Reaction of optically active oxiranes with thiofenchone and 1-methylpyrrolidine-2-thione: Formation of 1,3-oxathiolanes and thiiranes

Article abstract of DOI:10.1002/hlca.201100043

The SnCl₄-catalyzed reaction of (-)-thiofenchone (=1,3,3-trimethylbicyclo[2.2.1]heptane-2-thione; 10) with (R)-2-phenyloxirane ((R)-11) in anhydrous CH₂Cl₂ at -60° led to two spirocyclic, stereoisomeric 4-phenyl-1,3-oxathiolanes 12 and 13 via a regioselective ring enlargement, in accordance with previously reported reactions of oxiranes with thioketones (Scheme 3). The structure and configuration of the major isomer 12 were determined by X-ray crystallography. On the other hand, the reaction of 1-methylpyrrolidine-2-thione (14a) with (R)-11 yielded stereoselectively (S)-2-phenylthiirane ((S)-15) in 56% yield and 87-93% ee, together with 1-methylpyrrolidin-2-one (14b). This transformation occurs via an S_N2-type attack of the S-atom at C(2) of the aryl-substituted oxirane and, therefore, with inversion of the configuration (Scheme 4). The analogous reaction of 14a with (R)-2-{[(triphenylmethyl)oxy] methyl}oxirane ((R)-16b) led to the corresponding (R)-configured thiirane (R)-17b (Scheme 5); its structure and configuration were also determined by X-ray crystallography. A mechanism via initial ring opening by attack at C(3) of the alkyl-substituted oxirane, with retention of the configuration, and subsequent decomposition of the formed 1,3-oxathiolane with inversion of the configuration is proposed (Scheme 5). Copyright

Full text of DOI:10.1002/hlca.201100043

Helvetica Chimica Acta – Vol. 94 (2011)
773
Reaction of Optically Active Oxiranes with Thiofenchone and
1-Methylpyrrolidine-2-thione: Formation of 1,3-Oxathiolanes and Thiiranes
by Changchun Fu1), Anthony Linden, and Heinz Heimgartner*
Organisch-chemisches Institut der Universitꢀt Zꢁrich, Winterthurerstrasse 190, CH-8057 Zꢁrich
(phone: þ 41-44-6354282; fax: þ 41-44-6356812; e-mail: heimgart@oci.uzh.ch)
The SnCl4-catalyzed reaction of (ꢀ)-thiofenchone (¼1,3,3-trimethylbicyclo[2.2.1]heptane-2-thione;
10) with (R)-2-phenyloxirane ((R)-11) in anhydrous CH2Cl2 at ꢀ 608 led to two spirocyclic, stereo-
isomeric 4-phenyl-1,3-oxathiolanes 12 and 13 via a regioselective ring enlargement, in accordance with
previously reported reactions of oxiranes with thioketones (Scheme 3). The structure and configuration
of the major isomer 12 were determined by X-ray crystallography. On the other hand, the reaction of 1-
methylpyrrolidine-2-thione (14a) with (R)-11 yielded stereoselectively (S)-2-phenylthiirane ((S)-15) in
56% yield and 87 – 93% ee, together with 1-methylpyrrolidin-2-one (14b). This transformation occurs via
an SN2-type attack of the S-atom at C(2) of the aryl-substituted oxirane and, therefore, with inversion of
the configuration (Scheme 4). The analogous reaction of 14a with (R)-2-{[(triphenylmethyl)oxy]me-
thyl}oxirane ((R)-16b) led to the corresponding (R)-configured thiirane (R)-17b (Scheme 5); its
structure and configuration were also determined by X-ray crystallography. A mechanism via initial ring
opening by attack at C(3) of the alkyl-substituted oxirane, with retention of the configuration, and
subsequent decomposition of the formed 1,3-oxathiolane with inversion of the configuration is proposed
(Scheme 5).
1. Introduction. – Derivatives of 1,3-oxathiolanes, for example, the muscarine
analog 1 as a cholinergic agonist, have been known as biologically active compounds for
many years (see, e.g., [1]). However, the interest in these heterocycles increased
impressively in recent times. In particular, the nucleoside analogs of type 2 became the
focus of many medicinal chemists because of their remarkable activity as nucleoside-
analog reverse transcriptase inhibitors (nRTIs), which found application in the
treatment of hepatitis B and HIV (see, e.g., [2]).
For this reason, new synthetic approaches and optimizations of known syntheses for
1,3-oxathiolanes are of current interest [3]. The most common approach is the reaction
of a carbonyl compound with 2-sulfanylethanol [3b – 3g]. In this manner, optically
1
)
Present address: Verlag Helvetica Chimica Acta AG, Hofwiesenstrasse 26, CH-8042 Zꢁrich.
ꢂ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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active 2-(acyloxymethyl)-1,3-oxathiolanes of type 3 have been obtained after an
enzyme-catalyzed kinetic resolution of the racemate [3e]. Some years ago, we have
elaborated a regio- and stereoselective formation of 1,3-oxathiolanes via the Lewis
acid-catalyzed reaction of thiocarbonyl compounds with oxiranes [4]. Analogous ring
enlargement reactions have been reported to occur with CS2 [3h] and thioacetamide
[3i]. Whereas the SiO2-catalyzed reaction of thioketones with (S)-2-methyloxirane
yielded (S)-5-methyl-1,3-oxathiolane with retention of the configuration of the oxirane,
the reaction with (R)-2-phenyloxirane led to (S)-4-phenyl-1,3-oxathiolane with
inversion of the configuration [5a]. Similar results were obtained in the reactions with
thionolactones [5b]. These findings can be rationalized by a regioselective SN2-type
mechanism.
