Conformationally constrained oxides of 1,3-dithiane: Synthesis and NMR spectroscopic investigations

Article abstract of DOI:10.1002/ejoc.201200675

Conformationally constrained derivatives of 1,3-dithianes (5-tert-butyl- and 4,6-dimethyl-1,3-dithiane and dithiadecalin) have been oxidised with various oxidants to yield axial and equatorial sulfoxides, disulfoxides and sulfones. Axial sulfoxides were prepared by nucleophilic hydroxide addition to the corresponding 2-alkylidene derivatives with subsequent retro-aldol-type elimination. The reaction outcome is related to the relative energies of the derivatives, as demontstrated by DFT calculations. The NMR spectroscopic data of the compounds obtained were analysed to identify ⁴J couplings. It was found that only ⁴J W couplings can be observed regardless of whether there is an axial or an equatorial sulfoxide, sulfide or sulfone group present in between the respective C-H moieties. A previously postulated γ-gauche effect of axial sulfoxides (but not of equatorial sulfoxides or sulfones) leading to the shielding of carbon atoms is not unambiguously supported by the NMR spectroscopic data of conformationally fixed derivatives. Copyright

Full text of DOI:10.1002/ejoc.201200675

FULL PAPER
DOI: 10.1002/ejoc.201200675
Conformationally Constrained Oxides of 1,3-Dithiane: Synthesis and NMR
Spectroscopic Investigations
Roland Ulshöfer,[a] Tobias Wedel,[a] Bastian Süveges,[a] and Joachim Podlech*[a]
Dedicated to Professor Dr. Dieter Seebach on the occasion of his 75th birthday
Keywords: Sulfur heterocycles / Oxidation / Conformation analysis / NMR spectroscopy
4
Conformationally constrained derivatives of 1,3-dithianes (5-
tert-butyl- and 4,6-dimethyl-1,3-dithiane and dithiadecalin)
have been oxidised with various oxidants to yield axial and
equatorial sulfoxides, disulfoxides and sulfones. Axial sulfox-
ides were prepared by nucleophilic hydroxide addition to the
corresponding 2-alkylidene derivatives with subsequent
retro-aldol-type elimination. The reaction outcome is related
to the relative energies of the derivatives, as demontstrated
by DFT calculations. The NMR spectroscopic data of the
compounds obtained were analysed to identify J couplings.
It was found that only 4J W couplings can be observed re-
gardless of whether there is an axial or an equatorial sulfox-
ide, sulfide or sulfone group present in between the respec-
tive C–H moieties. A previously postulated γ-gauche effect of
axial sulfoxides (but not of equatorial sulfoxides or sulfones)
leading to the shielding of carbon atoms is not unambigu-
ously supported by the NMR spectroscopic data of conforma-
tionally fixed derivatives.
have an impact on spectroscopic data (NMR,[14] IR, UV
spectroscopy[15]). Stereoelectronic effects in sulfides, sulf-
oxides and sulfones have been investigated repeatedly.[16]
The sulfur-containing compounds used to date for the
elucidation of stereoelectronic effects were not in a fixed
(or otherwise unambiguously known) conformation, thus
precluding a concise treatment and thus hampering an inde-
pendent examination of the effect of functional groups.
Consequently, we have looked for conformationally con-
strained derivatives of 1,3-dithianes suitable for structural
and mechanistic investigations (Figure 1). Herein we pres-
ent the syntheses and spectroscopic data of such com-
pounds.
Introduction
Sulfides,[1] sulfoxides[2] and sulfones[3] are used as versa-
tile building blocks in numerous named and unnamed reac-
tions, for example, in the Julia reaction in all its varia-
tions,[4] the Ramberg–Bäcklund reaction[5] and the Pumm-
erer rearrangement.[6] The special arrangement of atoms in
1,3-dithianes, in their corresponding oxidised derivatives
and in related compounds like disulfoxides[7] has found sig-
nificant interest in various transformations, for example, in
the Corey–Seebach reaction[8] and in nucleophilic,[9,10] radi-
cal[11] and pericyclic[12] additions to alkylidene sulfoxides.
It turns out that not only is the constitution of these
compounds essential for their stability and reactivity, but
their configuration is as well, that is, the orientation of
C–S and S=O bonds relative to the bonds of other func-
tional groups (e.g., C–H, C–S, S=O bonds) or to (carban-
ionic) lone pairs. This has been attributed to stereoelec-
tronic effects between donor orbitals (or bonds) and ac-
ceptor orbitals (or bonds), which are favourable when the
corresponding groups adopt an antiperiplanar orienta-
tion.[13] These effects not only influence the stability, struc-
ture and reactivity of chemical compounds, but they also
A
number of investigations (including theoretical
work[17,18]) have been published on the syntheses, structural
features, spectroscopic data and reactivities of most of the
oxygenated 1,3-dithiane derivatives 1–10[19] and their con-
formationally constrained derivatives (11–13, 16, 17, 21, 23
and 31).[20]
Results and Discussion
Synthesis of Oxygenated 1,3-Dithiane Derivatives
[a] Institut für Organische Chemie, Karlsruher Institut für
Technologie (KIT),
We studied 4,6-dimethyl- (11–20) and 5-tert-butyl-1,3-di-
thianes 21–30 as conformationally constrained substrates in
which the dimethyl substrates should have (in comparison
with the tert-butyl compounds) a somewhat higher prefer-
ence for the conformation in which the methyl substituents
adopt equatorial positions and are thus more useful in the
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax: +49-721-608-47652
E-mail: joachim.podlech@kit.edu
Homepage: http://www.ioc.kit.edu/podlech/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200675.
Eur. J. Org. Chem. 2012, 6867–6877
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R. Ulshöfer, T. Wedel, B. Süveges, J. Podlech
FULL PAPER
sulfoxide 12 (Ͻ10%), which could not be separated after
purification of the crude material. When more than 1 equiv.
of sodium periodate was employed, a mixture of disulfox-
ides 16 and 17 was obtained in addition to the mixed sulf-
oxide/sulfone 19 (entry 3). Compound 19 could be easily
removed from the disulfoxides due to its considerably lower
polarity. However, chromatographic separation of the di-
sulfoxides 16 and 17, which have quite similar polarities,
turned out to be tedious; they could only be isolated in
poor yields (19 and 7%, respectively), rendering this
method only suitable for analytical purposes. The observa-
tion that more 16 than 17 is formed is in agreement with
the investigations of Aggarwal et al., who found that 6 is
thermodynamically more stable than 7,[19a] and with calcu-
lations that showed that the energy difference between dis-
ulfoxides 6 and 7 is about 3.6 kJ/mol (see Table 2).[18] The
disulfone 20 was obtained after the reaction of dithiane 11
with 30 equiv. of hydrogen peroxide in the presence of so-
dium tungstate as catalyst (entry 4).[27]
Figure 1. Oxygenated 1,3-dithianes 1–10 and their derivatives 11–
40 (substituted compounds 11–40 have the same S-substituted
pattern as the corresponding parent compounds 1–10).
Table 1. Oxidation of 1,3-dithiane-derived substrates.
subsequent investigations.[21] The trans-1,3-dithiadecalin de-
rivatives 31–40 can be expected to be highly constrained
conformers, but the reduced symmetry of these compounds
might lead to more laborious syntheses and purification
procedures.
Starting
material
Prod-
uct
Yield
[%][a]
69[b,c]
Conditions
1
11
1.2 equiv. NaIO4, THF/H2O
1:1, 24 h, room temp.
13
17
16
13
4
Most of the dimethyldithiane-derived oxidised com-
pounds were accessible starting from the parent 4,6-di-
methyl-1,3-dithiane (11), which was obtained from meso-
pentane-2,4-diol according to published protocols.[22] It has
already been noted that the oxidation of 1,3-dithiane and
its derivatives preferentially leads to equatorial sulfoxides,
for example, 11Ǟ13.[23] This is in accordance with calcula-
tions on the stability of the monosulfoxides: equatorial sulf-
oxide 3 is 7.8 kJ/mol more stable than the axial sulfoxide 2
(cf. Table 2),[18] which has been attributed to a highly ef-
ficient σS–C Ǟσ*S–O stereoelectronic interaction (Figure 2,
top), possible only when the bonds involved adopt an anti-
periplanar orientation. In contrast, oxygenated thianes
show a different stability pattern;[24] the axial thiane 1-oxide
is more stable than the equatorial substrate (ΔE = 1.3 kJ/
mol[18]), most probably due to a somewhat less effective
12
2
3
11
11
1.2 equiv. UHP, AcOH, 24 h,
room temp.
70[c]
17
17
1
3 equiv. NaIO4, THF/H2O 1:1,
24 h, room temp.
7[d]
16
19
20
19
26
40
4
5
6
11
13
13
30 equiv. H2O2, cat.
