8Ce
80
75
6
H(CF2)2
20
22
5p
H(CF2)2
5 h, 130 8Ce
88
–
a
In excess of diene if not mentioned other.
b
c
Determined by HPLC analyses if not mentioned other.
In benzene.
Mixture of endo/exo diastereomers, ratio was determined by the 19F NMR spectroscopy.
d
e
In a pressure tube, benzene.

V.M. Timoshenko et al. / Journal of Fluorine Chemistry 131 (2010) 172–183
175
from minutes to several days. In all cases completion of the
reaction could be easily detected by disappearance of the red
colour of dithioester. For instance, the reaction of dithioester 3h
with the conformationally rigid and more reactive cyclopentadiene
at room temperature has completed in a few minutes, whereas it
has taken up to 24 h for the same reaction with butadiene; the rate
of the reaction with DMB is intermediate (Table 3, entries 9, 13, 14).
Another noteworthy observation is that trifluodithioacetates are
generally more reactive than tetrafluorodithiopropionates. All
dihydrothiopyrans 5a–h,k,l are stable compounds, in contrast to
cyclopentadiene-based cycloadducts 5i,j. The red colour observed
at heating the compounds 5i,j above 40 8C indicates the retro-
Diels-Alder process yielding the starting dithioester.
(entries 4–8) with dienes, yielding 2-polyfluoroalkyl-2-(S-neo-
menthyl)-3,6-dihydro-2H-thiopyrans 5c–e as mixture of diaster-
eomers in excellent total yields and 50–60% de.
As the thia-Diels-Alder cycloaddition can be reversible, the
formed de should be controlled both kinetically and thermody-
namically. In the latter case, a thermodynamically more stable
adduct would prevail in the mixture. The kinetically controlled
formation of the adducts can proceed via two structurally different
transition states, which in turn differ by their free activation
energies. This might provide a more rapid formation of one of the
diastereomeric adducts, connected with the lower activation
energy barrier, resulting in formation of an unequal mixture of
diastereomeric adducts.
Cycloadducts 5i,j were obtained as mixtures of four stereo-
isomers – pair of endo/exo isomers and pair of diastereomers – with
predominance of one type of selectivity (entries 14 and 15), but the
NMR analysis of the mixtures did not allow to determine the
stereochemistry of major and minor isomers.
This aspect we have investigated in detail using quantum
chemistry (DFT) calculations. The thia-Diels-Alder cycloaddition of
thiocarbonyl compounds with butadiene was previously studied
using Hartree–Fock, MP2, MP4 and DFT (B3LYP) levels of
approximation [24]. Results obtained using B3LYP method and
modest 6-31G* basis sets were comparable with those calculated
at the more superior MP4 level of theory. According to these
calculations, the reaction proceeded with concerted cleavage of the
In contrast to dithioesters 3, thionoesters 4 are much less
reactive toward dienes. O-Isopropyl ester 4a, chosen as the model
compound to establish and optimize the conditions for cycloaddi-
tion, did not react with excess of DMB at room temperature even
for several weeks. Attempts to accelerate the reaction with
addition of such catalysts as Cu(OTf)2, BF3ꢁEt2O, Ti(OPr-i)4, ZnCl2
in different solvents have had no effect, too. The reaction has not
proceed or led to the decomposition of the substrate. Cycloaddition
has occurred only at elevated temperature in a pressure tube.
Heating a mixture of 4a with an excess of DMB in benzene at 130 8C
for 5 h has provided adduct 5p in 88% yield after purification with
column chromatography (Table 3, entry 22). Similar conditions we
have applied to other O-alkyl thionoesters synthesized. Holding
the mixture of bornyl esters 4d,e with DMB in benzene at 130 8C for
5 h has given dihydrothiopyrans 5n,o in good yields (Table 3,
entries 20 and 21). At the same time no desired cycloadduct has
been obtained with 2-methylbenzyl derivative 4f, due to low
thermal stability of the starting ester. The thermal reactions of O-
menthyl esters 4b,c with DMB proceed with considerable tarring
and yield complex mixtures of products containing only small
amounts of the target cycloadducts.
C55S
time, for definite thiono-derivatives, e.g., thiono-analogues of
Meldrum’s acid, malonic acid and other -dioxothiones, a step-
p-bond and building two C–C and C–S s-bonds. At the same
a,a
wise mechanism was predicted via thiiranium zwitterionic
intermediate [25].
We have studied the asymmetric induction theoretically using
the DFT (B3LYP/6-31G**) level of approximation on example of the
cycloaddition of DMB with dithioester 3f. In order to find the
conformations with the lowest total energies
conformers have been analyzed. Thermodynamic characteristics
E1 and G1) for reaction (1), calculated for the most favoured
a variety of
(D
D
conformations of starting material and products are collected in
Table 4. Our calculations indicate the exothermic character of the
reaction relative to s-trans-DMB, which is in line with the
experimentally observed equilibrium shift towards adduct 5c.
s-trans-DMB þ 3f ! 5c þ
D
E1ð
D
G1Þ
(1)
All dihydrothiopyran derivatives 5, as follows from NMR and
GC/MS data, arise as mixtures of two diastereomers, but they
cannot be separated with column chromatography. The observed
diastereomeric excess (de) has not practically changed when
reactions are carried out without solvent or in solution (benzene,
chloroform) or/and at use of catalysts (BF3ꢁEt2O, Cu(OTf)2, Ti(OPr-
i)4, ZnCl2). Therefore, the variation of steric and electronic factors
affects the cycloaddition diastereoselectivity.
A significantly reduced exothermicity observed from
D
E1 to
D
G1 values is referred to the corresponding entropy contribution to
the
DG values by forming an adduct from two isolated molecules.
The conformations of cycloadducts with the equatorial orientation
of the sulfur-containing substituent in the neomenthyl moiety
(NM) are approximately 1.7–1.8 kcal/mol less stable than those
with the axial position of this substituent (5cA–5cD, Fig. 2).
The differences in total energies calculated for adducts 5cA-(R)
and 5cB-(S) with the axial position of the CF3 group in the
thiopyran ring and 5cC-(R) and 5cD-(S) with CF3 group in the
equatorial position lie in the range of only about 0.4–0.5 kcal/mol
(Table 4, DDE to DDG values). For the most favourable (R)- and (S)-
adducts, 5cC and 5cD, the difference in DDG values is only
0.35 kcal/mol (see Table 4). We have carried out geometry re-
optimization for the most favourable structures 5cC and 5cD using
the larger basis 6-311G** basis sets and additionally performed
single-point energy calculations using the Dunning’s cc-pVTZ basis
sets (Table 5). In all cases a low influence of the asymmetric centre
configuration (atom C-1 in NM) on the thermodynamic stability of
the diastereomeric cycloadducts is obvious. Thus, it is not probably
responsible for the experimentally observed diastereomeric
excess.
The results summarized in Table
3 show that all the
thionoesters 3,4 demonstrate some extent of asymmetric induc-
tion. From the data listed in Table 3 it is seen that for all types of
thionoesters lengthening of the polyfluoroalkyl substituent from
CF3 to HCF2CF2 provides only modest differences in de. Changing
the heteroatom nature at the dienophilic thiocarbonyl group does
not affect significantly the diastereoselectivity of the cycloaddi-
tion: the similar low de values were found for S-bornyl and O-
bornyl cycloadducts 5m and n (entries 19 and 20). These
observations make it possible to conclude that for stereochemical
outcome of cycloaddition the nature of fluoroalkyl group and the
heteroatom are of less importance. The comparable values of de
have been observed for the camphoryl (5a), thioisobornyl (5k) and
thiobornyl (5m) adducts (entries 1, 16 and 19), which is an
evidence of the insignificant influence of a bulk substituent at the
thiolic sulfur in this series. Somewhat better selectivity has been
observed for S-phenylethyl cycloadduct 5f (entry 9), but these
changes are rather minor, too. The highest diastereoselectivity has
been observed in reactions of S-neomenthyl dithioesters 3f,g
More likely, the observed effect can be determined by transition
state structures (TS), preceding formation of diastereomers 5c. The
product which corresponds to the transition state with lower
activation energy, will arise in excess. The calculated equilibrium
TS structures with endo- (6A and 6B) and exo-orientation of the CF3

176
V.M. Timoshenko et al. / Journal of Fluorine Chemistry 131 (2010) 172–183
Table 4
Total energy values (E), Zero Point Energy (ZPE) and Thermal Correction to Gibbs Free Energy (TCGFE) correction values, corrected energy magnitudes (E + ZPE and E + TCGFB),
lowest vibration frequencies ( ), reaction energies (
1 and G1) and corresponding activation energies ( TS and TS), and relative energies (DDE and DDG) for different
n
DE
D
DE
DG
conformations of 5c and transition states 6.
Structure Substituent R/Sa E (a.u.)
ZPE (a.u.) E + ZPE (a.u.)
n
D
E
DD
E
TCGFB
E + TCGFB
D
G
DDG
position
(cmꢀ1
)
(kcal/mol) (kcal/mol) a.u.)
(a.u.)