In some cases, e.g., in the BF3-catalyzed reaction of thiobenzophenone with 1,2-
epoxycyclohexane (4), in addition to the expected 1,3-oxathiolane 5a, the correspond-
ing 1,3-dithiolane 5b and the 1,3-dioxolane 5c were formed as minor products [6]
(Scheme 1). It has been shown that 5b and 5c are secondary products, and a reaction
mechanism via the intermediate formation of 1,2-epithiocyclohexane (6) and
benzophenone was proposed2). Under milder conditions, 4 reacted with 1,3-dimethyl-
imidazolidine-2-thione (7a) to give 6 and 7b in high yield [4b].
Scheme 1
Transformations of oxiranes into thiiranes have been known for more than 60 years
[7], and several examples have been described. In most of the cases, thiourea was used
as the ꢃS-transfer reagentꢄ. Several new modifications of the procedure have been
reported in recent years [8]. Furthermore, the stereochemical course of this trans-
formation, which occurs with inversion of the configuration at both stereogenic centers,
has been studied extensively (see, e.g., [9]). For example, the reaction of the optically
active oxirane 8 with thiourea in MeOH at room temperature gave stereoselectively the
thiirane 9 (Scheme 2).
Instead of thiourea, heterocyclic thiones containing the NꢀC(S)ꢀX moiety (X ¼ N,
O, S) [4b][10] as well as thiourethanes [11] can be used as the ꢃS-transfer reagentꢄ.
2
)
The reaction of (2S,3S)-2,3-dimethyloxirane with CS2 in the presence of Bu4NBr and an Al(salen)
complex at 508 led to (4R,5S)-4,5-dimethyl-1,3-oxathiolane-2-thione, whereas, at 908, the
corresponding 1,3-dithiolane-2-thione was obtained [3h].

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Scheme 2
Here, we report an additional example of the ring enlargement of an optically active
oxirane in the reaction with a thioketone and the transformation into optically active
thiiranes by using 1-methylpyrrolidine-2-thione as the ꢃS-transfer reagentꢄ.
2. Results and Discussion. – 2.1. Reaction of (1R,4S)-Thiofenchone (¼(1R,4S)-
1,3,3-Trimethylbicyclo[2.2.1]heptane-2-thione; 10) with (R)-2-Phenyloxirane ((R)-11).
On dropping 0.5 equiv. of SnCl4 into a solution of 1.06 equiv. of 10 and 2 equiv. of (R)-
11 in anhydrous CH2Cl2 at ꢀ 608 under an N2 atmosphere, the orange color of the
solution slowly disappeared. After 1 h 40 min, the reaction was quenched by addition of
H2O. Chromatographic separation (CC and HPLC (Chiralcel OD)) gave the
diastereoisomeric spirocyclic 1,3-oxathiolanes 12 and 13 in 36 and 15% yield,
respectively (Scheme 3), and two additional impure diastereoisomers in very small
amounts.
Scheme 3
1
The structures of 12 and 13 were determined on the basis of their IR, H- and
13C-NMR, and mass spectra. In addition, the structure of 12 was established by a single-
crystal X-ray diffraction analysis (Fig. 1). The crystals were enantiomerically pure, and
the absolute configuration of the molecule has been determined independently by the
diffraction experiment, as expected, as (1R,2S,4S,4’S), i.e., the S-atom occupies the exo-
and the O-atom the endo-position with respect to the bicycloheptane skeleton. The
five-membered heterocycle has an envelope conformation with C(5) as the envelope
flap lying 0.587(2) ꢅ from the plane defined by the other four atoms.
The formation of 12 and 13 was rationalized by a nucleophilic attack of the
thiocarbonyl S-atom of 10 at C(2) of (R)-11 according to an SN2 mechanism, i.e., with
inversion of the configuration, leading to the (S)-configuration at C(4’), which, in the
case of 12, was confirmed by the X-ray analysis. Based on the results of previously
reported reactions, e.g., with thiocamphor [13], the structure 13 was assigned to the
minor isomer, i.e., the epimer of 12.

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Fig. 1. ORTEP Plot [12] of the molecular structure of 12 (arbitrary numbering of the atoms;
displacement ellipsoids with 50% probability)
2.2. Reaction of 1-Methylpyrrolidine-2-thione (14a) with (R)-11. After addition of
1.0 equiv. of (R)-11 (91% ee) to 1.25 equiv. of 14a at room temperature, the mixture
became warm. Then, dry CH2Cl2 was added while stirring, and thin layer chromatog-
raphy (TLC) showed complete conversion of (R)-11 after 1 h 15 min. After
evaporation of the solvent and chromatographic workup, (S)-2-phenylthiirane ((S)-
15) was obtained in 55% yield with 92.5% ee (HPLC, Chiralcel OD-H) as a colorless
oil (Scheme 4)3).
3
)
The transformation of (R)-11 to (S)-15 was described for the first time by Stewart via treatment with
KSCN [14a]. In 2005, a reaction, in which thiourea, in the presence of SiO2, was used as ꢃS-transfer
reagentꢄ, was reported by Iranpoor et al. [14b].

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777
Scheme 4
In an analogous experiment, 1.0 equiv. of (R)-11 was added to a solution of 1.05
equiv. of 14a in dry CH2Cl2 at 08. The mixture was stirred at 08 for 1 h and then left to
warm to room temperature; TLC control indicated only partial conversion of (R)-11.
Then, CH2Cl2 (3 ml) and SiO2 (2 g) were added to the mixture, and stirring at room
temperature was continued for 30 h. After this time, no (R)-11 could be detected by
TLC, and usual workup by column chromatography on silica gel gave (S)-15 in 56%
yield with 87.6% ee (HPLC, Chiralcel OD-H).