Na2WO4·2H2O, MeOH, 14 d,
room temp
1 equiv. UHP, HOAc, 24 h,
room temp.
17
28
16
14
3
86
1 equiv. KMnO4, acetone, cat.
H2O, 24 h, room temp.
[a] Yields of isolated and purified products. [b] Yield following pu-
rification by chromatography. Alternatively, pure 13 (74%) could
be obtained when the crude product was purified by crystallisation.
No disulfoxides were obtained by this protocol. [c] Axial sulfoxide
(Ͻ10%) was observed in the crude product but could not be sepa-
rated by chromatography. [d] The ratio of 17/16/19 in the crude
reaction mixture was approx. 6:46:48.
σ
H–C Ǟσ*S–O interaction (Figure 2, bottom).
The reaction outcome of the oxidation of the equatorial
sulfoxide 13 was strongly dependent on the oxidant used.
It has already been noted by Ogura et al.[25,28] for related
compounds that nucleophilic oxidants like permanganate
attack the sulfur of the more electrophilic sulfoxide and not
the sulfide in the molecule. Accordingly, when we exposed
sulfoxide 13 to potassium permanganate we obtained the
Figure 2. Stereoelectronic effects in sulfoxides.
The best results for the preparation of sulfoxide 13 were sulfone 14 in an excellent 86% yield (entry 6). The parent
achieved with sodium periodate[25] or a hydrogen peroxide/ sulfone 4 is thermodynamically more stable than the disulf-
urea complex (UHP) in the presence of acetic acid,[26] which oxides 5–7, as has been confirmed by calculations (see
gave sulfoxide 13 in yields of 74 and 70%, respectively Table 2)[18] and the finding of Aggarwal et al. that a mixture
(Table 1, entries 1 and 2). A minor product was the axial of disulfoxides 6 and 7 disproportionates to 4 upon treat-
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Conformationally Constrained Oxides of 1,3-Dithiane
ment with N2O4.[19a,29] In contrast, the more electrophilic
hydrogen peroxide/urea complex (which with acetic acid
leads to a putative peracid as intermediate[26]) reacted at the
nucleophilic sulfur of the sulfide to furnish a mixture of the
disulfoxides 16 and 17, albeit again in poor yield (entry 5).
The identities of the disulfoxides 16 and 17 and the sulfox-
ide/sulfone 19 were unambiguously proven by comparison
of the NMR spectra and by MS (Scheme 1). Oxidation of
the monosulfoxide 13 with known configuration (X-ray
crystal structure)[20c] furnished two disulfoxides, one sym-
metric and one non-symmetric (as is clear from the NMR
spectra), which have necessarily been assigned the struc-
tures 16 and 17, respectively. Because oxidation of these dis-
ulfoxides with UHP led to a single trioxide, this has to be
the sulfoxide/sulfone 19 with the sulfoxide S=O bond in an
equatorial position. This trioxide was also obtained in one
pot starting from dithiane 11 (Table 1, entry 3).
Scheme 2. Synthesis of an axial sulfoxide.
Oxidation with sodium periodate again led to the formation
of the equatorial sulfoxide 23 (77%), whereas sulfone 24
was accessed in quantitative yield by the oxidation of sulf-
oxide 23 with permanganate. The oxidation of dithiane 21
with the hydrogen peroxide/urea complex (in the presence
of tellurium oxide) led to a hardly separable mixture of dis-
ulfoxides 26 and 27 (10 and 30%). This protocol is a varia-
tion of a method published by Kim et al.,[31] who found
that the oxidation of sulfoxide with hydrogen peroxide and
tellurium oxide prevents overoxidation to sulfones. The oxi-
dation of dithiane 21 with hydrogen peroxide furnished the
mixed sulfoxide/sulfone 29 in 39% yield, whereas complete
oxidation was again possible with sodium tungstate. A satis-
factory 60% yield of disulfone 30 was obtained within only
15 h, whereas 2 weeks was necessary for the preparation of
the dimethyl derivative 20. The axial sulfoxide 22 was again
accessible by a bypass reaction (cf. Scheme 2), the addition
of hydroxide to the corresponding alkylidene-substituted
derivative 44 with subsequent elimination of acetone (55%).
The structure of sulfoxide 22 was unambiguously proven by
X-ray crystallographic analysis (Figure 3).[32]
Scheme 1. Structural elucidation of compounds 16, 17 and 19.
The axial sulfoxide 12 has already been obtained by Kos-
kimies by O-methylation of the equatorial sulfoxide 13 and
subsequent nucleophilic attack with hydroxide[20d] leading
to a 9:1 mixture of 12 and 13. We considered it useful to
have a further method for the preparation of this com-
pound in hand, for which we adapted the protocol of Bryan
et al.[19c] used for the separation of enantiomers of sulfoxide
2. They showed that hydroxyalkyl-substituted dithiane de-
rivative 41 suffers a retro-aldol-type fragmentation upon de-
protonation and heating (Scheme 2, bottom). Because we
had previously synthesised alkylidenedithianes 42–44 bear-
ing an axial oxygen,[15] we considered it possible that these
could be used for a similar transformation upon the formal
addition of water to the exo double bond. In fact, the 2-
propylidene-substituted sulfoxide 42 is clearly attacked by
hydroxide leading to a presumed hydroxyalkyl-substituted
carbanion, which, after trans-protonation and fragmenta-
tion, leads to the desired axial sulfoxide 12. Nevertheless,
the harsh reaction conditions led to the formation of col-
oured side-products, which could be removed by crystallisa-
tion. The product was obtained in a satisfactory yield of
73%. Methylene-substituted sulfoxide 43 turned out to be
stable when exposed to basic conditions, most probably due
to the higher carbonyl activity and thus due to a lower eli-
mination tendency of formaldehyde, shifting the equilib-
rium towards the starting materials.
Figure 3. Structure of axial sulfoxide 22 in the crystal.[32]
tert-Butyl-substituted oxygenated 1,3-dithiane derivatives
We attempted the preparation of diaxial disulfoxide 25
were prepared by essentially identical routes, with the par- by a similar strategy. We considered it likely that a 2-fluor-
ent dithiane 21 obtained by published protocols.[21,22a,30] enylidene-substituted 1,3-dithiane 46 (which was prepared
Eur. J. Org. Chem. 2012, 6867–6877
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R. Ulshöfer, T. Wedel, B. Süveges, J. Podlech
FULL PAPER
by Peterson olefination starting with dithiane 21) could not
be oxidised at the equatorial positions of the sulfur atoms
because this would lead to considerable steric hindrance
and therefore we expected instead an axial oxidation. In
fact, oxidation of fluorenylidene-dithiane 46 with m-chloro-
perbenzoic acid[25] led to symmetrical disulfoxide 47
(proven by MS and NMR spectroscopy) in which it could
not be decided whether its sulfoxide groups were diaxial or
diequatorial (Scheme 3). Reaction with hydroxide led to the
elimination of fluorenone, but unfortunately a dithiane de-
rivative could neither be identified in the crude mixture nor
be isolated. Consequently, the preparation of diaxial di-
sulfoxides 15 and 25 remains a challenging task.
derivatives could not be obtained in any of the parent dithi-
ane systems, the diaxial disulfoxide 15 (or 25/35) and the
mixed sulfoxide/sulfone 18 (or 28/38) with an axial sulfoxide
group. Calculations[18] showed that these isomers have the
highest energies within the respective group of isomers
(Table 2), most probably because
a
favourable
σ
S–C Ǟσ*S–O stereoelectronic interaction requiring an
equatorial S=O bond is not possible in these compounds.
Their synthesis remains a challenge.
Table 2. Calculated stabilities of the oxygenated 1,3-dithianes 1–
10.[18]
Eel [Hartree][a]
Erel [kJ/mol]
μ [debye][b]
1
–953.6390
–
2.3
2
3
–1028.8196
–1028.8226
7.8
0.0
4.7
4.4
4
5
6
7
–1104.0324
–1103.9925
–1103.9985
–1103.9971
0.0
105.0
89.1
92.7
5.3
4.9
7.0
5.0
8
9
–1179.2060
–1179.2099
10.3
0.0
6.5
4.9
Scheme 3. Attempted synthesis of diaxial disulfoxide 25.
10
–1254.4167
–
5.9
trans-Dithiadecalins are conformationally constrained
1,3-dithianes in which the sulfur atoms are no longer equiv-
alent. We therefore expected that the isolation and purifica-
tion procedures could possibly be more difficult. The parent
sulfide 31 was prepared according to a published protoc-
ol.[20e] Oxidation with 1 equiv. of sodium periodate led to a
mixture (89%, 55:45) of two mono-oxygenated products
(most probably a mixture of the equatorial sulfides 33a and
33b), which could not be separated by chromatography. The
oxidation of 31 with 2 equiv. of the hydrogen peroxide/urea
[a]
Electronic
energies:
B3LYP/6-31++G(d,p)//B3LYP/6-
31++G(d,p), gas-phase calculation. Results of calculations with
consideration of solvent effects are given in the Supporting Infor-
mation of ref.[18]. [b] Electric dipole moment.
