Molecular rods based on oligo-spiro-thioketals

Article abstract of DOI:10.1021/acs.joc.5b02670

We report on an extension of the previously established concept of oligospiroketal (OSK) rods by replacing a part or all ketal moieties by thioketals leading to oligospirothioketal (OSTK) rods. In this way, some crucial problems arising from the reversible formation of ketals are circumvented. Furthermore, the stability of the rods toward hydrolysis is considerably improved. To successfully implement this concept, we first developed a number of new oligothiol building blocks and improved the synthetic accessibility of known oligothiols, respectively. Another advantage of thioacetals is that terephthalaldehyde (TAA) sleeves, which are too flexible in the case of acetals can be used in OSTK rods. The viability of the OSTK approach was demonstrated by the successful preparation of some OSTK rods with a length of some nanometers.

Full text of DOI:10.1021/acs.joc.5b02670

Article
pubs.acs.org/joc
Molecular Rods Based on Oligo-spiro-thioketals
P. Wessig,* M. Gerngroß, D. Freyse, P. Bruhns, M. Przezdziak, U. Schilde, and A. Kelling
Institut fur Chemie, Universitat Potsdam, Karl-Liebknecht-Strasse 24-25, D-14476 Potsdam, Germany
̈
̈
S
* Supporting Information
ABSTRACT: We report on an extension of the previously
established concept of oligospiroketal (OSK) rods by replacing
a part or all ketal moieties by thioketals leading to
oligospirothioketal (OSTK) rods. In this way, some crucial
problems arising from the reversible formation of ketals are
circumvented. Furthermore, the stability of the rods toward hydrolysis is considerably improved. To successfully implement this
concept, we first developed a number of new oligothiol building blocks and improved the synthetic accessibility of known
oligothiols, respectively. Another advantage of thioacetals is that terephthalaldehyde (TAA) sleeves, which are too flexible in the
case of acetals can be used in OSTK rods. The viability of the OSTK approach was demonstrated by the successful preparation of
some OSTK rods with a length of some nanometers.
to construction.3 A typical OSK rod with a solubility enhancing
sleeve is depicted in Figure 1 (B).
INTRODUCTION
■
The term molecular rods generally refer to relatively rigid
molecules with a large aspect ratio (i.e., the ratio between
length and width). During the last decades, this substance class
has enjoyed constantly growing interest, and meanwhile, a wide
range of applications in material science, nanoelectronics, and
biosciences has been developed.1 In this context, an efficient
synthetic accessibility is the crucial prerequisite. The nano-
scopic scale of the molecular rods often requires many
repetitive synthetic steps, thus diminishing the overall yield.
Furthermore, the drastically decreasing solubility with increas-
ing length is a substantial challenge.
Some years ago, we developed a new type of molecular rods,
which are composed of spirocyclically connected saturated six-
membered rings. Because the construction of these rods is
based on the formation of ketals, we called these compounds
oligospiroketal (OSK) rods.2 Simple rods of this type with
more than six ring elements exhibit scarce solubility, and
therefore, longer rods are only accessible by introducing
solubility enhancing groups (SEG) in terminal positions
(Figure 1, A). These groups impede the introduction of
other functional groups and thus limit the application of those
rods. This problem could be circumvented by the development
of building blocks bearing lateral SEGs. Because these units
merge two shorter rods we have called them sleeves in analogy
OSK rods of type B allow for the implementation of
functional groups in terminal positions leading to a number of
interesting applications. Thus, the integration in biological
membranes4,5,7 as well as the usage as rigid spacer in FRET
systems8 were investigated. Recently, we used OSK rods as
building blocks in porous materials9 and dendrimers.10 It
should be noted that the solubility is also improved by
incorporating a flexible joint, leading to articulated rods.11
Despite the considerable success with OSK rods of types A
and B a serious problem should not be disregarded. The
formation of acetals from diols and ketones catalyzed by acids is
an equilibrium reaction. Beyond a certain number of ketal
groups per molecule this leads unavoidably to drastically
decreasing yields and very complex product mixtures. In our
experience, this limit is exceeded with more than six ketal
structures, i.e., it should be very difficult to prepare OSK rods
longer than A and B with the same building blocks.
On the other hand, thioacetals are very stable toward both
acidic and basic conditions, however, relatively sensitive toward
oxidants.12 Cyclic thioacetals (e.g., 1,3-dithianes) gained
particular importance in organic synthetis, e.g., in the Corey−
Seebach reaction.13 The formation of cyclic thioacetals from
dithiols and aldehydes or ketones is, in contrast to the oxygen
counterpart, no equilibrium reaction, and therefore, the above-
mentioned problems with the synthesis of longer OSK rods
should not occur with thioacetals. Herein, we describe a
powerful approach to circumvent the “equilibrium problem”,
the partial or complete replacement of acetals by thioacetals
leading to oligo-spiro-thioketal (OSTK) rods. Herein, the term
OSTK rod denotes an OSK rod where at least one ketal moiety
is replaced by a thioketal (but not necessarily all ketals).
Figure 1. Typical OSK rods with terminal (A) and lateral (B)
solubility enhancing groups (SEG).
Received: November 21, 2015
© XXXX American Chemical Society
A
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ketals and thioketals, we were, therefore, also interested in 2,2-
bis(sulfanylmethyl)-1,3-propanediol 6, which has also rarely
been mentioned in literature.17 Using the optimized conditions
for 3, we obtained 6 with 71% yield based on the commercially
available 2,2-bis(bromomethyl)propane-1,3-diol 4. Similarly, we
prepared the third fundamental building block 918 from 1,3-
dibromopropan-2-ol 7. With 9 it should be possible to
construct OSTK rods by repetitive formation of thioketals
with ketones and subsequent oxidation of the secondary
alcohol to the next ketone. However, we will show that the
selective oxidation of alcohols in the presence of thioacetals is
certainly not an easy task. Therefore, we also prepared 2,2-
bis(sulfanylmethyl)-1,3-dioxolane 12 from the known 2,2-
bis(bromomethyl)-1,3-dioxolane 10, which is prepared from
commercially available 1,3-dibromoacetone.19 Compound 12
could be used in a similar way as 9, but the restoration of the
ketone moiety should occur by removal of the dioxolane
protecting group. We are also interested in OSTK rods with
different functional groups in the terminal positions. This could
be achieved by a stepwise formation of thioketal and ketal
function from building block 6. However, we found that an
exclusive reaction of the thiols in 6 is difficult to accomplish
(see next section). Therefore, we prepared compound 13 by
selective protection of the hydroxyl groups with TBDMS
groups in nearly quantitative yield.
RESULTS AND DISCUSSION
■
Building Blocks. Pentaerythritol is one of the central
building blocks of the OSK rod backbone, and it was evident to
use its tetrathia analogue 2,2-bis(mercaptomethyl)-1,3-pro-
panedithiol 3 en route toward OSTK rods. A literature survey
on the preparation and usage of 3 revealed surprisingly few
references. Essentially all syntheses of 3 are based on SN
reactions between tetraelectrophiles derived from pentaery-
thritol and different sulfur nucleophiles.14 Already in 1937,
Backer and Evenhuis14a reported on the synthesis of 3 from
2,3,7,8-tetrathiaspiro[4.4]nonane 215 by reduction with Na/
NH3. Some years later, a preparation of 3 by the reaction of 1,3-
dibromo-2,2-bis(bromomethyl)propane and sodium tetrasul-
fide, followed by catalytic reduction of the resulting polysulfide
mixture, has been described.14b In 1970, Fujihara et al. reported
on the synthesis of 3 from the same tetrabromide by reaction
with Na2S2 to give 2 and subsequent reduction with LiAlH4.14c
Wade et al. used the tetracetyl derivative of 3 directly in the
synthesis of thioketals.14d This tetracetate was also prepared by
Gaz et al.14e (no yields given) and converted to 3 by treatment
with LiAlH4.
According to our experience, all methods described up to
now are difficult to reproduce and provide 3 only with low
yields and/or contaminated with other sulfur-containing
compounds. This is probably one of the reasons why 3 was
so rarely used. After numerous attempts, we succeeded in
developing an optimized procedure. Starting from tetramesylate
116 (the above-mentioned and commercially available but
relatively expensive tetrabromide can also be used), we
obtained 2,3,7,8-tetrathiaspiro[4.4]nonane 2 by treatment of
1 with a Na2Sx solution in DMF, prepared from Na2S (2 equiv)
and S8 (4 equiv), by stirring for 2 h at 80 °C. The crude
compound 2 was reduced without purification with LiAlH4 and
gave the target compound 3 reproducible with 64% yield
(Scheme 1).
Trispiranes. Equipped with the building blocks 3, 6, 9, 12,
and 13, we next investigated the synthesis and properties of
simple trispiranes starting with cyclohexanone 14 (Scheme 2).
Scheme 2. Synthesis of Trispiranes 15 and 16 and Spirane 18
As we will demonstrate below, it is not necessary to replace
all ketals by thioketals to avoid the problems mentioned above.
Bearing in mind the complementary formation and reactivity of
Scheme 1. Synthesis of Building Blocks 3, 6, 9, 12, and 13
i
Method A: 3 equiv of BF3Et2O, 94%. Method B: cat. TsOH, 88%.
Method C: cat. I2, 86%.
The tetrathiatrispirane 15, which could be regarded as the
parent compound of OSTK rods, was prepared for the first
time by Backer and Evenhuis14a and later mentioned only
once.20 A substituted trispirane was reported by Grosu et al.,14e
whereas spiranes such as 16 with both ketal and thioketal
moieties are hitherto unknown. We applied three different
methods for the synthesis of 15 (BF3·Et2O, cat. TsOH, cat. I2)
and obtained the target compound always with very good
yields. Because the formation of thioketals takes place under
much milder conditions than the ketal formation, we
hypothesized that the dithiapentaerythritol 6 primarily reacts
only with the thiol groups to give 18. The reaction between 14
and 6 afforded, however, the trispirane 16. Compound 18 could
B
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be obtained by selective hydrolytic removal of the 1,3-dioxane
ring in 16.