A reaction mechanism for the stereoselective S-transfer reaction is proposed in
Scheme 4 (see also [4b])4). The ring opening of (R)-11 by nucleophilic attack of the S-
atom of 14a at C(2) occurs via inversion of the configuration, leading to the
intermediate zwitterion A [5b][16]. Ring closure gives the spirocyclic 1,3-oxathiolane
B, which undergoes rearrangement to yield the new zwitterion C. The latter then
decomposes to give the isolated product (S)-15 and 1-methylpyrrolidin-2-one (14b).
2.3. Reaction of 14a with (RS)-2-[(tert-Butoxy)methyl]oxirane ((RS)-16a). The
SiO2-catalyzed reaction of 14a with (RS)-16a (molar ratio 1.1:1) in dry CH2Cl2 at room
temperature for 3.5 h afforded 2-[(tert-butoxy)methyl]thiirane ((RS)-17a) in 62.8%
yield after purification by column chromatography on silica gel (hexane/Et2O 13 :1 and
10 :1; Scheme 5).
2.4. Reaction of 14a with (R)-2-[(Triphenylmethoxy)methyl]oxirane ((R)-16b). In
an analogous manner, the reaction of 14a and (R)-16b (molar ratio 1.2 :1) in dry
CH2Cl2 at room temperature in the presence of SiO2 yielded, after 1 d, stereoselectively
(R)-2-[(triphenylmethoxy)methyl]thiirane ((R)-17b) in 87.3% yield with [a]2D1 ¼ þ4.2
(c ¼ 1.0, CH2Cl2) (Scheme 5)5). Unfortunately, the determination of the ee value of
(R)-17b by means of HPLC (Chiralcel OD-H) failed.
4
)
A detailed experimental and computational study of the mechanism of the transformation (R)-
11 ! (S)-15 with NH4SCN in H2O was published recently by Schreiner and co-workers [15].
This transformation, by using thiourea in MeOH, was reported by Harfouche et al. [17]. The authors
claimed to have obtained (R)-17b from (R)-16b, but in their Scheme 1, they presented the (S)-
enantiomers. Furthermore, the melting point of (R)-17b was given as 65 – 668 and the [a]D value of
the isolated product as ꢀ 26.58 (c ¼ 1, CH2Cl2). In our case, (R)-17b showed a melting point of
108.6 – 109.68.
5
)

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Scheme 5
The structure of (R)-17b was determined on the basis of 1H- and 13C-NMR, and ESI
mass spectra, and the absolute configuration was unambiguously established by X-ray
crystallography (Fig. 2). The compound in the crystal is enantiomerically pure, and the
molecule has the (R)-configuration.
Fig. 2. ORTEP Plot [12] of the molecular structure of (R)-17b (arbitrary numbering of the atoms;
displacement ellipsoids with 50% probability)

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779
A reaction mechanism of the formation of (R)-17b (and (RS)-17a) is depicted in
Scheme 5. In contrast to the reaction of 14a and (R)-11, the S-atom of 14a attacked
preferably the less hindered C(3)-atom of (R)-16b to give the zwitterionic intermediate
D with retention of the configuration (see also [5b][16]). Cyclization of D gave the
spirocyclic 1,3-oxathiolane E, which underwent ring opening to afford F. The latter then
decomposes to yield the product (R)-17b via an SN2 mechanism, in which the anionic S-
atom attacks the stereogenic C-atom with inversion of the configuration.
2.5. Reaction of 14a with 1,2-Epoxycyclohexane (¼ 7-Oxabicyclo[4.1.0]heptane; 4).
As expected, the analogous SiO2-catalyzed reaction of 14a with 4 (molar ratio 1.1:1.0)
in dry CH2Cl2 occurred smoothly at room temperature and gave, after 27 h and
purification by means of column chromatography on SiO2 (hexane/Et2O 23 :1), pure 7-
thiabicyclo[4.1.0]heptane (6) [4b] in 73.7% yield (Scheme 6).
Scheme 6
3. Conclusions. – In addition to previously reported examples, the Lewis acid-
catalyzed reaction of the oxirane (R)-11 with (ꢀ)-thiofenchone (10) confirms the
generality of the regio- and stereoselective formation of 1,3-oxathiolanes from oxiranes
and thioketones ([4a] and refs. cit. therein). Whereas 2-aryl- and 2-vinyloxiranes yield
4-substituted 1,3-oxathiolanes with inversion of the configuration, the reaction with 2-
alkyloxiranes lead to 5-alkyl-1,3-oxathiolanes with retention of the configuration.
Analogous reactions providing 1,3-oxathiolanes occur with heterocyclic thiones such as
1,3-thiazole-5(4H)-thiones [18], 1,3-dithiolane-2-thiones [16], and thiolactones [5b].
On the other hand, heterocyclic thiones containing a neighboring N-atom react with
oxiranes, in general, to give thiiranes via a S-transfer reaction [4b][10]. This reaction
also occurs with 1-methylpyrrolidine-2-thione (14a), which was established as a
convenient and efficient S-transfer reagent and led to, in the whole, the inversion of
configuration of the monosubstituted oxiranes (R)-11 and (R)-16b with either aryl or
alkyl substitution.
We propose that all these transformations proceed via an initially formed zwitterion
G6), which cyclizes to give the 1,3-oxathiolane H (Scheme 7). In the cases of X, Y¼ C,
O, S, this product is stable, whereas with X and/or Y¼ NR, the 1,3-oxathiolane
undergoes a subsequent ring opening to give the rearranged zwitterions I. The latter,
via an intramolecular SN2 reaction, yields the thiirane and the heterocyclic oxo
compound.
To the best of our knowledge, there is only one exception of this rule: (Z)-5-
benzylidene-3-phenyl-2-thioxo-1,3-thiazolidin-4-one (¼ 5-benzylidene-3-phenylrhoda-
6
)
This regioisomer is formed with 2-phenyl- and 2-vinyloxiranes, whereas, in the case of 2-
alkyloxiranes, the zwitterion bears the residue at the alkoxy-C-atom.