NMR Spectroscopic Investigations
It has been claimed by Tormena and co-workers[19b] for
complex led to a mixture of three disulfoxides: one isomer 1,3-dithiane and its oxidised derivatives that there is a long-
4
could be separated and was obtained in pure form (25%), range JHH coupling[33] between two axial hydrogen atoms
most likely compound 37. A small fraction (4%), a mixture when there is an axial S=O or sulfone group (similarly bear-
of two further isomers, could not be purified, but could be a ing an axial S=O group) in between (Figure 4, bottom) and
mixture of isomers 36a and 36b. Exhaustive oxidation with between two equatorial hydrogen atoms if there is an equa-
hydrogen peroxide and catalytic amounts of sodium tung- torial S=O or sulfone group (similarly bearing an equatorial
state led to the disulfone 40 in 90% yield. Compared with S=O group) in between (Figure 4, top). This was inferred
compound 20, its solubility in organic solvents turned out from the spectra of 1, 3, 7, 9 and 10 and from ac-
to be significantly higher.
companying NBO calculations. We now had several confor-
We have thus accessed a range of conformationally con- mationally constrained dithiane derivatives in hand that
strained oxygenated 1,3-dithiane derivatives, for which we were perfectly suitable for NMR investigations and found
could determine most of the substitution patterns. Only two that the above assumption is not supported by our analysis
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Conformationally Constrained Oxides of 1,3-Dithiane
Yet another trend in the NMR spectroscopic data, which
has been claimed for similar substrates (e.g., for some of
the parent dithiane derivatives 1–10),[16b,38] is not clearly
supported by the data obtained for the compounds with
well-defined conformations. A γ-gauche effect had been
postulated showing a dependency of the 13C NMR shift of
a carbon at the γ position on a sulfoxide’s oxygen atom
(Figure 5). The presence of an axial sulfoxide S=O group
should therefore lead to a significant shielding effect
(smaller ppm values). This has been attributed to the equa-
torial sulfur lone pair involved in a stereoelectronic effect
(nS Ǟσ*C–C), which should give rise to a higher electron
density at the γ carbon (β to the sulfoxide group). Conse-
quently, the presence of sulfones or of equatorial S=O
groups should not have that effect because there is either
no lone pair present or it is not in a suitable orientation.
4
Figure 4. W coupling (top) and putative JHax–Hax coupling (bot-
tom) in dithiane derivatives.
(Table 3). We did not observe J couplings (4J2-Hax–4-Hax or
4
4J2-Heq–4-Hax coupling) in dithianes bearing equatorial sub-
stituents at C-4 and C-6 (i.e., in compounds 11–20), but
4
generally found a J coupling in substrates bearing equato-
rial hydrogen atoms at C-4 and/or C-6 (numbering accord-
ing to the numbering in the 1,3-dithiane), either as a doub-
let of doublets or pseudo-triplet, or as a doublet, depending
on whether two (in tert-butyldithianes) or one (in dithiade-
calins) equatorial hydrogen atom is available for W cou-
pling. The data we have available neither support the pres-
ence of observable 4JHax–Hax couplings nor a dependency of
the configuration of the sulfoxide group between the respec-
tive hydrogen atoms. To assure these observations, the 2-
Hax and 2-Heq atoms were unambiguously assigned by
Figure 5. γ-gauche effect in sulfoxides.[39]
Nevertheless, in our investigations we have found no
evaluation of NOESY spectra. The only unexpected obser- clear relationship between the constitution and configura-
5
vation was a J coupling between the axial 2-H and 5-H tion of dithiane derivatives and their spectroscopic data
atoms (1 Hz) in compound 17, which was not observed or [given in Table 3 as δ(C-5) values]. Neither the number of
resolved in any of the other compounds.
axial (sulfoxide) S=O groups present in the respective com-
Table 3. Selected NMR spectroscopic data for the oxygenated 1,3-dithiane derivatives.
δ(C-5)
2-H
δ(2-H)
4J
δ(C-5)
2-H δ(2-H) 4J [Hz]
δ(C-5)
2-H
δ(2-H) 4J [Hz]
δ(C-5)
[ppm]
[ppm] [Hz] [ppm]
[ppm]
[ppm]
[ppm]
[ppm]
1
2
3
26.6[34]
11
12
13
14
16
17
19
20
eq
ax
eq
ax
eq
ax
eq
ax
eq
ax
eq
ax
eq
ax
eq
ax
3.56
4.09
3.77
3.92
3.99
3.78
3.70
4.13
4.67
3.55
4.76
3.93
4.78
4.00
5.51
5.23
44.6[33]
32.2
45.4
44.8
31.1
31.0
33.3
32.8
21
22
23
24
26
27
29
30
eq
ax
eq
ax
eq
ax
eq
ax
eq
ax
eq
ax
eq
ax
eq
ax
3.35
4.00
3.65
3.72
4.03
3.52
3.73
3.99
4.77
3.92
4.79
3.70
4.70
3.86
5.39
5.05
1.8 (t)
47.5
34.4
50.4
50.4
35.7
34.8
38.3
39.4
31
eq
ax
3.41
4.14
1.9 (d)
43.1[20e]
[a]
1.9, 1.9 (dd)
3.0, 1.4 (dd)
3.6, 1.3 (dd)
3.7, 2.0 (dd)
2.5 (t)
[a]
6
14.6[35]
[b]
7
37
40
eq
ax
4.81
3.89
2.9 (d)
3.7 (d)
38.3
32.8
[c]
3.4, 2.4 (dd)
3.2 (t)
10 17.6[36]
eq
ax
5.47
5.13
[a] The spectroscopic data for compound 2/3 (conformers) have been published previously:[19d,37] δ(C-5) = 27.1 ppm, δ(2-H) = 3.65,
4.01 ppm. This might suggest the presence of conformation 3 in solution. [b] An X-ray crystallographic analysis clearly proves the presence
of conformation 5 in the crystal of compound 5/7.[16b] This is not supported by calculated energies (for the compound in the gas phase
and in solution, Table 2).[18] The presence of a diequatorial conformation in solution is mainly supported in the literature.[19b] δ(C-5) =
5
7.9 ppm.[16b] [c] J coupling between the equatorial 2-H and the axial 5-H atom (d, 1 Hz).
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R. Ulshöfer, T. Wedel, B. Süveges, J. Podlech
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high-resolution mass spectra were recorded with a Finnigan MAT-
90 spectrometer.
pounds nor the number of equatorial lone pairs gives a
clear correlation with the NMR spectroscopic data. Al-
though the trend is clear for compounds 12–14 and 16 (and
their respective derivatives 22–24 and 26), in which one ax-
ial S=O group (12 and 16; 22 and 26) leads to higher fre-
quency shifts at C–5, it is not for compounds 11, 17, 19 and
20 (nor for 21, 27, 29 and 30). Dithianes 11 and 21 should
exhibit higher frequency shifts at C-5, whereas compounds
17, 19, 20, 27, 29 and 30 (no equatorial lone pairs) corre-
spondingly should be deshielded and thus show higher fre-
quency shifts. Once again, it seems necessary to have the
reference compounds 15 and 18 (or 25 and 28) in hand. A
detailed investigation, including calculations and simula-
tions of the NMR spectroscopic data for compounds 1–40,
is currently ongoing in our laboratories.
General Procedure (GP1) for Oxidation Reactions with NaIO4:
NaIO4 in H2O was added dropwise with stirring at 0 °C to a solu-
tion of the substrate in THF or MeOH and the mixture was stirred
for 12–18 h at room temp. A white precipitate separated and the
filtrate was extracted with EtOAc (3ϫ). The organic layers were
dried (Na2SO4) and concentrated.
General Procedure (GP2) for the Preparation of Axial Sulfoxides:
Ground KOH (4 equiv.) was added with stirring at room temp. to
a solution of the vinyl sulfoxide (1 equiv.) in tBuOH (4 mL/mmol).
The mixture was heated for 12 h at 70 °C, cooled to room temp.,
poured into a saturated aqueous NH4Cl solution and extracted
with CH2Cl2 (3ϫ). The combined organic layers were dried
(Na2SO4), concentrated and purified.
cis-4,6-Dimethyl-1,3-dithiane (11): Dimethyldithiane 11 was pre-
pared according to a published protocol.[21,22] 1H NMR (250 MHz,
3
2
[D6]acetone): δ = 1.24 (d, J = 6.9 Hz, 6 H, 2 Me), 1.35 (td, J =
Conclusions
3
2
3
5
13.8, J = 11.3 Hz, 1 H, 5-Hax), 2.11 (tdd, J = 13.8, J = 2.3, J
= 0.9 Hz, 1 H, 5-Heq), 2.84 (qdd, J = 11.3, J = 6.9, J = 2.3 Hz,
2 H, 4-Hax, 6-Hax), 3.56 (d, J = 14.1 Hz, 1 H, 2-Heq), 4.13 (d, J
= 14.1 Hz, 1 H, 2-Hax) ppm. 13C NMR[34] (25 MHz, CDCl3): δ =
21.9 (2 Me), 33.3 (C-2), 39.2 (C-4, C-6), 44.6 (C-5) ppm.