(kcal/mol) (kcal/mol)
5cA
5cB
5cC
5cD
6A
CF3 ax
R
S
R
S
ꢀ1799.332099 0.443670 ꢀ1798.888429
ꢀ1799.331945 0.443765 ꢀ1798.888180
ꢀ1799.332498 0.443700 ꢀ1798.888798
ꢀ1799.331624 0.443648 ꢀ1798.887976
16.9 ꢀ17.94b
18.1 ꢀ17.78b
12.8 ꢀ18.17b
12.8 ꢀ17.65b
0.23
0.39
0.00
0.52
0.00
0.51
0.78
1.49
0.388128 ꢀ1798.943971 ꢀ3.14b
0.388484 ꢀ1798.943461 ꢀ2.82b
0.388278 ꢀ1798.944220 ꢀ3.30b
0.387970 ꢀ1798.943654 ꢀ2.95b
0.382210 ꢀ1798.890786 27.30d
0.382768 ꢀ1798.889408 28.16d
0.383083 ꢀ1798.888798 28.54d
0.382747 ꢀ1798.887840 29.14d
0.16
0.48
0.00
0.35
0.00
0.86
1.25
1.85
CF3 ax
CF3 eq
CF3 eq
CF3 endo
CF3 endo
CF3 exo
CF3 exo
[R]c ꢀ1799.272996 0.439656 ꢀ1798.833397 ꢀ352.3
[S]c ꢀ1799.272176 0.439599 ꢀ1798.832577 ꢀ315.6
[R]c ꢀ1799.271881 0.439732 ꢀ1798.832149 ꢀ310.0
[S]c ꢀ1799.270587 0.439565 ꢀ1798.831022 ꢀ264.9
14.47d
14.99d
15.26d
15.96d
6B
6C
6D
a
Configuration of the C-20 asymmetric centre in thiopyran moiety.
b
c
Reaction (1) energy (
Configuration resulting from the transition state.
ETS and TS) calculated for reaction (1).
Activation energy (D DG
D D
E1 or G1).
d
group (6C and 6D) are shown in Fig. 3. 6A and 6B indicate similar
C–C and C–S distances whereas for 6C and 6D C–S distances have
been found to be significantly shorter than C–C ranges. At first
glance, this fact could predict the C–S bonded stable intermediate
as a minimum at the potential energy surface. However, this is not
a case and corresponding structures can be located neither directly
nor scanning the corresponding intrinsic reaction coordinates.
Thus, the concerted mechanism of the Diels-Alder cycloaddition,
i.e. the formation of the C–C and C–S
cyclization process, has been postulated basing on the calculation
data obtained.
The total energies calculated for 6C and 6D, where sterically
more demanding S-neomenthyl moiety is exo-oriented, are higher
than those found for 6A and 6B, with endo-position of this
substituent. Thus, only the former transition state structures play a
role in the course of reaction. In turn, 6B, preceding the (S)-adduct,
s
-bonds during the single
Fig. 2. Calculated (B3LYP/6-31G**) equilibrium Diels-Alder adducts with equatorial (5cA and 5cB) and axial equatorial (5cC and 5cD) position of the CF3 group corresponding
to the lowest total energies. (R) and (S) correspond to the configuration at the C-20 asymmetric centre of thiopyran moiety.

V.M. Timoshenko et al. / Journal of Fluorine Chemistry 131 (2010) 172–183
177
Table 5
Total energy values (E), Zero Point Energy (ZPE) correction values, corrected energy magnitudes (E + ZPE), lowest vibration frequencies (
corresponding activation energies (
ETS and TS), and relative energies (DDE) for different conformations of 5c and transition states 6.
n
), reaction (1) energies (
D
E1), and
D
DG
Structure
B3LYP/6-311G**
B3LYP/cc-pVTZ//B3LYP/6-311G**
E (a.u.)
E + ZPE (a.u.)
n
(cmꢀ1
)
DE (kcal/mol)
DDE (kcal/mol)
E (a.u.)
D
Ea (kcal/mol)
DDEa (kcal/mol)
5cA
5cB
5cC
5cD
6A
ꢀ1799.618442
ꢀ1799.618185
ꢀ1799.619499
ꢀ1799.618795
ꢀ1799.562230
ꢀ1799.560903
ꢀ1799.560742
ꢀ1799.559543
ꢀ1799.177587
ꢀ1799.177194
ꢀ1799.178411
ꢀ1799.177849
ꢀ1799.125392
ꢀ1799.124222
ꢀ1799.123830
ꢀ1799.122859
5.8
15.2
17.4
11.8
ꢀ14.55b
ꢀ14.30b
ꢀ15.06b
ꢀ14.71b
16.32c
0.52
0.76
0.00
0.35
0.00
0.73
0.98
1.59
ꢀ1799.728190
ꢀ1799.727415
ꢀ1799.729414
ꢀ1799.728528
ꢀ1799.672901
ꢀ1799.671658
ꢀ1799.671535
ꢀ1799.670061
ꢀ14.02b
ꢀ13.54b
ꢀ14.79b
ꢀ14.24b
18.22c
0.77
1.25
0.00
0.56
0.00
0.78
0.86
1.78
ꢀ319.5
ꢀ350.8
ꢀ315.2
ꢀ273.4
6B
17.06c
19.00c
6C
17.30c
17.91c
19.08c
20.01c
6D
a
Calculated using uncorrected E values.
b
c
Reaction (1) energy (
Activation energy (
D
E1).
E
TS) for reaction (1).
D
possesses the higher activation energy values,
those for 6A (DDE = 0.51 kcal/mol; DDG = 0.86 kcal/mol). Re-
D
E
TS and
D
G
TS, than
experimentally observed diastereomeric excess. In general, the
authors want to emphasize that the calculated activation energy
optimization of the structures using larger (6-311G**) basis sets
values (DE DG
TS and TS) as those should be taken up with care, due
yields similar
D
ETS and DDE values (Table 5). Probably, the
to the rather low level of approximation used for calculations. But
the constant contributions of inaccuracies of the B3LYP method
and restricted basis sets may be partially cancelled out going to the
difference found in the activation energies can cause preferable
formation of the (R)-adduct which in turn determines the
Fig. 3. Calculated (B3LYP/6-31G**) transition state structures for the Diels-Alder cycloaddition with exo-(6A and 6B) and endo-position of the CF3 group (6C and 6D)
˚
corresponding to the lowest total energies. The C–C and C–S distances (A) connected with the intrinsic reaction coordinate (in parentheses distances calculated at the B3LYP/
6-311G** level of theory): 6A 2.384, 2.412 (2.408, 2.345); 6B 2.323, 2.428 (2.353, 2.362); 6C 2.435, 2.366 (2.433, 2.340); 6D 2.506, 2.360 (2.498, 2.330).

178
V.M. Timoshenko et al. / Journal of Fluorine Chemistry 131 (2010) 172–183
relative energies (DDE and DDG values), which are of importance
for the discussion of the experimental results.
removed under reduced pressure and crude dithioester was
purified by silica gel column chromatography. The less polar red
fraction was collected. Yields of dithioesters 3a–i are given in
Table 1.
In order to support this statement we have carried out the
reaction of dithioesters 3a, 3c, 3f and 3h with DMB at low
temperature, and 3h with DMB in boiling toluene. In the former
case, reaction times have significantly increased. It should be also
noted that de has not changed for compounds 3a and 3c (entries 2
and 17, Table 3) whereas it has been slightly improved for esters 3f
and 3h (entries 6 and 10). On the other hand, the de value in case of
3h clearly decreases with rising temperature (entries 9–11). These
experimental observations are in accordance with the kinetically
controlled cycloaddition resulting in the formation of diastereo-
meric excess for the adducts.
4.2.1. [(1S)-7,7-Dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl
trifluoroethanedithioate (3a)
Red liquid, Rf 0.65 (CCl4:EtOAc, 10:1). 19F NMR (CDCl3):
d
ꢀ66.14 (s, CF3). 1H NMR (CDCl3):
d 0.94 (3H, s, CH3), 1.10 (3H, s,
CH3), 1.38–1.47 (1H, m), 1.54–1.63 (1H, m), 1.81–1.90 (1H, m), 1.94
(1H, d, J = 19.0 Hz, endo-H-3), 1.97–2.10 (1H, m), 2.18 (1H, t,
J = 4.2 Hz, H-4), 2.44 (1H, dm, J = 19.0 Hz, exo-H-3), 3.33 (1H, d,
J = 13.8 Hz, H-10), 3.53 (1H, d, J = 13.8 Hz, H-10). GC/MS (m/e): 296
(M+, 25%). Anal. Calcd for C12H15F3OS2: C, 48.63; H, 5.10; S, 21.64.
Found: C, 48.09; H, 5.12; S, 21.42.
3. Conclusion
In summary, we have shown that the nucleophilic substitution
at the thiocarbonyl group in polyfluorothioalkanoyl chlorides is a
versatile method for the preparation of the S- and O-thionocar-
boxylates. This methodology has allowed us to synthesize a series
of thionoesters with various optically active substituents which
can serve as chiral auxiliaries in asymmetric syntheses. We have
observed the first example of asymmetric induction in the thia-
Diels-Alder cycloaddition involving polyfluoroalkylthionocarbox-
ylates which have provided 2-fluoroalkyl-2-alkylsulfanyl-3,6-
dihydro-2H-thiopyrans in low to modest de (6–60%). The influence
of nature of the diene and dienophile and reaction conditions on
the asymmetric induction of cycloaddition have been examined. It
has been found that electronic factors have a minimal effect on a
stereoselectivity of the cycloaddition. Quantum chemistry (DFT)
calculations indicate that the differences in activations energies
are larger than the relative energies of the cyclic adducts at all used
levels of theory. This makes it possible to suggest that the
stereoselectivity found for the formation of thiopyranes is
kinetically driven: the observed de is referred to the slightly
different activation free energies inherent to the corresponding
transition states. This conclusion is in line with the experimentally
found dependence of de on temperature.
4.2.2. [(1S)-7,7-Dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl
2,2,3,3-tetrafluoropropanedithioate (3b)
Red liquid, Rf 0.70 (CCl4:EtOAc, 10:1). 19F NMR (CDCl3):
d
ꢀ112.33 (AB, J = 264.0 Hz, CF2), ꢀ138.48 (2F, dm, J = 52.8 Hz,
HCF2). 1H NMR (CDCl3):
d
0.97 (3H, s, CH3), 1.09 (3H, s, CH3), 1.38–
1.46 (1H, m), 1.53–1.62 (1H, m), 1.81–1.91 (1H, m), 1.94 (1H, d,
J = 19.0 Hz, endo-H-3), 1.97–2.10 (1H, m), 2.17 (1H, t, J = 4.2 Hz),
2.44 (1H, dt, J = 18.6 Hz, exo-H-3), 3.33 (1H, d, J = 13.8 Hz, H-10),
3.53 (1H, d, J = 13.8 Hz, H-10), 6.31 (1H, tt, J = 52.8, 5.3 Hz, HCF2).