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Helvetica Chimica Acta – Vol. 94 (2011)
Scheme 7
nine) reacts with 2-methyl- and 2-phenyloxirane, respectively, to give stable spirocyclic
1,3-oxathiolanes in a regio- and stereoselective manner [19]. This observation may be
rationalized by the reduced availability of the lone electron pair of the N-atom because
of its lactam nature.
We thank the analytical services of our institute for NMR and mass spectra, and elemental analyses,
and F. Hoffmann-La Roche AG, Basel, for financial support.
Experimental Part
1. General. See [20]. Prep. HPLC: Chiralcel OD. Enantiomeric excesses (ee): anal. HPLC on a
Chiralcel OD-H column. Optical rotations: Perkin-Elmer-241 polarimeter (c ¼ 1, in THF). IR Spectra:
Perkin-Elmer-781 FT-IR spectrophotometer; film or KBr; ˜n in cmꢀ1. NMR Spectra: Bruker DPX-300 or
ARX-300 instruments at 300 (1H) and 75.5 MHz (13C) in CDCl3; d in ppm rel. to Me4Si as internal
standard, J in Hz. ESI-MS: Finnigan TSQ-700 instrument; m/z (rel. %). Elemental analyses were
performed at the Institute of Organic Chemistry, University of Zꢁrich.
2. Starting Materials. The optically active (þ)-2-phenyloxirane ((R)-11, 97% ee, Fluka) and (þ)-2-
[(triphenylethoxy)methyl]oxirane ((R)-16b, 98% ee, Aldrich) as well as the racemic 2-[(tert-butoxy)-
methyl]oxirane ((R,S)-16a, Aldrich) were commercially available.
3. Preparation of 1-Methylpyrrolidine-2-thione (14a). To a soln. of 1-methylpyrrolidin-2-one (2.48 g,
25 mmol) in THF (250 ml) was added Lawessonꢄs reagent (5.06 g, 12.5 mmol). The mixture was stirred at
30 – 358 for 38 min. Then, silica gel (SiO2; 5 g) was added to the mixture, and THF was removed. The
resulting residue was subjected to CC (SiO2; hexane/AcOEt 4 :1, 2.2 :1, 1.7:1, and 1.4 :1) to give pure
14a. Yield: 1.67 g (58%).
4. Reaction of (ꢀ)-(1R,4S)-1,3,3-Trimethylbicyclo[2.2.1]heptane-2-thione (10; (ꢀ)-thiofenchone)
with (R)-2-Phenyloxirane ((R)-11, 91% ee7)). To a stirred soln. of 10 (178 mg, 1.06 mmol) and (R)-11
(0.23 ml, 2 mmol) was added a soln. of 1m SnCl4 (0.5 ml, 0.5 mmol) at ꢀ 608 under N2. The color of the
orange soln. disappeared after stirring at the same temp. for 1 h 40 min. Then, the reaction was quenched
by addition of H2O, and the mixture was washed with sat. aq. NaCl soln. (4ꢁ). The combined org. layers
were dried (MgSO4) and evaporated in vacuo. Separation of the residue by CC (SiO2; hexane/CH2Cl2
25 :1) and subsequent HPLC (Chiralcel OD; hexane) gave (1R,2S,4S,4’S)-1,3,3-trimethyl-4’-phenyl-
spiro[bicyclo[2.2.1]heptane-2,2’-[1,3]oxathiolane] (12) and (1R,2R,4S,4’S)-1,3,3-trimethyl-4’-phenylspiro-
[bicyclo[2.2.1]heptane-2,2’-[1,3]oxathiolane] (13), and two additional impure diastereoisomers in very
small amounts.
Data of 12. Yield: 110 mg (36%). Colorless crystals. M.p. 36.9 – 38.78. [a]2D3 ¼ ꢀ123.9 (c ¼ 1, THF).
IR (KBr): 3059w, 3030w, 2997m, 2976s, 2962s, 2929s, 2876s, 1598w, 1579w, 1490m, 1469s, 1448s, 1383w,
1374w, 1362w, 1318w, 1296w, 1281w, 1249w, 1161w, 1151m, 1115m, 1093s, 1074s, 1050w, 1032m, 1003w,
1
992w, 958w, 942w, 921w, 906m, 895m, 866m, 824m, 812w, 787m, 722s, 699s. H-NMR (300 MHz): 7.41 –
7.38 (m, HꢀC(2’’), HꢀC(6’’)); 7.31 – 7.18 (m, HꢀC(3’’), HꢀC(4’’), HꢀC(5’’)); 4.65 (t-like, J ¼ 5.8,
HꢀC(4’)); 4.21 – 4.14 (m, CH2(5’)); 2.10 – 2.00 (m, 1 H); 1.81 – 1.73 (m, 2 H); 1.52 – 1.08 (m, 5 H); 1.23,
7
)
During storage in the refrigerator, (R)-11 racemized partially.

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1.18, 1.05 (3s, 3 Me). 13C-NMR (75 MHz): 140.4 (s, C(1’’)); 128.4 (d, C(3’’), C(5’’)); 127.7 (d, C(2’’),
C(6’’)); 127.2 (d, C(4’’)); 111.7 (s, C(2)); 77.4 (t, C(5’)); 54.1 (s, C(1)); 52.8 (d, C(4’)); 49.5 (d, C(4)); 46.9 (s,
C(3)); 42.7 (t, CH2); 32.3 (q, Me); 30.2 (t, CH2); 26.0 (t, CH2); 22.3, 21.2 (2q, 2 Me). CI-MS (NH3): 289
(17, [M þ H]þ), 171 (7), 170 (100), 153 (9), 104 (8).