3
3
3
We have obtained oxidised derivatives of conformation-
ally constrained 1,3-dithianes suitable for, for example, in-
vestigations of stereoelectronic effects. All oxidation states
could be realised, except for derivatives of the diaxial disul-
foxide 5 and the axial sulfoxide/sulfone 8. An NMR analy-
sis has shown that 4J W couplings are observed when equa-
torial hydrogen atoms are present, regardless of whether
there is an axial or equatorial sulfoxide, sulfide or sulfone
group in between the respective C–H moieties; 4J couplings
between axial hydrogen atoms are not observed. A pre-
viously postulated γ-gauche effect of axial sulfoxides (but
not of equatorial sulfoxides or sulfones) leading to a shield-
2
2
rac-(1R,4S,6R)-4,6-Dimethyl-1,3-dithiane 1-Oxide (12): Sulfoxide
42[15] (204 mg, 1.00 mmol) was reacted according to GP2 with
KOH (224 mg, 4.00 mmol) to yield
a crude brownish solid
(181 mg), which was purified by chromatography (SiO2, CH2Cl2/
MeOH, 50:1) to furnish sulfoxide 12 (120 mg, 0.730 mmol, 73%) as
a colourless solid, which was recrystallised (cyclohexane/CH2Cl2)
if necessary; m.p. 128–130 °C (cyclohexane/CH2Cl2). Rf (CH2Cl2/
MeOH, 20:1) = 0.37. IR (DRIFT): ν = 2963 (s), 1446 (m), 1375
˜
(m), 1245 (m), 1043 (s), 1012 (s) cm–1. 1H NMR (400 MHz,
3
3
ing of carbon atoms is not unambiguously supported by CDCl3): δ = 1.27 (d, J = 6.8 Hz, 3 H, CH3), 1.35 (d, J = 6.8 Hz,
the NMR spectroscopic data available for these conforma-
tionally fixed derivatives.
2
3
3
5
3 H, CH3), 1.62 (dddd, J = 14.8, J = 2.4, J = 2.4, J = 0.8 Hz,
2
3
3
1 H, 5-Heq), 2.09 (ddd, J = 14.8, J = 11.7, J = 11.7 Hz, 1 H, 5-
3
3
3
Hax), 2.33–2.44 (m, 1 H, 6-H), 2.94 (dqd, J = 11.7, J = 6.8, J =
2
2
2.4 Hz, 1 H, 4-H), 3.77 (d, J = 14.3 Hz, 1 H, 2-Ha), 3.92 (d, J =
14.3 Hz, 1 H, 2-Hb) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.1
(CH3), 21.1 (CH3), 32.2 (CH2, C-5), 37.8 (CH, C-4), 49.3 (CH2, C-
2), 52.0 (CH, C-6) ppm. MS (FAB): m/z (%) = 165 (100)
[M + 1]+. C6H12OS2 (164.29): calcd. C 43.86, H 7.36, S 39.03;
found C 43.98, H 6.96, S 39.11.
Experimental Section
General: Tetrahydrofuran (THF) was distilled from sodium benzo-
phenone ketyl radical and CH2Cl2 was distilled from CaH2. Ab-
breviations and acronyms: mcpba, m-chloroperbenzoic acid; UHP,
hydrogen peroxide/urea complex. All moisture-sensitive reactions
were carried out under oxygen-free argon or N2 using oven-dried
glassware and a vacuum line. Flash column chromatography[40] was
carried out by using Merck silica gel 60 (230–400 mesh) and TLC
was carried out by using commercially available Merck F254 pre-
coated sheets. 1H and 13C NMR spectra were recorded with a
rac-(1S,4S,6R)-4,6-Dimethyl-1,3-dithiane 1-Oxide (13): Dithiane 11
(593 mg, 4.00 mmol) and NaIO4 (898 mg, 4.20 mmol) were reacted
according to GP1 to give a crude product (575 mg), which was
recrystallised (cyclohexane/CH2Cl2) to yield sulfoxide 13 (484 mg,
2.95 mmol, 74%) as colourless needles. If the crude product was
purified by chromatography, 13 was obtained together with the dis-
Bruker Cryospek WM-250, AM-400 or DRX 500 spectrometer. ulfoxides given in Table 1; m.p. 155–157 °C (cyclohexane/CH2Cl2).
NOESY spectra were recorded with a Bruker DRX 500 or
600 MHz Avance III spectrometer. Chemical shifts are given
in ppm downfield of tetramethylsilane. 13C NMR spectra were re-
corded with broad-band proton decoupling and were assigned by
R (CH Cl /MeOH, 20:1) = 0.29. IR (DRIFT): ν = 2960 (s), 2905
˜
f 2 2
(s), 1453 (m), 1254 (m), 1034 (s) cm–1. 1H NMR (400 MHz,
3
3
CDCl3): δ = 1.22 (d, J = 6.8 Hz, 3 H, CH3), 1.46 (d, J = 6.8 Hz,
2
3
3
3 H, CH3), 1.93 (ddd, J = 15.1, J = 12.2, J = 11.5 Hz, 1 H, 5-
Hax), 2.28 (dddd, J = 15.1, J = 2.5, J = 2.5, J = 0.5 Hz, 1 H,
1
2
3
3
5
means of DEPT-135 and DEPT-90 experiments. JC,H coupling
3
3
3
constants were measured by means of coupled HMQC experi-
ments[41,42] or coupled HSQC experiments (Bruker pulse program
hsqcetgpi2; power level pl12 set to 120 dB to prevent decoup-
ling).[42,43] Melting points were measured with a Büchi apparatus.
IR spectra were recorded with a Bruker IFS-88 spectrometer. Ele-
5-Heq), 2.69 (ddd, J = 12.2, J = 6.8, J = 2.5 Hz, 1 H, 6-H), 3.06
(ddd, 3J = 11.5, 3J = 6.8, 3J = 2.5 Hz, 1 H, 4-H), 3.78 (d, 2J =
12.7 Hz, 1 H, 2-Hax), 3.99 (d, J = 12.7 Hz, 1 H, 2-Heq) ppm. 13C
2
NMR (100 MHz, CDCl3): δ = 16.8 (CH3), 20.0 (CH3), 38.6 (CH,
C-4), 45.4 (CH2, C-5), 50.0 (CH2, C-2), 60.4 (CH, C-6) ppm. MS
mental analyses were performed with a Heraeus, CHN-O-rapid or (FAB): m/z (%) = 165 (100) [M + 1]+. C6H12OS2 (164.29): calcd. C
Elementar Vario MICRO spectrometer. Electrical ionisation and
43.86, H 7.36; found C 43.81, H 7.34.