13C NMR (CDCl3):
d 19.76 (CH3), 20.13 (CH3), 26.73 (CH2), 26.84
(CH2), 32.92 (t, J = 2.1 Hz, C-10), 42.93 (C-3), 43.61 (C-4), 48.36 (C-
7), 60.65 (C-1), 109.89 (tt, J = 254.0, 33.0 Hz, HCF2), 112.93 (tt,
J = 259.0, 27.0 Hz, CF2), 216.30 (C55O), 218.24 (t, J = 24.0 Hz, C55S).
GC/MS (m/e): 328 (M+, 22%). Anal. Calcd for C13H16F4OS2: C, 47.55;
H, 4.91; S, 19.53. Found: C, 47.57; H, 5.16; S, 19.39.
4.2.3. (1S)-Exo-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl
trifluoroethanedithioate (3c)
Red liquid, Rf 0.70 (hexane). 19F NMR (CDCl3):
d
ꢀ65.68 (s, CF3).
1H NMR (CDCl3):
d 0.88 (3H, s, CH3), 0.92 (3H, s, CH3), 0.93 (3H, s,
CH3), 0.99–1.34 (3H, m), 1.47–1.83 (3H, m), 2.03 (1H, m), 4.12 (1H,
dd, J = 9.0, 5.2 Hz, endo-H-2). GC/MS (m/e): 282 (M+, 29%). Anal.
Calcd for C12H17F3S2: C, 51.04; H, 6.07; S, 22.71. Found: C, 51.10; H,
6.09; S, 22.56.
4. Experimental
4.1. General
4.2.4. (1S)-Exo-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 2,2,3,3-
tetrafluoropropanedithioate (3d)
19F NMR spectra (188.14 MHz) were recorded on a Varian
Red liquid, Rf 0.75 (hexane). 19F NMR (CDCl3):
d
ꢀ111.76 (AB,
Gemini-200 spectrometer with C6F6
(
d
F = ꢀ162.9 ppm relative to
J = 259.6 Hz, CF2), ꢀ138.66 (2F, dm, J = 53.7 Hz, HCF2). 1H NMR
CFCl3) as internal standard. 1H NMR (299.94 MHz) spectra were
obtained on a Varian VXR-300 spectrometer, 13C NMR, APT, COSY,
(CDCl3): d 0.88 (3H, s, CH3), 0.91 (3H, s, CH3), 0.94 (3H, s, CH3), 0.99–
1.34 (2H, m), 1.47–1.83 (3H, m), 2.07 (1H, m), 4.16 (1H, dd, J = 9.3,
5.0 Hz, endo-H-2), 6.31 (1H, tt, J = 53.7, 5.7 Hz, HCF2). GC/MS (m/e):
314 (M+, 28%). Anal. Calcd for C13H18F4S2: C, 49.66; H, 5.77; S,
20.40. Found: C, 49.69; H, 5.78; S, 20.21.
HETCOR spectra were obtained on
a Bruker Avance 400
spectrometer (100.62 MHz for 13C and 400.13 MHz for 1H) in
CDCl3 solutions with Me4Si as internal standard. Silica gel Merck 60
(40–63
mm) was used for chromatography. Thin-layer chroma-
tography using precoated plastic plates (Polygram1 Sil G/UV254)
were visualised by UV light or by an I2 vapour. Diastereomeric ratio
of cycloadducts 5 was determined by HPLC analysis on the Agilent
1100 instrument (UV, detection wavelength: 215 nm) on Zorbax
4.2.5. (1S)-Endo-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl
trifluoroethanedithioate (3e)
Red liquid, Rf 0.70 (hexane). 19F NMR (CDCl3):
d
ꢀ66.05 (s, CF3).
1H NMR (CDCl3):
d 0.91 (3H, s, CH3), 0.93 (3H, s, CH3), 0.99 (3H, s,
Eclipse XDB-C18 column (4.6 mm ꢂ 250 mm, 5
m
m) using MeCN–
CH3), 1.12 (1H, dd, J = 13.9, 4.4 Hz, endo-H-3), 1.19–1.32 (1H, m, H-
5), 1.47–1.72 (3H, m, H-5,6), 1.73–1.91 (2H, m, H-4,6), 2.66 (1H,
ddd, J = 13.9, 11.0, 4.0 Hz, exo-H-3), 4.09 (1H, dt, J = 11.0, 4.0 Hz,
exo-H-2). GC/MS (m/e): 282 (M+, 32%). Anal. Calcd for C12H17F3S2:
C, 51.04; H, 6.07; S, 22.71. Found: C, 51.09; H, 6.09; S, 22.50.
H2O or MeOH–H2O as mobile phases (1 ml/min) at 25 8C. MS data
were obtained on the Hewlett-Packard 5890\5972 apparatus (GC/
MS) at 70 eV in the electron impact mode.
4.2. Synthesis of dithioesters 3 (Table 1). Common procedure
4.2.6. (1S,2S,5R)-2-Isopropyl-5-methylcyclohexyl
A solution of corresponding thiole (10 mmol) in inert solvent
(10 ml) was treated with excess chloride 1 (11 mmol) at room
temperature. The reaction was monitored by 19F NMR spectrosco-
py. After the reaction time indicated in Table 1, the solvent was
trifluoroethanedithioate (3f)
Red liquid, Rf 0.75 (hexane). 19F NMR (CDCl3):
d
ꢀ66.15 (s, CF3).
0.69 (3H, d, J = 6.6 Hz, CH3), 0.89 (3H, d,
J = 6.3 Hz, CH3), 0.93 (3H, d, J = 6.9 Hz, CH3), 1.00–1.46 (6H, m),
1H NMR (CDCl3):
d

V.M. Timoshenko et al. / Journal of Fluorine Chemistry 131 (2010) 172–183
179
1.61–2.03 (3H, m), 4.48 (1H, m, CH–S). GC/MS (m/e): 284 (M+, 19%).
4.3.2. Method B. From iminoesters. General procedure
Anal. Calcd for C12H19F3S2: C, 50.68; H, 6.73; S, 22.55. Found: C,
50.72; H, 6.77; S, 22.38.
4.3.2.1. O-[(1S)-1,7,7-Trimethylbicyclo[2.2.1]hept-2-yl]-trifluoro-
ethanethioate (4d). NaH (10 mg, 60% in mineral oil, 0.25 mmol)
was added in one portion under argon to a solution of (1S)-borneol
(3.08 g, 20 mmol) in anhydrous THF (8 ml). The resulting suspen-
sion was stirred at r.t. for 5 min to completion of hydrogen
evolution and then cooled down to 0 8C. The gaseous CF3CN,
generated at heating of trifluoroacetamide (2.5 g, 22 mmol) with
P2O5 (3.2 g, 22 mmol), was passed into mixture and it was allowed
to stirr at r.t. for 8 h. A mixture was acidified with 0.02 ml of AcOH
and evaporated to give in a residue a heavy oil of iminoester which
was analysed by 1H NMR spectroscopy and used in the next step
without purification. The crude iminoester was dissolved in
mixture of THF (5 ml) and AcOH (5 ml) at stirring and dry H2S
was passed through solution at ꢀ5 to 0 8C to complete absorbtion.
The reaction mixture was allowed to stir at r.t. for 10 h, volatile
products were removed in vacuum (10–15 mmHg) and the residue
was submitted to column chromatography over silica gel with
hexane as eluent to give 3.84 g (73%) of thionoester 4d. Yellow
4.2.7. (1S,2S,5R)-2-Isopropyl-5-methylcyclohexyl 2,2,3,3-
tetrafluoropropanedithioate (3g)
Red liquid, Rf 0.80 (hexane). 19F NMR (CDCl3):
d
ꢀ109.93 (1F, AB,
J = 261.0 Hz, CF2), ꢀ113.93 (1F, AB, J = 261.0 Hz, CF2), ꢀ138.67 (2F,
dm, J = 53.1 Hz, HCF2). 1H NMR (CDCl3):
0.68 (3H, d, J = 6.9 Hz,
d
CH3), 0.89 (3H, d, J = 6.6 Hz, CH3), 0.93 (3H, d, J = 6.3 Hz, CH3), 1.00–
1.15 (2H, m), 1.25–1.59 (4H, m), 1.83 (1H, dm, J = 15 Hz), 1.89–2.03
(2H, m), 4.51 (1H, m, CH–S), 6.31 (1H, tt, J = 53.1, 4.5 Hz, HCF2). GC/
MS (m/e): 316 (M+, 18%). Anal. Calcd for C13H20F4S2: C, 49.35; H,
6.37; S, 20.27. Found: C, 49.39; H, 6.40; S, 20.02.
4.2.8. 1-Phenylethyl trifluoroethanedithioate (3h)
Red liquid, Rf 0.35 (hexane). 19F NMR (CDCl3):
d
ꢀ66.19 (s, CF3).