From compound 15, we obtained crystals suitable for X-ray
crystal structure analysis. Compound 15 shows C2 symmetry
and axial chirality. C1 is located on the 2-fold axis. For both
cyclohexane rings a torsion angle (C9−C4−C4′−C9′) of
−21.303(4)° can be observed. Both dithiane rings are almost
orthogonal to each other, characterized by an angle of 89.68°
around the C1 atom formed by the C1/C2/C3 and C1/C2′/
C3′ planes. The bond angles around C1 range from 108.99(8)
to 113.02(2)°. The bond lengths are as expected (C−C:
1.518(2)−1.536(2) Å; C−S: 1.806(1)−1.827(1)°) (Figures 2
and 3, for details see Supporting Information).
Figure 4. Solubility of trispiranes 15−17.
To verify the high stability of thioketal moieties toward
hydrolysis, we treated a solution of trispirane 15 in dichloro-
methane for a longer time with concentrated hydrochloric acid.
Even after 18 days we could not detect any decomposion in the
1H NMR spectrum.
Figure 2. X-ray crystal structure analysis of compound 15 (molecular
Then, we prepared a variety of trispiranes to demonstrate the
compatibility of the OSTK skeleton with different reaction
conditions and functional groups. Thus, 4-pivaloyloxy-cyclo-
hexanone 192 reacted smoothly with 3 to give the trispirane
20a with good yields (Scheme 3). After removal of the Piv
group with DIBALH, we succeeded with the Swern oxidation
to diketone 21, whereas the conversion to the corresponding
ditosylate failed. N-Protected piperidine-4-ones such as 223 and
242 are also suitable reactants and gave the trispiranes 23 and
25 with good to excellent yields. The reaction of N-Cbz-
protected piperidin-4-one 24 with 6 afforded the trispirane 26,
containing both a ketal and a thioketal moiety by analogy with
the reaction with cyclohexanone described above. Furthermore,
it was possible to remove the Cbz protecting groups in 25 with
HBr/HOAc giving the free diamine 27, albeit with moderate
yield.
structure with thermal ellipsoids drawn at the 50% probability level).
As already mentioned, a low solubility is a serious problem
for the synthesis and application of molecular rods. To evaluate
the influence of exchanging oxygen atoms by sulfur atoms on
the solubility of OS(T)K rods, we compared trispiranes 15 and
16 and the known compound 1721 concerning its solubility in
various solvents (Figure 4). All three compounds have a low
solubility in MeOH underlining the rather hydrophobic
character of the backbone of OS(T)K rods, but whereas 17
is highly soluble in DCM and THF, the solubility is nearly
halved by replacement of one ketal by a thioketal (16) and
drops below one-tenth in the case of dithioketal 15. This effect
results from considerably reduced electronegativity of sulfur (χ
= 2.58, which is nearly the same value as for carbon, χ = 2.55)
compared with oxygen (χ = 3.44). Consequently, C−S bonds
are essentially nonpolar in contrast to highly polarized C−O
bonds. It must therefore be assumed that decreasing solubility
with increasing length is an even greater problem for OSTK
rods.
Sleeves. As discussed in the preceding section, sleeves
bearing solubility enhancing groups (SEG) are of pivotal
importance for longer OSK rods and all the more for OSTK
rods. Until now, we have developed four different sleeves C−F,
whose structures are summarized in Figure 5.3,6 The DBD
sleeve C was repeatedly used in OSK rods, whereas the
Figure 3. Crystal packing of compound 15.
C
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a
Scheme 3. Synthesis of Various Trispiranes
Scheme 4. Synthesis of Model Compounds 29 and 31
a
Key: (i) (1) BuLi, (2) DMF, (3) 2,2-dimethyl-1,3-propanediol, (4)
BuLi, (5) DMF, (6) 2,2-dimethyl-1,3-propanediol, 42%; (ii) TFA,
64%; (iii) 2,2-dimethyl-1,3-propanedithiol, I2, 75%.
dithioacetal 31 by reaction with 2,2-dimethylpropane-1,3-
dithiol.23
Regarding the suitability of TAA sleeves for molecular rods,
three preferred conformations T1, T2, and C have to be
discussed (Figure 6). For this we defined a pseudodihedral
Figure 6. Preferred conformations T1, T2, and C of TAA sleeves.
angle α, which is given by the atoms 1−4. For conformers T1
and T2 α is nearly 180°, whereas for C the angle α is 0°.
Furthermore, the distances between heteroatoms X and the
substituent in the ortho position of the aromatic ring (Me in
this case) have to be considered. This distance is large for both
saturated rings in T1 but small for one (C) or both rings (T2)
in the remaining two conformers.
Figure 5. Sleeves C−F with solubility enhancing groups (SEG).
Due to the larger space requirement of atoms X compared
with the hydrogen atom at the acetal carbon atom, T1 should
be the most favored conformer. At first, we compared 29 and
31 by molecular modeling. For this purpose, a conformational
analysis was performed using the MMFF94x force field,24 and
all conformers within an energy window of 5 kcal/mol above
the global minimum were collected. We obtained four
geometries for 31 and seven geometries for 29. These 11
structures were then optimized at DFT level (B3LYP/6-31G*).
In the case of 31, the conformation 31-A, corresponding to T1,
clearly dominates (97% based on Boltzmann distribution at 298
K). A second conformer 31-B, which corresponds to C (Figure
7), was found to have a markedly higher energy (+2.1 kcal/mol,
2.8%). For the oxygen counterpart 29 we found two clearly
different conformations 29-A (46.4%) and 29-B (44.1%) with
nearly the same energy. A third conformer 29-C with a slightly
higher energy (+ 1.0 kcal/mol) contributes with 8%. These
results, which are also substantiated by NOESY measurements
(see the Supporting Information), confirm the assumption that
synthesis of sleeves D and E is rather expensive. However, the
most readily accessible sleeves are acetals of 2,5-disubstituted
terephtalaldehyde (F, TAA sleeve). Unfortunately, OSK rods
with this sleeve are relatively flexible due to less hindered
rotation around the C−C bonds between aromatic ring and
acetal C atoms (see arrows in Figure 5), indicated by a large
Levy−Martin parameter (OSK rod with C: LM = 23; OSK rod
with F: LM = 44).6
Bearing in mind the 30% larger covalent radius and the 20%
larger van der Waals radius of sulfur compared with oxygen, we
hypothesized that TAA sleeves with thioacetals instead of
acetals could be considerably more rigid. To prove this
assumption, we prepared two model compounds 29 and 31
commencing with commercially available 2,3-dibromo-p-xylene
28 (Scheme 4). The synthesis of 29 comprised lithiation,
formylation with DMF, and acetalization with 2,2-dimethyl-
propane-1,3-diol. Hydrolysis of 29 afforded 2,5-dimethylter-
ephthalaldehyde 30,22 which was subsequently converted to the
D
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OSTK Rods. After having established the synthesis of
fundamental building blocks (3, 6, 9, 12, and 13) and sleeves
(35) we turned our attention to the synthesis of longer OSTK
rods. Basically, the construction of OSTK can be performed by
two ways: (1) by repeated acetalization steps, either based on
the different reactivity of diols and dithiols (e.g., with 6; but we
have already demonstrated that implementation of this
approach is rather difficult), or by intermediate deprotection
(e.g., with 12 or 13) and (2) by alternate oxidation and
acetalization steps (e.g., with 9). Bearing in mind the variety of
oxidation methods for secondary alcohols, we first explored the
latter approach. For this we prepared the model compound 36
from 9 and benzaldehyde and investigated their oxidation to
ketone 37 (Scheme 6).29 The very often used Dess−Martin
a
Scheme 6. Synthesis of Dithiane 35
Figure 7. Dominating conformations for 29 and 31 (B3LYP/6-31G*).
a
Key: (i) I2, PhCHO, 98%; (ii) oxidation conditions, see Table 2.
the replacement of oxygen by sulfur results in considerably
more rigid TAA sleeves.
Encouraged by these findings, we next prepared some
terephthalaldehydes 35 bearing solubility-enhancing groups.
The synthetic strategy is outlined in Scheme 5 and is known
periodinane30 was ruled out right from the start because it is
known that hypervalent iodine reagents are able to cleave
thioacetals.31,32 To our great surprise, nearly all other
established methods either failed or gave the target compound
in very low yields (methods 1−7 exhibited low conversion and
in the case of method 8 cleavage of the thioketal was observed).
The Albright−Goldman oxidation33 using DMSO and acetic
anhydride was the only successful method, which provided the
ketone 37 with 52% yield (Table 2).
a
Scheme 5. Synthesis of Terephthalaldehydes 35
Table 2. Optimization of the Oxidation of 36
entry
oxidant
conditions
rt, 72 h
yield (%)
1
2
3
4
5
6
7
8
9
PCC
CrO3/pyridine
rt, 72 h
Jones reagent
rt, 48 h
Al(iPr)3/acetone, toluene
Pb(OAc)4/benzene
RuC62H42O634/acetone
TEMPO, NaOCl, NaBr, NaHCO3
(COCl)2/DMSO
rfx, 20 h
2
5
rfx, 48 h
rfx, 48 h
0 °C to rt, 2 h
−78 °C, 2 h
rt, 20 h
a
Key: (i) RMgX, cat. Ni(dppp)Cl2; (ii) Br2; (iii) (1) BuLi, (2) DMF,
(3) 2,2-dimethyl-1,3-propanediol, (4) BuLi, (5) DMF, (6) 2,2-
dimethyl-1,3-propanediol, (7) TFA.
Ac2O/DMSO
52
Based on these findings we next compared building blocks 9
and 12 regarding their suitability to prepare diketone 40c with
iOct-TAA sleeve. We found that both routes are practicable and
the overall yields range from 40 to 50%. However, 1,3-
dibromoacetone, which is the parent substance for the
preparation of 12, is considerably more expensive than 1,3-
dibromopropan-2-ol 7, which is used for the preparation of 9
(cf. Scheme 1). Therefore, we prefer building block 9 and
prepared compounds 40a,b in this way. The best overall yield
(64%) was observed with 40b (Scheme 7, Table 3). To
illustrate the influence of alkyl residues R, we determined the
solubility of compounds 40 in dichloromethane. Whereas 40a,b
show nearly the same values, the isooctyl group in 40c
drastically increases the solubility (Table 3).
from the literature for 35a (R = Bu).6,25 Starting with 1,4-
dichlorobenzene 32, the residues R were introduced by a
Kumada coupling followed by the same approach as already
used for the preparation of 30 (Scheme 4). Furthermore, we
prepared two further terephthaldehydes with longer (35b, R =
Pent) and branched (35c, R = iOct) residues (Scheme 5, Table
1).