6872
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6867–6877

Conformationally Constrained Oxides of 1,3-Dithiane
rac-(4S,6R)-4,6-Dimethyl-1,3-dithiane 1,1-Dioxide (14): KMnO4
(553 mg, 3.50 mmol) dissolved in H2O (10 mL) was added at 0 °C
to a solution of sulfoxide 13 (575 mg, 3.50 mmol) in acetone
oxides 16 and 17 (55 mg, 0.31 mmol, 31%), which were separated
as described above. 19: M.p. 218–222 °C. Rf (CH2Cl2/MeOH, 20:1)
= 0.40 (staining: KMnO soln.). IR (DRIFT): ν = 2964 (m), 2906
˜
4
(30 mL). After stirring for 24 h at room temp., the mixture was (m), 1454 (m), 1316 (s), 1297 (s), 1054 (s) cm–1. 1H NMR
3
filtered to remove MnO2 and the precipitate was washed with a
small volume of acetone. The filtrate was concentrated, dissolved in
CH2Cl2, dried (Na2SO4) and concentrated to yield a crude product
(618 mg), which was purified by chromatography (SiO2, CH2Cl2/
MeOH, 50:1) to yield sulfone 14 (544 mg, 3.02 mmol, 86%) as a 6-H), 3.18 (dqd, J = 12.4, J = 6.8, J = 2.8 Hz, 1 H, 4-H or 6-
colourless solid and unreacted 13 (70 mg, 0.42 mmol, 12%). 14:
M.p. 198–200 °C. Rf (CH2Cl2/MeOH, 50:1) = 0.35 (staining:
(400 MHz, CDCl3): δ = 1.42 (d, J = 6.8 Hz, 3 H, CH3), 1.56 (d,
3J = 6.9 Hz, 3 H, CH3), 1.98 (ddd, 2J = 16.2, 3J = 12.4, 3J =
3
3
12.4 Hz, 1 H, 5-Hax), 2.19 (ddd, 2J = 16.2, J = 2.8, J = 2.8 Hz, 1
3
3
3
H, 5-Heq), 2.88 (dqd, J = 12.4, J = 6.9, J = 2.8 Hz, 1 H, 4-H or
3
3
3
2
2
H), 4.00 (d, J = 13.1 Hz, 1 H, 2-Ha), 4.78 (d, J = 13.1 Hz, 1 H,
2-Hb) ppm. 13C NMR (100 MHz, CDCl3): δ = 10.3 (CH3), 15.7
KMnO soln.). IR (DRIFT): ν = 2968 (s), 1454 (m), 1321 (s), 1293 (CH3), 33.3 (CH2, C-5), 56.8 (CH), 59.4 (CH), 68.5 (CH2, C-
˜
4
(s), 1144 (s), 1115 (s), 1035 (m) cm–1. 1H NMR (400 MHz, CDCl3):
δ = 1.29 (d, 3J = 6.9 Hz, 3 H, CH3), 1.38 (d, 3J = 6.8 Hz, 3 H,
CH3), 2.25 (ddd, 2J = 14.7, 3J = 3.4, 3J = 2.7 Hz, 1 H, 5-Heq), 2.33
(m, 1 H, 5-Hax), 3.05–3.14 (m, 1 H, 4-H or 6-H), 3.15–3.25 (m, 1
2) ppm. MS (EI, 90 °C): m/z (%) = 196 (20) [M]+, 134 (12), 69
(100). C6H12O3S2 (196.29): calcd. C 36.71, H 6.16, S 32.67; found
C 36.64, H 5.96, S 32.78.
H, 4-H or 6-H), 3.70 (d, 2J = 14.6 Hz, 1 H, 2-Heq), 4.13 (d, J =
2
meso-(4S,6R)-4,6-Dimethyl-1,3-dithiane 1,1,3,3-Tetraoxide (20):
Na2WO4·2H2O (33 mg, 0.10 mmol) was added to a solution of di-
thiane 11 (148 mg, 1.00 mmol) in MeOH (10 mL) and aqueous
H2O2 (35%, 31 mmol) was added at 0 °C. After stirring for 14 d,
aqueous 10% Na2SO3 solution was added and the mixture was
extracted with CH2Cl2 (4ϫ 20 mL). The combined organic layers
were dried (Na2SO4) and the solvent was removed to yield a crude
white solid (85 mg, 0.40 mmol, 40%). Chromatographic purifica-
tion (SiO2, CH2Cl2/MeOH, 50:1) was possible but complicated by
the poor solubility of disulfone 20 in CH2Cl2; m.p. 270–280 °C (de-
comp.). Rf (CH2Cl2/MeOH, 20:1) = 0.40 (staining: I2). 1H NMR
(400 MHz, [D6]DMSO): δ = 1.24 (d, 3J = 6.9 Hz, 6 H, 2 CH3), 1.78
14.6 Hz, 1 H, 2-Hax) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.4
(CH3), 20.0 (CH3), 38.1 (CH), 44.8 (CH2, C-5), 50.7 (CH2, C-2),
57.1 (CH) ppm. MS (EI, 80 °C): m/z (%) = 180 (60) [M]+, 101 (100).
C6H12O2S2 (180.29): calcd. C 39.97, H 6.71, S 35.57; found C 39.94,
H 6.40, S 35.53.
rac-(1R,3R,4S,6R)-4,6-Dimethyl-1,3-dithiane 1,3-Dioxide (16) and
meso-(1S,3R,4S,6R)-4,6-Dimethyl-1,3-dithiane 1,3-Dioxide (17):
Freshly ground UHP (366 mg, 3.89 mmol) was added at room
temp. to a solution of sulfoxide 13 (619 mg, 3.77 mmol) in HOAc
(10 mL) and the mixture was stirred for 24 h, concentrated, neutral-
ised with saturated aqueous NaHCO3 solution and extracted with
CH2Cl2 (4ϫ 20 mL). The combined organic layers were dried
(Na2SO4) and concentrated to yield a crude product (439 mg),
which was purified by chromatography (SiO2, CH2Cl2/MeOH, 50:1
to 20:1) to yield disulfoxides 17 (189 mg, 1.05 mmol, 28%) and 16
(21 mg, 0.12 mmol, 3%) as colourless solids together with a frac-
tion containing both compounds (185 mg, 16/17, ca. 70:30).
2
3
2
3
(td, J = 15.6, J = 12.1 Hz, 1 H, 5-Hax), 2.28 (td, J = 15.6, J =
2.7 Hz, 1 H, 5-Heq), 3.43–3.54 (m, 2 H, 4-H, 6-H), 5.23 (d, 2J =
14.1 Hz, 1 H, 2-Ha), 5.51 (d, 2J = 14.1 Hz, 1 H, 2-Hb) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 9.7 (2 CH3), 32.8 (CH2, C-5),
55.8 (2 CH), 68.0 (CH2, C-2) ppm. MS (FAB): m/z (%) = 213 (90)
[M + 1]+.
5-tert-Butyl-1,3-dithiane (21): tert-Butyldithiane 21 was prepared
according to a published protocol.[21,22a,30] 1H NMR (600 MHz,
CDCl3): δ = 0.93 (s, 9 H, tBu), 1.73 (dtt, J = 11.3, J = 2.4, J = 1.0,
1JC,H = 131.1 Hz, 1 H, 5-Hax), 2.61 (ddd, J = 13.8, J = 11.3, J =
16: M.p. 196–200 °C. Rf (CH2Cl2/MeOH, 20:1)
= 0.08. IR
(DRIFT): ν = 2949 (m), 2891 (m), 1455 (m), 1032 (s) cm–1. 1H
˜
NMR (400 MHz, CDCl3): δ = 1.40 (d, 3J = 7.0 Hz, 3 H, CH3),
3
2
3
3
1.53 (d, J = 6.8 Hz, 3 H, CH3), 1.99 (ddd, J = 16.1, J = 2.4, J
= 2.4 Hz, 1 H, 5-Heq), 2.57 (ddd, 2J = 16.1, 3J = 12.1, 3J = 12.1 Hz,
1 H, 5-Hax), 2.86–2.96 (m, 1 H, 4-H or 6-H), 2.96–3.06 (m, 1 H,
4-H or 6-H), 3.55 (d, 2J = 13.0 Hz, 1 H, 2-Hax), 4.67 (d, 2J =
13.0 Hz, 1 H, 2-Heq) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.2
(CH3), 16.5 (CH3), 31.1 (CH2, C-5), 52.5 (CH), 59.9 (CH), 63.6
(CH2, C-2) ppm. MS (FAB): m/z (%) = 181 (100) [M + 1]+.
C6H12O2S2 (180.29): calcd. C 39.97, H 6.71; found C 40.06, H 6.78.
1
1
1.0, JC,H = 137.2 Hz, 1 H, 4-Hax, 6-Hax), 2.82–2.85 (m, JC,H
≈
=
1
134 Hz, 2 H, 4-Heq, 6-Heq), 3.35 (dt, J = 13.8, J = 1.8, JC,H
1
144.9 Hz, 1 H, 2-Heq), 4.00 (d, J = 13.8, JC,H = 154.3 Hz, 1 H, 2-
Hax) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.1 [C(CH3)3], 31.2
(CH2, C-4, C-6), 31.4 (CH2, C2), 34.2 [C(CH3)3], 47.5 (CH, C-
5) ppm.
rac-(1R,5S)-5-tert-Butyl-1,3-dithiane 1-Oxide (22): Vinyl sulfoxide
44[15] (3.55 g, 15.3 mmol) was reacted according to GP2 with KOH
(2.56 g, 45.8 mmol) to yield a crude brownish solid (3.65 g), which
was purified by chromatography (SiO2, CH2Cl2/MeOH, 50:1) to
furnish a yellow solid (2.54 g), which was recrystallised (cyclohex-
ane/CH2Cl2) to yield sulfoxide 22 (1.62 g, 8.46 mmol, 55%) as
colourless needles; m.p. 169–171 °C (cyclohexane/CH2Cl2). Rf
17: M.p. 199–210 °C. Rf (CH2Cl2/MeOH, 20:1)
= 0.13. IR
(DRIFT): ν = 2962 (m), 2899 (m), 1458 (m), 1054 (s), 1032 (s) cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 1.49 (d, 3J = 6.9 Hz, 6 H, 2
2
3
5
CH3), 1.46–1.55 (m, 1 H, 5-Hax), 2.21 (dtd, J = 17.1, J = 2.6, J
3
3
3
= 1.0 Hz, 1 H, 5-Heq), 2.93 (dqd, J = 12.4, J = 6.9, J = 2.6 Hz,
2
5
2 H, 4-H, 6-H), 3.93 (dd, J = 10.8, J = 1.0 Hz, 1 H, 2-Hax), 4.76
(CH Cl /MeOH, 50:1) = 0.11. IR (DRIFT): ν = 2959 (s), 1479 (m),
2
˜
(d, J = 10.8 Hz, 1 H, 2-Heq) ppm. 13C NMR (100 MHz, CDCl3):
2
2
1367 (m), 1028 (s) cm–1. H NMR (400 MHz, CDCl3): δ = 0.93 (s,
1
δ = 15.6 (2 CH3), 31.0 (CH2, C-5), 59.0 (2 CH), 67.6 (CH2, C-
2) ppm. MS (EI, 80 °C): m/z (%) = 180 (7) [M]+, 131 (30), 69 (100).
