Stereospecific cyclodehydration of 1,4-sulfanylalcohols to thiolanes: mechanistic insights

Article abstract of DOI:10.1016/j.tet.2008.07.088

A series of thiolanes were prepared by cyclodehydration of sulfanylalcohols in the presence of catalytic amounts of p-toluenesulfonic acid or by using K10 clay. The sulfur heterocycles were synthesised in good to excellent yields using either a conventional Dean-Stark method or microwave irradiation under solvent-free conditions. The reaction could be performed regio- and stereoselectively and its mechanism was investigated by means of enantio- and diastereomerically enriched substrates. In contrast to previous studies, our results are consistent with an intramolecular S_N2-type mechanism as a general pathway.

Full text of DOI:10.1016/j.tet.2008.07.088

Tetrahedron 64 (2008) 9999–10003
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereospecific cyclodehydration of 1,4-sulfanylalcohols to thiolanes:
mechanistic insights
*
Jean-Jacques Filippi , Elisabet Dun˜ach, Xavier Fernandez, Uwe J. Meierhenrich
LCMBA, Universite´ de Nice-Sophia Antipolis, CNRS, UMR 6001, Institut de Chimie de Nice, Faculte´ des Sciences, Parc Valrose, F-06108 NICE Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of thiolanes were prepared by cyclodehydration of sulfanylalcohols in the presence of catalytic
amounts of p-toluenesulfonic acid or by using K10 clay. The sulfur heterocycles were synthesised in good
to excellent yields using either a conventional Dean–Stark method or microwave irradiation under
solvent-free conditions. The reaction could be performed regio- and stereoselectively and its mechanism
was investigated by means of enantio- and diastereomerically enriched substrates. In contrast to
previous studies, our results are consistent with an intramolecular SN2-type mechanism as a general
pathway.
Received 21 March 2008
Received in revised form 16 July 2008
Accepted 18 July 2008
Available online 26 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
obtained by reduction of thionolactones.21 Although the cyclo-
dehydration of compounds having the 1,4-thiol-alcohol pattern has
A large number of volatile organic sulfur compounds (VOSCs) is
known to occur in plants, food and aroma extracts. In most cases,
VOSCs have been described to provide a strong contribution to the
organoleptic profile of these extracts due to their powerful olfac-
tory properties.1–3 Cyclic sulfides such as thiolanes (tetrahy-
drothiophenes) and thianes are found in abundance in crude oil
distillates to which they are known to give malodour.4–6 However,
like many other sulfur heterocycles such as thiophenes, thiazoles
and thiapyrans, they can exhibit interesting olfactory properties at
low concentrations and thus contribute to the aromatic profile of
exotic fruits,7 wines8 and meat.9 In the frame of flavour and
fragrance chemistry, we have been looking for new synthetic
methodologies allowing the systematic preparation of sulfur het-
erocycles. In the last years, our work resulted in the development of
novel routes to thiono-10,11 and thiolactones,12 thioethers,13 thio-
esters14 and sultines.15
According to the literature, thiolanes can be prepared by
thiophene hydrogenation,16 reaction of 1,4-dihalogenated com-
pounds17 or activated 1,4-diols18–20 with sulfur reagents, or cyclo-
isomerisation of olefinic thiols.13 Our strategy was to prepare
thiolanes from chiral 1,4-sulfanylalcohols21,22 as their natural
homologuesd1,3-sulfanylalcoholsdare known to be precursors of
natural odourant sulfur heterocycles such as oxathianes23 and
sultines.15
already been described in the literature,24–26 to the best of our
knowledge, no previous study reported the synthesis of volatile
thiolane derivatives under catalytic conditions.
2. Results and discussion
We found that 1,4-sulfanylalcohols 1a–g provide direct access to
thiolane derivatives 2a–g upon treatment with catalytic amounts of
p-toluenesulfonic acid (p-TSA) or Montmorillonite K10 (Scheme 1).
Two activation methods were applied for these preparations:
conventional oil-bath heating and solvent-free microwave irradi-
ation. Our results are summarised in Table 1.
R'
10 mol% p-TSA
OH
or K10
SH
R
Δ or μ-waves,
toluene or neat
R
S
R'
1a-g
2a-g
Scheme 1. Cyclodehydration of 1,4-sulfanylalcohols 1 to thiolanes 2.
We first investigated the cyclodehydration of 1,4-sulfanylalco-
hols 1a–d to the corresponding thiolanes 2a–d using a Dean–Stark
trap over refluxing toluene in the presence of 10 mol % p-TSA. Un-
der these conditions, a clean reaction took place, giving complete
conversion of the substrates after ca. 5 h, affording the expected
thiolanes in 80–94% yields with purities ꢀ98% as checked by GC
(Table 1, entries 1–4). We further investigated the possibility to
achieve this cyclodehydration in a microwave oven as previously
used with some acid-promoted reactions.27–29 Thus, a series of
Here, we report on the preparation of a series of thiolanes 2a–g
by cyclodehydration of 1,4-sulfanylalcohols 1a–g previously
* Corresponding author. Tel.: þ33 492076129; fax: þ33 492076151.
