Synthesis and acidity of conformationally constrained 1,3-oxathiane S-oxides

Article abstract of DOI:10.1016/j.tetlet.2016.10.114

Conformationally constrained 5-tert-butyl 1,3-oxathiane was synthesized and oxidation led to the diastereoisomeric sulfoxides and the respective sulfone. Stereoelectronic effects are discussed for these compounds and their corresponding 2-carbanions. pK_avalues are calculated for these compounds and compared with the respective 1,3-dithiane-derived sulfide, the sulfoxides, and the sulfone.

Full text of DOI:10.1016/j.tetlet.2016.10.114

Accepted Manuscript
Synthesis and acidity of conformationally constrained 1,3-oxathiane S-oxides
Daniel Weingand, Joachim Podlech
PII:
S0040-4039(16)31447-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.114
TETL 48284
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
8 September 2016
27 October 2016
31 October 2016
Please cite this article as: Weingand, D., Podlech, J., Synthesis and acidity of conformationally constrained 1,3-
oxathiane S-oxides, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.10.114
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Synthesis and acidity of conformationally
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constrained 1,3-oxathiane S-oxides
Daniel Weingand, Joachim Podlech

1
Tetrahedron Letters
Synthesis and acidity of conformationally constrained 1,3-oxathiane S-oxides
Daniel Weinganda and Joachim Podlecha, 
aInstitut für Organische Chemie, Karlsruher Institut für Technologie (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Conformationally constrained 5-tert-butyl 1,3-oxathiane was synthesized and oxidation led to
the diastereoisomeric sulfoxides and the respective sulfone. Stereoelectronic effects are
discussed for these compounds and their corresponding 2-carbanions. pKa values are calculated
for these compounds and compared with the respective 1,3-dithiane-derived sulfide, the
sulfoxides, and the sulfone.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Sulfur heterocycles
Sulfoxides
Sulfones
Acidity
Stereoelectronic effects
1. Introduction
Physical and chemical properties of compounds like structure,
stability, and reactivity are significantly influenced by
stereoelectronic, dipole, charge, and steric effects.1 We have
investigated stereoelectronic interactions in -anions of sulfides,
sulfoxides, and sulfones,2 where the stability is ruled by
interaction of the anionic lone pair with S‒C and S=O bonds.
These effects are favorably investigated in derivatives of
conformationally fixed 1,3-dithianes.3‒5 These have a rigid
conformation and the antiperiplanar orientation of bonds and the
lone pairs favor possible stereoelectronic interactions. In fact, a
carbanion is best stabilized, when the lone pair is in an
antiperiplanar orientation to a C‒S bond or ‒ even better – to an
S=O bond of a sulfoxide, allowing for an nC → *S‒C or an
nC → *S‒O interaction, respectively. Nevertheless, in dithiane S-
oxides a possible nC → *S‒O interaction might be countervailed
by two nC → *S‒C interactions, what makes an independent
investigation of these effects difficult. We thus considered the
corresponding 1,3-oxathianes to be more suitable for the
examination of these effects since an nC → *O‒C stereoelectronic
effect is small as compared with the respective nC → *S‒C
interaction.6,7 The compounds of interest 1‒4 together with
dithianes 5‒8 and the respective anions are given in Figure 1.
Figure 1. Conformationally constrained 1,3-oxathiane and 1,3-dithiane,
their S-oxides and the corresponding carbanions.
2. Conformationally constrained 1,3-oxathiane S-oxides
4,6-Dimethyl-substituted 1,3-oxathianes have already been
prepared by Juaristi et al. starting with (E)-pent-3-en-2one8 and
by Pasanen et al. from (E)-pent-3-en-2-ol.9 They obtained the
desired cis-substrate 12, which could be separated from the two
trans-isomers 13 and 14 by distillation. We decided to develop a
differing protocol starting with 2,4-pentanediol 9 (Scheme 1).
Activation of one hydroxyl group as tosylate and substitution
with thioacetate yielded a mixture of diastereoisomers 10 and 11,
which was separated by chromatography. Subsequent hydrolysis
with 1.4M hydrogen chloride in methanol led to the
hydroxythiols, which were reacted with dimethoxymethane
yielding the respective oxathianes 12‒14. A high dilution of the
hydroxythiols had to be maintained in these reactions to avoid di-
and polymerization, which was achieved by their slow addition
through the reflux condenser (using
a syringe pump).
———
 Corresponding author. Tel.: +49-721-608-43209; fax: +49-721-608-47652; e-mail: joachim.podlech@kit.edu