C6H12O2S2 (180.29): calcd. C 39.97, H 6.71, S 35.57; found C 39.90,
H 6.44, S 36.11.
2
3
9 H, tBu), 2.29 (dd, J = 13.8, J = 12.1 Hz, 1 H, 4-Hax or 6-Hax),
2.38–2.47 (m, 1 H, 5-H), 2.63 (dd, J = 13.6, J = 10.9 Hz, 1 H, 4-
2
3
Hax or 6-Hax), 2.68–2.76 (m, 1 H, 4-Heq or 6-Heq), 3.12–3.20 (m, 1
2
4
4
H, 4-Heq or 6-Heq), 3.65 (ddd, J = 14.1, J = 1.9, J = 1.9 Hz, 1
rac-(3R,4S,6R)-4,6-Dimethyl-1,3-dithiane 1,1,3-Trioxide (19): Di-
thiane 11 (148 mg, 1.00 mmol) and NaIO4 (642 mg, 3.00 mmol)
were reacted according to GP1 to give a crude product (116 mg),
which was purified by chromatography (SiO2, CH2Cl2/MeOH) to
yield trioxide 19 (50 mg, 0.26 mmol, 26%) and a mixture of disulf-
H, 2-Heq), 3.72 (d, 2J = 14.1 Hz, 1 H, 2-Hax) ppm. 13C NMR
(100 MHz, CDCl3):
δ = 26.9 [C(CH3)3], 29.4 (CH2), 33.4
[C(CH3)3], 34.4 (CH, C-5), 47.0 (CH2, C-2), 47.4 (CH2) ppm. MS
(FAB): m/z (%) = 193 (100) [M + 1]+. C8H16OS2 (192.34): calcd. C
49.96, H 8.38, S 33.34; found C 50.25, H 7.97, S 32.69.
Eur. J. Org. Chem. 2012, 6867–6877
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6873

R. Ulshöfer, T. Wedel, B. Süveges, J. Podlech
FULL PAPER
2
4
1
rac-(1S,5S)-5-tert-Butyl-1,3-dithiane 1-Oxide (23): Dithiane 21 (dt, J = 10.6, J = 2.5, JC,H = 149.4 Hz, 2-Heq) ppm. 13C NMR
(3.81 g, 21.6 mmol) and NaIO4 (4.75 g, 22.2 mmol) were reacted
according to GP1 to give a crude product (4.38 g), which was puri-
fied by chromatography (SiO2, cyclohexane/EtOAc) to yield sulfox-
ide 23 (3.21 g, 16.7 mmol, 77%) as a colourless solid. Rf (cyclohex-
(100 MHz, CDCl3): δ = 27.2 [C(CH3)3], 34.1 [C(CH3)3], 34.8 (CH,
C-5), 53.4 (CH2, C-4, C-6), 69.1 (CH2, C-2) ppm.
rac-(3R,5R)-5-tert-Butyl-1,3-dithiane 1,1,3-Trioxide (29): Aqueous
H2O2 (30%, 450 mL) was added to a solution of dithiane 21
(176 mg, 1 mmol) in PhOH (1.13 g) and the mixture was stirred for
10 min. A saturated NaHSO3 solution (1 mL) and NaOH solution
(10%, 4.35 mL) were added. The mixture was extracted (3ϫ
CH2Cl2) and the organic layers were dried, concentrated and the
residue purified by chromatography (SiO2, hexanes/ethyl acetate,
1:2 to 0:1) to yield 29 (87 mg, 39%). Rf = 0.32 (EtOAc/hexanes,
1
ane/EtOAc, 1:5) = 0.24. H NMR (250 MHz, CDCl3): δ = 0.97 (s,
3
3
3
3
9 H, tBu), 2.03 (dddd, J = 12.3, J = 11.3, J = 2.9, J = 2.0 Hz,
1 H, 5-Hax), 2.37 (dd, 2J = 12.3, 3J = 12.3 Hz, 1 H, 4-Hax or 6-
Hax), 2.39 (dd, 2J = 13.7, 3J = 11.3 Hz, 1 H, 4-Hax or 6-Hax), 2.57–
2
2.66 (m, 1 H), 3.46–3.54 (m, 1 H), 3.52 (d, J = 12.4 Hz, 1 H, 2-
2
4
4
Hax), 4.03 (ddd, J = 12.4, J = 3.0, J = 1.4 Hz, 1 H, 2-Heq) ppm.
13C NMR (125 MHz, CDCl3): δ = 27.1 [C(CH3)3], 29.8 (CH2, C-
4), 34.3 [C(CH3)3], 51.0 (CH2, C-6), 50.4 (CH, C-5), 56.0 (CH2, C-
2) ppm.
2:1). IR (DRIFT): ν = 2966 (m), 1310 (s), 1154 (m), 1123 (m), 1059
˜
1
(m), 857 (m) cm–1. H NMR (400 MHz, CDCl3): δ = 0.97 (s, 9 H,
3
3
3
3
1
tBu), 2.01 (dddd, J = 12.7, J = 12.6, J = 2.6, J = 1.8, JC,H
=
=
=
129.4 Hz, 1 H, 5-Hax), 2.54 (dd, 2J = 12.8, 3J = 12.7, JC,H
1
rac-5-tert-Butyl-1,3-dithiane 1,1-Dioxide (24): KMnO4 (1.15 g,
7.28 mmol) dissolved in H2O (20 mL) was added at 0 °C to a solu-
tion of sulfoxide 23 (1.40 g, 7.28 mmol) in acetone (60 mL). After
stirring for 24 h at room temp., the mixture was filtered to remove
MnO2 and the precipitate was washed with a small volume of ace-
tone. The filtrate was concentrated, dissolved in CH2Cl2, dried
(Na2SO4) and concentrated to yield crude sulfone 24 (1.52 g,
7.28 mmol, quant.), which was essentially pure; m.p. 130–132 °C.
139.2 Hz, 1 H, 4-Hax), 2.84 (dd, 2J = 14.3, 3J = 12.6, JC,H
1
2
4
3
4
137.6 Hz, 1 H, 6-Hax), 3.15 (dddd, J = 14.3, J = 3.4, J = 2.6, J
1
2
4
= 1.5, JC,H = 140.0 Hz, 1 H, 6-Heq), 3.63 (dddd, J = 12.8, J =
2.4, 3J = 1.8, J = 1.5, JC,H = 139.6 Hz, 1 H, 4-Heq), 3.86 (d, J =
4
1
2
12.8, 1JC,H = 149.1 Hz, 1 H, 2-Hax), 4.70 (ddd, J = 12.8, J = 3.4,
4J = 2.4, 1JC,H = 148.8 Hz, 1 H, 2-Heq) ppm. 13C NMR (125 MHz,
CDCl3): δ = 27.1 [C(CH3)3], 33.7 [C(CH3)3], 38.3 (CH, C-5), 52.7
(CH2, C-6), 54.2 (CH2, C-4), 69.3 (CH2, C2) ppm. MS (EI): m/z
2
4
R (CH Cl /MeOH, 50:1) = 0.80. IR (DRIFT): ν = 2963 (s), 1305
˜
f
2
2
(s), 1159 (m), 1123 (s), 859 (s) cm–1. H NMR (250 MHz, CDCl3):
1
(%) = 224 (25) [M]+. HRMS (EI): calcd. for 12C8 H1616O332S2
1
3
3
2
δ = 0.96 (s, 9 H, tBu), 2.44 (dddd, J = 12.4, J = 11.4, J = 2.4,
224.0541; found 224.0539. C8H16O3S2 (224.34): calcd. C 42.83, H
7.19; found C 43.13, H 7.21.