E-mail address: jfilippi@unice.fr (J.-J. Filippi).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.088

10000
J.-J. Filippi et al. / Tetrahedron 64 (2008) 9999–10003
Table 1
Synthesis of thiolanes from 1,4-sulfanylalcohols
Entry
Sulfanylalcohols
R
R0
Activating method
Conditions
Thiolanes
Yielda (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1a
1b
1e
1a
n-Pr
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
H
H
H
H
D
D
D
D
p-TSA, toluene, 5 h
p-TSA, toluene, 5 h
p-TSA, toluene, 5 h
p-TSA, toluene, 5 h
p-TSA, 90 s
2a
2b
2c
2d
2a
2b
2e
2a
80
84
94
89
74
84
92
65
88
90
88
84
85
91
98
91
90b
n-Pent
n-Hex
n-Hept
n-Pr
n-Pent
n-Bu
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
D
p-TSA, 90 s
p-TSA, 90 s
n-Pr
K10 clay, 90 s
K10 clay, 90 s
K10 clay, 90 s
K10 clay, 90 s
K10 clay, 90 s
K10 clay, 90 s
K10 clay, 90 s
p-TSA, toluene, 5 h
p-TSA, 90 s
9
1c
1f
n-Hex
n-Oct
n-Bu
n-Bu
n-Bu
n-Hex
n-Hex
n-Hex
n-Hex
2c
2f
10
11
12
13
14
15
16
17
1g (syn/anti, 4/6)
rac-syn-1g (97% de)
rac-anti-1g (99% de)
(R)-1c (98% ee)
(R)-1c (98% ee)
(R)-1c (98% ee)
(R)-1c (98% ee)
2g (cis/trans 6/4)
rac-trans-2g (87% de)b
b
rac-cis-2g (82% de)
(S)-2c (80% ee)c
(S)-2c (98% ee)c
MW
D
(S)-2c (70% ee)c
p-TSA, solvent
free, 180 ꢂC, 5 min
(S)-2c (86% ee)cþ9% 2-hexyltetrahydrofuran
a
Determined after purification by silica gel column chromatography.
Determined by GC.
Determined by enantioselective GC after derivatisation of the thiolane into its corresponding thiolane-1-oxide (see Section 4 for details).
b
c
sulfanylalcohols 1 were directly submitted to solvent-free and
microwave irradiation conditions with 10 mol % p-TSA in open glass
tubes. In a typical experiment, the reaction mixture was irradiated
for 90 s (3ꢁ30 s) at maximum power (850 W) until no water
evolved from it. Purification was achieved by using a short silica gel
column, and thiolanes 2 were obtained in good yields ranging from
74 to 92% (Table 1, entries 5–7). Comparing the results obtained for
substrates 1a–b (entries 1, 2, 5 and 6), both procedures were similar
in terms of yield, but dramatically differed in terms of reaction time.
Both procedures afforded selectively the expected thiolanes 2 with
nearly no formation of the corresponding tetrahydrofurans as
checked by GC (<1%). In further attempts, the reaction was carried
out with Montmorillonite K10 instead of p-TSA, as this acidic clay
has been described to efficiently promote various acid-catalysed
reactions,30 and reported to be particularly useful for solvent-free
microwave procedures.
Thus, mixtures of sulfanylalcohol 1 and 1.5 wt equivalent of K10
clay were subsequently exposed to microwave irradiation for 90 s.
The corresponding thiolanes 2a, c and f were isolated by solvent
extraction of the crude material in 65–90% yields (Table 1, entries
8–10). It is worth mentioning that, here again, the corresponding
tetrahydrofurans were produced in only trace amounts.
Conventional and microwave procedures using either p-TSA or
Montmorillonite K10 afforded similar results in terms of selectivity.
However, microwave procedures using open glass tubes offered
less advantageous conditions for the synthesis of very volatile
thiolanes, i.e., 2-propylthiolane 2a was assumed to evaporate dur-
ing irradiation, resulting in lower yields of 74 and 65% (entries 5
and 8).
mechanism. Alcohol protonation in acidic media produces favour-
able conditions for a subsequent nucleophilic substitution. Usually,
primary and tertiary alcohols are intended to proceed, respectively,
through SN2 and SN1 mechanisms. In contrast, the reactivity of
secondary alcohols is not so well defined and actually depends on
several reaction parameters. To our knowledge, previous studies on
thiolane preparation from cyclodehydration of 1,4-sulfanylalcohols
reported the use of substrates having a tertiary alcohol.24–26 Con-
sequently, the reaction mechanism, when studied, was described to
involve a carbocation as the reaction intermediate.25,26
When a 4/6 mixture of syn- and anti-isomers 1g was submitted
to cyclodehydration with p-TSA (entry 11), the reaction afforded 2g
as a mixture of diastereomers presenting the same 4/6 ratio, in-
dicative of a specific mechanism during ring closure. In order to
investigate this experimental observation, both syn- and anti-di-
astereomers of 1g were independently synthesised from whisky
thionolactone 3g, previously obtained by thionation of whisky
lactone.10,31 The two diastereomers of 3g were separated by silica
gel column chromatography and further reduced with LiAlH4 to
rac-syn-1g (97% de) and rac-anti-1g (99% de),22 as shown in Scheme
2. Submitting the isomer rac-syn-1g to cyclodehydration (under
K10, MW, 90 s) afforded selectively trans-2g in 84% isolated yield
and 87% de (entry 12). On the other hand, when the same reaction
was run with rac-anti-1g, rac-cis-2g was isolated in 85% yield and
presented 82% de (entry 13 and Scheme 2). The stereo- and
regiospecificity observed in both cases clearly support a major
intramolecular SN2-type mechanism giving almost complete in-
version of configuration during the formation of the thiolane ring.