1H NMR (CDCl3):
d 1.76 (3H, d, J = 7.2 Hz, CH3), 5.03 (1H, q,
J = 7.2 Hz, CH–S), 7.29–7.37 (5H, m, C6H5). GC/MS (m/e): 250 (M+,
23%). Anal. Calcd for C10H9F3S2: C, 47.98; H, 3.62; S, 25.62. Found:
C, 48.00; H, 3.64; S, 25.40.
liquid, Rf 0.65. 19F NMR (CDCl3):
d
ꢀ72.31 (s, CF3). 1H NMR (CDCl3):
d
0.91 (3H, s, CH3), 0.92 (3H, s, CH3), 0.94 (3H, s, CH3), 1.02 (1H, dd,
J = 14.0, 3.4 Hz, endo-H-3), 1.23–1.31 (1H, m, H-5), 1.39–1.48 (1H,
m, H-6), 1.78–1.86 (2H, m, H-5,6), 1.98–2.05 (1H, m, H-4), 2.49 (1H,
ddd, J = 14.0, 9.9, 3.0 Hz, exo-H-3), 5.36 (1H, dt, J = 9.9, 3.0 Hz, exo-
H-2). GC/MS (m/e): 266 (M+, 29%). Anal. Calcd for C12H17F3OS: C,
54.12; H, 6.43; S, 12.04. Found: C, 54.14; H, 6.47; S, 11.89.
4.2.9. 1-Phenylethyl 2,2,3,3-tetrafluoropropanedithioate (3i)
Red liquid, Rf 0.40 (hexane). 19F NMR (CDCl3):
d
ꢀ112.40 (2F, m,
CF2), ꢀ138.60 (2F, dm, J = 53.1 Hz, HCF2). 1H NMR (CDCl3):
d 1.76
(3H, d, J = 7.2 Hz, CH3), 5.05 (1H, q, J = 7.2 Hz, CH–S), 6.27 (1H, tt,
J = 53.1, 5.1 Hz, HCF2), 7.29–7.36 (5H, m, C6H5). GC/MS (m/e): 282
(M+, 18%). Anal. Calcd for C11H10F4S2: C, 46.80; H, 3.57; S, 22.72.
Found: C, 46.81; H, 3.57; S, 22.60.
4.3.2.2. O-[(1S)-1,7,7-Trimethylbicyclo[2.2.1]hept-2-yl]-2,2,3,3-tet-
rafluoropropanethioate (4e). According to procedure described for
4d, from 3.08 g (20 mmol) of (1S)-borneol the thionoester 4e (4.30 g,
70%) was obtained as yellow liquid, Rf 0.55 (hexane). 19FNMR(CDCl3):
4.3. Synthesis of thionoesters 4 (Table 2)
d
ꢀ116.99 (2F, m, CF2), ꢀ137.62 (2F, dm, J = 53.1 Hz, HCF2). 1H NMR
4.3.1. Method A. From chlorides 1a,b
(CDCl3):d0.90 (3H, s, CH3), 0.92(3H, s, CH3),0.94(3H,s,CH3), 1.03 (1H,
Common procedure as for synthesis of dithioesters was
employed. Reaction conditions are displayed in Table 2. Purifica-
tion by distillation (for 4a) or with column chromatography (for
4b,c).
dd, J = 14.0, 3.4 Hz, endo-H-3), 1.06–1.31 (1H, m, H-5), 1.39–1.50 (1H,
m, H-6), 1.77–1.86 (2H, m, H-5,6), 1.94–2.03 (1H, m, H-4), 2.44–2.55
(1H, ddd, J = 14.0, 9.5, 4.0 Hz, exo-H-3), 5.39 (1H, dt, J = 9.5, 2.8 Hz, exo-
H-2), 6.13 (1H, tt, J = 53.1, 4.8 Hz, HCF2). 13C NMR (CDCl3):
d 13.52,
19.00, 19.68 (CH3), 27.59 (C-5), 27.87 (C-6), 36.19 (C-3), 44.95 (C-4),
48.17 (C-7), 49.65 (C-1), 90.97 (C-2), 109.56 (tt, J = 255.0, 27.6 Hz,
CF2), 109.66 (tt, J = 251.0, 35.5 Hz, HCF2), 200.53 (t, J = 28.0 Hz, C55S).
GC/MS (m/e): 298 (M+, 28%). Anal. Calcd for C13H18F4OS: C, 52.34; H,
6.08; S, 10.75. Found: C, 52.38; H, 6.10; S, 10.50.
4.3.1.1. O-Isopropyl 2,2,3,3-tetrafluoropropanethioate (4a). Yellow
liquid, bp 130–131 8C. 19F NMR (CDCl3):
d
ꢀ117.35 (2F, dt, J = 8.5,
5.0 Hz, CF2), ꢀ138.05 (2F, dt, J = 53.0, 8.5 Hz, CF2H). 1H NMR
(CDCl3):
d 1.43 (3H, d, J = 6.2 Hz, CH3), 5.69 (1H, septet, J = 6.2 Hz,
CH), 6.14 (1H, tt, J = 53.0, 5.0 Hz, HCF2). 13C NMR (CDCl3):
d 20.75
(CH3), 78.38 (CH–O), 109.34 (tt, J = 258.0, 28.2 Hz, CF2), 109.54 (tt,
J = 252.0, 35.7 Hz, HCF2), 199.82 (t, J = 28.0 Hz, C55S). GC/MS (m/e):
204 (M+, 10%). Anal. Calcd for C6H8F4OS: C, 35.29; H, 3.95; S, 15.70.
Found: C, 35.30; H, 3.98; S, 15.50.
4.3.2.3. O-(1-Phenylethyl) 2,2,3,3-tetrafluoropropanethioate (4f). It
was obtained according to procedure described for 4d. Yellow
liquid, Rf 0.40 (hexane). 19F NMR (CDCl3):
d
ꢀ117.14 (2F, m, CF2),
ꢀ137.83 (2F, dm, J = 53.1 Hz, CF2H). 1H NMR (CDCl3):
d 1.73 (3H, d,
J = 6.8 Hz, CH3), 6.14 (1H, tt, J = 53.1, 4.8 Hz, HCF2), 6.49 (1H, q,
J = 6.8 Hz, CH–O), 7.28–7.44 (5H, m, C6H5). GC/MS (m/e): 266 (M+,
30%). Anal. Calcd for C11H10F4OS: C, 49.62; H, 3.79; S, 12.04. Found:
C, 49.68; H, 3.83; S, 11.89.
4.3.1.2. O-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl]-trifluoro-
ethanethioate (4b). Yellow liquid, Rf 0.55 (hexane). 19F NMR
(CDCl3):
d
ꢀ72.62 (s, CF3). 1H NMR (CDCl3):
d 0.77 (3H, d,
J = 6.9 Hz, CH3), 0.92 (3H, d, J = 7.2 Hz, CH3), 0.95 (3H, d, J = 6.9 Hz,
CH3), 1.00–1.22 (3H, m), 1.42–1.64 (1H, m), 1.65–1.95 (4H, m), 2.17
(1H, dm, J = 11.7 Hz), 5.37 (1H, m, CH-O). GC/MS (m/e): 268 (M+,
15%). Anal. Calcd for C12H19F3OS: C, 53.71; H, 7.14; S, 11.95. Found:
C, 53.78; H, 7.18; S, 11.70.
4.4. Cycloadducts 5a–m (Table 3). Common procedure
Dithioester 3a–i (1 mmol) and excess (2 mmol) of DMB or
cyclopentadiene (for cycloadducts 5i,j) were allowed to react at the
temperature and for the time indicated in Table 3 until red colour
of the reaction mixture disappeared. For cycloadducts 5e,h the
dithioester (1 mmol) was added to a solution of 1,3-butadiene
(0.16 g, 3 mmol) in 5 ml of benzene and the reaction flask was
sealed. After reaction was finished volatile products were removed
in vacuum (0.03–0.05 mmHg) and the crude cycloadduct was
analysed by HPLC and NMR spectroscopy to determine the isomers
ratio. Additional purification was performed in case of need with
column chromatography over silica gel.
4.3.1.3. O-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl]-2,2,3,3-tet-
rafluoropropanethioate (4c). Yellow liquid, Rf 0.65 (hexane). 19F
NMR (CDCl3):
d
ꢀ116.58 (2F, AB, J = 266.0 Hz, CF2), ꢀ137.38 (2F,
dm, J = 53.2 Hz, CF2H). 1H NMR (CDCl3):
d
0.75 (3H, d, J = 6.9 Hz,
CH3), 0.92 (3H, d, J = 7.1 Hz, CH3), 0.95 (3H, d, J = 6.9 Hz, CH3), 0.99–
1.21 (3H, m), 1.45–1.62 (1H, m), 1.64–1.91 (4H, m), 2.16 (1H, dm,
J = 9.6 Hz), 5.42 (1H, m, CH-O), 6.14 (1H, tt, J = 53.2, 5.0 Hz, HCF2).
GC/MS (m/e): 300 (M+, 17%). Anal. Calcd for C13H20F4OS: C, 51.98;
H, 6.71; S, 10.68. Found: C, 52.01; H, 6.73; S, 10.49.

180
V.M. Timoshenko et al. / Journal of Fluorine Chemistry 131 (2010) 172–183
4.4.1. (1S)-1-({[4,5-Dimethyl-2-trifluoromethyl-3,6-dihydro-2H-
thiopyran-2-yl]thio}methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-one
(5a)
Colourless solid, yield 80%. Rf 0.60–0.65 (CCl4:EtOAc, 10:1),
mp 40–48 8C, mixture of isomers in the ratio 44:56 from HPLC,
solvent MeCN:H2O (85:15), tr 15.8 (minor) and 16.4 (major) min.
19F NMR (CDCl3) (here and further in the text the signals of
4.4.3. 2-{[(1S,2S,5R)-2-Isopropyl-5-methylcyclohexyl]thio}-4,5-
dimethyl-2-trifluoromethyl-3,6-dihydro-2H-thiopyran (5c)
Colourless oil, yield 92%. Rf 0.65–0.70 (CCl4), mixture of isomers
in the ratio 22:78 from HPLC, solvent MeCN:H2O (92:8), tr 26.4
(minor) and 28.6 (major) min. 19F NMR (CDCl3):
d
ꢀ73.51 (s, CF3),
ꢀ73.62* (s, CF3). 1H NMR (CDCl3):
d 0.83–1.02 (d, 3CH3 of both
isomers), 1.04–1.29 (m, 4H of both isomers), 1.55–2.17 (m, 4H of
both isomers), 1.75 (s, CH3 of both isomers), 1.78 (s, CH3 of both
isomers), 2.38 (d, J = 16.6 Hz, H-30 of both isomers), 2.70* (d,
J = 16.6 Hz, H-30), 2.76 (d, J = 16.6 Hz, H-30), 3.02 (d, J = 15.8 Hz, H-
60), 3.06* (d, J = 15.8 Hz, H-60), 3.26* (d, J = 15.8 Hz, H-60), 3.33 (d,
J = 15.8 Hz, H-60), 3.48* (m, H-1), 3.54 (m, H-1). GC/MS (m/e): 366
(M+, 2%), 194 (M+–C10H20S, 89%), 179 (60%), 138 (C10H18+, 40%).