Crystals of 12 suitable for the X-ray crystal-structure determination were grown from EtOH.
1
Data of 13. Yield: 47 mg (15%). Purity 91% on the basis of H-NMR spectra. [a]2D3 ¼ ꢀ2.6 (c ¼ 1,
THF). IR: 3085w, 3063w, 3028w, 2958s, 2874s, 1602m, 1494m, 1468s, 1455s, 1385m, 1373m, 1364m, 1289w,
1278w, 1241w, 1201w, 1148w, 1113m, 1093s, 1070s, 1032m, 999m, 956w, 908m, 887m, 865m, 819w, 759m,
698s. 1H-NMR (300 MHz): 7.44 – 7.40 (m, HꢀC(2’’), HꢀC(6’’)); 7.34 – 7.22 (m, HꢀC(3’’), HꢀC(4’’),
HꢀC(5’’)); 4.45 – 4.37 (m, HꢀC(4’), 1 HꢀC(5’)); 3.80 – 3.71 (m, 1 HꢀC(5’)); 1.90 – 1.22 (m, 7 H); 1.16,
1.13, 1.08 (3s, 3 Me). 13C-NMR (75 MHz): 137.2 (s, C(1’’)); 128.5 (d, C(3’’), C(5’’)); 128.1 (d, C(2’’),
C(6’’)); 127.6 (d, C(4’’)); 111.7 (s, C(2)); 79.5 (t, C(5’)); 54.8 (s, C(1)); 53.0 (d, C(4’)); 48.9 (d, C(4)); 47.1 (s,
C(3)); 40.5 (t, CH2(7)); 33.4 (t, CH2); 28.5 (q, Me); 25.6 (t, CH2); 24.0, 16.6 (2q, 2 Me). CI-MS (NH3): 291
(6), 290 (20), 289 (100, [M þ H]þ), 171 (9), 170 (82), 153 (6), 104 (9).
5. Reactions of 14a. 5.1. With (R)-2-Phenyloxirane ((R)-11) in the Absence of SiO2. When (R)-11
(0.24 g, 2.0 mmol, 91% ee) was added to 14a (0.29 g, 2.5 mmol) at r.t., the mixture became warm. Then,
dry CH2Cl2 (20 ml) was added under stirring, and TLC showed complete conversion of (R)-11. After
stirring the mixture at r.t. for 1 h 15 min, CH2Cl2 was evaporated in vacuo. (S)-2-Phenylthiirane ((S)-15)
[14]3) was separated by CC (SiO2; hexane/Et2O 200 :1, 40 :1, and 25 :1) in 55% yield (150 mg) with
92.5% ee (HPLC, Chiralcel OD-H; tR(R) 19.6 min, tR(S) 20.73 min; eluent, hexane; flow rate, 0.5 ml/
min; 19 atm; 202 nm; [a]2D3 ¼ þ28.5 (c ¼ 1.0, heptane)) as a colorless oil8).
5.2. With (R)-11 in the Presence of SiO2. To a soln. of 14a (0.24 g, 2.1 mmol) in dry CH2Cl2 (3 ml) was
added (R)-11 (0.24 g, 2.0 mmol) at 08. The mixture was stirred at 08 for 1 h and then left to warm to r.t.
After stirring overnight at r.t., (R)-11 was not completely converted (TLC). Then, CH2Cl2 (3 ml) and
SiO2 (2 g) were added to the mixture, and the reaction was continued at r.t. After 30 h, no (R)-11 could
be detected by TLC, the mixture was filtered, and the residue was washed with Et2O (4ꢁ). Then, the
combined filtrate was evaporated in vacuo, and (S)-15 was separated by CC (SiO2; hexane/Et2O): 148 mg
(56%), 87.6% ee (Chiralcel OD-H; tR(R) 20.5 min, tR(S) 21.8 min; eluent, hexane; flow rate, 0.5 ml/min;
19 atm; 202 nm; [a]2D3 ¼ þ26.5 (c ¼ 1.0, heptane)).
5.3. With (RS)-2-[(tert-Butoxy)methyl]oxirane ((RS)-16a). The reaction of 14a (135 mg, 1.1 mmol)
with (RS)-16a (129 mg, 1.0 mmol) in anh. CH2Cl2 (15 ml) and SiO2 (4.5 g) for 3.5 h at r.t., yielded, after
purification by CC (SiO2, hexane/Et2O 13 :1 and 10 :1), 91 mg (62.8%) of pure 2-[(tert-butoxy)me-
thyl]thiirane ((RS)-17a). 1H-NMR (300 MHz, CDCl3): 3.66 (dd, J ꢂ 10.0, 5.5, 1 HꢀC(1’)); 3.23 (dd, J ꢂ
10.0, 6.5, 1 HꢀC(1’)); 3.07 – 2.98 (m, HꢀC(2)); 2.52 (d-like, J ꢂ 6.1, 1 HꢀC(3)); 2.20 (d, d-like, J ꢂ 5.3, 1.1,
1 HꢀC(3)); 1.20 (s, Me3C).
5.4. With (R)-2-[(Triphenylmethoxy)methyl]oxirane ((R)-16b). The reaction of 14a (69 mg,
0.6 mmol) with (R)-16b (158 mg, 0.5 mmol) in anh. CH2Cl2 (15 ml) and SiO2 (4.5 g) for 1 d at r.t.,
yielded, after purification by CC (SiO2, hexane/Et2O 4 :3) 145 mg (87.3%) of pure (R)-2-[(triphenyl-
methoxy)methyl]thiirane ((R)-17b) [17]5). [a]2D1 ¼ þ4.2 (c ¼ 1.0, CH2Cl2). [a]2D1 ¼ þ6.1 (c ¼ 1.0, THF).