In the latter case, a higher steric hindrance in the transition state
could explain a decrease of selectivity between SN2 and SN1,
resulting in a higher racemisation (Scheme 3).
As the reaction turned out to work well with each applied
procedure, we were interested in getting more insights into its
OH
K10
rac-trans-2g
SH
LiAlH4
rac-cis 3g
MW
THF
S
S
O
rac-syn-1g
S
97% de
98% yield
84% yield
97% de
87% de
S
O
OH
rac-anti-1g
cis/trans
whisky thionolactone
3g
LiAlH4
THF
K10
MW
rac-trans 3g
99% de
rac-cis-2g
SH
O
S
95% yield
99% de
85% yield
82% de
Scheme 2. Stereospecific synthesis of cis- and trans-whisky thiolanes 2g.

J.-J. Filippi et al. / Tetrahedron 64 (2008) 9999–10003
10001
OH
cyclodehydration with p-TSA using an oil-bath set to 180 ꢂC. De-
spite a lower selectivity due to the formation of 2-hexyltetrahy-
drofuran (9%), (S)-2c was obtained with 86% ee (entry 17). As
a consequence, the loss of enantioselectivity observed for both
microwave procedures (entries 14 and 16) indicated that a carbo-
cationic SN1 mechanism participated in the reaction as a minor
pathway, estimated to contribute in 7–15%. As previously men-
tioned for microwave-assisted synthesis, it is likely that carboca-
tionic mechanisms having polar transition states may be favourably
enhanced under microwave irradiation.32
Finally, these results confirmed a major SN2 pathway involving
the inversion of configuration during ring closure of 1,4-sulfanyl-
alcohols containing secondary hydroxyl groups. Indeed, the type of
mechanism involved in the cyclodehydration depends on the
substitution pattern of the OH group, the nature and the strength of
the acid used, and the activation method (conventional heating
versus microwave irradiation).
OH
syn-isomer
anti-isomer
H
R
SH
R
SH
H
R'
R'
H+
H+
R'
H
H
R
R
SH
SH
H2O
H2O
R'
SN2
SN2
R'
R'
H
R
OH2
OH2
S
S
H
H
R
H
–H+
–H2O
–H+
–H2O
R'
R'
3. Conclusion
cis
trans
R
R
We described a new and efficient acid-catalysed regiospecific
and stereoselective synthesis of thiolane derivatives from 1,4-sul-
fanylalcohols. The reaction can be performed either under con-
ventional conditions (p-TSA, toluene, Dean–Stark) or more rapidly
under microwave irradiation in the presence of Montmorillonite
K10. The mechanism of ring formation has been examined and
involves mainly an intramolecular SN2 process with inversion of
configuration during water displacement. The possibility to prepare
enantio- and diastereomerically enriched sulfur heterocycles has
been demonstrated.
S
S
Scheme 3. Stereospecific ring closure of 2,3-disubstituted thiolanes.
The possibility of considering a mechanism involving a first
dehydration step with formation of a carbocationic intermediate
(or an olefin) should therefore be considered as a minor pathway
for these reactions.
To elucidate the reaction mechanism in more detail, we exam-
ined the cyclodehydration of (R)-1c enantiomerically enriched to
98% ee. (R)-1c was obtained from the reduction of (R)-
g-thio-
nodecalactone 3c, synthesised from commercial (R)- -decalactone
g
4. Experimental
4.1. General
4c (Scheme 4).11 The cyclodehydration of (R)-1c in the presence of
K10 under microwave irradiation produced the optically active
thiolane (S)-2c ([a]2D0 ꢃ59.8) isolated in 91% yield (entry 14, Scheme
4). In spite of the numerous chiral stationary phases tested, its
enantiomeric excess failed to be determined by direct enantiose-
lective GC analysis. Thus, (S)-2c was derivatised into its
Solvents and chemicals were used as received otherwise in-
dicated. p-TSA and Montmorillonite K10 were purchased from
Sigma–Aldrich. p-TSA was dried according to the described
procedure.33 Toluene and THF were distilled over sodium/benzo-
phenone prior to use in reaction. Sulfanylalcohols 1a–g were pre-
pared as described elsewhere.21,22 The microwave oven used for
this study was an unmodified household Samsung M181DN oven
running at maximum power (850 W), so as to obtain the most
homogeneous irradiation as possible. 1H and 13C NMR spectra were
measured in CDCl3 with Bruker AC200 and DRX 500 spectrometers
locked on the solvent signal. EIMS was obtained from an Agilent
6890N/5973N GC/MS system operated at 70 eV as the strength of
electron impact and with a 35–350 amu detection range. Optical
rotation of thiolane (S)-2c was measured on an Ameria AA10 po-
larimeter using a 0.1 M dichloromethane solution in a thermo-
stated room (20 ꢂC). Elemental analyses were performed at the
Institut de Chimie des Substances Naturelles (Gif-sur-Yvette,
France), and at the Chemistry Department of the University of Nice
(France) using a Thermo Electron microanalyser EA1112.