Anal. Calcd for C18H29F3S2: C, 58.98; H, 7.97; S, 17.50. Found: C,
56.01; H, 7.99; S, 17.32.
major isomer are marked with asterisk):
d
ꢀ73.81 (s, CF3),
ꢀ79.19 (s, CF3). 1H NMR (CDCl3):
d 0.90* (s, CH3), 0.93 (s, CH3),
1.04* (s, CH3), 1.06 (s, CH3), 1.34–1.41 (m, 1H of both isomers),
1.52–1.64 (m, 1H of both isomers), 1.69 (s, CH3), 1.70* (s, CH3),
1.76 (s, CH3), 1.78* (s, CH3), 1.86 (d, J = 18.5 Hz endo-H-3), 1.87*
(d, J = 18.5 Hz, endo-H-3), 1.93–2.04 (m, CH2 of both isomers),
2.07 (m, H-4 of both isomers), 2.18* (d, J = 17.7 Hz, H-30), 2.23 (d,
J = 17.7 Hz, H-30), 2.34* (m, exo-H-3), 2.40 (m, exo-H-3), 2.73 (d,
J = 12.5 Hz, H-10 of both isomers), 2.78–2.91 (m, H-30,60 of both
isomers), 2.99 (d, J = 12.5 Hz, H-10), 3.06* (d, J = 12.5 Hz, H-10),
3.37 (d, J = 16.1 Hz, H-60), 3.51* (d, J = 16.1 Hz, H-60). 13C NMR
4.4.4. 2-{[(1S,2S,5R)-2-Isopropyl-5-methylcyclohexyl]thio}-4,5-
dimethyl-2-(1,1,2,2-tetrafluoroethyl)-3,6-dihydro-2H-thiopyran (5d)
Colourless oil, yield 90%. Rf 0.72–0.78 (CCl4), mixture of isomers
in the ratio 25:75 from HPLC, solvent MeCN:H2O (92:8), tr 19.8
(CDCl3):
d 19.23, 19.30, 19.98, 20.05, 20.07, 20.08, 20.20, 20.44
(CH3 of both isomers), 26.11, 26.90, 26.96, 27.58 (C-5,6 of both
isomers), 27.86* (q, J = 2.0 Hz, C-60), 28.34 (q, J = 2.0 Hz, C-60),
29.66* (s, C-30), 29.67 (s, C-30), 37.29 (q, J = 1.5 Hz, C-10), 37.41*
(C-10), 43.15* (C-3), 43.19 (C-3), 43.38* (C-4), 43.75 (C-4),
48.08* (C-7), 48.09 (C-7), 59.41* (q, J = 27.2 Hz, C-20), 59.22 (q,
J = 27.1 Hz, C-20), 60.43* (C-1), 60.97 (C-1), 122.77, 123.05,
123.52, 123.85 (C-40,50 of both isomers), 126.85 (q, J = 281.0 Hz,
CF3), 126.93* (q, J = 281.0 Hz, CF3), 217.07 (C55O), 217.18* (C55O).
GC/MS (m/e): 378 (M+, 2%), 195 (M+–C10H15OS, 21%), 194 (M+–
(minor) and 21.6 (major) min. 19F NMR (CDCl3):
d
ꢀ109.35 (1F, AB,
J = 259.0 Hz, CF2), ꢀ113.51 (1F, AB, J = 259.0 Hz, CF2), ꢀ117.45* (1F,
AB, J = 263.0 Hz, CF2), ꢀ120.41* (1F, AB, J = 263.0 Hz, CF2),
ꢀ131.70–136.87 (2AB of both isomers, J = 299.0, 54.3 Hz, HCF2).
1H NMR (CDCl3):
d 0.84–0.96 (d, 3CH3 of both isomers), 0.98–1.23
(m, 4H of both isomers), 1.58–2.09 (m, 4H of both isomers), 1.75 (s,
CH3 of both isomers), 1.77 (s, CH3 of both isomers), 2.35 (d,
J = 17.0 Hz, H-30 of both isomers), 2.80* (d, J = 17.0 Hz, H-30), 2.83
(d, J = 17.2 Hz, H-30), 2.98 (d, J = 15.5 Hz, H-60), 3.01* (d, J = 15.5 Hz,
H-60), 3.33 (d, J = 15.5 Hz, H-60), 3.34* (d, J = 15.5 Hz, H-60), 3.41 (m,
H-1), 3.47* (m, H-1), 6.53 (tt, J = 52.6, 5.9 Hz, HCF2), 6.57* (tt,
J = 52.6, 5.9 Hz, HCF2). GC/MS (m/e): 398 (M+, 2%), 227 (M+–
C
C
10H16OS, 68%), 193 (C8H9F3S+, 20%), 179 (100%). Anal. Calcd for
18H25F3OS2: C, 57.12; H, 6.66; S, 16.94. Found: C, 57.15; H,
6.70; S, 16.75.
4.4.2. (1S)-1-({[4,5-Dimethyl-2-(1,1,2,2-tetrafluoroethyl)-3,6-
dihydro-2H-thiopyran-2-yl]thio}methyl)-7,7-
C
C
10H19S, 100%), 226 (M+–C10H20S, 81%), 211 (64%). Anal. Calcd for
19H30F4S2: C, 57.26; H, 7.59; S, 16.09. Found: C, 57.29; H, 7.61; S,
dimethylbicyclo[2.2.1]heptan-2-one (5b)
15.98.
Colourless oil, yield 75%. Rf 0.60–0.65 (CCl4:EtOAc, 10:1),
mixture of isomers in the ratio 42:58 from HPLC, solvent
MeCN:H2O (85:15), tr 23.2 (minor) and 25.6 (major) min. 19F
4.4.5. 2-{[(1S,2S,5R)-2-Isopropyl-5-methylcyclohexyl]thio}-2-
trifluoromethyl-3,6-dihydro-2H-thiopyran (5e)
NMR (CDCl3):
d
ꢀ115.73 (1F, AB, J = 266.0 Hz, CF2), ꢀ117.16* (1F,
Colourless oil, yield 90%, mixture of isomers in the ratio 22:78
from HPLC, solvent MeCN:H2O (85:15), tr 28.0 (minor) and 29.3
AB, J = 263.0 Hz, CF2), ꢀ120.41* (1F, AB, J = 263.0 Hz, CF2),
ꢀ121.26 (1F, AB, J = 266.0 Hz, CF2), ꢀ133.54 (2F, ddm,
J = 300.0, 53.3 Hz, HCF2 of both isomers), ꢀ136.21* (1F, ddm,
J = 300.0, 53.3 Hz, HCF2), ꢀ137.37 (1F, ddm, J = 300.5, 53.3 Hz,
(major) min. 19F NMR (CDCl3):
1H NMR (CDCl3):
d
ꢀ73.40* (s, CF3), ꢀ73.50 (s, CF3).
d
0.86–0.92 (d, 2CH3 of both isomers), 0.98–1.00
(d, CH3 of both isomers), 1.12–1.38 (m, 4H of both isomers), 1.65–
2.17 (m, 4H of both isomers), 2.49 (dm, J = 16.5 Hz, H-30 of both
isomers), 2.83 (dm, J = 16.5 Hz, H-30 of both isomers), 3.17 (m, H-60
of both isomers), 3.47 (m, H-1,H-60 of both isomers), 5.77, 5.93 (m,
H-50,60 of both isomers). GC/MS (m/e): 338 (M+, 2%), 167 (M+–
HCF2). 1H NMR (CDCl3):
d 0.91, 0.92, 1.03, 1.04 (s, C(CH3)2 of
both isomers), 1.36–1.43 (m, 1H of both isomers), 1.50–1.65 (m,
1H of both isomers), 1.69 (s, CH3 of both isomers), 1.76 (s, CH3),
1.77* (s, CH3), 1.85 (d, J = 18.3 Hz endo-H-3), 1.87* (d, J = 18.3 Hz,
endo-H-3), 1.93–2.03 (m, CH2 of both isomers), 2.07 (H-4 of both
isomers), 2.17* (d, J = 18.1 Hz, H-30), 2.20 (d, J = 19.1 Hz, H-30),
2.38 (dm, J = 18.3 Hz, exo-H-3 of both isomers), 2.68 (d,
J = 12.7 Hz, H-10), 2.75–2.87 (m, H-30,60,10 of both isomers),
3.01* (d, J = 12.7 Hz, H-10), 3.34* (d, J = 15.9 Hz, H-60), 3.48 (d,
J = 16.3 Hz, H-60), 6.52* (tdd, J = 53.3, 8.4, 3.5 Hz, HCF2), 6.64
C
10H19S, 63%), 138 (C10H18+, 10%). Anal. Calcd for C19H28F4S2: C,
56.77; H, 7.44; S, 18.95. Found: C, 56.80; H, 7.48; S, 18.70.
