Sulfur Tuning of [1,3]-Dioxolo[4.5-f]benzodioxole (DBD) Fluorescent Dyes

Article abstract of DOI:10.1002/ejoc.202001418

The replacement of oxygen by sulfur atoms of [1,3]-dioxolo[4.5-f]benzodioxole (DBD) fluorescent dyes is an efficient way to adjust the photophysical properties (sulfur tuning). While previously developed S⁴-DBD dyes exhibit considerably red-shifted absorption and emission wavelength, the heavy atom effect of four sulfur atoms cause low fluorescence quantum yields and short fluorescence lifetimes. Herein, we demonstrate that the replacement of less than four sulfur atoms (S¹-DBD, 1,2-S²-DBD, and 1,4-S²-DBD dyes) permits a fine-tuning of the photophysical properties. In some cases, a similar influence on the wavelength without the detrimental effect on the quantum yields and lifetimes is observed. Furthermore, the synthetic accessibility of S¹- and S²-DBD dyes is improved, compared with S⁴-DBD dyes. For coupling with biomolecules a series of reactive derivatives of the new dyes were developed (azides, OSu esters, alkynes, maleimides).

Full text of DOI:10.1002/ejoc.202001418

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doi.org/10.1002/ejoc.202001418
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Sulfur Tuning of [1,3]-Dioxolo[4.5-f]benzodioxole (DBD)
Fluorescent Dyes
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Pablo Wessig,*[a] Leonard John,[a] Eric Sperlich,[a] and Alexandra Kelling[a]
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Dedicated to Professor Bernd Giese on the occasion of his 80th birthday.
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The replacement of oxygen by sulfur atoms of [1,3]-dioxolo[4.5-
f]benzodioxole (DBD) fluorescent dyes is an efficient way to
adjust the photophysical properties (sulfur tuning). While
previously developed S4-DBD dyes exhibit considerably red-
shifted absorption and emission wavelength, the heavy atom
effect of four sulfur atoms cause low fluorescence quantum
yields and short fluorescence lifetimes. Herein, we demonstrate
that the replacement of less than four sulfur atoms (S1-DBD, 1,2-
S2-DBD, and 1,4-S2-DBD dyes) permits a fine-tuning of the
photophysical properties. In some cases, a similar influence on
the wavelength without the detrimental effect on the quantum
yields and lifetimes is observed. Furthermore, the synthetic
accessibility of S1- and S2-DBD dyes is improved, compared with
S4-DBD dyes. For coupling with biomolecules a series of reactive
derivatives of the new dyes were developed (azides, OSu esters,
alkynes, maleimides).
Introduction
physical parameters the bleaching stability (i.e. the chemical
stability against extensive irradiation) and the synthetic accessi-
bility are important criteria. Hardly any dye is exhibiting ideal
values for all photophysical parameters. Therefore, there is a
continued need for new fluorescent dyes or improvement of
existing dye classes.
Fluorescent dyes nowadays are indispensable tools especially in
biosciences, medicine but also in many other areas.[1] Above all,
the usage of these dyes in fluorescence microscopy[2] including
fluorescence lifetime imaging microscopy (FLIM)[3] and several
techniques summarized as super resolution microscopy[4] is
vastly superior to classic optical microscopy. This is mainly due
to the much higher sensitivity of fluorescence compared with
other kinds of signal generation. The selection of a suitable dye
for a certain application depends on a series of physical and
chemical properties. The most important criteria are the
absorption and emission wavelength (λabs, λem). Long-wave
absorption and emission are desirable in most cases, because
the penetration depth (e.g. in biological tissue) increases with
increasing wavelength. A large Stokes shift (i.e. the difference
between λabs and λem) is important for STED microscopy[4a] and
to minimize self-quenching. A long fluorescence lifetime τF is
advantageous for FLIM because it enhances the signal-to-noise
ratio regarding the undesirable natural background
fluorescence. The signal-to-noise ratio of fluorescence micro-
scopy is mainly influenced by the brightness of the dye, which
is defined by the product of fluorescence quantum yield ΦF and
molar attenuation coefficient ɛ. In addition to these photo-
Some years ago we developed a new class of dyes, which
are based on the [1,3]-dioxolo[4.5-f]benzodioxole skeleton
bearing electron withdrawing groups (EWG) in positions 4,8
and named them DBD dyes (Figure 1).[5a,b] The outstanding
features of these dyes are very large Stokes shifts, long
fluorescence lifetimes and high bleaching stability. Meanwhile,
we developed numerous applications such as probes for
sensing lipophilic environment,[5c] conformational changes of
proteins,[5d,e] detecting carbohydrate-lectin interactions,[5f]
dsDNA,[5o] and alkaline cations.[5g,h] Furthermore, fluorescence
lifetime based assays[5i,j] and FRET pairs[5k–n] were developed. In
addition to those application-oriented developments we always
were interested in fundamental research to improve the photo-
physical properties of DBD dyes. Looking at the structure of
DBD dyes there are basically three ways to influence their
photophysical properties: varying the EWGs (“EWG tuning”),
[a] Prof. Dr. P. Wessig, L. John, E. Sperlich, A. Kelling
Institut für Chemie
Universität Potsdam
Karl-Liebknecht-Str. 24–25, 14476 Potsdam, Germany
E-mail: ag-wessig.chem.uni-potsdam.de
E-mail: wessig@uni-potsdam.de
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202001418
© 2020 The Authors. European Journal of Organic Chemistry published by
Wiley-VCH GmbH. This is an open access article under the terms of the
Creative Commons Attribution Non-Commercial NoDerivs License, which
permits use and distribution in any medium, provided the original work is
properly cited, the use is non-commercial and no modifications or adap-
tations are made.