corresponding thiolane-1-oxide 5c as
diastereomers, which resulted in a baseline resolution on a Hydro-
dex- -6tBDM capillary column (Macherey-Nagel, Germany). An
80% ee was determined for the major diastereomer (trans),
indicating thus the same ee for (S)-2c.
In order to further examine the enantioselectivity of the re-
action, we performed the cyclodehydration of (R)-1c using all the
above-mentioned procedures. With 10 mol % p-TSA in refluxing
toluene (entry 15), (S)-2c was obtained with 98% ee. On the other
hand, when p-TSA was used under microwave irradiation and sol-
vent-free conditions, (S)-2c showed a 70% ee, indicative of a partial
racemisation (entry 16).
Exposing (R)-1c to microwave irradiation with p-TSA under
solvent-free conditions (entry 15) resulted in a final temperature of
180ꢄ5 ꢂC. As we wanted to determine a possible microwave effect
on the reaction mechanism, (R)-1c was submitted to
a cis/trans mixture of
b
OH
LR
LiAlH4
HMDO
SH
O
S
THF
O
O
MW
(R)-1c
(R)-4c
(R)-3c
ee
Activation
Conditions (trans-5c)
p-TSA
Δ
p-TSA, toluene
p-TSA, solvent free
p-TSA, solvent free
K10, solvent free
98%
86%
70%
80%
Derivatisation
or K10
Δ
+
S
O
S
O
mCPBA
MW
MW
S
MW
CH2Cl2
trans-5c
cis-5c
or Δ
(S)-2c
Scheme 4. Synthesis of (S)-2-hexylthiolane and its derivatisation for enantiomeric excess determination.

10002
J.-J. Filippi et al. / Tetrahedron 64 (2008) 9999–10003
4.2. Dean–Stark procedure
4.3.5. 1-Sulfanylundecan-4-ol 1d
1H NMR (200 MHz, CDCl3):
d
0.86 (m, 3H, CH3), 1.33 (t, 1H,
In a 50 mL two-necked round-bottom flask equipped with
a Dean–Stark trap, a mixture of sulfanylalcohol 1 (5 mmol) and
p-TSA (0.5 mmol) was dissolved in 30 mL toluene. The reaction was
run in refluxing toluene under magnetic stirring until no starting
compound was detected in aliquots withdrawn from the reaction
mixture and analysed by GC (about 5 h for complete conversion).
The mixture was then washed with 0.1 N NaOH and the organic
layer was dried over magnesium sulfate. After solvent evaporation,
the crude product was purified by silica gel column chromatogra-
phy using distilled n-hexane or petroleum ether (40–60 grade) as
the eluting solvent. Thiolanes 2 were obtained as nearly colourless
oils after solvent evaporation.
J¼7.9 Hz, SH), 1.20–1.90 (m, 17H, 8ꢁCH2, OH), 2.56 (dt, 2H,
J¼7.0 Hz, J¼7.8 Hz, CH2SH), 3.60 ppm (m, 1H, CHOH). 13C NMR
(200 MHz, CDCl3):
d 14.1 (C11), 22.7 (C10), 24.8 (C1), 25.7 (C6),
29.3 (C7), 29.7 (C8), 30.2 (C2), 31.9 (C9), 36.1 (C3), 37.7 (C5),
71.5 ppm (C4). MS (EI, 70 eV): m/z (%) 41 (33.8), 43 (35.2), 55
(26.9), 57 (15.8), 60 (41.0), 69 (29.6), 71 (20.2), 87 (100), 101 (23.7),
ꢅ
129 (14.3), 204 (Mþ , 0.1).
4.3.6. 1-Sulfanyldodecan-4-ol 1f
1H NMR (200 MHz, CDCl3):
d 0.88 (m, 3H, CH3), 1.36 (t, 1H,
J¼7.8 Hz, SH), 1.20–1.90 (m, 19H, 9ꢁCH2, OH), 2.56 (dt, 2H, J¼7.0 Hz,
J¼7.7 Hz, CH2SH), 3.60 ppm (m, 1H, CHOH). 13C NMR (200 MHz,
CDCl3):
d 14.1 (C12), 22.7 (C11), 24.7 (C1), 25.6 (C6), 29.3 (C8), 29.6
(C7), 29.7 (C9), 30.2 (C2), 31.9 (C10), 36.0 (C3), 37.6 (C5), 71.5 ppm
(C4). MS (EI, 70 eV): m/z (%) 41 (30.0), 43 (32.7), 55 (26.8), 57 (16.7),
60 (42.0), 69 (23.8), 71 (18.6), 83 (12.7), 87 (100), 101 (23.9), 218
4.3. Microwave procedure
ꢅ
Sulfanylalcohols 1 (5 mmol) and p-TSA (0.5 mmol) or Mont-
morillonite K10 (1.5 equiv w/w) were placed in a Pyrex glass tube
(160ꢁ15 mm i.d.). When K10 clay was used, both 1 and K10 were
thoroughly mixed to obtain a powder material. The tube was then
placed at the centre of the oven cavity and irradiated at 850 W for
90 s, using a sequential irradiation to check the evolution of water
from the reaction mixture. In the case of p-TSA, the resulting
mixture was dissolved in chloroform and treated as indicated
above. In the case of Montmorillonite K10, the residue was tritu-
rated with hexane (2ꢁ10 mL) and directly filtered over Celite.