2
Tetrahedron Letters
Determination of the configurations was best made at that stage,
respective dithiane derivatives (Table 1). For this we used a
method described previously.14 All structures were optimized
with the B3LYP15/6-311G++(d,p)16,17 basis set and single point
calculations were performed at the B3LYP/AUG-cc-pVTZ
level18 using des Gaussian 09 package.19 We considered dimethyl
sulfoxide as solvent using the CPCM-SCRF method.20 As
expected the acidity of the oxathianes substantially increases
from the sulfide via the sulfoxides to the sulfone derivatives. A
comparison of sulfoxides 2 and 3 is more meaningful: The axial
sulfoxide 3 is 3.7 pKa units more acidic than the respective
equatorial sulfoxide 2 and a deprotonation of the axial
(antiperiplanar) proton in 3 is significantly favored over an
equatorial deprotonation (pKa = 1.5). This can mainly be
explained by the mentioned nC → *S‒O interaction, which is
highest, when S=O bond and anionic lone pair are in an
antiperiplanar orientation. The (C‒H → *S‒O) stereoelectronic
effect stabilizing the protonated species is significantly smaller
and thus has a vanishing effect on the pKa value. Hardly any
stereoelectronic stabilizing is possible involving the equatorial
S=O bond in sulfoxide 2. An nC → *S‒C interaction is possible
especially with an equatorial lone pair making the deprotonation
of the equatorial hydrogen in 2 more likely. Since this stabilizing
effect is less significant, the difference in the acidities of the axial
and the equatorial protons is (pKa = 0.5) smaller. The significant
difference for the deprotonation of the equatorial protons in
compounds 2 and 3 is quite astonishing, since a similar
nC → *S‒C interaction would be expected in both cases.
Nevertheless, it has been observed previously4 that this
interaction is more pronounced, when the sulfur bears an axial
oxygen as compared to an S(Oeq)‒C bond. Furthermore, we have
shown previously that an nC(eq) → *S‒O(ax) stereoelectronic
effect is significant, while an nC(eq) → *S‒O(eq) interaction is
close to zero.4 No systematic influence of the carbanions’ dipole
momentums on the acidity of the respective compounds is
1
since the pattern of the coupling constants in H NMR spectra
allowed for an unambiguous assignment, which would have been
much more difficult in the respective precursors.
Scheme 1. Synthesis of 4,6-dimethyl-substituted 1,3-oxathianes. a) TsCl,
pyridine, CH2Cl2, 0 °C to rt, 12 h, 35%; b) KSAc, DMF, 80 °C, 40 min, 53%;
c) separation by chromatography (26% 10, 27% 11); d) 1.4M HCl in MeOH,
rt, 12 h, then (MeO)2CH2, F3B·OEt2, CH2H2, , 30 min, 88% 12.
Though the preference of the diequatorial over the respective
flipped diaxial conformation in dimethyl-substituted six-
membered rings was reported to be higher than in the respective
tert-butyl-substituted compounds,10 the conformational rigidity in
the latter is more than sufficient for the aimed investigations.11
Since the synthesis of 5-tert-butyl-1,3-oxathianes is simpler than
that of the dimethyl derivatives (especially since separation of the
isomers turned out to be easier to achieve) we decided to
continue our investigations with 5-tert-butyl-substituted
substrates. The hydroxythiole 15, whose synthesis was reported
previously,12 was reacted with dimethoxymethane furnishing
oxathiane 1 (Scheme 2) with quantitative yield. Oxidation with
one equivalent sodium periodinate yielded
a mixture of
sulfoxides 2 and 3 (79:21), which could be separated by column
chromatography. These sulfoxides could be further oxidized with
potassium permanganate to the respective sulfone 4, which was
similarly obtained in one step from the sulfide using two
equivalents of an oxidizing agent like sodium periodinate,
potassium permanganate, or Oxone.