Colorless crystals. M.p. 108.6 – 109.68. IR (KBr): 3084w, 3057m, 3032w, 3021w, 2925w, 2913w, 2864w,
1595w, 1490s, 1447s, 1395w, 1320w, 1214m, 1178w, 1154m, 1091s, 1076s (sh), 1031m, 1001w, 988m, 900m,
1
777m, 765s, 744m, 710s, 701s. H-NMR (300 MHz, CDCl3): 7.47 – 7.43 (m, 6 arom. H); 7.31 – 7.19 (m, 9
arom. H); 3.37 (dd, J ¼ 9.9, 5.4, 1 HꢀC(1’)); 3.12 (dd, J ¼ 10.0, 6.5, 1 HꢀC(1’)); 3.06 – 2.98 (m, HꢀC(2));
2.46 (d-like, J ꢂ 6.1, 1 HꢀC(3)); 2.10 (dd, J ꢂ 5.3, 1.1, 1 HꢀC(3)). 13C-NMR (75.5 MHz, CDCl3): 143.9 (s,
3 arom. C); 128.6 (d, 6 arom. CH); 127.8 (d, 6 arom. CH); 127.0 (d, 3 arom. CH); 86.8 (s, Ph3C); 68.3 (t,
CH2(1’)); 32.8 (d, CH(2)); 23.7 (t, CH2(3)). ESI-MS (MeOH/CH2Cl2): 355 (17, [M þ Na]þ), 304 (8), 282
(7), 243 (100, Ph3Cþ). Anal. calc. for C22H20OS (332.47): C 79.48, H 6.06, S 9.64; found: C 79.34, H 5.93, S
9.64.
Crystals of (R)-17b suitable for the X-ray crystal-structure determination were grown from Et2O/
hexane.
8
)
In [14b], it was claimed that (S)-15 was obtained with [a]D ¼ þ39.3 (heptane), which was correlated
with an ee of 90%.

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Helvetica Chimica Acta – Vol. 94 (2011)
5.5. With 1,2-Epoxycyclohexane (¼ 7-Oxabicyclo[4.1.0]heptane; 4). The reaction of 4 (190 mg,
1.65 mmol) with 14a (147 mg, 1.5 mmol) in anh. CH2Cl2 (15 ml) and SiO2 (4.0 g) for 27 h at r.t., yielded,
after purification by CC (SiO2; hexane/Et2O 23 :1), 126 mg (73.7%) of pure 7-thiabicyclo[4.1.0]heptane
(6) [4b].
6. X-Ray Crystal-Structure Determination of 12 and (R)-17b (Table and Figs. 1 and 2)9). All
measurements were performed on a Nonius KappaCCD area-detector diffractometer [21] using
graphite-monochromated MoKa radiation (l 0.71073 ꢅ) and an Oxford Cryosystems Cryostream 700
Table. Crystallographic Data of Compounds 12 and (R)-17b
12
(R)-17b
Crystallized from
EtOH
C18H24OS
288.45
colorless, plate
0.05 ꢁ 0.17 ꢁ 0.30
160(1)
Et2O/hexane
C22H20OS
332.46
colorless, prism
0.15 ꢁ 0.22 ꢁ 0.28
160(1)
Empirical formula
Formula weight [g molꢀ1
Crystal color, habit
Crystal dimensions [mm]
Temp. [K]
]
Crystal system
Space group
monoclinic
P21
monoclinic
P21
Z
2
2
Reflections for cell determination
36425
16937
2q Range for cell determination [8]
4 – 55
4 – 55
Unit cell parameters:
a [ꢅ]
b [ꢅ]
c [ꢅ]
7.2196(2)
6.3380(2)
16.6427(6)
91.161(2)
761.38(4)
1.258
0.207
f and w
55
8.7354(3)
10.6394(3)
9.5620(2)
98.159(2)
879.69(4)
1.255
0.189
f and w
55
b [8]
V [ꢅ3]
DX [g cmꢀ3
]
m(MoKa) [mmꢀ1
Scan type
]
2q(max) [8]
Transmission factors (min; max)
Total reflections measured
Symmetry-independent reflections
Reflections with I > 2s(I)
Reflections used in refinement
Parameters refined; restraints
Final R(F) [I > 2s(I) reflections]
wR(F2) (all data)
0.912; 0.991
16865
3432
2740
3432
185; 1
0.0414
0.0873
0.0360; 0.1237
1.033
0.906; 0.973
19556
4039
3466
4038
218; 1
0.0431
0.1016
0.0589; 0.0238
1.099
Weighting parameters [a; b]a)
Goodness-of-fit
Secondary extinction coefficient
Final Dmax/s
0.025(4)
0.002
0.26; ꢀ 0.34
0.36(2)
0.001
0.27; ꢀ 0.29
D1 (max; min) [e ꢅꢀ3
]
a) w ¼ [s2(F2o ) þ (aP)2 þ bP]ꢀ1, where P ¼ (Fo2 þ 2F2c )/3.
9
)
CCDC-809596 and 809597 contain the supplementary crystallographic data for this article. These
data can be obtained free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.