Table 1. Yields and References for Compounds 33−35
R
33
34
35
a
b
c
Bu
Pent
ref25
63%
ref28
77%
ref6
47%
32%
a
Diketone 40b smoothly reacts with dithiol 13, whereby the
silyl protecting groups are simultaneously removed during
workup giving the tetrol 41. The suitability of building block 41
iOct
ref26
ref27
a
iOct = 2-ethylhexyl.
E
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Scheme 7. Synthesis of Diketone 40
Scheme 9. Synthesis of OSTK Rods 45 and 46
Table 3. Yields of Compounds 38−40 and Solubility of 40
b
b,
c
b,
d
e
R
38
39
40
40
S [40]
a
b
c
Bu
Pent
94
91
44
70
42
18.6
19.2
Table 4. Yields of Compounds 44−46
a
iOct
>99
56
c
80
286.0
b
b
b
a
b
d
e
R
44
45
46
iOct = 2-ethylhexyl. Yield (%). From 38. From 39. Solubility in
DCM in g/l.
a
b
c
Bu
Pent
63
>99
>99
>99
>99
60
a
iOct
to prepare longer OSTK rods could be convincingly proven by
the reaction with cyclohexanone 14 and N-chloroacetylpiper-
idin-4-one 22, giving rods 42 and 43 in good to excellent yields
(Scheme 8). It should be noted that OSK rods with TAA
sleeves and a similar length than rod 43 were hitherto not
accessible.
a
b
iOct = 2-ethylhexyl. Yield (%).
presented a powerful extension of our OSK rod concept by
replacement of one or more acetals by thioacetals and named
these constructs oligospirothioketal (OSTK) rods. The under-
lying building blocks, the tetrathiol 3 and the dithiols 6, 9, 12,
and 13 were hitherto not readily accessible. After numerous
attempts we succeeded in the development of a reliable
synthetic route to these thiols. Subsequently we prepared some
trispiranes using building blocks 6 and 9. This showed that the
solubility is appreciably diminished if ketals are replaced by
thioketals, which is not surprising in view of the low polarity of
the C−S bond. Consequently, solubility enhancing building
blocks (sleeves) are of great importance. We demonstrated that
sleeves based on 2,5-disubstitued terephthalaldehydes (TAA),
which are relatively straightforward to prepare, are suitable for
this purpose. After having solved the basic problems, we
prepared several OSTK rods some of them with a length of
more than 3 nm (based on molecular modeling), proving the
capability of the OSTK rod concept.
Scheme 8. Synthesis of OSTK Rods 42 and 43 (R = Pent)
Equipped with a reliable access to thiol-containing building
blocks and solubility enhancing sleeves we are currently
investigating the scope of the OSTK concept concerning the
rod length. Particular attention will be paid to mediate the
solubility of rods in aqueous environment in view of
biochemical and biological applications.
Finally, we prepared tetrols 44 from sleeves 35 and dithiol 13
and explored the acetalization with ketones. The reaction of
44b with cyclohexanone 14 gave the OSTK rod 45 with
moderate yield, whereas 44a,c provided by reaction with 22
nearly quantitatively OSTK rods 46a,c (Scheme 9, Table 4).
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out under a
nitrogen atmosphere unless otherwise noted. NMR spectra were
recorded on an NMR spectrometer with the specified measurement
frequency and solvents. The residual solvent signals were used as
reference. Multiplicities are reported as follows: singlet (s), doublet
(d), doublet of doublets (dd), triplet (t), quadruplet (q), and multiplet
(m). Column chromatography was performed on silica gel with a
particle size of 40−63 μm. IR spectra were recorded as KBr pellets on
an IR spectrometer with a monochromator. High-resolution mass
spectra (HRMS) were recorded on a Mass spectrometer equipped
with a quadropol.
CONCLUSION
■
The previously developed oligospiroketal (OSK) rods proved
to be versatile molecular rods.2−11 However, the length of these
rods is limited due to the lability of acetals during the synthesis
and the reversibility of the formation reaction. On the other
hand, it is well known that thioacetals are much more stable,
and the formation reaction is not reversible. Herein we have
F
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2,2-Bis(((methylsulfonyl)oxy)methyl)propane-1,3-diyl Dime-
thanesulfonate (1). To an ice-cooled suspension of pyridine (60
mL) and pentaerythritol (10 g, 73.45 mmol) was added dropwise a
solution of methanesulfonyl chloride (23.88 mL, 308.49 mmol) in
pyridine (20 mL). After being stirred overnight, a mixture of ice and
HCl was added, and the precipitate was filtered off and washed with
water, DCM, and Et2O to yield 1 (32.4 g, 98%) as a white solid. Mp:
1,2-Dithiolan-4-ol (8). To DMF (100 mL) were added sulfur
(1.47 g, 45.90 mmol) and Na2S (60%, 5.97 g, 45.90 mmol). The
reaction mixture was stirred for 2 h at 80 °C and turned deep blue.
After addition of 1,3-dibromopropan-2-ol 7 (10 g, 45.90 mmol), the
mixture was heated to 120 °C and stirred overnight. To the mixture
was added ice, and the water layer was extracted with DCM four times.
The combined organic layers were washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The crude product
was used immediately in the next step without further purification.
1,3-Dimercaptopropan-2-ol (9). In an ice-cooled Flask, LiAlH4
(3.49 g, 92.06 mmol) was suspended in dry THF (100 mL), and 8
(crude product) in dry THF (40 mL) was slowly added. After the
mixture was refluxed for 2 h and cooled to room temperature, water
and concentrated HCl were added. The resulting mixture was
extracted with DCM four times, and the combined organic layers
were dried over MgSO4. After concentration in vacuo, the crude
product was purified by column chromatography (DCM/MeOH) to
yield 9 (2.9 g, 51%) as a yellow oil. The reduction can also be carried
1
208−209 °C. H NMR (300 MHz, DMSO-d6, ppm): 3.27 (s, 12 H),
4.29 (s, 8 H). 13C NMR (75 MHz, DMSO-d6, ppm): 37.1, 43.0, 66.9.
IR (cm−1): 3025, 1471, 1387, 1348, 1412, 988, 972, 925, 750, 867,
835.
2,3,7,8-Tetrathiaspiro[4.4]nonane (2). To DMF (100 mL) were
added sulfur (4.29 g, 133.87 mmol) and Na2S (60%, 8.70 g, 66.89
mmol). The resulting mixture turned deep blue and was stirred for 2 h
at 100 °C. After addition of 1 (15 g, 33.44 mmol) and additional
stirring for 40 h at the same temperature, ice was added to the mixture.
After extraction with DCM four times, the combined organic layers
were washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The obtained crude brown oil was used immediately
in the next step without further purification. HRMS (EI): calcd for
C5H8S4 [M]+ 195.9509, found 195.9503.
2,2-Bis(mercaptomethyl)propane-1,3-dithiol (3). Method A.
NaBH4 (5.06 g, 133.84 mmol) was dissolved in water (50 mL) and
added dropwise to an ice-cooled solution of 2 (crude product) in THF
(60 mL). After being stirred for 4 h at room temperature, the mixture
was quenched with HCl (1 M) and the aqueous layer was extracted
with DCM three times. The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The crude product was crystallized
from EtOH to yield 3 (3.86 g, 60% over two steps) as a white solid
(mp 71 °C). Method B. A solution of the crude product from 2 (500
mg) in THF (8 mL) was added dropwise to an ice-cooled suspension
of LiAlH4 (298 mg, 7.64 mmol) and dry THF (15 mL). After 4 h of
stirring at room temperature, water and HCl (6 M) was carefully
added to the mixture, and the resulting solution was extracted with
DCM three times. The collected organic layers were dried over
MgSO4 and concentrated in vacuo. After crystallization with EtOH, 3
(310 mg, 64% over two steps) was obtained as a white solid. Mp: 71
°C. 1H NMR (300 MHz, CDCl3, ppm): 1.27 (t, J = 8.8 Hz, 4 H), 2.66
(d, J = 8.8 Hz, 8 H). 13C NMR (75 MHz, CDCl3, ppm): 27.9, 43.0.
HRMS (EI): calcd for C5H12S4 [M]+ 199.9822, found 199.9812. IR
(cm−1): 1420, 1363, 1279, 1178, 974, 911, 809, 665, 605.
(1,2-Dithiolane-4,4-diyl)dimethanol (5). To DMF (100 mL)
were added sulfur (2.45 g, 76.35 mmol) and Na2S (60%, 4.97 g, 38.18
mmol). The reaction mixture was stirred for 2 h at 80 °C and turned
deep blue. After addition of bis(bromomethyl)propane-1,3-diol 4 (10
g, 38,18 mmol), the mixture was heated to 120 °C overnight. To the
mixture was added ice, and the water layer was extracted with DCM
three times. The combined organic phases were washed with brine,
dried over MgSO4, and concentrated under reduced pressure. The
crude product was purified by column chromatography (DCM/
MeOH) to yield 5 (5.4 g, 60%) as a yellow solid. Mp: 84 °C. 1H NMR
(300 MHz, MeOD-d4, ppm): 2.93 (s, 4 H), 3.59 (s, 4 H). 13C NMR
(75 MHz, MeOD-d4, ppm): 44.9, 59.3, 65.0. HRMS (EI): calcd for
C5H10O2S2 [M]+ 166.0120, found 166.0128. IR (cm−1): 3288, 2933,
2715, 1457, 1420, 1372, 1231, 1191, 1086, 843, 697, 605.
2,2-Bis(mercaptomethyl)propane-1,3-diol (6). LiAlH4 (1.03 g,
27.07 mmol) was suspended in ice-cooled, dry THF (25 mL), and 5
(3 g, 18.04 mmol) in dry THF (25 mL) was slowly added. After the
mixture was refluxed for 2 h and cooled to room temperature, water
and HCl (concd) were added. The resulting mixture was extracted
with DCM four times, and the combined organic layers were dried
over MgSO4. After concentration in vacuo, the crude product was
purified by column chromatography (DCM/MeOH) to yield 6 (2.17
g, 71% over two steps) as a white solid. The reduction can also be
carried out with NaBH4 (4 equiv) with similar yields. Mp: 123 °C. 1H
NMR (300 MHz, DMSO-d6, ppm): 1.96 (t, J = 8.9 Hz, 2 H), 2.43 (d, J
= 8.9 Hz, 4 H), 3.29 (s, 4 H), 4.48 (bs, 2 H). 13C NMR (75 MHz,
DMSO-d6, ppm): 25.8, 44.5, 60.9. HRMS (EI): calcd for C5H12O2S2
[M]+ 168.0279, found 168.0274. IR (cm−1): 3288, 2938, 2880, 2562,
1458, 1417, 1373, 1231, 1296, 1024, 689.