All compounds have been characterised by 1H and 13C NMR and
EIMS. Partial spectral characterisation of starting sulfanylalcohols 1
has already been reported.21 Thiolanes 2a–f are known compounds
(2a: CAS 1551-34-4; 2b: CAS 3050-98-4; 2c: CAS 876-37-9; 2d: CAS
24767-96-2; 2e: CAS 1613-49-6; 2f: CAS 5143-23-7), however, only
partial spectral data are given in the literature. New compounds cis-
2g and trans-2g were characterised by NMR, EIMS and elemental
analysis.
(Mþ , 0.1).
4.3.7. syn-3-Methyl-1-sulfanyloctan-4-ol 1g
1H NMR (500 MHz, CDCl3):
d
0.89 (d, 3H, J¼6.8 Hz, CHCH3), 0.93
(t, 3H, J¼7.1 Hz, CH2CH3), 1.25–1.40 (m, 3H, CH3CH2CH2), 1.35 (t,
J¼7.7 Hz, SH), 1.43–1.48 (m, 4H, CH3CH2CH2CH2, OH), 1.56 (dtd,
1H, J¼5.6 Hz, J¼8.4 Hz, J¼13.7 Hz, CH2CH2SH), 1.69 (m, 1H,
CH2CH(OH)CH(CH3)CH2CH2SH), 1.76 (dddd, 1H, J¼5.3 Hz, J¼6.7 Hz,
J¼8.5 Hz, J¼13.3 Hz, CH2CH2SH), 2.54 (dddd, 1H, J¼6.8 Hz,
J¼7.5 Hz, J¼8.5 Hz, J¼12.9 Hz, CH2SH), 2.65 (dddd, 1H, J¼5.6 Hz,
J¼7.8 Hz, J¼8.7 Hz, J¼13.3 Hz, CH2SH), 3.52 ppm (m, 1H, CHOH). 13
C
NMR (CDCl3): d 13.3 (C9, CHCH3), 14.2 (C8, CH2CH3), 22.8 (C1), 22.9
(C7), 28.6 (C6), 34.2 (C5), 37.1 (C3), 37.8 (C2), 74.8 ppm (C4). EIMS
m/z (%): 41 (26.2), 55 (19.9), 56 (70.9), 57 (33.7), 69 (69.2), 81 (15.3),
ꢅ
85 (14.6), 87 (19.7), 90 (17.1), 101 (100), 176 (Mþ , 0.1).
4.3.8. anti-3-Methyl-1-sulfanyloctan-4-ol 1g
1H NMR (500 MHz, CDCl3):
d
0.92 (d, 3H, J¼6.7 Hz,
CHCH3), 0.93 (t, 3H, J¼6.9 Hz, CH2CH3), 1.25–1.58 (m, 9H,
CH3CH2CH2CH2CH(OH)CH(CH3)CH2), 1.35 (t, J¼7.6 Hz, SH), 1.69 (m,
1H, CHCH3), 1.79 (dddd, 1H, J¼3.8 Hz, J¼7.2 Hz, J¼9.1 Hz,
J¼13.2 Hz, CH2CH2SH), 2.50 (ddt, 1H, J¼7.5 Hz, J¼9.1 Hz,
J¼12.9 Hz, CH2SH), 2.68 (dddd, 1H, J¼5.1 Hz, J¼7.8 Hz, J¼9.0 Hz,
J¼12.9 Hz, CH2SH), 3.52 ppm (ddd, 1H, J¼2.7 Hz, J¼5.1 Hz,
4.3.1. 1-Sulfanylheptan-4-ol 1a
See Ref. 21 for spectral characterisation.