Helvetica Chimica Acta – Vol. 94 (2011)
783
cooler. The data collection and refinement parameters are given in the Table, and views of the molecules
are shown in Figs. 1 and 2. Data reduction was performed with HKL Denzo and Scalepack [22]. The
intensities were corrected for Lorentz and polarization effects, and absorption corrections based on the
multi-scan method [23] were applied. The structures were solved by direct methods using SIR92 [24],
which revealed the positions of all non-H-atoms. The non-H-atoms were refined anisotropically. All of
the H-atoms were placed in geometrically calculated positions and refined using a riding model where
each H-atom was assigned a fixed isotropic displacement parameter with a value equal to 1.2 Ueq of its
parent C-atom (1.5 Ueq for the Me groups in 12). The refinement of each structure was carried out on F2
using full-matrix least-squares procedures, which minimized the function Sw(F2o ꢀ Fc2 )2. A correction for
secondary extinction was applied in both cases. In (R)-17b, one reflection, whose intensity was
considered to be an extreme outlier, was omitted from the final refinement. Refinement of the absolute
structure parameters [25] yielded a value of 0.01(7) and 0.00(7), resp., which confidently confirmed that
the refined models correspond with the true enantiomorphs. Neutral atom scattering factors for non-H-
atoms were taken from [26a], and the scattering factors for H-atoms were taken from [27]. Anomalous
dispersion effects were included in Fc [28]; the values for f’ and f’’ were those of [26b]. The values of the
mass attenuation coefficients are those of [26c]. All calculations were performed using the SHELXL97
[29] program.
REFERENCES
[1] J. A. Durden Jr., M. H. J. Weiden, J. Agric. Food. Chem. 1969, 17, 94; H. Bekemeier, D. Koester,
Pharmazie 1976, 31, 317; M. Pigini, L. Brasili, M. Gianella, F. Gualtieri, Eur. J. Med. Chem. 1981, 16,
415; E. Teodori, F. Gualtieri, P. Angeli, L. Brasili, M. Gianella, M. Pigini, J. Med. Chem. 1986, 29,
1610; F. Gualtieri, M. N. Romanelli, E. Teodori, Farmaco 1989, 44, 897.
[2] J. van Heerden, J. C. Breytenbach, D. D. NꢄDa, J. W. Breytenbach, J. L. du Preez, Med. Chem. 2010,
6, 91; F. Hu, Y. Du, H. Yuan, Q. Li, Faming Zhuanli Shenqing 2010, CN 101805334 (Chem. Abstr.
2010, 153, 359046); Y. Zhang, J. Zhu, M. Huo, Faming Zhuanli Shenqing 2010, CN 101766632
(Chem. Abstr. 2010, 153, 250723); S. Rama, R. R. Vennapureddy, A. P. Sayyed, M. K. Ankaraju, S. B.
Madasu, J. R. Vascuri, S. Meenakshisunderam, PTC Int. Appl. 2010, 082128 (Chem. Abstr. 2010, 153,
204594); I. Giordano, A. J. Hennessy, PTC Int. Appl. 2010, 043714 (Chem. Abstr. 2010, 152, 477113);
D. Zhang, Faming Zhuanli Shenqing Gongkai Shuomingshu 2010, CN 101671332 (Chem. Abstr.
2010, 152, 429729); J. You, S. Jiang, Faming Zhuanli Shenqing Gongkai Shuomingshu 2009, CN
101407513 (Chem. Abstr. 2009, 150, 495107).
[3] a) Y. Pustovit, A. Alexeenko, S. Trofymchuk, O. Lukin, A. A. Tolmachev, Synthesis 2010, 1159;
b) A. I. Carrillo, E. Serrano, R. Luque, J. G. Matꢆnez, Chem. Commun. 2010, 46, 5163; c) M.
Alajarin, B. Bonillo, P. Sanchez-Andrada, A. Vidal, J. Org. Chem. 2010, 75, 3737; d) H. Xiao, Y. Guo,
X. Liang, C. Qi, J. Solid State Chem. 2010, 183, 1721; e) J. R. Peterson, US Pat. Appl. 2010, 143978
(Chem. Abstr. 2010, 153, 60523); f) F. Shirini, P. Sadeghzadeh, M. Abedini, Chin. Chem. Lett. 2009,
20, 1457; g) S. K. Singh, K. N. Singh, Phosphorus, Sulfur, Silicon Relat. Elem. 2009, 184, 2339; h) M.
North, P. Villuendas, Synlett 2010, 623; i) A. Dandia, R. Singh, S. Bhaskaran, Ultrasonics Sonochem.
2010, 17, 399.
[4] a) A. Fedorov, C. Fu, H. Heimgartner, Helv. Chim. Acta 2006, 89, 456; b) S. Malaschichin, C. Fu, A.
Linden, H. Heimgartner, Helv. Chim. Acta 2005, 88, 3253; c) A. Fedorov, C. Fu, A. Linden, H.
Heimgartner, Eur. J. Org. Chem. 2005, 1613; d) C. Fu, M. Blagoev, A. Linden, H. Heimgartner,
Phosphorus, Sulfur, Silicon Relat. Elem. 2005, 180, 1309, and refs. cited therein.
[5] a) C. Fu, A. Linden, H. Heimgartner, Helv. Chim. Acta 2003, 86, 2833; b) C. Fu, A. Linden, H.
Heimgartner, Helv. Chim. Acta 2004, 87, 2296.
[6] M. Blagoev, A. Linden, H. Heimgartner, Helv. Chim. Acta 1999, 82, 2316.
[7] W. Davies, W. E. Savige, J. Chem. Soc. 1949, 278; F. G. Bordwell, H. M. Andersen, J. Am. Chem. Soc.
1953, 75, 4959; C. G. Moore, M. Porter, J. Chem. Soc. 1958, 2062; J. A. Durden Jr., H. A. Stansbury
Jr., W. H. Catlette, J. Am. Chem. Soc. 1959, 81, 1943.
[8] H. Yu, S. Cao, L. Zhang, G. Liu, J. Xu, Synthesis 2009, 2205; B. Zeynizadeh, S. Yeghaneh,
Phosphorus, Sulfur, Silicon Relat. Elem. 2009, 184, 362; A. T. Guseinova, K. I. Alieva, I. A. Rzaeva,

784
Helvetica Chimica Acta – Vol. 94 (2011)
A. M. Magerramov, I. A. Aliev, V. M. Farzaliev, M. A. Allakhverdiev, Russ. J. Appl. Chem. 2009, 82,
1587; C. Forbes, Q. Shi, J. F. Fisher, M. Lee, D. Hesek, L. I. Llarrull, M. Toth, M. Gossing, R.