1
out with NaBH4 (4 equiv) with similar yields. H NMR (300 MHz,
CDCl3, ppm): 1.49 (t, J = 8.7 Hz, 2 H), 2.63−2.81 (m, 4 H), 3.67−
3.75 (m, 1 H). 13C NMR (75 MHz, CDCl3, ppm): 29.8, 72.9. HRMS
(EI): calcd for C3H8OS2 [M]+ 124.0017, found 124.0016.
1,4-Dioxa-7,8-dithiaspiro[4.4]nonane (11). To DMF (10 mL)
were added sulfur (123 mg, 3.85 mmol) and Na2S (60%, 300 mg, 3.85
mmol). The reaction mixture was stirred for 2 h at 100 °C and became
deep blue. After addition of 10 (1 g, 3.85 mmol), the mixture was
heated to 120 °C for 24 h. To the mixture was added ice, and the
water layer was extracted with DCM three times. The combined
organic phases were dried over MgSO4 and concentrated under
reduced pressure. The crude product was used immediately in the next
1
step without further purification. H NMR (300 MHz, CDCl3, ppm):
3.18 (s, 4 H) 4.02 (s, 4 H). 13C NMR (75 MHz, CDCl3, ppm): 45.8,
65.4. HRMS (EI): calcd for C5H8O2S2 [M]+ 163.9966, found
163.9958.
(1,3-Dioxolane-2,2-diyl)dimethanethiol (12). NaBH4 (728 mg,
19.28 mmol) was dissolved in NaOH solution (5%, 15 mL) and added
dropwise to an ice-cooled solution of 11 (crude product) in THF (15
mL). After being stirred overnight at room temperature, the mixture
was washed with DCM three times. The aqueous layer was carefully
acidified with HCl (1 M) to pH 3−4 and was extracted with DCM
three times. The combined organic layers were dried over MgSO4 and
concentrated in vacuo. The crude product was purified by column
chromatography (DCM) to yield 12 (291 mg, 45% over two steps) as
a yellowish oil. 1H NMR (300 MHz, CDCl3, ppm): 1.56 (t, J = 8.7 Hz,
2 H), 2.86 (d, J = 8.6 Hz, 4 H), 4.07 (s, 4 H). 13C NMR (75 MHz,
CDCl3, ppm): 30.0, 66.2, 109.7. HRMS (ESI): calcd for C5H11O2S2
[M + H+] 167.0201, found 167.0195. IR (cm−1): 2973, 2888, 1412,
1271, 1196, 1115, 1115, 1027, 948, 601.
2,2-Bis(((tert-butyldimethylsilyl)oxy)methyl)propane-1,3-di-
thiol (13). To 6 (1g, 5.94 mmol), tert-butylchlorodimethylsilane (1.97
g, 13.07 mmol) and imidazole (2.02 g, 29.71 mmol) were added dry
DMF (3 mL). After 2 h of stirring at room temperature, ice was added,
and the mixture was extracted with n-hexane three times. The
combined organic layers were dried over MgSO4 and concentrated in
vacuo. Purification by column chromatography (DCM) yields 13 (2.26
g, 96%) as a colorless oil. 1H NMR (300 MHz, CDCl3, ppm): 0.07 (s,
12 H), 0.91 (s, 18 H), 1.19 (t, 3J = 9.0 Hz, 2 H), 2.53 (d, 3J = 9.3 Hz, 4
H), 3.48 (s, 4 H). 13C NMR (75 MHz, CDCl3, ppm): −5.6, 18.2, 25.4,
25.9, 45.2, 61.6. HRMS (EI): calcd for C17H41O2S2Si2 [M + H]+
397.2081, found 397.2083. IR (cm−1): 2956, 2930, 2850, 1468, 1356,
1250, 1077, 833, 770, 668.
7,11,18,21-Tetrathiatrispiro[5.2.2.512.29.26]henicosane
(15). Method A. To 3 (500 mg, 2.49 mmol) and cyclohexanone 14
(0.54 mL, 5.23) in dry chloroform (15 mL) was added dropwise BF3·
Et2O (0.92 mL, 7.48 mmol). After being stirred for 20 min at room
temperature, the mixture was charged with NaOH solution (5%) and
the separated aqueous layer was extracted with DCM two times. The
combined organic layers were washed with brine, dried with MgSO4,
and concentrated in vacuo. The residue was washed with n-hexane to
yield 15 (820 mg, 94%) as a white solid. Method B. To 3 (245 mg,
G
DOI: 10.1021/acs.joc.5b02670
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The Journal of Organic Chemistry
Article
1.22 mmol) and cyclohexanone 14 (0.26 mL, 2.57 mmol) in dry
chloroform (10 mL) was added a catalyticly amount of p-TsOH. The
mixture was refluxed for 1.5 h and, after cooling to room temperature,
washed two times with saturated NaHCO3 solution, water, and brine.
The organic layer was dried over MgSO4 and concentrated in vacuo.
The residue was washed with cold n-hexane to yield 15 (380 mg, 88%)
as a white solid. Method C. To 3 (300 mg, 1.5 mmol) and
cyclohexanone 14 (0.33 mL, 3.16 mmol) in dry chloroform (10 mL)
was added I2 (95 mg, 374 μmol). After being stirred for 1.5 h at room
temperature, the mixture was charged with Na2S2O3 solution, and the
separated organic layer was washed with water and brine and dried
over MgSO4. Concentration in vacuo and charging the residue with
cold n-hexane, yields 15 (450 mg, 1.25 mmol, 86%) as a white solid.
Mp: 209 °C. 1H NMR (300 MHz, CDCl3, ppm): 1.44−1.49 (m, 4 H),
1.59−1.67 (m, 8 H), 1.95−1.99 (m, 8 H), 2.89 (s, 8H). 13C NMR (75
MHz, CDCl3, ppm): 22.3, 25.8, 25.92, 34.5, 37.6, 51.5. HRMS (EI):
calcd for C17H28S4 [M]+: 360.1074, found 360.106. IR (cm−1): 2928,
2848, 1444, 1430, 857, 822, 776, 758, 700.
H), 3.04 (s, 4 H), 3.12 (s, 4 H), 3.90−4.05 (m, 2 H); insufficient
solubility for 13C spectrum. HRMS (EI): calcd for C17H28O2S4 [M]+
392.0972, found 392.0973. IR (cm−1): 3359, 2858, 1697, 1432, 1405,
1276, 1223, 1067, 957, 697.
7,11,18,21-Tetrathiatrispiro[5.2.2.512.29.26]henicosane-
3,15-dione (21). Oxalyl chloride (0.09 mL, 1.03 mmol) in dry DCM
(15 mL) was cooled to −78 °C. DMSO (0.1 mL, 1.36 mmol) in dry
DCM (5 mL) was added dropwise, and the mixture was stirred at this
temperature for 30 min. Compound 20b (130 mg, 331 μmol) in dry
DMSO (15 mL) was added dropwise, and the mixture was additionally
stirred for 30 min. After addition of dry triethylamine (0.45 mL, 3.31
mmol), the reaction was allowed to warm to room temperature and
stirred overnight. The reaction mixture was washed with HCl (1 M)
and brine and dried with MgSO4. After concentration in vacuo, the
residue was purified by column chromatography (DCM/MeOH) to
1
yield 21 (80 mg, 62%) as a white solid. Mp: 275−276 °C. H NMR
(300 MHz, CDCl3, ppm): 2.29−2.41 (m, 8 H), 2.50−2.59 (m, 8 H),
2.92−3.02 (s, 8 H). 13C NMR (75 MHz, CDCl3, ppm): 34.9, 36.9,
37.7, 49.3, 209.2. HRMS (EI): calcd for C17H24O2S4 [M]+ 388.0659,
found 388.0648. IR (cm−1): 2900, 1717, 1438, 1403, 1335, 1184, 801,
765, 735, 698, 651.
7,21-Dioxa-11,18-dithiatrispiro[5.2.2.512.29.26]henicosane
(16). To 6 (500 mg, 2.97 mmol), cyclohexanone (0.64 mL, 6.24
mmol), and a catalyticly amount of p-TsOH was added toluene (40
mL). After the mixture was refluxed for 4 h, the solvent was removed
in vacuo. To the residue was added DCM, and the mixture was washed
with saturated NaHCO3 solution, water, and brine. The organic layer
was dried with MgSO4 and concentrated under reduced pressure.
Purification by column chromatography (n-hexane/EtOAc) yielded 16
1, 1′ -(7, 11, 18 , 21-Tetrat hia-3, 15-diazatrispiro-
[5.2.2.512.29.26]henicosane-3,15-diyl)bis(2-chloroethan-1-
one) (23). Compounds 3 (50 mg, 249 μmol), 22 (96 mg, 548 μmol),
and a catalyticly amount of p-TsOH were refluxed in chloroform (5
mL) in a Dean−Stark apparatus for 4 h. The mixture was washed with
saturated NaHCO3 solution, water, and brine. The organic layer was
dried with MgSO4 and the solvent was removed in vacuo. The crude
product was purified by column chromatography (DCM/MeOH) to
1
(620 mg, 64%) as a white solid. Mp: 130 °C. H NMR (300 MHz,
CDCl3, ppm): 1.36−1.47 (m, 4 H), 1.49−1.56 (m, 4 H), 1.60−1.64
(m, 4 H), 1.68−1.74 (m, 4 H), 1.90−1.95 (m, 4 H), 2.69 (s, 4 H), 3.81
(s, 4 H). 13C NMR (75 MHz, CDCl3, ppm): 22.2, 22.4, 25.6, 25.7,
29.0, 31.0, 32.3, 37.6, 51.5, 65.9, 98.5. HRMS (EI): calcd for
C17H28S2O2 [M]+ 328.1531, found 328.1541. IR (cm−1): 2935, 2863,
1108, 2846, 1443, 1269, 1256, 1156, 1130, 1087, 1068, 1037, 961, 917,
822.