4.3.2. 1-Sulfanyloctan-4-ol 1e
1H NMR (200 MHz, CDCl3):
d 0.91 (m, 3H, CH3), 1.37 (t, 1H,
J¼7.9 Hz, SH), 1.25–1.85 (m, 11H, 5ꢁCH2, OH), 2.56 (dt, 2H, J¼6.8 Hz,
J¼8.6 Hz, CHOH). 13C NMR (CDCl3):
d 14.2 (C8, CH2CH3), 15.3 (C9,
J¼7.9 Hz, CH2SH), 3.60 ppm (m, 1H, CHOH). 13C NMR (CDCl3):
d
14.0
CHCH3), 22.8 (C1 and C7), 28.3 (C6), 33.6 (C5), 36.5 (C2), 37.8 (C3),
75.9 ppm (C4). EIMS m/z (%): 41 (28.6), 43 (14.1), 55 (19.8), 56
(46.1), 57 (27.9), 69 (56.7), 81 (14.3), 87 (16.1), 90 (13.6), 101
(C8), 22.7 (C7), 24.7 (C1), 27.8 (C6), 30.1 (C2), 36.0 (C3), 37.3 (C5),
71.4 ppm (C4). EIMS m/z (%): 39 (16.8), 41 (40.5), 43 (32.0), 43
(54.1), 57 (16.5), 60 (27.7), 69 (30.3), 71 (21.8), 87 (100), 101 (24.9),
ꢅ
(100), 176 (Mþ , 0.1).
ꢅ
162 (Mþ , 0.1).
4.3.9. 2-Propylthiolane 2a (CAS: 1551-34-4)
4.3.3. 1-Sulfanylnonan-4-ol 1b
1H NMR (CDCl3, 200 MHz):
d
0.85 (t, 3H, J¼7.0 Hz, CH3),1.14–2.11
1H NMR (200 MHz, CDCl3):
d
0.90 (m, 3H, CH3), 1.37 (t, 1H,
(m, 8H, H3 cycle, H4 cycle, CH2-CH2-CH3), 2.79 (m, 2H, H5 cycle),
3.28 ppm (tt, 1H, J¼5.8 Hz, J¼7.7 Hz, H2 cycle). 13C NMR (CDCl3):
J¼7.8 Hz, SH), 1.20–1.90 (m, 13H, 6ꢁCH2, OH), 2.56 (dt, 2H, J¼6.9 Hz,
J¼7.8 Hz, CHOH). 13C NMR (CDCl3):
d
14.1 (C9), 22.6 (C8), 24.8 (C1),
d 14.1 (CH3), 22.4 (CH2-CH2-CH3), 30.4 (C4 cycle), 32.2 (C5 cycle),
25.3 (C6), 30.1 (C2), 31.9 (C7), 36.0 (C3), 37.6 (C5), 71.5 ppm (C4).
37.5 (C3 cycle), 40.1 (CH2-CH2-CH3), 49.2 ppm (C2 cycle). EIMS m/z
EIMS m/z (%): 41 (24.8), 43 (27.1), 55 (29.0), 60 (31.2), 71 (24.4), 83
(%): 39 (4.1), 41 (5.1), 45 (6.0), 55 (4.0), 59 (4.3), 85 (4.6), 87 (100), 88
ꢅ
ꢅ
(15.4), 87 (100), 101 (21.4), 115 (18.0), 129 (12.8), 176 (Mþ , 0.1).
(5.9), 89 (4.6), 130 (Mþ , 22.5).
4.3.4. 1-Sulfanyldecan-4-ol 1c
4.3.10. 2-Butylthiolane 2e (CAS: 3050-98-4)
1H NMR (200 MHz, CDCl3):
d
0.88 (m, 3H, CH3), 1.36 (t, 1H,
1H NMR (CDCl3, 200 MHz):
d 0.87 (m, 3H, CH3), 1.19–2.15 (m,
J¼7.8 Hz, SH), 1.20–1.90 (m, 15H, 7ꢁCH2, OH), 2.56 (dt, 2H, J¼6.9 Hz,
10H, H3 cycle, H4 cycle, -CH2-CH2-CH2-CH3), 2.85 (m, 2H, H5 cycle),
J¼7.8 Hz, CH2SH), 3.60 ppm (m, 1H, CHOH). 13C NMR (CDCl3):
d 14.1
3.32 ppm (tt, 1H, J¼5.9 Hz, J¼7.9 Hz, H2 cycle). 13C NMR (CDCl3):
(C10), 22.6 (C9), 24.8 (C1), 25.6 (C6), 29.3 (C7), 30.2 (C2), 31.8 (C8),
36.0 (C3), 37.6 (C5), 71.4 ppm (C4). EIMS m/z (%): 41 (29.2), 43 (30.0),
55 (35.0), 60 (37.5), 69 (13.9), 71 (24.7), 87 (100), 97 (11.1),101 (19.5),
d 14.2 (CH3), 22.8 (CH2-CH2-CH2-CH3), 30.4 (C4 cycle), 31.5 (CH2-
CH2-CH2-CH3), 32.2 (C5 cycle), 37.5 (C3 cycle), 37.6 (CH2-CH2-CH2-
CH3), 49.6 ppm (C2 cycle). EIMS m/z (%): 41 (13.2), 45 (10.9), 53
(5.5), 55 (6.4), 59 (5.7), 87 (100), 88 (6.4), 89 (4.8), 101 (8.3), 144
ꢅ
20
129 (23.3), 190 (Mþ , 0.1). [
(99% ee).
a]
ꢃ4.16 for (R)-1-sulfanyldecan-4-ol
D
ꢅ
(Mþ , 21.3).