Fridman. S. Mobashery, Chem. Biol. Drug Design 2009, 74, 527.
[9] a) H. Jiang, N. Holub, M. W. Paixao, C. Tiberi, A. Falcicchio, K. A. Jørgensen, Chem.–Eur. J. 2009,
15, 9638; b) Z.-H. Sun, B. Wang, J. Org. Chem. 2008, 73, 2462; c) M. Fukudome, T. Onizuka, S.
Kawamura, D.-Q. Yuan, K. Fujita, Tetrahedron Lett. 2007, 48, 6665; d) S. Escher, Y. Niclass, M.
van de Waal, C. Starkenmann, Chem. Biodiversity 2006, 3, 943; e) E. Elhalem, M. J. Comin, J. B.
Rodriguez, Eur. J. Org. Chem. 2006, 4473; f) M. Lee, M. M. Bernardo, S. O. Meroueh, S. Brown, R.
Fridman, S. Mobashery, Org. Lett. 2005, 7, 4463.
[10] N. K. Rozhkova, K. Sabirov, K. L. Seitanidi, Khim. Geterotsikl. Soedin. 1983, 1479 (Chem. Abstr.
1984, 100, 139012); R. C. Cambie, P. S. Rutledge, G. A. Strange, P. D. Woodgate, Heterocycles 1982,
19, 1501; N. A. Aliev, R. G. Aflyatunova, K. Giyasov, Fungitsidy 1980, 46 (Chem. Abstr. 1981, 94,
192196).
[11] P. Kalicki, M. Karchier, K. Michalak, J. Wicha, J. Org. Chem. 2010, 75, 5388.
[12] C. K. Johnson, ꢃORTEP II. Report ORNL-5138ꢄ, Oak Ridge National Laboratory, Oak Ridge,
Tennessee, 1976.
[13] C. Fu, A. Linden, H. Heimgartner, Helv. Chim. Acta 2003, 86, 2258.
[14] a) J. M. Stewart, J. Org. Chem. 1963, 28, 596; b) N. Iranpoor, H. Firouzabadi, A. Jafari, Phosphorus,
Sulfur, Silicon Relat. Elem. 2005, 180, 1809 and refs. cited therein.
[15] C. M. Kleiner, L. Horst, C. Wꢁrtele, R. Wende, P. R. Schreiner, Org. Biomol. Chem. 2009, 7, 1397.
[16] V. Oremus, A. Linden, H. Heimgartner, Helv. Chim. Acta 1991, 74, 1500.
´
[17] J. Harfouche, D. Herault, M. L. Tommasino, S. Pellet-Rostaing, M. Lemaire, Tetrahedron:
Asymmetry 2004, 15, 3413.
[18] P.-C. Tromm, H. Heimgartner, Helv. Chim. Acta 1990, 73, 2287; M. Blagoev, A. Linden, H.
Heimgartner, Helv. Chim. Acta 1999, 82, 1458; M. Blagoev, A. Linden, H. Heimgartner, Helv. Chim.
Acta 2000, 83, 3163; C. Fu, A. Linden, H. Heimgartner, Heterocycles 2002, 58, 333.
[19] C. Fu, M. V. Thrane, A. Linden, H. Heimgartner, Tetrahedron 2004, 60, 5407.
[20] D. Moya Argilagos, R. W. Kunz, A. Linden, H. Heimgartner, Helv. Chim. Acta 1998, 81, 2388.
[21] R. Hooft, KappaCCD Collect Software, Nonius BV, Delft, The Netherlands, 1999.
[22] Z. Otwinowski, W. Minor, in ꢃMethods in Enzymologyꢄ, Vol. 276, ꢃMacromolecular Crystallographyꢄ,
Part A, Eds. C. W. Carter Jr., R. M. Sweet, Academic Press, New York, 1997, p. 307.
[23] R. H. Blessing, Acta Crystallogr., Sect. A 1995, 51, 33.
[24] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. C. Burla, G. Polidori, M. Camalli,
SIR92, J. Appl. Crystallogr. 1994, 27, 435.
[25] H. D. Flack, G. Bernardinelli, Acta Crystallogr., Sect. A 1999, 55, 908; H. D. Flack, G. Bernardinelli,
J. Appl. Crystallogr. 2000, 33, 1143.
[26] a) E. N. Maslen, A. G. Fox, M. A. OꢄKeefe, in ꢃInternational Tables for Crystallographyꢄ, Ed. A. J. C.
Wilson, Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 6.1.1.1, p. 477; b) D. C. Creagh,
W. J. McAuley, in ꢃInternational Tables for Crystallographyꢄ, Ed. A. J. C. Wilson, Kluwer Academic
Publishers, Dordrecht, 1992, Vol. C, Table 4.2.6.8, p. 219; c) D. C. Creagh, J. H. Hubbell, in
ꢃInternational Tables for Crystallographyꢄ, Ed. A. J. C. Wilson, Kluwer Academic Publishers,
Dordrecht, 1992, Vol. C, Table 4.2.4.3, p. 200.
[27] R. F. Stewart, E. R. Davidson, W. T. Simpson, J. Chem. Phys. 1965, 42, 3175.
[28] J. A. Ibers, W. C. Hamilton, Acta Crystallogr. 1964, 17, 781.
[29] G. M. Sheldrick, SHELXL97, Program for the Refinement of Crystal Structures, University of
Gçttingen, Gçttingen, 1997.
Received January 28, 2011