Figure 1. Structure of DBD dyes and adjusting screws for influencing the
photophysical properties.
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changing the length of the bridge between the ring hetero
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atoms (“bridge tuning”), and replacing the DBD core oxygen by
sulfur atoms (“sulfur tuning”) (Figure 1). Recently, we demon-
strated that absorption and emission wavelength of DBD dyes
can be efficiently influenced (λem =480–610 nm) by EWG
tuning.[6]
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With the aim to further shift absorption and emission to
longer wavelength we tackled the “sulfur tuning” and first
examined the maximum of replacing all four oxygen by sulfur
atoms (S4-DBD dyes, see Figure 2).[7] Despite a considerable red-
shift of absorption and emission this approach also revealed
some disadvantages: An enhanced spin-orbit coupling (heavy
atom effect) of the sulfur atoms increases the efficiency of
intersystem crossing (ISC) to the triplet state. This causes a
significant lowering of the fluorescence quantum yields and
lifetimes.[7b] Moreover, the quite efficient synthesis of S4-DBD
dyes mandatorily requires the use of extremely malodorous
tert-butylthiol.[7a] It should be noted that very recently an
alternative route has been published.[7d] Therefore we hypothe-
sized that the replacement of already less than four sulfur
atoms could satisfactorily improve the spectroscopic and
synthetic issues.
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°
Scheme 1. Synthesis of compound 6. i thiourea, HOAc, 100 C, 1 h, 82%. ii 1.
NaOH, 2. 2,2-dimethoxypropane, cat. PPTSA, 66%. iii K2[ON(SO3)2]), 86%. iv
PtO2/H2. v BrClCH2, K2CO3, 77%, 2 steps.
Next, we pursued the introduction of different EWGs. For
this purpose 6 was first lithiated (n-BuLi, TMEDA, n-hexane),
followed by treatment with electrophiles (DMF, N-methoxy-N-
methyl butanamide, ethyl chloroformate). Besides the desired
4,8-disubstituted compounds 9 we always obtained the mono-
substituted compounds 7 and 8 as by-products (Scheme 2).
The unequivocal distinction between 7 and 8 was possible
based on the X-ray structure analysis of 7a and 7b (see below).
Herein we describe the synthesis and properties of S1-, 1,2-
S2- and 1,4-S2-DBD dyes (Figure 2) as well as the influence of
bridge tuning.
1,2-S2-DBD dyes
Results and Discussion
More than 30 years ago Klar and co-workers reported on the
surprisingly smooth reaction of various catechol ethers with
disulfur dichloride giving dibenzo[c,g][1,2,5,6]tetrathiocines.[11]
Since then, this method was mentioned only three times.[12] En
route to 1,2-S2-DBD dyes we successfully applied the method to
1,2-benzodioxole 10 and 2,3-dihydro-1,4-benzodioxine 13. The
resulting tetrathiocines 11 and 14 could readily be reduced to
the dithiols 12 and 15. Due to its performance we used this
approach to explore the influence of the bridge length on the
photophysical properties (“bridge tuning”, cf. Figure 1). Accord-
ingly, four parent compounds 16–19 were prepared (Scheme 3).
Once again, the introduction of formyl groups provided
mixtures of mono- and disubstituted products. Best results
were achieved with two five-membered rings (16), while the
reactants with six-membered heterocyclic rings (17–19) gave
consistently worse results (Scheme 4). The reason could be a
partial deprotonation of the ethylene bridge.
S1-DBD dyes
The parent heterocycle [1,3]dioxolo[4,5-f][1,3]benzoxathiole
(“S1-DBD”, Figure 2) was mentioned only once in the literature[8]
(besides two patents without synthetic details), but the
synthetic route specified there is unsuitable for our purposes.
After numerous unsuccessful attempts we identified the long-
established reaction of 1,4-benzoquinone 1 with thiourea as
method of choice on the way to S1-DBD dyes.[9] Saponification
of the resulting thiocarbonate 2 and protection as acetonide
gave compound 3 in good yields. The introduction of the third
oxygen atom took place by oxidation of 3 to quinone 4 using
Frémy’s salt (K2[ON(SO3)2]).[10] After reduction to catechol 5
(which was used without further purification) and bridging
using BrClCH2 we obtained the target compound 6 (Scheme 1).
Scheme 2. Synthesis of compounds 7–9. i 1. n-BuLi, TMEDA, n-hexane, 2.
DMF (a) or N-methoxy-N-methyl butanamide (b) or ethyl chloroformate (c).
Figure 2. Structure of Sn-DBD dye parent compounds.