J.-J. Filippi et al. / Tetrahedron 64 (2008) 9999–10003
10003
4.3.11. 2-Pentylthiolane 2b (CAS: 3050-98-4)
1H NMR (CDCl3, 200 MHz):
0.88 (m, 3H, CH3), 1.20–2.17 (m,
(td, 1H, J¼5.4 Hz, J¼9.5 Hz, H2 cycle). 13C NMR (CDCl3):
d
13.4
d
(CH-CH3), 14.2 (CH2-CH3), 22.9 (CH2-CH2-CH2-CH3), 29.7 (C5 cycle),
31.4 (CH2-CH2-CH2-CH3), 31.9 (CH2-CH2-CH2-CH3), 37.3 (C4 cycle),
40.3 (C3 cycle), 52.9 ppm (C2 cycle). EIMS m/z (%): 41 (5.0), 45 (3.1),
55 (5.0), 59 (6.2), 67 (7.6), 81 (3.0), 101 (100), 102 (7.2), 103 (4.5), 158
12H, H3 cycle, H4 cycle, CH2-CH2-CH2-CH2-CH3), 2.85 (m, 2H, H5
cycle), 3.33 ppm (tt, 1H, J¼5.8 Hz, J¼7.7 Hz, H2 cycle). 13C NMR
(CDCl3): d 14.1 (CH3), 22.7 (CH2-CH2-CH2-CH2-CH3), 29.0 (CH2-CH2-
ꢅ
CH2-CH2-CH3), 30.4 (C4 cycle), 31.9 (CH2-CH2-CH2-CH2-CH3), 32.2
(C5 cycle), 37.5 (C3 cycle), 37.8 (CH2-CH2-CH2-CH2-CH3), 49.5 ppm
(C2 cycle). EIMS m/z (%): 39 (4.1), 41 (8.1), 45 (5.9), 55 (4.6), 87
(Mþ ,19.3). Anal. Calcd for C9H18S (mixture of cis/trans 2g): C, 68.28;
H, 11.46; S, 20.26. Found: C, 68.29; H, 11.29; S, 20.10.
trans-2-Butyl-3-methylthiolane 2g (trans-whisky thiolane): 1H
ꢅ
(100), 88 (6.3), 89 (4.1), 115 (5.7), 129 (3.5), 158 (Mþ , 12.6).
NMR (CDCl3):
d
0.92 (t, 3H, J¼7.0 Hz, CH2-CH3), 0.97 (d, 3H, J¼6.6 Hz,
CH-CH3), 1.25–1.45 (m, 5H, CH2-CH2-CH2-CH3), 1.65 (dtd, 1H,
J¼7.6 Hz, J¼9.5 Hz, J¼12.2 Hz, H4 cycle), 1.78–1.82 (m, 2H, CH2-CH2-
CH2-CH3 and H3 cycle), 2.18 (m, 1H, H40 cycle), 2.80–2.89 ppm (m,
4.3.12. 2-Hexylthiolane 2c (CAS: 876-37-9)
1H NMR (CDCl3, 200 MHz):
d 0.88 (m, 3H, CH3), 1.20–2.17 (m,
14H, H3 cycle, H4 cycle, -CH2-CH2-CH2-CH2-CH2-CH3), 2.85 (m, 2H,
3H, H2 cycle and H5 cycle). 13C NMR (CDCl3):
d 14.2 (CH2-CH3), 17.6
H5 cycle), 3.33 ppm (tt, 1H, J¼5.8 Hz, J¼7.7 Hz, H2 cycle). 13C NMR
(CH-CH3), 22.9 (CH2-CH2-CH2-CH3), 29.9 (C5 cycle), 31.8 (CH2-CH2-
CH2-CH3), 36.2 (CH2-CH2-CH2-CH3), 39.1 (C4 cycle), 44.6 (C3 cycle),
55.9 ppm (C2 cycle). EIMS m/z (%): 41 (5.3), 45 (2.8), 55 (6.3), 59 (7.7),
(CDCl3):
d 14.1 (CH3), 22.7 (-CH2-CH2-CH2-CH2-CH2-CH3), 29.3
(-CH2-CH2-CH2-CH2-CH2-CH3), 29.3 (-CH2-CH2-CH2-CH2-CH2-CH3),
30.4 (C4 cycle), 31.9 (-CH2-CH2-CH2-CH2-CH2-CH3), 32.2 (C5 cycle),
37.5 (C3 cycle), 37.9 (-CH2-CH2-CH2-CH2-CH2-CH3), 49.5 ppm (C2
cycle). EIMS m/z (%): 39 (4.0), 41 (9.9), 45 (5.7), 55 (5.0), 67 (3.6), 87
ꢅ
67 (9.5), 69 (2.6), 101 (100), 102 (7.7), 103 (4.5), 158 (Mþ , 15.7).
Supplementary data
ꢅ
(100), 88 (6.6), 89 (4.2), 129 (10.3), 172 (Mþ , 10.6).
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.07.088.