3J = 2.4, JC,H = 137.4 Hz, 1 H, 5-Hax), 2.55 (dd, J = 14.0, J =
1
2
3
1
2
3
11.4, JC,H = 141.3 Hz, 1 H, 4-Hax), 2.81 (dd, J = 14.3, J = 12.4,
1JC,H = 135.8 Hz, 1 H, 6-Hax), 2.82 (dddd, J = 14.0, J = 2.4, J
2
3
4
5-tert-Butyl-1,3-dithiane 1,1,3,3-Tetraoxide (30): Na2WO4·2H2O
(33 mg, 0.10 mmol) was added to a solution of dithiane 21 (176 mg,
1.00 mmol) in MeOH (7 mL). The mixture was cooled to 0 °C,
aqueous H2O2 (35%, 3 mL, 30 mmol) was added dropwise and the
mixture was stirred at room temp. for 15 h whereupon the forma-
tion of a white precipitate was observed. CH2Cl2 (5 mL) and aque-
ous Na2SO3 solution (10%, 5 mL) were added and the mixture was
extracted with CH2Cl2 (20ϫ 10 mL). The combined organic layers
were dried (Na2SO4), concentrated and purified by chromatog-
raphy (SiO2, CH2Cl2/MeOH, 40:1 to 10:1) to yield disulfone 30
(145 mg, 0.60 mmol, 60%) as a colourless solid. The product has a
very low solubility in common organic solvents like MeOH, ace-
tone and CH2Cl2. Rf = 0.25 (CH2Cl2/MeOH, 40:1). IR (DRIFT):
= 1.9, 4J = 1.3, JC,H = 139.0 Hz, 1 H, 4-Heq), 3.26 (dddd, 2J =
1
14.3, J = 3.6, 3J = 2.4, J = 1.9, JC,H = 135.7 Hz, 1 H, 6-Heq),
4
4
1
2
4
4
1
3.73 (ddd, J = 14.4, J = 3.6, J = 1.3, JC,H = 145.4 Hz, 1 H, 2-
Heq), 3.99 (d, 2J = 14.4, JC,H = 150.7 Hz, 1 H, 2-Hax) ppm. 13C
1
NMR (125 MHz, CDCl3): δ = 26.9 [C(CH3)3], 29.2 (CH2), 33.9
[C(CH3)3], 50.3 (CH2), 50.4 (CH, C-5), 54.7 (CH2, C-2) ppm. MS
(FAB): m/z (%) = 208 (38) [M]+. HRMS (FAB): calcd. for
12C8 H1616O232S2 208.0592; found 208.0590. C8H16O2S2 (208.34):
1
calcd. C 46.12, H 7.74; found C 46.18, H 7.69.
rac-(1R,3R)-5-tert-Butyl-1,3-dithiane 1,3-Dioxide (26) and rac-
(1S,3R,5R)-5-tert-Butyl-1,3-dithiane 1,3-Dioxide (27): Dithiane 21
(176 mg, 1.00 mmol) was dissolved in MeCN (2 mL) and TeO2
(16 mg, 0.10 mmol) and UHP (400 mg, 4.25 mmol) were added and
the mixture was stirred for 24 h at room temp. Brine (10 mL) was
added and the mixture was extracted with CH2Cl2 (3ϫ 10 mL).
The combined organic layers were dried (Na2SO4), concentrated
and purified by chromatography (SiO2, CH2Cl2/MeOH, 50:1 to
10:1) to yield 27 (62 mg, 0.30 mmol, 30%) and 26 (21 mg,
0.1 mmol, 10%) as essentially pure compounds.
ν = 2982 (wm), 1322 (s), 1154 (m), 1118 (m), 886 (m), 870 (m), 846
˜
(m) cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 0.90 (s, 9 H, tBu),
1
2.09 (tt, 3J = 12.0, 3J = 2.2, JC,H = 134.0 Hz, 1 H, 5-Heq), 3.33
1
(dd, 2J = 14.2, 3J = 12.0, JC,H = 139.5 Hz, 2 H, 4-Hax, 6-Hax),
2
4
3
1
3.44 (ddd, J = 14.2, J = 3.2, J = 2.2, JC,H = 137.7 Hz, 2 H, 4-
2
1
Heq, 6-Heq), 5.05 (d, J = 13.8, JC,H = 148.5 Hz, 1 H, 2-Hax), 5.39
(dt, 2J = 13.8, 4J = 3.2, JC,H = 147.9 Hz, 1 H, 2-Heq) ppm. 13C
1
NMR (100 MHz, CDCl3): δ = 26.7 [C(CH3)3], 33.1 [C(CH3)3], 39.4
(CH, C-5), 52.4 (2 CH2, C-4, C-6), 68.3 (CH2, C-2), 130.2 (2 CH),
132.1 (2 CH), 135.8 (2 CH), 137.3 (C), 142.8 (2 C), 152.2 (C) ppm.
MS (FAB): m/z (%) = 224 (13) [M – 16]+. C8H16O4S2 (240.34):
calcd. C 39.98, H 6.71; found C 40.29, H 6.73.
26: Rf (CH2Cl2/MeOH, 20:1) = 0.10. 1H NMR (250 MHz, CDCl3):
3
3
3
δ = 1.04 (s, 9 H, tBu), 2.08 (dddd, J = 12.7, J = 12.6, J = 2.9,
3J = 1.9 Hz, 1 H, 5-H), 2.61 (dd, J = 12.8, J = 12.7 Hz, 1 H, 4-
2
3
2
3
Hax or 6-Hax), 2.91 (dd, J = 14.3, J = 12.6 Hz, 1 H, 4-Hax or 6-
2
4
3
4
Hax), 3.22 (dddd, J = 14.3, J = 3.1, J = 2.9, J = 2.0 Hz, 1 H,
4-Heq or 6-Heq), 3.70 (ddd, J = 12.8, J = 3.7, J = 1.9 Hz, 1 H,
4-Heq or 6-Heq), 3.92 (d, J = 12.8 Hz, 1 H, 2-Hax), 4.77 (ddd, J
= 12.8, 4J = 3.7, 4J = 2.0 Hz, 1 H, 2-Heq) ppm. 13C NMR (75 MHz,
CDCl3): δ = 27.2 [C(CH3)3], 33.7[C(CH3)3], 35.7 (CH, C-5), 47.4.
54.8 (CH2, C-4, C-6), 63.3 (CH2, C-2) ppm.
(1S,3R,4aS,8aR)-4a,5,6,7,8,8a-Hexahydro-2H,4H-1,3-benzodithiine
1,3-Dioxide (37): Freshly ground UHP (1.25 g, 12.9 mmol) was
added at room temp. to a solution of dithiadecalin 31 (1.12 g,
6.44 mmol) in HOAc (10 mL) and CH2Cl2 (20 mL), and the mix-
ture was stirred at that temperature for 5 d, concentrated, neutral-
ised with a saturated aqueous NaHCO3 solution and extracted with
CH2Cl2 (4ϫ 20 mL). The combined organic layers were dried
(Na2SO4) and concentrated to a crude colourless solid (609 mg),
which was purified by chromatography (SiO2, CH2Cl2/MeOH, 50:1
to 20:1) to yield compound 37 (330 mg, 1.60 mmol, 25%) as a white
2
4
3
2
2
27: Rf (CH2Cl2/MeOH, 20:1) = 0.15. 1H NMR (400 MHz, CDCl3):
δ = 0.98 (s, 9 H, tBu), 1.46 (tt, 3J = 12.5, 3J = 1.8, 1JC,H = 127.1 Hz,
2
3
1
1 H, 5-Hax), 2.56 (dd, J = 12.5, J = 12.5, JC,H = 141.0 Hz, 2 H,
2
4
3
1
4-Hax), 3.50 (ddd, J = 12.5, J = 2.5, J = 1.8, JC,H = 139.5 Hz,
2 H, 4-Heq), 3.70 (d, J = 10.6, JC,H = 150.9 Hz, 1 H, 2-Hax), 4.79 solid together with a fraction (50 mg) that is most probably a mix-
2
1
6874 Eur. J. Org. Chem. 2012, 6867–6877
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Conformationally Constrained Oxides of 1,3-Dithiane
ture of isomers 33a and 33b. 37: M.p. 210–220 °C (decomp.). Rf =
poured into a saturated aqueous solution of NH4Cl and extracted
0.24 (CH Cl /MeOH, 20:1). IR (DRIFT): ν = 2965 (m), 2944 (m),
with EtOAc (3ϫ 20 mL). The combined organic layers were dried
˜
2
2
2901 (m), 1037 (s) cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.26– (Na2SO4) and concentrated to yield a crude oil (2.85 g), which was
1.44 (m, 4 H), 1.58–1.72 (m, 1 H), 1.84–1.92 (m, 1 H), 1.93–2.05
(m, 2 H), 2.48–2.60 (m, 2 H), 2.72 (dd, J = 12.6, J = 12.5 Hz, 1
purified by recrystallisation (EtOH/cyclohexane) to yield ketene
S,S-acetal 46 (1.46 g, 4.31 mmol, 63%) as a yellow solid; m.p. 139–
2
3
2
3
4
H, 4-Hax), 3.33 (ddd, J = 12.6, J = 2.7, J = 2.9 Hz, 1 H, 4-Heq),
142 °C (EtOH/CH2Cl2). Rf = 0.43 (cyclohexane/EtOAc, 10:1). IR
3.89 (d, 2J = 10.5 Hz, 1 H, 2-Hax), 4.81 (dd, 2J = 10.5, 4J = 2.9 Hz, (ATR): ν = 3051 (w), 2952 (m), 1519 (s), 1439 (m) cm–1. H NMR
1
˜
1 H, 2-Heq) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.8 (CH2),
(400 MHz, CDCl3): δ = 1.01 (s, 9 H, tBu), 2.11–2.20 (m, 1 H, 5-
25.2 (CH2), 26.6 (CH2), 29.7 (CH), 33.0 (CH2), 58.6 (CH2), 66.1 H), 3.09–3.21 (m, 4 H, 4-H2, 6-H2), 7.26–7.34 (m, 4 H, Ar), 7.73–
(CH), 68.6 (CH2) ppm. MS (EI, 140 °C): m/z (%) = 206 (8) 7.77 (m, 2 H, Ar), 8.51–8.55 (m, 2 H, Ar) ppm. 13C NMR
[M]+, 157 (23), 95 (100). HRMS (FAB): calcd. for 12C8 H1416O232S2 (100 MHz, CDCl3): δ = 27.1 [C(CH3)3], 31.7 (2 CH2), 34.4
1
206.0435; found 206.0432. C8H14O2S2 (206.33): calcd. C 46.57, H
6.84, S 31.08; found C 46.59, H 7.48, S 31.35.