obvious from the calculated values.
A comparison with
previously investigated dithiane derivatives4 supports these
conclusions: nC → *S‒C interactions to both of the sulfur atoms
significantly stabilize an equatorial lone pair21 and make the
respective mode of deprotonation in the equatorial sulfoxide 6
much more relevant (pKa = 3.2). These interactions are
countervailed by a significant nC → *S‒O stereoelectronic effect
possible in the axial sulfoxide 7. Deprotonations of the equatorial
and the axial proton, respectively, are similarly possible; the
difference in the pKa values here is only 0.6. The preferential
equatorial deprotonation in dithianes (e. g. 5) without interfering
oxygen atoms has been calculated and explained repeatedly.4,14,21
Scheme 2. Synthesis of 5-tert-butyl-substituted 1,3-oxathiane S-oxides. a)
(MeO)2CH2, F3B·OEt2, CHCl3, , 30 min, quant.; b) 1 eq. NaIO4, THF/H2O
(1:1), rt, 12 h, 62% 2 + 16% 3; c) 2 eq. NaIO4 or KMnO4 or Oxone (92%); d)
KMnO4, acetone/H2O (1:1), rt, 48 h, 68% (from 2).
Table 1. Calculated pKa values of oxathiane and dithiane and
of their S-oxides
[a]
[a]
Oxathiane
pKa
µ [D] [a,b]
Dithiane
pKa
µ [D]
[a,b]
3. Acidity of 1,3-oxathiane and 1,3-dithiane S-oxides
1→1anionax
1→1anioneq
2→2anionax
2→2anioneq
3→3anionax
3→3anioneq
4→4anionax
4→4anioneq
46.9
45.3
40.1
40.6
36.4
37.9
33.3
31.9
13.2
16.1
15.3
17.4
13.3
16.3
14.4
16.9
5→5anionax
5→5anioneq
6→6anionax
6→6anioneq
7→7anionax
7→7anioneq
8→8anionax
8→8anioneq
41.7
36.9
34.8
31.6
31.7
31.1
28.4
24.8
12.6
15.0
14.4
16.2
12.9
15.1
13.9
15.9
The relative orientation of the S=O bonds has a crucial
influence on the compounds’ properties. Stereoelectronic
interactions with participation of an axial S=O bond lead to a
weakening of the axial C2‒H bond (C‒H → *S‒O) and to a
stabilization of an axial anionic lone pair in the respective
deprotonated species (nC → *S‒O). Similar interactions are
significantly less relevant in the equatorial sulfoxide. The
weakening of the axial C‒H bond and the stabilization of an axial
1
lone pair can be observed, e.g., in NMR spectra (smaller JC‒H
coupling constants),13 in IR spectra, via their structural
parameters (longer C‒H bonds), and especially by comparison of
the pKa values. We calculated pKa values of oxathianes 1‒4, both
for deprotonation of the axial and the equatorial proton,
respectively, and compared the obtained values with those of the
a B3LYP/AUG-cc-pVTZ//B3LYP/6-311G++(d,p) with CPCM-SCRF
(solvent=DMSO). The results for these compounds were put into relation
with calculated and measured values for fluorene. The pKa values must not be
taken as absolute numbers; only their relative differences are meaningful c.f.
Ref. 14.

3
b Dipole moments of the respective carbanions.
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Acknowledgments
1.
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG).
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Supplementary Material
Supplementary data associated with this article (experimental
procedures, spectroscopic data, archive entries for all calculated
minimum structures) can be found, in the online version, at
http://dx.doi.org/■■■.
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Conformationally flexible 1,3-oxathianes have been investigated
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7607‒7611; Masnabadi, N.; Manesh, A. T.; Azarakhshi, F. Phosphorus,
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Weinheim, 2002.

4
Tetrahedron Letters
Highlights
- Rigid oxathianes allow for the investigation of
stereoelectronic effects
- Acidity of sulfoxides is strongly influenced by the
orientation of the functional group
- Anionic lone pairs are stabilized by interaction
with antiperiplanar S=O bonds