1
yield 23 (95 mg, 74%) as a white solid. Mp: 214−219 °C. H NMR
(300 MHz, CDCl3, ppm): 2.03−2.16 (m, 8 H), 2.91−2.99 (m, 8 H),
3.58−3.66 (m, 4 H), 3.69−3.79 (m, 4 H), 4.07 (s, 4 H). 13C NMR (75
MHz, CDCl3, ppm): 24.7, 34.3, 35.4, 36.2, 37.4, 38.7, 40.9, 42.8, 46.0,
49.0, 164.9. HRMS (EI): calcd for C19H28N2O2Cl2S4 [M]+ 514.0411,
found 514.0421.
(1,5-Dithiaspiro[5.5]undecane-3,3-diyl)dimethanol (18). To
16 (50 mg, 152 μmol) were added MeOH (5 mL) and TFA (1 mL).
The mixture was stirred at 60 °C for 48 h and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (DCM/MeOH) to yield 18 (35 mg, 93%) as a white solid. Mp:
D i b e n z y l 7 , 1 1 , 1 8 , 2 1 - T e t r a t hi a- 3 , 1 5 - d i a z a t r i -
spiro[5.2.2.512.29.26]henicosane-3,15-dicarboxylate (25). To
3 (457 mg, 2.28 mmol) and 24 (1.12 g, 4.79 mmol) in dry chloroform
(15 mL) was added dropwise BF3.Et2O (0.72 mL, 5.7 mmol). After
being stirred for 20 min at room temperature, the mixture was charged
with NaOH solution (5%), and the separated aqueous layer was
extracted with DCM two times. The combined organic layers were
washed with brine, dried with MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography (DCM/MeOH) to
1
188 °C. H NMR (300 MHz, DMSO-d6, ppm): 1.35−1.44 (m, 2 H),
1.47−1.59 (m, 4 H), 1.79−1.94 (m, 4 H), 2.58 (s, 4 H), 3.46 (s, 4 H).
13C NMR (75 MHz, DMSO-d6, ppm): 22.4, 25.8, 29.0, 35.8, 38.0,
51.1, 63.0. HRMS (EI): calcd for C11H20S2O2 [M]+ 248.0905, found
248.0902.
1
yield 25 (1.4 g, 2.22 mmol, 97%) as a white solid. Mp: 147 °C. H
7,11,18,21-Tetrathiatrispiro[5.2.2.512.29.26]henicosane-
3,15-diylbis(2,2-dimethylpropanoate) (20a). To 3 (242 mg, 1.21
mmol) and 19 (502 mg, 2.54 mmol) in dry chloroform (15 mL) were
added dropwise BF3·Et2O (0.46 mL, 3.62 mmol). After being stirred
for 20 min at room temperature, the mixture was charged with NaOH
solution (5%), and the separated aqueous layer was extracted with
DCM two times. The combined organic layers were washed with
brine, dried with MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography (DCM/MeOH) to yield 20a
NMR (300 MHz, CDCl3, ppm): 1.99−2.07 (m, 8 H), 2.92 (s, 8 H),
3.58−3.69 (m, 8 H), 5.14 (s, 4 H), 7.29−7.42 (m, 10 H). 13C NMR
(75 MHz, CDCl3, ppm): 25.9, 34.3, 36.8, 40.5, 49.3, 67.2, 127.9, 128.1,
128.5, 136.7, 155.1. HRMS (EI): calcd for C31H38N2O4S4 [M]+
630.1714, found 630.1701. IR (cm−1): 2940, 1462, 1418, 1273,
1223, 1194, 1127, 1055, 1010, 751, 764, 696.
Dibenzyl 7,21-Dioxa-11,18-dithia-3,15-diazatri-
spiro[5.2.2.512.29.26]henicosane-3,15-dicarboxylate (26).
Compound 6 (800 mg, 4.75 mmol), 24 (2.33 mL, 9.98 mmol), and
a catalyticly amount of p-TsOH were refluxed with toluene (20 mL) in
a Dean−Stark apparatus for 4 h. The slurry was concentrated in vacuo,
and DCM was added. The mixture was washed with saturated
NaHCO3 solution, water, and brine. The organic layer was dried with
MgSO4, and the solvent was removed in vacuo. The crude product was
purified by column chromatography (DCM/MeOH) to yield 26 (1.82
1
(540 mg, 80%) as a white solid. Mp: 263−264 °C. H NMR (300
MHz, CDCl3, ppm): 1.21 (s, 18 H), 1.73−1.83 (m, 4 H), 1.85−2.03
(m, 8 H), 2.08−2.19 (m, 4 H), 2.9 (d, 8 H), 4.81−4.89 (m, 2 H). 13C
NMR (75 MHz, CDCl3, ppm): 26.0, 26.7, 27.2, 33.7, 34.5, 34.7, 38.8,
50.4, 69.6, 177.8. HRMS (EI): calcd for C27H44O4S4 [M]+ 560.2122,
found 560.2138. IR (cm−1): 2975, 2954, 2940, 1727, 1478, 1424, 1401,
1279, 1220, 1157, 895.
1
g, 64%) as a white solid. Mp: 108 °C. H NMR (300 MHz, CDCl3,
7,11,18,21-Tetrathiatrispiro[5.2.2.512.29.26]henicosane-
3,15-diol (20b). Compound 20a (500 mg, 891 μmol) was dissolved
in dry DCM (50 mL) and cooled to −78 °C. DIBALH (1 M in n-
hexane, 4.46 mL, 4.46 mmol) was added, and the mixture was stirred 2
h at this temperature. After the mixtur was warmed to room
temperature, MeOH (0.4 mL) was added, and the resulting slurry was
treated with 20% tartaric acid. The precipitate was filtered, washed
with 20% tartaric acid, water, DCM, and Et2O, and dried in vacuo to
yield 20b (320 mg, 92%) as a white solid. Mp: 260−261 °C. 1H NMR
(300 MHz, Pyridine-d5, ppm): 1.96−2.22 (m, 12 H), 2.40−2.60 (m, 4
ppm): 1.80−1.89 (m, 4 H), 1.99−2.06 (m, 4 H), 2.74 (s, 4 H), 3.48−
3.56 (m, 4 H), 3.57−3.64 (m, 4 H), 3.86 (s, 4 H), 5.14 (s, 4 H), 7.32−
7.40 (m, 10 H). 13C NMR (75 MHz, CDCl3, ppm): 29.0, 30.8, 40.2,
40.7, 49.3, 66.0, 67.2, 97.0, 127.8, 128.0, 128.5, 136.7, 155.0. HRMS
(EI): calcd for C31H38N2O6S2 [M]+ 598.2171, found 598.2193. IR
(cm−1): 3288, 2933, 1457, 1420, 1372, 1231, 1086, 843, 697, 605.
7,11,18,21-Tetrathia-3,15-diazatrispiro[5.2.2.512.29.26]-
henicosane (27). Compound 25 (250 mg, 396 μmol) in HBr (33%
in acetic acid, 20 mL) was heated to 60 °C for 2 h. After the mixture
H
DOI: 10.1021/acs.joc.5b02670
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The Journal of Organic Chemistry
Article
was cooled to room temperature, water was added and the resulting
solution was carefully treated with NaOH solution to pH 10 under ice
cooling. The precipitate was collected washed two times with
petroleum ether, DCM, and water and dried in vacuo to yield 27
and brine and dried over MgSO4. Concentration in vacuo yielded 33a
(61.40 g, 81%) as colorless oil, which was immediately used in the next
1
step. H NMR (300 MHz, CDCl3, ppm): 0.97 (t, J = 7.3 Hz, 6 H),
1.32−1.47 (m, 4 H), 1.57−1.69 (m, 4 H), 2.62 (t, J = 7.7 Hz, 4 H),
7.13 (s, 4 H). 13C NMR (75 MHz, CDCl3, ppm): 18.6, 23.2, 25.8,
31.3, 44.7, 48.2, 129.8, 133.4, 136.4 (33a was already described in ref
1
(103 mg, 72%) as a white solid. Mp: >280 °C dec. H NMR (300
MHz, DMSO-d6, ppm): 2.21 (bs, 8 H), 3.03 (bs, 8 H), 3.11 (bs, 8 H).
1
13C NMR (151 MHz, DMSO-d6, ppm): 21.7, 24.1, 33.7, 40.4, 47.2.
25, H NMR data are essentially identical to our data).
HRMS (EI): calcd for C15H26N2S4 [M]+ 362.0979, found 362.0973. IR
(cm−1): 3389, 2938, 2813, 1615, 1430, 1283, 1148, 1029, 862, 779.
2,2′-(2,5-Dimethyl-1,4-phenylene)bis(5,5-dimethyl-1,3-diox-
ane) (29). Compound 28 (18 g, 68.19 mmol) was dissolved in dry
THF (200 mL) and cooled to −60 °C. BuLi solution (1.6 M in n-
hexane, 46.88 mL, 75.01 mmol) was added slowly, and after for 15 min
of stirring dry DMF (10.52 mL, 136.39 mmol) was added. The
reaction was warmed to room temperature, stirred for 2 h, and charged
with HCl (concd). The mixture was extracted with Et2O two times,
and the combined organic layers were washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue was
used without further purification and refluxed overnight in a Dean−
Stark apparatus with toluene (130 mL), neopentyl glycol (14.2 g,
136.39 mmol), and a catalytic amount of p-TsOH. The mixture was
washed with saturated NaHCO3 solution, water, and brine, dried over
MgSO4, and concentrated in vacuo. The residue was treated a second
time as described above the starting compound, and the obtained
crude product was crystallized in n-hexane to yield 29 (9.74 g, 42%) as
1,4-Dipentylbenzene (33b). Prepared like 33a, yielding 33b
(63%) as a colorless liquid, which was used in the next step without
1
further purification. H NMR (300 MHz, CDCl3, ppm): 0.95 (t, J =
6.7 Hz, 6 H), 1.34−1.42 (m, 8 H), 1.61−171 (m, 4 H), 2.62 (t, J = 7.6
Hz, 8 H), 7.14 (s, 4 H). 13C NMR (75 MHz, CDCl3, ppm): 14.0, 22.6,
31.3, 31.6, 35.5, 128.2, 140.1.