4.4.6. 4,5-Dimethyl-2-[(1-phenylethyl)thio]-2-trifluoromethyl-3,6-
dihydro-2H-thiopyran (5f)
Colourless oil, yield 95%, mixture of isomers in the ratio 39:61
from HPLC, solvent MeCN:H2O (75:25), tr 20.1 (minor) and 21.1
(tdd, J = 53.3, 9.9, 2.0 Hz, HCF2). 13C NMR (CDCl3):
d 19.25, 19.30,
19.80, 20.09, 20.17, 20.18, 20.28, 20.29 (CH3 of both isomers),
26.76, 26.92, 26.96, 27.36 (C-5 + C-6 of both isomers), 27.97*
(dd, J = 4.0, 1.4 Hz, C-60), 28.17 (d, J = 4.0 Hz, C-60), 29.08 (C-10),
29.28* (C-10), 36.88* (dt, J = 3.0, 2.0 Hz C-30), 37.00 (dt, J = 3.0,
2.5 Hz, C-30), 43.15, 43.16 (C-3 of both isomers), 43.48* (C-4),
43.58 (C-4), 48.07 (C-7), 48.25* (C-7), 59.50* (t, J = 22.0 Hz, C-20),
59.94 (t, J = 22.0 Hz, C-20), 60.42* (C-1), 60.63 (C-1), 109.58 (tm,
J = 252.0 Hz, HCF2 of both isomers), 120.48 (tm, J = 260.0 Hz, CF2
of both isomers), 122.51, 122.93, 123.66, 124.03 (C-40,50 of both
isomers), 216.91* (C55O), 217.03 (C55O). GC/MS (m/e): 410 (M+,
2%). Anal. Calcd for C19H26F4OS2: C, 55.59; H, 6.38; S, 15.62.
Found: C, 55.62; H, 6.40; S, 15.50.
(major) min. 19F NMR (CDCl3):
1H NMR (CDCl3):
d
ꢀ74.09 (s, CF3), ꢀ74.58* (s, CF3).
d
1.32 (s, CH3), 1.58 (d, J = 7.1 Hz, CH3–CH), 1.64*
(br, 2CH3–C55), 1.66* (d, J = 7.1 Hz, CH3–CH), 1.72 (s, CH3), 2.12 (d,
J = 17.8 Hz, H-30), 2.14* (d, J = 17.8 Hz, H-30), 2.58–2.98 (m, H-30 of
both isomers + 3H-60), 3.46 (1H, d, J = 16.0 Hz, H-60), 4.28 (q,
J = 7.1 Hz, CH–Me), 4.32* (q, J = 7.6 Hz, CH–CH3), 7.27 (m, C6H5 of
both isomers). 13C NMR (CDCl3):
d 19.12 (s, CH3), 19.18* (s, CH3),
19.55 (s, CH3), 20.03* (s, CH3), 24.69* (s, CH3), 25.51 (s, CH3), 29.99*
(s, C-60), 30.39 (s, C-60), 36.68 (q, J = 1.5 Hz, C-30), 37.60* (q,
J = 1.5 Hz, C-30), 45.44* (q, J = 1.0 Hz, CHS), 45.60 (q, J = 1.0 Hz, CHS),
59.23 (q, J = 28.0 Hz, C-20), 60.66* (q, J = 27.0 Hz, C-20), 122.65,
122.98, 123.45, 124.19 (C-40,50 of both isomers), 126.57* (q,

V.M. Timoshenko et al. / Journal of Fluorine Chemistry 131 (2010) 172–183
181
J = 281.0 Hz, CF3), 126.69 (q, J = 283.0 Hz, CF3), 126.95, 127.00,
127.02, 127.10, 128.52, 128.65 (CH–Ar of both isomers), 144.66 (C–
Ar), 145.71* (C–Ar). GC/MS (m/e): 332 (M+, 2%), 227 (M+–C8H9,
14%), 194 (M+–C8H10S, 89%), 105 (C8H9+, 100%). Anal. Calcd for
2.38 (d, J = 8.1 Hz, 1H-7), 2.40* (d, J = 9.0 Hz, 1H-7), 3.24* (m, H-4),
3.54 (m, H-4), 4.16 (m, H-1 of both isomers), 4.34* (q, J = 7.1 Hz,
CH–CH3), 4.46 (q, J = 7.1 Hz, CH–CH3), 5.84* (m, H-6), 5.94 (m, H-
6), 6.33* (tdd, J = 53.4, 6.5, 5.1 Hz, HCF2), 6.47 (tdd, J = 53.4, 8.1,
3.0 Hz, HCF2), 6.45 (m, H-5 of both isomers), 7.21–7.36 (m, H–Ar of
C16H19F3S2: C, 57.81; H, 5.76; S, 19.29. Found: C, 57.82; H, 5.77; S,
19.25.
both isomers). 13C NMR (CDCl3):
d 24.59* (CH3), 24.62 (CH3),
47.60* (t, J = 2.3 Hz, C-1), 47.65 (C-1), 51.65* (C-7), 52.07 (C-7),
54.05* (t, J = 1.5 Hz, C-4), 54.90 (C-4), 55.05* (C–Me), 55.43 (t,
J = 2.0 Hz, C–Me), 72.51* (dd, J = 21.3, 18.0 Hz, C-3), 73.14 (t,
J = 19.0 Hz, C-3), 109.60 (tt, J = 252.0, 32.5 Hz, HCF2), 109.72* (tt,
J = 253.0, 33.0 Hz, HCF2), 114.5–121.0 (m, CF2 of both isomers),
126.94, 127.19, 127.33, 127.37. 128.75, 128.76 (CH–Ar of both
isomers), 132.09 (C-6), 132.23* (C-6), 138.99* (t, J = 2.5 Hz, C-5),
139.19 (t, J = 2.0 Hz, C-5), 144.10 (C–Ar), 144.83* (C–Ar). GC/MS
(m/e): 282 (M+–C5H6, 4%), 105 (C8H9+, 100%). Anal. Calcd for
4.4.7. 4,5-Dimethyl-2-[(1-phenylethyl)thio]-2-(1,1,2,2-
tetrafluoroethyl)-3,6-dihydro-2H-thiopyran (5g)
Colourless oil, yield 98%, mixture of isomers in the ratio 46:54
from HPLC, solvent MeCN:H2O (85:15), tr 8.5 (minor) and 9.3
(major) min. 19F NMR (CDCl3):
d
ꢀ117.30* (1F, AB, J = 266.0 Hz,
CF2), ꢀ119.68 (1F, AB, J = 266.0 Hz, CF2), ꢀ121.10 (1F of both
isomers, AB, J = 266.0 Hz), ꢀ133.46 (1F, AB d, J = 299.0, 53.1 Hz,
HCF2), ꢀ134.50* (1F, AB d, J = 299.0, 53.1 Hz, HCF2), ꢀ135.78* (1F,
AB d, J = 299.0, 53.1 Hz, HCF2), ꢀ136.38 (1F, AB d, J = 299.0, 53.1 Hz,
C
16H16F4S2: C, 55.15; H, 4.63; S, 18.41. Found: C, 55.18; H, 4.68; S,
HCF2). 1H NMR (CDCl3):
d
1.32 (s, CH3), 1.57* (d, J = 7.2 Hz, CH3CH),
18.25.
1.63 (d, J = 7.2 Hz, CH3CH), 1.64 (s br, CH3 of both isomers), 1.72* (s,
CH3), 2.09* (1H, AB, J = 18.0 Hz, H-30), 2.15 (1H, AB, J = 19.0 Hz, H-
30), 2.60–2.94 (m, H-30 of both isomers + 3H-60), 3.49 (1H, AB,
J = 16.2 Hz, H-60), 4.24 (2 q, J = 7.2 Hz, CH–CH3 of both isomers),
6.14* (1H, tdd, J = 53.1, 7.6, 4.4 Hz, HCF2), 6.47 (1H, tdd, J = 53.1, 7.2,
4.5 Hz, HCF2), 7.26 (m, C6H5 of both isomers). GC/MS (m/e): 364
(M+, 2%), 259 (M+–C8H9, 10%), 226 (M+–C8H10S), 211 (100%), 105
(C8H9+, 85%). Anal. Calcd for C17H20F4S2: C, 56.02; H, 5.53; S, 17.60.
Found: C, 56.05; H, 5.56; S, 17.50.
4.4.11. 4,5-Dimethyl-2-trifluoromethyl-2-{[(1S)-exo-1,7,7-
trimethylbicyclo[2.2.1]hept-2-yl]thio}-3,6-dihydro-2H-thiopyran
(5k)
Pale-yellow oil, yield 98%, mixture of isomers in the ratio 41:59
from HPLC, solvent MeOH:H2O (87:13), tr 36.0 (major) and 37.6
(minor) min. 19F NMR (CDCl3):
1H NMR (CDCl3):
d
ꢀ74.08 (s, CF3), ꢀ74.34* (s, CF3).
d
0.82 (s, CH3 of both isomers), 0.84* (s, CH3),
0.90* (s, CH3), 0.97 (s, CH3), 0.99 (s, CH3), 1.11–1.43 (m, CH2 of both
isomers), 1.61–1.77 (m, CH2 + 2CH3 of both isomers), 1.93–1.99 (m,
CH2 of both isomers), 2.15–2.24 (m, H-30 of both isomers), 2.73–
2.90 (m, H-30 + H-60 of both isomers), 3.00–3.05 (m, 2H-60 of both
4.4.8. 2-[(1-Phenylethyl)thio]-2-trifluoromethyl-3,6-dihydro-2H-
thiopyran (5h)
Pale-yellow oil, yield 98%, mixture of isomers in the ratio 34:66
from HPLC, solvent MeCN:H2O (75:25), tr 24.6 (minor) and 26.2
isomers), 3.33 (dd, J = 15.2, 14.8, H-2 of both isomers). GC/MS (m/
e): 364 (M+, 2%), 194 (M+–C10H18S, 100%), 179 (80%), 137 (C10H17
,
+
(major) min. 19F NMR (CDCl3):
1H NMR (CDCl3):
d
ꢀ74.15 (s, CF3), ꢀ74.94* (s, CF3).