[C(CH3)3], 45.4 (CH), 119.1 (2 CHAr), 125.4 (2 CHAr), 126.1 (2
CHAr), 126.7 (2 CHAr), 130.3 (C), 138.0 (2 C), 138.8 (2 C), 143.6
(C) ppm. MS (FAB): m/z (%) = 338 (100) [M]+. HRMS (FAB):
(4aS,8aR)-4a,5,6,7,8,8a-Hexahydro-2H,4H-1,3-benzodithiine
1,1,3,3-Tetraoxide (40): Na2WO4·2H2O (33 mg, 0.10 mmol) was
added to a solution of dithiadecalin 31 (174 mg, 1.00 mmol) in
MeOH (15 mL). The mixture was cooled to 0 °C, aqueous H2O2
(35%, 3 mL, 31 mmol) was added dropwise and the mixture was
stirred at room temp. for 3 weeks. An aqueous Na2SO3 solution
(10%, 5 mL) and H2O (30 mL) were added and the mixture was
extracted with CH2Cl2 (4ϫ 20 mL). The combined organic layers
were dried (Na2SO4) and concentrated to yield essentially pure 40
(216 mg, 0.91 mmol, 91%) as a colourless solid; m.p. 270–280 (de-
comp.). Rf = 0.40 (CH2Cl2/MeOH, 50:1). 1H NMR (400 MHz,
[D6]DMSO): δ = 1.05–1.18 (m, 1 H), 1.20–1.48 (m, 3 H), 1.66–1.75
12
calcd. for
C
21
1H2232S2 338.1163; found 338.1160. C21H22S2
(338.53): calcd. C 74.51, H 6.55, S 18.94; found C 74.46, H 6.49, S
18.83.
meso-5-tert-Butyl-2-(9H-fluoren-9-ylidene)-1,3-dithiane 1,3-Dioxide
(47): mcpba (70%, 910 mg, 3.70 mmol) dissolved in Et2O (11 mL)
was added slowly at –78 °C to a solution of the ketene S,S-acetal
46 (624 mg, 1.85 mmol) in CH2Cl2 (20 mL). The mixture was
stirred for 24 h after warming to room temp., diluted with CH2Cl2
(20 mL) and poured into a saturated aqueous NaHCO3 solution.
The phases were separated and the organic layer extracted with
NaHCO3 solution (3ϫ), dried (Na2SO4) and concentrated to yield
a crude yellow solid (696 mg), which was purified by chromatog-
raphy (SiO2, CH2Cl2/MeOH, 100:0 to 50:1) and recrystallisation
(CH2Cl2/cyclohexane) at room temp. to yield disulfoxide 47
(382 mg, 1.03 mmol, 56%) as a yellow solid; m.p. 180–190 °C (de-
3
(m, 1 H), 1.82–1.91 (m, 2 H), 2.01–2.13 (m, 2 H), 3.20 (ddd, J =
3
3
2
3
12.2, J = 11.2, J = 3.5 Hz, 1 H, 8a-H), 3.32 (dd, J = 14.4, J =
11.8 Hz, 1 H, 4-Hax), 3.43 (ddd, 2J = 14.4, J = 2.9, J = 3.7 Hz, 1
3
4
2
2
H, 4-Heq), 5.13 (d, J = 14.0 Hz, 1 H, 2-Hax), 5.47 (dd, J = 14.0,
4J = 3.7 Hz, 1 H, 2-Heq) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 19.8 (CH2), 23.8 (CH2), 24.4 (CH2), 30.8 (CH2), 32.8 (CH),
56.0 (CH2), 62.5 (CH), 68.9 (CH2) ppm. MS (FAB): m/z (%) = 239
(22) [M + 1]+. C8H14O4S2 (238.32): calcd. C 40.32, H 5.92, S 26.91;
found C 40.45, H 5.70, S 26.90.
comp.). R = 0.33 (CH Cl /MeOH, 20:1). IR (ATR): ν = 2951 (w),
˜
f
2
2
1
1444 (m), 1060 (s), 1033 (s) cm–1. H NMR (400 MHz, CDCl3): δ
= 1.08 (s, 9 H, tBu), 2.85–2.95 (m, 2 H, 4-Hax, 6-Hax), 3.55–3.64
(m, 1 H, 5-H), 3.71–3.78 (m, 2 H, 4-Heq, 6-Heq), 7.20–7.28 (m, 2
H, Ar), 7.37–7.43 (m, 2 H, Ar), 7.55–7.60 (m, 2 H, Ar), 8.18–8.22
(m, 2 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.4 (CH),
27.2 [C(CH3)3], 33.0 [C(CH3)3], 50.9 (2 CH2), 120.1 (2 CH), 128.1
(2 CH), 130.2 (2 CH), 132.1 (2 CH), 135.8 (2 CH), 137.3 (C), 142.8
(2 C), 152.2 (C) ppm. MS (FAB): m/z (%) = 371 (100) [M + 1]+.
trans-5-tert-Butyl-2-trimethylsilyl-1,3-dithiane (45): In analogy to a
published procedure,[44] nBuLi (14.4 mmol) was added with stirring
at –78 °C to a solution of dithiane 21 (2.53 g, 14.3 mmol) in anhy-
drous THF (20 mL) and stirring was continued for 1 h at –78 °C
and for 30 min at 0 °C. The mixture obtained was transferred por-
tionwise through a syringe to a cooled (–78 °C) solution of TMSCl
(2.19 mL, 17.2 mmol) in anhydrous THF (10 mL). The mixture was
warmed to room temp. overnight, poured into H2O (100 mL) and
extracted with cyclohexane (3ϫ 50 mL). The combined organic
layers were extracted with H2O (4ϫ 30 mL), dried (K2CO3) and
concentrated to yield a pale-yellow crude solid, which was immedi-
ately purified by distillation (bulb-to-bulb distillation, 130 °C/
130 Pa) to furnish silane 45 (2.47 g, 9.94 mmol, 69%) as a colour-
less solid, which is stable at 7 °C for several months; m.p. 110–
Supporting Information (see footnote on the first page of this arti-
cle): Spectra of compounds 12–17, 19, 20, 22, 23, 26, 27, 29, 30,
37, 46 and 47.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG), (grant number PO 463/9-1) and by the Landesgraduierten-
stiftung Baden-Württemberg (grant to R. U.). The help of Sebas-
tian Ehni and Tony Reinsperger in the measurement and evaluation
of NOESY spectra is gratefully acknowledged.
116 °C. IR (DRIFT): ν = 2960 (s), 1477 (m), 1365 (s), 1248
˜
(s) cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.17 (s, 9 H, SiMe3),
0.89 (s, 9 H, tBu), 1.67–1.76 (m, 1 H, 5-H), 2.52–2.61 (m, 2 H),
2.80–2.88 (m, 2 H), 3.56 (s, 1 H, 2-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = –3.06 (SiMe3), 27.0 [C(CH3)3], 32.4 (2 CH2), 33.5
(CH), 34.1 [C(CH3)3], 47.1 (CH) ppm. MS (EI, 25 °C): m/z (%) =
248 (42) [M]+, 175 (20) [C8H15S2]+, 143 (100).
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Eur. J. Org. Chem. 2012, 6867–6877
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6875

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Received: May 23, 2012
Published Online: October 29, 2012
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www.eurjoc.org
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