1,4-Bis(2-ethylhexyl)benzene (33c). Prepared like 33a with
additional fractionated distillation in vacuo, yielding 33c as a yellow oil
(67%). Bp (6 × 10−3 mbar): 120−125 °C. 1H NMR (300 MHz,
CDCl3, ppm): 0.89 (t, J = 7.50 Hz, 12 H) 1.22−1.34 (m, 16 H) 1.53−
1.61 (m, 4 H), 2.52 (d, J = 7.2 Hz, 4 H), 7.07 (s, 4 H). 13C NMR (75
MHz, CDCl3, ppm): 10.8, 14.1, 23.0, 25.5, 28.9, 32.4, 39.7, 41.0, 128.9,
138.9. HRMS (EI): calcd for C22H38 [M]+ 302.2979, found 302.2977
(33c was already described in ref 26 without any analytical data).
1,4-Dibromo-2,5-dibutylbenzene (34a). To ice-cooled 33a (61.
40 g, 324 mmol) and I2 (819 mg, 3.23 mmol, 0.5 mol %) was added
dropwise bromine (33.05 mL, 645 mmol) under stirring with rigorous
exclusion of light. Afterward, the mixture was stirred at room
temperature for 48 h. NaOH solution (20%) was added, and the
aqueous layer was extracted with Et2O three times. The combined
organic layers were washed with water, dried over MgSO4, and
concentrated in vacuo. The crude product 34a (99 g, 88%) was
obtained as a white solid and was used in the next step without further
purification. 1H NMR (300 MHz, CDCl3, ppm): 0.98 (t, J = 7.3 Hz, 6
H), 1.36−1.49 (m, 4 H), 1.54−1.66 (m, 4 H), 2.68 (t, J = 7.6 Hz, 4
H), 7.39 (s, 2 H). 13C NMR (75 MHz, CDCl3, ppm): 13.9, 22.4, 31.9,
35.2, 123.1, 133.8, 141.3 (34a was already reported in ref 33; NMR
data are essentially identical to our data).
1
yellowish needles. Mp: 180−182 °C. H NMR (300 MHz, CDCl3,
ppm): 0.81 (s, 6 H), 1.33 (s, 6 H), 2.38 (s, 6 H), 3.64−3.80 (m, 8 H),
5.48 (s, 2 H), 7.42 (s, 2 H). 13C NMR (75 MHz, CDCl3, ppm): 18.3,
21.9, 23.2, 30.2, 77.8, 100.0, 127.8, 133.0, 136.4. HRMS (EI): calcd for
C20H31O4 [M + H]+ 335.2211, found 335.2190. IR (cm−1): 2980,
2860, 2106, 1700, 1655, 1467, 1467, 1412, 1357, 1231, 1214, 1189,
1095.
2,5-Dimethylterephthalaldehyde (30). Compound 29 (4.5 g
13.45 mmol) was refluxed in water (2.6 mL) and TFA (20 mL) for 15
min. The mixture was concentrated in vacuo, and the residue was
charged with DCM. The mixture was washed with saturated NaHCO3
solution and brine, dried over MgSO4, and concentrated under
reduced pressure. The crude product was crystallized in n-hexane to
1,4-Dibromo-2,5-dipentylbenzene (34b). Prepared like 34a
yielding 34b (77%) as a colorless liquid, which was used in the next
1
step without further purification. H NMR (300 MHz, CDCl3, ppm):
1
yield 30 (1.4 g, 64%) as yellow crystals. Mp: 98−100 °C. H NMR
0.94 (t, J = 6.9 Hz, 6 H), 1.33−1.41 (m, 8 H), 1.55−1.67 (m, 4 H),
2.66 (t, J = 7.7 Hz, 4 H), 7.38 (s, 2 H). 13C NMR (75 MHz, CDCl3,
ppm): 14.0, 22.5, 29.5, 31.5, 35.5, 123.1, 129.8, 133.8, 141.4.
(300 MHz, CDCl3, ppm): 2.68 (s, 6 H), 7.67 (s, 2 H), 10.31 (s, 2 H).
13C NMR (75 MHz, CDCl3, ppm): 18.7, 134.6, 136.8, 138.0, 192.1.
HRMS (EI): calcd for C10H10O2 [M]+ 162.0681, found 162.0681. IR
(cm−1): 2979, 2931, 1690, 1459, 1439, 1417, 1395, 1288, 1163, 997,
893.
1,4-Dibromo-2,5-bis(2-ethylhexyl)benzene (34c). Prepared
like 34a, though 2.3 equiv of bromine was used. Compound 34b
(87%) was obtained as yellow oil, which was used in the next step
without further purification. 1H NMR (300 MHz, CDCl3, ppm):
0.88−0.94 (m, 12 H), 1.27−1.37 (m, 16 H), 1.66−1.73 (m, 2 H), 2.60
(d, J = 7.2 Hz, 4 H), 7.34 (s, 2 H). 13C NMR (75 MHz, CDCl3, ppm):
10.7, 14.1, 23.0, 25.5, 28.6, 32.3, 39.2, 39.8, 123.3, 134.9, 140.4;
MS(EI): calcd for C22H36Br2 (M+) 458.1184, found 458.1188 (34c
was already reported in ref 27 without any analytical data).
2,5-Dibutylterephthalaldehyde (35a). Compound 34a (100.2
g, 287.83 mmol) was dissolved in dry THF (1000 mL) and cooled to
−60 °C. BuLi solution (1.6 M in n-hexane, 198 mL, 316.6 mmol) was
added slowly, and after stirring for 15 min dry DMF (46.5 mL, 604.4
mmol) was added to mixture. The reaction was warmed to room
temperature, stirred for 2 h, and charged with HCl (concd). The
mixture was concentrated in vacuo, and the residue was extracted with
Et2O two times. The combined organic layers were washed with water,
dried over MgSO4, and concentrated under reduced pressure. The
residue was used without further purification and refluxed overnight in
a Dean−Stark apparatus with toluene (700 mL), neopentyl glycol (45
g, 431.75 mmol), and a catalytic amount of p-TsOH. The mixture was
washed with saturated NaHCO3 solution, dried over MgSO4, and
concentrated in vacuo. The residue was treated a second time as
described above, and the obtained crude product was crystallized in n-
hexane. The obtained intermediate was refluxed with TFA (200 mL)
and water (30 mL) for 30 min. After being cooled to room
temperature, the mixture was concentrated under reduced pressure
and residue was charged with DCM. The organic layer was neutralized
with saturated NaHCO3 solution, washed with water, and dried over
2,2′-(2,5-Dimethyl-1,4-phenylene)bis(5,5-dimethyl-1,3-di-
thiane) (31). To dry chloroform (20 mL) were added 30 (100 mg,
616.58 mmol), 2,2-dimethylpropane-1,3-dithiol, and I2 (39 mg, 0.15
mmol), and the solution was stirred overnight at room temperature.
The mixture was charged with Na2S2O3 solution, and the aqueous
layer was extracted with DCM two times. The combined organic layers
were washed with brine, dried with MgSO4, and concentrated under
reduced pressure. The crude product was purified by column
chromatography (n-hexane/DCM, 2:1) to yield 31 (185 mg, 75%)
1
as yellow needles. Mp: 261−266 °C. H NMR (300 MHz, CDCl3,
ppm): 1.13 (s, 6 H), 1.40 (s, 6 H), 2.41 (s, 6 H), 2.50 (d, J = 14.1 Hz,
4 H), 3.02 (d, J = 14.1, 4 H), 5.13 (s, 2 H), 7.44 (s, 2 H). 13C NMR
(75 MHz, CDCl3, ppm): 18.6, 23.2, 25.8, 31.3, 44.7, 48.2, 129.8, 133.4,
136.4. HRMS (EI): calcd for C20H30S4 [M]+ 398.1230, found
398.1217. IR (cm−1): 2975, 2957, 2923, 1500, 1461, 1445, 1378,
1359, 1262, 1191, 1174, 992.
1,4-Dibutylbenzene (33a). To magnesium (25.3 g, 1 mol) and a
catalyticly amount of I2, was added 5 mL of a solution of 1-
brombutane (95 mL, 887 mmol) in dry Et2O (400 mL). After the start
of the reaction, the rest of the solution was added dropwise, and the
mixture was refluxed for 1 h. After cooling to 0 °C, [Ni(dppp)Cl2 (250
mg, 0.46 mmol, 0.1 mol %) and a solution of 1,4-dichlorbenzene (59 g,
401 mmol) in dry Et2O (300 mL) and dry THF (50 mL) was added,
followed by refluxing for 48 h. To the mixture were added ice, water,
and HCl (3 M). The water layer was extracted with Et2O two times,
and the combined organic layers were washed with EDTA solution
I
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The Journal of Organic Chemistry
Article
MgSO4, and the solvent was removed in vacuo. Purification with
column chromatography (n-hexane/EtOAc) yields 35a (10.64 g, 15%)
as a waxy white solid. 1H NMR (300 MHz, CDCl3, ppm): 0.95 (t, J =
7.3 Hz, 6 H), 1.35−1.49 (m, 4 H), 1.56−1.69 (m, 4 H), 3.05 (t, J = 7.8
Hz, 4 H), 7.73 (s, 2 H), 10.36 (s, 2 H). 13C NMR (75 MHz, CDCl3,
ppm): 13.8, 22.5, 31.5, 34.4, 133.1, 136.8, 143.3, 191.6. HRMS (EI):
calcd for C16H22O2 [M]+ 246.1620, found 246.1624. IR (cm−1): 3354,
2939, 2874, 1681, 1454, 1402, 1306, 1159, 868, 723 (35a was already
reported in ref 6 with essentially the same analytical data).
2,5-Dipentylterephthalaldehyde (35b). Prepared like 35a
yielding 35b (22%) as a waxy white solid. 1H NMR (300 MHz,
CDCl3, ppm): 0.87−0.94 (m, 6 H), 1.31−1.41 (m, 8 H), 1.59−1.69
(m, 4 H), 3.04 (t, J = 7.8 Hz, 4 H), 7.74 (s, 2 H), 10.37 (s, 2 H). 13C
NMR (75 MHz, CDCl3, ppm): 13.9, 22.4, 31.6, 31.8, 32.0, 133.1,
136.7, 143.4, 191.7. HRMS (EI): calcd for C18H26O2 [M]+ 274.1933,
found 274.1927. IR (cm−1): 3347, 2961 2919, 2853, 1674, 1457, 1401,
1312, 1155, 865.