81%). Anal. Calcd for C18H27F3S2: C, 59.31; H, 7.47; S, 17.59. Found:
C, 59.35; H, 7.49; S, 17.36.
d
1.62 (d, J = 7.2 Hz, CH3), 1.67* (d, J = 7.2 Hz, CH3),
2.29 (m, H-30 of both isomers), 2.64–2.91 (m, H-30 of both isomer
+2H-60 of major isomer), 3.10 (dm, J = 16.6 Hz, H-60), 3.51 (dm,
J = 16.6 Hz, H-60), 4.32 (q, J = 7.2 Hz, CH–CH3), 4.34* (q, J = 7.2 Hz,
CH–CH3), 5.47 (m, H-4), 5.67* (m, H-4), 5.80 (m, H-4 of both
isomer), 7.28 (m, C6H5 of both isomers). GC/MS (m/e): 304 (M+, 2%).
Anal. Calcd for C14H15F3S2: C, 55.24; H, 4.97; S, 21.07. Found: C,
55.26; H, 4.99; S, 20.90.
4.4.12. 4,5-Dimethyl-2-(1,1,2,2-tetrafluoroethyl)-2-{[(1S)-exo-1,7,7-
trimethylbicyclo[2.2.1]hept-2-yl]thio}-3,6-dihydro-2H-thiopyran (5l)
Colourless oil, yield 85%. Rf 0.33 (hexane), mixture of isomers in
the ratio 40:60 from HPLC, solvent MeOH:H2O (87:13), tr 27.0
(major) and 28.2 (minor) min. 19F NMR (CDCl3):
d
ꢀ118.67* (1F,
AB, J = 263.5 Hz, CF2), ꢀ119.82 (1F, AB, J = 259.0 Hz, CF2), ꢀ121.49
(2F, AB of both isomers), ꢀ132.47 (1F, ddm, J = 297.0, 54.0 Hz,
HCF2), ꢀ133.42* (1F, ddm, J = 297.0, 54.0 Hz, HCF2), ꢀ136.69* (1F,
ddm, J = 297.0, 54.0 Hz, HCF2), ꢀ137.55 (1F, ddm, J = 297.0,
4.4.9. 3-[(1-Phenylethyl)thio]-3-trifluoromethyl-2-
thiabicyclo[2.2.1]hept-5-ene (5i)
Pale-yellow oil, yield 90%. Rf 0.40–0.45 (hexane:CH2Cl2, 5:1),
54.0 Hz, HCF2). 1H NMR (CDCl3):
d 0.82* (s, CH3), 0.84 (s, CH3),
mixture of four isomers. Data for two main isomers are given. 19
F
0.88* (s, CH3), 0.90 (s, CH3), 0.94 (s, CH3), 0.95* (s, CH3), 1.09–1.37
(m, CH2 of both isomers), 1.62–1.76 (m, CH2 of both isomers), 1.70
(s, CH3 of both isomers), 1.76 (s, CH3 of both isomers), 1.93–2.02
(m, CH2 of both isomers), 2.12 (1H, d, J = 17.7 Hz, H-30), 2.18* (1H,
d, J = 17.7 Hz, H-30), 2.78–2.87 (m, H-30 + H-60 of both isomers),
2.99–3.04 (m, H-2 of both isomers), 3.32* (1H, d, J = 14.7 Hz, H-60),
3.37 (1H, d, J = 14.7 Hz, H-60), 6.52* (1H, tdd, J = 54.0, 8.4, 3.5 Hz,
NMR (CDCl3):
d
ꢀ63.95 (s, CF3), ꢀ65.71* (s, CF3). 1H NMR (CDCl3):
d
1.58 (d, J = 7.1 Hz, CH3), 1.68 (d, J = 9.5 Hz, 1H-7), 1.71* (d,
J = 7.1 Hz, CH3), 1.83* (d, J = 9.5 Hz, 1H-7), 2.36 (d, J = 9.5 Hz, 1H-
7), 2.37* (d, J = 9.5 Hz, 1H-7), 3.03 (m, H-4), 3.52* (m, H-4), 4.13 (m,
H-1), 4.19* (m, H-1), 4.39 (q, J = 7.1 Hz, CH–CH3), 4.47* (q,
J = 7.1 Hz, CH–CH3), 5.77 (m, H-6), 5.94* (m, H-6), 6.42 (dd,
J = 5.3, 2.8 Hz, H-5), 6.52* (dd, J = 5.0, 2.8 Hz, H-5), 7.21–7.41 (m, H–
HCF2), 6.57 (1H, tdd, J = 54.0, 8.3, 3.4 Hz, HCF2). 13C NMR (CDCl3):
d
Ar of both isomers). GC/MS (m/e): 250 (M+–C5H6, 2%), 105 (C8H9
,
14.37 (CH3), 14.75* (CH3), 19.20* (CH3), 19.32 (CH3), 19.74 (CH3),
19.86* (CH3), 20.31 (CH3), 20.40* (CH3), 20.98 (CH3), 21.00* (CH3),
27.45 (C-5), 27.51* (C-5), 29.24* (C-60), 29.42 (C-60), 36.86 (m, C-60
of both isomers), 38.45 (C-6), 38.69* (C-6), 42.88* (m, C-30), 44.15
(C-30), 46.21* (C-4), 46.32 (C-4), 47.38* (C-7), 47.39 (C-7), 50.54
(C-1), 50.59* (C-1), 52.95* (q, J = 1.0 Hz, C-2), 53.19 (q, J = 1.5 Hz,
C-2), 60.49* (t, J = 22.0 Hz, C-20), 60.61 (t, J = 21.0 Hz, C-20), 109.43
(tdd, J = 253.0, 32.0, 30.2, Hz, HCF2), 109.62* (tdd, J = 253.0, 33.0,
30.0 Hz, HCF2), 117.13* (tm, J = 261.0 Hz, CF2), 117.16 (tm,
J = 261.0 Hz, CF2), 122.51, 122.57, 123.71, 124.13 (C-40,50 of both
+
100%). Anal. Calcd for C15H15F3S2: C, 56.94; H, 4.78; S, 20.27.
Found: C, 56.99; H, 4.82; S, 20.01.
4.4.10. 3-[(1-Phenylethyl)thio]-3-(1,1,2,2-tetrafluoroethyl)-2-
thiabicyclo[2.2.1]hept-5-ene (5j)
Pale-yellow oil, yield 85%. Rf 0.40–0.45 (hexane:CH2Cl2, 5:1),
mixture of four isomers. Data for two main isomers are given. 19
F
NMR (CDCl3):
d
ꢀ105.56 (1F, AB, J = 263.0 Hz, CF2), ꢀ106.23* (1F,
AB, J = 263.0 Hz, CF2), ꢀ114.46* (1F, AB, J = 263.0 Hz, CF2), ꢀ116.09
(1F, AB, J = 263.0 Hz, CF2), ꢀ136.41 (1F, d AB, J = 299.5, 53.4 Hz,
HCF2), ꢀ137.28* (2F, dm, J = 53.4 Hz, HCF2), ꢀ139.04 (1F, d AB,
isomers). GC/MS (m/e): 396 (M+, 2%), 227 (M+–C10H17S, 73%), 226
(M+–C10H18S, 100%), 137 (C10H17
, 60%). Anal. Calcd for
+
J = 299.5, 53.4 Hz, HCF2). 1H NMR (CDCl3):
d
1.56–1.65 (m, 1H-7 of
C
19H28F4S2: C, 57.55; H, 7.12; S, 16.17. Found: C, 57.56; H, 7.13;
both isomers), 1.63* (d, J = 7.1 Hz, CH3), 1.70 (d, J = 7.1 Hz, CH3),
S, 16.02.

182
V.M. Timoshenko et al. / Journal of Fluorine Chemistry 131 (2010) 172–183
4.4.13. 4,5-Dimethyl-2-trifluoromethyl-2-{[(1S)-endo-1,7,7-
trimethylbicyclo[2.2.1]hept-2-yl]thio}-3,6-dihydro-2H-thiopyran
(5m)
1.28 (m, H-5,6 of both isomers), 1.52–1.83 (m, H-4,6 of both
isomers), 1.78 (s, 2CH3 of both isomers), 2.06–2.23 (m, exo-H-3 of
both isomers), 2.37–2.62 (m, H-30 of both isomers), 2.99–3.21 (m,
H-60 of both isomers), 4.03* (dm, J = 9.3 Hz, exo-H-2), 4.21 (dm,
J = 9.6 Hz, exo-H-2), 6.15 (td, J = 53.3, 4.5 Hz, HCF2), 6.18* (td,
Pale-yellow oil, yield 96%, mixture of isomers in the ratio 45:55
from HPLC, solvent MeCN:H2O (95:5), tr 24.3 (minor) and 25.3
(major) min. 19F NMR (CDCl3):
1H NMR (CDCl3):
d
ꢀ74.31* (s, CF3), ꢀ74.42* (s, CF3).
J = 53.3, 4.3 Hz, HCF2). 13C NMR (CDCl3):
d 13.59 (CH3), 13.73*
d
0.87, 0.88, 0.89, 0.91, 0.92, 0.94 (s, CH3 of both
(CH3), 18.67 (CH3), 18.70* (CH3), 18.93* (CH3), 19.03 (CH3), 19.78
(CH3), 19.83* (CH3), 20.20* (CH3), 20.24 (CH3), 27.09* (CH2), 27.16
(CH2), 28.25 (CH2 of both isomers), 31.80* (CH2), 32.32 (CH2),
37.88* (m, CH2), 38.09 (m, CH2), 38.64* (CH2), 39.05 (CH2), 45.05*
(C-4), 45.23 (C-4), 47.24* (C-7), 47.32 (C-7), 49.44* (C-1), 49.64 (C-
1), 79.41 (C-2), 80.64* (C-2), 92.34* (t, J = 7.6 Hz, C-20), 93.35 (dd,
J = 22.5, 24.0 Hz, C-20), 109.76 (tt, J = 252.5, 32.0 Hz, HCF2), 109.79*
(tt, J = 252.0, 31.0 Hz, HCF2), 113.0–118.7 (tm, CF2 of both isomers),
126.89, 127.09, 127.55, 127.56 (C-40,50 of both isomers). GC/MS (m/
e): 380 (M+, 2%), 227 (M+–C10H17O, 36%), 153 (C10H17O+, 66%). Anal.