4.3.13. 2-Heptylthiolane 2d (CAS: 24767-96-2)
1H NMR (CDCl3, 200 MHz):
d 0.88 (m, 3H, CH3), 1.20–2.17 (m,
16H, H3 cycle, H4 cycle, -CH2-CH2-CH2-CH2-CH2-CH2-CH3), 2.85 (m,
2H, H5 cycle), 3.33 ppm (tt, 1H, J¼5.8 Hz, J¼7.7 Hz, H2 cycle). 13C
References and notes
NMR (CDCl3): d 14.1 (CH3), 22.8 (-CH2-CH2-CH2-CH2-CH2-CH2-CH3),
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29.3 (-CH2-CH2-CH2-CH2-CH2-CH2-CH3), 29.5 (-CH2-CH2-CH2-CH2-
CH2-CH2-CH3), 29.6 (-CH2-CH2-CH2-CH2-CH2-CH2-CH3), 30.5 (C4
cycle), 31.9 (-CH2-CH2-CH2-CH2-CH2-CH2-CH3), 32.2 (C5 cycle), 37.5
(C3 cycle), 37.9 (-CH2-CH2-CH2-CH2-CH2-CH2-CH3), 49.5 ppm (C2
cycle). EIMS m/z (%): 41 (7.6), 45 (3.8), 55 (4.6), 87 (100), 88 (6.9), 89
ꢅ
(4.3), 101 (4.0), 129 (7.0), 143 (7.1), 186 (Mþ , 9.0).
4.3.14. 2-Octylthiolane 2f (CAS: 5143-23-7)
1H NMR (CDCl3, 200 MHz):
d 0.88 (m, 3H, CH3),1.20–2.17 (m,18H,
H3 cycle, H4 cycle, -CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH3), 2.85
(m, 2H, H5 cycle), 3.33 ppm (tt, 1H, J¼5.7 Hz, J¼7.7 Hz, H2
cycle). 13C NMR (CDCl3):
d 14.1 (CH3), 22.8 (-CH2-CH2-CH2-CH2-CH2-
11. Filippi, J.-J.; Fernandez, X.; Lizzani-Cuvelier, L.; Loiseau, A.-M. Flavour Fragrance
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CH2-CH2-CH3), 29.3 (-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH3), 29.6
(-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH3), 29.7 (-CH2-CH2-CH2-CH2-
CH2-CH2-CH2-CH3), 29.8 (-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH3),
30.5 (C4 cycle), 32.0 (-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH3), 32.2
(C5 cycle), 37.5 (C3 cycle), 37.9 (-CH2-CH2-CH2-CH2-CH2-CH2-CH2-
CH3), 49.5 ppm (C2 cycle). EIMS m/z (%): 41 (8.3), 45 (3.6), 55 (5.3), 67
12. Filippi, J.-J.; Fernandez, X.; Dunach, E. Tetrahedron Lett. 2006, 47, 6067–6070.
13. Weiwer, M.; Coulombel, L.; Dunach, E. Chem. Commun. 2006, 332–334.
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4166–4169.
ꢅ
(3.3), 87 (100), 88 (7.3), 89 (4.3), 129 (7.2), 157 (5.5), 200 (Mþ , 7.8).
4.3.15. Diastereoselective synthesis of 2-butyl-3-methylthiolane
cis- and trans-diastereomers of 3-methyl-4-butyl-
nobutyrolactone (whisky thionolactone) were separated by silica
gel column chromatography (Silica gel 60, 40–63 m, Merck; 1 g of
g
-thio-
19. Jeong, L. S.; Lee, H. W.; Jacobson, K. A.; Kim, H. O.; Shin, D. H.; Lee, J. A.; Gao,
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m
thionolactone/50 g of silica gel) by using a mixture of hexane/Et2O
(95/5 v/v) as eluent (elution order: trans- then cis-whisky thio-
nolactone). Fractions of about 7 mL were collected and analysed by
TLC. Each diastereomer was separately submitted to LiAlH4 re-
duction to afford syn- and anti-3-methyl-1-sulfanyloctan-4-ol 1g.
syn- and anti-1g were submitted to cyclodehydration as described
for the K10/microwave procedure to yield trans- and cis-2g.
cis-2-Butyl-3-methylthiolane 2g (cis-whisky thiolane): 1H NMR
(CDCl3):
d
0.92 (t, 3H, J¼7.1 Hz, CH2-CH3), 0.97 (d, 3H, J¼7.1 Hz, CH-
CH3), 1.25–1.45 (m, 5H, CH2-CH2-CH2-CH3), 1.65 (m, 1H, CH2-CH2-
CH2-CH3), 1.82 (tdd, 1H, J¼5.3 Hz, J¼6.7 Hz, J¼12.2 Hz, H4 cycle),
1.98 (dtd, 1H, J¼5.1 Hz, J¼7.7 Hz, J¼12.6 Hz, H40 cycle), 2.33 (m, 1H,
H3 cycle), 2.84 (ddd, 1H, J¼5.0 Hz, J¼7.5 Hz, J¼10.3 Hz, H5 cycle),
2.89 (ddd, 1H, J¼6.8 Hz, J¼8.0 Hz, J¼10.2 Hz, H50 cycle), 3.34 ppm
29. Loupy, A. Microwaves in Organic Synthesis; 2002.
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