1.43 (m, 8 H), 1.63−1.68 (m, 4 H), 2.66−2.71 (m, 4 H), 2.92−3.00
3
(m, 4 H), 3.33 (d, J = 14.1 Hz, 4 H), 3.99 (bs, 2 H), 5.19 (s, 2 H),
7.44 (s, 2 H). 13C NMR (75 MHz, CDCl3, ppm): 14.0, 22.5, 31.0,
31.7, 32.5, 39.4, 46.7, 55.3, 129.6, 136.1, 138.1: HRMS (EI): calcd for
C24H38O2S4 [M]+ 486.1749, found 486.1751. IR (cm−1): 3276, 2937,
2844, 1461, 1397, 1175, 1044, 747, 635.
4,4′-(2,5-Bis(2-ethylhexyl)-1,4-phenylene)bis(cyclohexan-1-
1
ol) (38c). Prepared like 38a yielding 38c (99%) as an orange oil. H
NMR (300 MHz, CDCl3, ppm): 0.90−0.98 (m, 12 H), 1.33−1.59 (m,
16 H), 1.50−1.59 (m, 2 H), 2.57−2.62 (m, 4 H), 2.93−2.99 (m, 4 H),
3.30 (d, 3J = 14.1 Hz, 4 H), 3.98 (bs, 2 H), 5.18 (s, 2 H), 7.41 (s, 2 H).
13C NMR (75 MHz, CDCl3, ppm): 11.1, 14.13, 23.0, 26.0, 29.0, 32.6,
37.1, 39.4, 40.8, 46.8, 55.3, 130.9, 136.1, 137.0. HRMS (EI): calcd for
C30H50O2S4 [M]+ 570.2688, found 570.2687. IR (cm−1): 3288, 2933,
2858, 1490, 1465, 1378, 1318, 1172, 1040, 750.
8,8′-(2,5-Bis(2-ethylhexyl)-1,4-phenylene)bis(1,4-dioxa-7,9-
dithiaspiro[4.5]decane) (39c). To 35c (54 mg, 150 μmol) and 12
(50 mg, 301 μmol) in dry chloroform (5 mL) was added I2 (4 mg, 15
μmol, 10 mol %). After the mixture was stirred for 1.5 h at room
temperature, Na2S2O3 solution was added. The organic layer was
washed with NaOH solution (5%), dried with MgSO4, and
concentrated in vacuo. The crude product was purified by column
chromatography (DCM) to yield 39c (55 mg, 56%) as a beige solid.
Mp: 155−158 °C. 1H NMR (300 MHz, CDCl3, ppm): 0.84−1.01 (m,
12 H), 1.19−1.37 (m, 16 H), 1.52−1.57 (m, 2 H), 2.49−2.61 (m, 4
H), 2.65−2.80 (m, 4 H), 3.13−3.23 (m, 4 H), 4.07 (dd, J = 5.3, 1.00
Hz, 8 H), 5.31 (s, 2H), 7.46 (m, 2 H). 13C NMR (75 MHz, CDCl3,
ppm): 11.2, 14.0, 23.0, 25.9, 29.1, 32.7, 37.3, 38.7, 40.9, 47.4, 64.9,
65.6, 99.8, 130.5, 134.8, 137.2. HRMS (EI): calcd for C34H54O4S4
[M]+ 654.2899, found 654.2898. IR (cm−1): 3454, 2955, 1461, 1305,
1248, 1098, 1020, 979, 740, 681.
2,5-Bis(2-ethylhexyl)terephthalaldehyde (35c). Prepared like
1
35a yielding 35b (32%) as a brown oil. H NMR (300 MHz, CDCl3,
ppm): 0.82−0.94 (m, 12 H), 1.21−1.39 (m, 16 H), 1.51−1.60 (m, 2
H), 2.98 (d, J = 7.2 Hz, 4 H), 7.72 (s, 2 H), 10.40 (s, 2 H). 13C NMR
(75 MHz, CDCl3, ppm): 10.7, 14.0, 22.9, 25.5, 28.7, 32.2, 35.9, 42.1,
133.5, 136.9, 142.5, 191.6. HRMS (EI): calcd for C24H38O2 [M]+
358.2866, found 358.2869. IR (cm−1): 3375, 2958, 2928, 2857, 1688,
1461, 1377, 1172, 1106, 783.
2-Phenyl-1,3-dithian-5-ol (36). To benzaldehyde (39 mg, 366
μmol) and 9 (50 mg, 403 μmol) in dry chloroform (5 mL) was added
I2 (5 mg, 19 μmol, 5 mol %). The mixture was stirred at room
temperature for 1 h, and Na2S2O3 solution was added. The organic
layer was dried with MgSO4 and concentrated in vacuo. After
purification with column chromatography (DCM), the two diaster-
eomers of 36 (75 mg, 97%) were obtained as a white solid. 85 K1. Mp:
99.5 °C. 1H NMR (300 MHz, CDCl3, ppm): 2.97 (dd, J = 13.9 Hz, J =
4.2 Hz, 2 H), 3.32 (d, J = 13.9 Hz, 2 H), 3.99 (bs, 1 H), 5.08 (s, 1 H),
7.32−7.41 (m, 3 H), 7.46−7.51 (m, 2 H). 13C NMR (75 MHz, CDCl3,
2,2′-(2,5-Dibutyl-1,4-phenylene)bis(1,3-dithian-5-one) (40a).
To 38a (75 mg, 164 μmol) in dry DMSO (5 mL) was added acetic
anhydride (155 μL, 1.63 mmol), and the reaction was stirred at room
temperature for 20 h. The mixture was concentrated in vacuo, and the
residue was purified with column chromatography (DCM), to yield
1
ppm): 39.0, 50.7, 55.4, 127.7, 128.8, 128.8. 85 K2. Mp: 139 °C. H
NMR (300 MHz, CDCl3, ppm): 2.94 (d, 3J = 6.5 Hz, 4 H,), 4.11 (dt,
1
40a (33 mg, 44%) as a yellowish waxy solid. H NMR (300 MHz,
3
3J = 12.9 Hz, J = 6.5 Hz, 1 H), 5.07 (s, 1 H), 7.30−7.41 (m, 3 H),
CDCl3, ppm): 0.95−1.05 (m, 6 H), 1.40−1.50 (m, 4 H), 1.58−1.70
(m, 4 H), 2.70−2.79 (m, 4 H), 3.40 (d, 3J = 14.2 Hz, 4 H), 3.80 (d, 3J
= 14.2 Hz, 4 H), 5.85 (s, 2 H), 7.54 (s, 2 H); insufficient solubility for
13C spectrum. HRMS (EI): calcd for C22H30O2S4 [M]+: 454.1123,
7.54−7.58 (m, 2 H). 13C NMR (75 MHz, CDCl3, ppm): 37.2, 49.7,
65.8, 127.8, 128.5, 128.7, 137.1. HRMS (EI): calcd for C10H12OS2
[M]+ 212.0330, found 212.0328.
2-Phenyl-1,3-dithian-5-one (37). To dry DMSO (5 mL) and 36
(25 mg, 118 μmol) was added acetic anhydride (56 μL, 589 μmol),
and the mixture was stirred at room temperature for 20 h. Afterward,
the mixture was concentrated under reduced pressure and purified
with column chromatography (DCM) to yield 37 (13 mg, 52%) as a
found 454.1124. IR (cm−1): 3392, 2956, 2922, 2851, 1703, 1465, 1399,
1247, 1181, 773.
2,2′-(2,5-Dipentyl-1,4-phenylene)bis(1,3-dithian-5-one)
(40b). Prepared like 40a yielding 40b (70%) as a yellowish waxy solid.
1H NMR (300 MHz, CDCl3, ppm): 0.91−1.01 (m, 6 H), 1.38−1.50
1
3
yellow oily solid. H NMR (300 MHz, CDCl3, ppm): 3.46 (d, J =
(m, 8 H), 1.60−1.73 (m, 4 H), 2.65−2.78 (m, 4 H), 3.40 (d, 3J = 14.2
3
14.6 Hz, 2 H), 3.72 (d, J = 14.6 Hz, 2 H), 5.63 (s, 1 H), 7.33−7.42
Hz, 2 H), 3.81 (d, 3J = 14.2 Hz, 4 H), 5.85 (s, 4 H), 7.54 (s, 2 H). 13
C
(m, 3 H), 7.54−7.57 (m, 2 H). 13C NMR (75 MHz, CDCl3, ppm):
35.5, 38.2, 48.9, 127.6, 128.9. HRMS (EI): calcd for C10H10OS2 [M]+
210.0168, found 210.0170.
NMR (75 MHz, CDCl3, ppm): 14.0, 22.5, 31.0, 31.7, 32.5, 39.0, 45.6,
104.45, 129.8, 135.3, 138.7. HRMS (EI): calcd for C24H34O2S4[M]+
482.1436, found 482.1430. IR (cm−1): 3417, 2954, 2925, 2853, 1713,
1462, 1400, 1246, 1176, 786.
4,4′-(2,5-Dibutyl-1,4-phenylene)bis(cyclohexan-1-ol) (38a).
To 35a (150 mg, 609 μmol) and 9 (159 mg, 1.28 mmol) in dry
chloroform (35 mL) was added I2 (15 mg, 61 μmol, 10 mol %). After
the mixture was stirred for 1 h at room temperature, Na2S2O3 solution
was added. The organic layer was dried with MgSO4 and concentrated
in vacuo. The crude product was purified by column chromatography
(DCM/MeOH) to yield the two diastereomers of 38a (262 mg, 94%)
2,2′-(2,5-Bis(2-ethylhexyl)-1,4-phenylene)bis(1,3-dithian-5-
one) (40c). Prepared like 40a yielding 40b (42%) as an orange waxy
solid. 1H NMR (300 MHz, CDCl3, ppm): 0.87−0.99 (m, 12 H),
1.20−1.38 (m, 16 H), 1.57−1.68 (m, 2 H), 2.62−2.69(m, 4 H), 3.37
(d, 3J = 14.2 Hz, 4 H), 3.79 (d, 3J = 14.2 Hz, 4 H), 5.85 (s, 2 H), 7.51
(s, 2 H). 13C NMR (75 MHz, CDCl3, ppm): 11.0, 14.1, 23.0, 25.9,
28.9, 32.6, 37.1, 39.1, 40.8, 45.9, 130.7, 135.0, 137.4, 201.6. HRMS
(EI): calcd for C30H46O2S4 [M]+ 566.2375, found 566.2367. IR
(cm−1): 3399, 2956, 2926, 2859, 1708, 1459, 1374, 1244, 1175, 1019.