Calcd for C19H28F4OS: C, 59.98; H, 7.42; S, 8.43. Found: C, 60.01; H,
7.43; S, 8.21.
isomers), 1.22–1.44 (m, endo-H-3 + H-5 of both isomers), 1.54–
1.74 (m, H-4,5,6 of both isomers), 1.70 (s, CH3 of both isomers),
1.76* (s, CH3), 1.78 (s, CH3), 2.20* (AB, J = 17.5 Hz, H-30), 2.24 (AB,
J = 17.5 Hz, H-30), 2.43 (m, exo-H-3 of both isomers), 2.68–2.98 (m,
H-6,30,60 of both isomers), 3.17 (dm, J = 10.9 Hz, exo-H-2), 3.24*
(dm, J = 10.5 Hz, exo-H-2), 3.36* (AB, J = 16.2 Hz, H-60), 3.40 (AB,
J = 16.2 Hz, H-60). GC/MS (m/e): 364 (M+, 2%), 194 (M+–C10H18S,
100%), 179 (62%). Anal. Calcd for C18H27F3S2: C, 59.31; H, 7.47; S,
17.59. Found: C, 59.32; H, 7.48; S, 17.42.
4.5. Cycloadducts 5n–p (Table 3). Common procedure
A solution of thionoester 4a,d,e (1 mmol) and DMB (0.33 g,
4 mmol) in dry benzene (2 ml) was heated in a pressure tube at
125–130 8C for 5 h. After cooling the solvent and excess of DMB
were removed under reduced pressure. NMR spectra of crude
mixture were recorded to establish the ratio of isomers before
purification of cycloadducts over silica gel column chromatogra-
phy with hexane as eluent.
4.5.3. 2-Isopropoxy-4,5-dimethyl-2-(1,1,2,2-tetrafluoroethyl)-3,6-
dihydro-2H-thiopyran (5p)
Pale-yellow oil, yield 88%. Rf 0.5 (hexane). 19F NMR (CDCl3):
d
ꢀ122.18 (1F, AB, dd, J = 267.1, 10.5 Hz, CF2), ꢀ127.27 (1F, AB, ddd,
J = 267.1, 20.3, 8.3 Hz, CF2), ꢀ135.16 (1F, AB, ddd, J = 299.0, 53.5,
12.0 Hz, HCF2), ꢀ137.66 (1F, AB, ddt, J = 299.0, 53.5, 11.0 Hz, HCF2).
1H NMR (CDCl3):
d 1.13 (6H, d, J = 6.2 Hz, CH3), 1.78 (3H, s, CH3),
1.80 (3H, s, CH3), 2.49 (2H, m, H-3), 3.09 (2H, m, H-6), 4.17 (1H,
septet, J = 6.2 Hz, CH-O), 6.14 (tdd, J = 53.5, 8.1, 4.0 Hz, HCF2). GC/
MS (m/e): 286 (M+, 2%). Anal. Calcd for C12H18F4OS: C, 50.34; H,
6.34; S, 11.20. Found: C, 50.36; H, 6.36; S, 11.05.
4.5.1. 4,5-Dimethyl-2-trifluoromethyl-2-{[(1S)-endo-1,7,7-
trimethylbicyclo[2.2.1]hept-2-yl]oxy}-3,6-dihydro-2H-thiopyran
(5n)
Pale-yellow oil, yield 80%. Rf 0.30–0.40 (hexane), mixture of
isomers in the ratio 47:53 from HPLC, solvent MeCN:H2O (92:8), tr
4.6. Details of calculations
19.3 (minor) and 21.2 (major) min. 19F NMR (CDCl3):
d
ꢀ77.19 (s,
CF3), ꢀ78.21* (s, CF3). 1H NMR (CDCl3):
d
0.72* (s, CH3), 0.81 (s,
Allthestructureswerefully optimizedwiththeGAUSSIAN-03set
of programs [26] using the DFT (B3LYP [27,28]) level of approxima-
tion and 6-31G** basis sets [29–32]. The energy values were
corrected adding the Zero Point Energy (ZPE) correction values or on
the Thermal Correction to Gibbs Free Energy (TCGFE) correction
CH3), 0.82 (s, 2CH3 of both isomers), 1.05–1.26 (m, endo-H-3 + H-5
of both isomers), 1.54–1.71 (m, H-4,5,6 of both isomers), 1.79 (s,
2CH3 of both isomers), 1.85–1.98 (m, H-6 of both isomers), 2.04–
2.19 (m, exo-H-3 of both isomers), 2.38 (AB, J = 14.7 Hz, H-30), 2.41*
(AB, J = 14.7 Hz, H-30), 2.52 (AB, J = 14.7 Hz, H-30), 2.53* (AB,
J = 14.7 Hz, H-30), 3.08 (AB, J = 14.1 Hz, H-60 of both isomers), 3.10*
(AB, J = 14.1 Hz, H-60 of both isomers), 4.09 (dm, J = 9.1 Hz, exo-H-
values. Differences between corrected energy values yielded
DE and
DG magnitudes, respectively. All the transition states were located
using an effective procedure published recently [33]. First the
geometry was optimized with an only frozen C–S reaction
2), 4.13* (dm, J = 9.4 Hz, exo-H-2). 13C NMR (CDCl3):
d 13.31 (CH3),
˚
13.42* (CH3), 18.67* (CH3), 18.76 (CH3), 18.98* (CH3), 19.04 (CH3),
19.81 (CH3), 19.90* (CH3), 20.67 (CH3 of both isomers), 26.84 (CH2),
26.87* (CH2), 28.25* (CH2), 28.31 (CH2), 30.99* (CH2), 31.52 (CH2),
36.81* (q, CH2, J = 1.5 Hz), 38.92 (q, CH2, J = 1.5 Hz), 39.21 (q, CH2,
J = 1.2 Hz), 39.25* (CH2), 45.14* (C-4), 45.16 (C-4), 47.21* (C-7),
47.34 (C-7), 49.61 (C-1), 49.70* (C-7), 80.46* (C-2), 81.48 (C-2),
90.66 (q, J = 27.0 Hz, C-20), 90.93* (q, J = 27.0 Hz, C-20), 125.26* (q,
J = 287.0 Hz, CF3), 126.78 (q, J = 287.0 Hz, CF3), 126.37, 126.82,
127.27, 127.41 (C-40,50 of both isomers). GC/MS (m/e): 348 (M+, 2%),
195 (M+–C10H17O, 22%), 153 (C10H17O+, 48%). Anal. Calcd for
coordinate fixed to 2.45 A. Thereafter the geometry was fully
optimized as a transition state structure, calculating force constants
by the first optimization cycle. The most favoured structures were
re-optimized using the larger 6-311G** standard basis sets. As
default within the GAUSSIAN packet the mentioned basis sets are
defined as the proper 6-311G Pople basis sets [34] for hydrogen and
the second period atoms (C, F) and the (12s,9p) McLean-Chandler
basis set [35] for sulfur, expanded with the appropriate polarization
functions. All stationary points were characterized by the vibration
frequencies, derived calculating the first and second derivatives
analytically (zero and one imaginary frequency for the local minima
and transition states, respectively). Additionally, structures 5A–D
and 6A–D optimized at the B3LYP/6-311G** level of theory were
usedfortheenergysingle-point calculationsusingmoreaccuratecc-
pVTZ Dunning’s basis sets [36]. The optimized structures were
pictured using the VMD program [37].
C
18H27F3OS: C, 62.04; H, 7.81; S, 9.20. Found: C, 62.06; H, 7.83; S,
8.98.
4.5.2. 4,5-Dimethyl-2-(1,1,2,2-tetrafluoroethyl)-2-{[(1S)-endo-1,7,7-
trimethylbicyclo[2.2.1]hept-2-yl]oxy}-3,6-dihydro-2H-thiopyran (5o)
Pale-yellow oil, yield 75%. Rf 0.35–0.45 (hexane), mixture of
isomers in the ratio 40:60 from HPLC, solvent MeCN:H2O (92:8), tr
12.2 (minor) and 13.3 (major) min. 19F NMR (CDCl3):
d
ꢀ121.86
Acknowledgements
(1F, AB, J = 263.5, 8.0 Hz, CF2), ꢀ122.14* (1F, AB, J = 266.5, 8.0 Hz,
CF2), ꢀ126.77* (1F, AB, J = 266.5, 8.0 Hz, CF2), ꢀ127.01 (1F, AB,
J = 256.0, 8.0 Hz, CF2), ꢀ136.05* (d AB, J = 295.0, 53.3 Hz, HCF2),
We greatly thank Enamine Ltd. (Kyiv) for performing GC/MS
measurements and HPLC studies. We are also very grateful to
Professor Dr. W.W. Schoeller and Professor Dr. U. Manthe,
University of Bielefeld (Germany) for the access to the computer
cluster and GAUSSIAN-03 set of program.
ꢀ136.24 (d AB, J = 296.3, 53.3 Hz, HCF2). 1H NMR (CDCl3):
d0.79* (s,
CH3), 0.81 (s, CH3), 0.82 (s, CH3), 0.83* (s, CH3), 0.84 (s, CH3 of both
isomers), 0.90–1.06 (m, endo-H-3 + H-5 of both isomers), 1.12–

V.M. Timoshenko et al. / Journal of Fluorine Chemistry 131 (2010) 172–183
183
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