((2,5-Dipentyl-1,4-phenylene)bis(1,5,8,10-tetrathiaspiro-
[5.5]undecane-9,3,3-triyl))tetramethanol (41). To 40b (100 mg,
207 μmol) and 13 (181 mg, 456 μmol) in dry chloroform (15 mL)
was added I2 (5 mg, 21 μmol, 10 mol %). After the mixture was stirred
for 2 h at room temperature, HF (35 μL, 830 μmol, 50%) was added.
Stirring was continued for 2 h, and the precipitate was collected,
washed with saturated NaHCO3 solution and DCM, and dried in
vacuo. Compound 41 (95 mg, 58%) was obtained as a yellowish solid,
1
as a beige solid. Mp: 201 °C. H NMR (300 MHz, DMSO-d6, ppm):
0.89−0.96 (m, 6 H), 1.28−1.42 (m, 4 H), 1.45−1.58 (m, 4 H), 2.59−
2.73 (m, 4 H), 2.77 (dd, 3J = 14.0 Hz, 3J = 3.5 Hz, 4 H), 3.38 (d, 3J =
14 Hz, 4 H), 3.85 (bs, 2 H), 4.72 (bs, 2 H), 5.39 (s, 2 H), 7.29 (s, 0.5
H), 7.37 (s, 1.5 H). 13C NMR (75 MHz, DMSO-d6, ppm): 14.4, 22.4,
31.9, 33.8, 37.8, 38.1, 46.0, 55.5, 66.8, 129.3, 129.8, 135.7, 137.5, 137.8,
138.2. HRMS (EI): calcd for C22H34O2S4 [M]+ 458.1436, found
458.1433. IR (cm−1): 3291, 2911, 2866, 1453, 1385, 1183, 1048, 901,
769, 641.
4,4′-(2,5-Dipentyl-1,4-phenylene)bis(cyclohexan-1-ol) (38b).
Prepared like 38a yielding 38b (91%) as a beige solid. Mp: 180−182
1
°C. H NMR (300 MHz, CDCl3, ppm): 0.93−0.97 (m, 6 H), 1.39−
J
DOI: 10.1021/acs.joc.5b02670
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The Journal of Organic Chemistry
Article
which was used immediately in the next step without further
purification. Insufficient solubility for NMR spectroscopy.
piperidin-4-one 22 and 44a were used as reactants, yielding 46a (99%)
as a beige solid. Mp: > 260 °C dec. H NMR (300 MHz, CDCl3,
1
3,3′-(2,5-Dipentyl-1,4-phenylene)bis(11,18-dioxa-2,4,7,21-
tetrathiatrispiro[5.2.2.512.29.26]henicosane) (42). Compound
41 (50 mg, 63.8 μmol), cyclohexanone 14 (14 mg, 140 μmol),
benzene (15 mL), and a catalytic amount of p-TsOH was refluxed in a
Dean−Stark apparatus for 20 h. After the reaction has finished, the
mixture was concentrated in vacuo, charged with DCM, washed with
NaHCO3 solution, and dried over MgSO4. After removal of the
solvent in vacuo, the crude product was purified with column
chromatography (DCM/MeOH) to yield 42 (45 mg, 75%) as a beige
ppm): 0.96−1.03 (m, 6 H), 1.37−1.44 (m, 4 H), 1.56−1.61 (m, 4 H),
1.90−2.04 (m, 8 H), 2.62−2.67 (m, 4 H), 2.84−3.11 (m, 8 H), 3.46−
3.81 (m, 12 H,), 4.10 (s, 4 H), 4.23−4.45 (m, 4 H), 5.21 (s, 2 H), 7.42
(s, 2 H). 13C NMR (75 MHz, CDCl3, ppm): 14.0, 22.6, 27.6, 32.2,
33.4, 37.3, 39.1, 41.0, 48.3, 63.3, 69.3, 96.9, 129.6, 135.7, 138.1, 164.9.
HRMS (ESI): calcd for C40H59Cl2N2O6S4 [M + H]+ 861.2628, found
861.2609. IR (cm−1): 2918, 2876, 1667, 1445, 1358, 1112, 1025, 885,
727, 660.
1,1′-((2,5-Bis(2-ethylhexyl)-1,4-phenylene)bis(8,15-dioxa-
2,4-dithia-12-azadispiro[5.2.59.26]hexadecane-3,12-diyl))bis-
(2-chloroethan-1-one) (46c). Prepared like 42 though 1-(2-
chloroacetyl)piperidin-4-one 22 and 44c were used as reactants,
yielding 46c (99%) as a beige solid. Mp: >290 °C dec. 1H NMR (300
MHz, CDCl3, ppm): 0.88−0.99 (m, 12 H), 1.20−1.39 (m, 16 H), 1.58
(bs, 2 H), 1.87−2.06 (m, 8 H) 2.42−2.61 (m, 8 H), 2.80−2.89 (m, 4
H), 2.90−3.25 (m, 4 H), 3.52−3.69 (m, 8 H), 3.70−3.93 (m, 4 H),
4.09 (s, 2 H), 4.21−4.51 (m, 4 H), 5.21 (s, 2 H). 13C NMR (75 MHz,
CDCl3, ppm): 11.0, 14.1, 22.9, 25.8, 27.4, 28.9, 37.3, 40.6, 40.8, 48.3,
63.2, 69.2, 96.7, 130.8, 135.7, 136.9, 164.9. HRMS (ESI): calcd for
C48H75Cl2N2O6S4 [M + H]+ 973.3880, found 973.3887. IR (cm−1):
2929, 2866, 1641, 1445, 1359, 1265, 1112, 1025, 897, 724.
1
solid. Mp: 193 °C. H NMR (300 MHz, CDCl3, ppm): 0.930 (bs, 6
H), 1.24−1.90 (m, 32 H), 2.57−2.61 (m, 8 H), 2.88 (bs, 4 H), 3.21
3.49 (m, 8 H), 3.53−4.41 (m, 8 H), 5.22 (bs, 2 H) 7.41 (bs, 2 H). 13C
NMR (75 MHz, CDCl3, ppm): 14.0, 22.4, 30.9, 31.9, 32.7, 43.4, 48.8,
65.7, 98.7, 129.6, 136.0, 138.9. HRMS (ESI): calcd for C46H71O4S8 [M
+ H]+ 943.3113, found 943.3149. IR (cm−1): 3316, 2925, 2861, 1455,
1298, 1160, 1112, 1037, 916, 796.
1,1′-((2,5-Dipentyl-1,4-phenylene)bis(11,18-dioxa-2,4,7,21-
tetrathia-15-azatrispiro[5.2.2.512.29.26]henicosane-3,15-
diyl))bis(2-chloroethan-1-one) (43). Prepared like 42 though 1-(2-
chloroacetyl)piperidin-4-one 22 was used as reactant, yielding 43
(97%) as a white solid. Mp: >285 °C dec. 1H NMR (300 MHz,
CDCl3, ppm): 0.91−0.99 (m, 6 H), 1.36−1.42 (m, 8 H), 1.51−1.64
(m, 4 H), 1.86−2.00 (m, 8 H), 2.49−2.68 (m, 12 H), 3.28−3.45 (m, 8
H), 3.54 (bs, 4 H), 3.66 (bs, 4 H), 3.80−3.92 (m, 8 H), 4.10 (s, 3 H),
4.17 (s, 1 H), 5.26 (s, 2 H), 7.44 (s, 2 H). 13C NMR (75 MHz, CDCl3,
ppm): 14.1, 22.5, 31.0, 31.3, 31.9, 32.7, 40.9, 41.0, 43.4, 44.8, 48.3,
48.9, 66.0, 96.8, 129.8, 135.3, 138.6, 165.0. HRMS (ESI): calcd for
C48H71Cl2N2O6S8 [M + H]+ 1097.2449, found 1097.2473. IR (cm−1):
2933, 2870, 1724, 1649, 1469, 1284, 1168, 1123, 894, 730.
ASSOCIATED CONTENT
* Supporting Information
■
S
NMR spectra, NOESY spectra, solubility of 15−17, details of
X-ray crystal structure analysis of 15. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.joc.5b02670.
((2,5-Dibutyl-1,4-phenylene)bis(1,3-dithiane-2,5,5-triyl))-
NMR spectra, NOESY spectra, solubility of 15−17,
details of X-ray crystal structure analysis of 15 (PDF)
X-ray data for 15 (CIF)
tetramethanol (44a). Prepared like 41 though 35a was used as
1
reactant, yielding 44a (48%) as a yellow solid. Mp: >292 °C dec. H
3
NMR (300 MHz, DMSO-d6, ppm): 0.92 (t, J = 7.2 Hz, 6 H), 1.31−
1.43 (m, 4 H), 1.45−1.56 (m, 4 H), 2.61−2.67 (m, 8 H), 3.07 (d, 3J =
14.0 Hz, 4 H), 3.32 (s, 4 H), 3.89 (s, 4 H), 4.25 (bs, 4 H), 5.30 (s, 2
H), 7.33 (s, 2 H). 13C NMR (75 MHz, DMSO-d6, ppm): 14.8, 22.8,
32.3, 34.2, 35.8, 47.7, 60.3, 67.2, 130.1, 137.4, 138.5. HRMS (EI):
calcd for C26H42O4S4 [M]+ 546.1960, found 546.1976. IR (cm−1):
3306, 2930, 2877, 1499, 1465, 1427, 1295, 1089, 1032, 724.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wessig@uni-potsdam.de.
■
Notes
The authors declare no competing financial interest.
((2,5-Dipentyl-1,4-phenylene)bis(1,3-dithiane-2,5,5-triyl))-
tetramethanol (44b). Prepared like 41 though 35b was used as
reactant, yielding 44b (99%) as a yellow solid. Mp: >288 °C dec.
Insufficient solubility for NMR spectroscopy. HRMS (ESI): calcd for
C28H47O4S4 [M + H]+ 575.2352, found 575.2351. IR (cm−1): 3343,
2926, 2855, 1915, 1610, 1397, 1292, 1021, 836, 697.
REFERENCES
■
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