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Scheme 5. Synthesis of 1,2-S2-DBD dyes 28–30. i 1. n-BuLi, TMEDA, n-hexane,
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2. N-methyl-N-methoxy butanamide (a) or ethyl chloroformate (b). ii NaOH,
°
ACN/H2O (1:1), 60 C, 4 h, quant.
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followed by treatment with Pd(OAc)2 in the presence of
benzoquinone. Unfortunately, the yields of the desired thiocar-
bonate 32 were rather low (23%). The next steps, comprising of
replacement of the thiocarbonate by an acetonide (33) and
introduction of the formyl groups (34) proceeded disappoint-
ingly poor (Scheme 6). In summary, 1,4-S2-DBD dyes are
significantly worse accessible than 1,2-S2-DBD dyes.
Scheme 3. Synthesis of compounds 16–19. i S2Cl2, HOAc, r.t. 12 h. ii NaBH4,
°
DMF, 100 C, 2 h. iii acetone, DCM, BF3Et2O (cat.), iv BrCH2CH2Br, K2CO3, DMF,
°
90 C, 3 h.
Reactive S1-DBD and 1,2-S2-DBD dyes for bioconjugation
Most biological and biochemical applications of fluorescent
dyes require functional groups for coupling with biomolecules.
Because dialdehydes 9a and 21 exhibit the best synthetic
accessibility we prepared a collection of bioreactive S1-DBD and
1,2-S2-DBD dyes with these chromophores. The synthesis of 1,2-
S2-DBD dyes started with dithiol 12. The acetalization with
pivaloyl protected 5-hydroxypentan-2-one gave compound 35a
and, after deprotection, the alcohol 35b. Formyl groups were
introduced in the usual way giving dialdehyde 36. After several
unsuccessful attempts we identified a previously developed
cyclohexanone derivative[5m] as suitable building block for
reactive S1-DBD dyes. Using catechol 5 (Scheme 1) we prepared
silyl-protected spirane 43. After installation of the formyl groups
and deprotection we obtained the alcohol 44b.
Scheme 4. Synthesis of 1,2-S2-DBD aldehydes. i n-BuLi, TMEDA, n-hexane, r.t.
°
ii n-BuLi, TMEDA, n-hexane, À 10 C.
These two compounds 36 and 44b were used as platform
to synthesize propargyl carbonates 37, 45 (for CuAAc with
azides[14]), OSu esters 39, 47 (for reaction with amines), the azide
It should be noted that the replacement of five- by six-
membered heterocycles does not cause significant improve-
ment of the photophysical properties (vide infra). As the yields
of these compounds are also rather low, we focused our efforts
on 1,2-S2-DBD dyes bearing a dioxole and a dithiole ring.
Accordingly, the ketones 28a, 29a and the esters 28b, 29b
were prepared. Moreover, 29b could be quantitatively saponi-
fied to the dicarboxylic acid 30 (Scheme 5).
1,4-S2-DBD dyes
The preparation of 1,4-S2-DBD dyes turned out to be difficult.
After numerous attempts we identified the Pd-catalyzed intra-
molecular oxidative CÀ H-sulfuration[15] as a viable route. For this
purpose we used compound 3, an intermediate of S1-DBD dyes
(cf. Scheme 1). First, 3 was converted into thiocarbamate 31
Scheme 6. Synthesis of 1,4-S2-DBD dialdehyde 34. i dimethylthiocarbamoyl
chloride, N,N-diisopropylethylamine, 75%. ii Pd(OAc)2, TsOH, benzoquinone,
HOAc, toluene, 23%. iii 1. NaOH, 2. acetone, PPTSA, 21%. iv 1. n-BuLi,
°
TMEDA, n-hexane, 0 C, 2. DMF, 27%.
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41 (for CuAAc with alkynes[14]), and maleimides 42, 48 (for
reaction with thiols, e.g. cystein, Scheme 7 and Scheme 8).
7a, 7b and 21 in the solid is very similar. In all three
compounds, parallel stacking interactions between the aromatic
molecules are formed (see Supporting information for illustra-
tions). In addition, the molecules arrange themselves in such a
way that the S atoms of different molecules come very close to
each other (Figure 3).
In compounds 7a and 7b this leads to the formation of
dimers in which the S···S distance is shorter than the sum of the
van der Waals radii, in 21 the distance is much larger. The
reason for this arrangement are weak CÀ H···O-hydrogen bridges
between the molecules with H···O distances ranging from
2.57 Å to 2.69 Å which are typical for these bonds.[16] All three
X-ray structures exhibit a striking feature with respect to the
conformation of the acyl groups. The oxygen atoms of the acyl
groups in o-position to sulfur are always directed towards sulfur
atoms despite the considerable larger van der Waals radius of S
compared to O (1.80 Å vs. 1.52 Å). The distances of both atoms
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Structure of Sn-DBD dyes
For the three compounds 7a, 7b and 21, X-ray structure
analyses were performed. The arrangement of the molecules of
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are much shorter than the sum of the van der Waals radii (rSO
=
Scheme 7. Syntheses of reactive S2-DBD dyes 37–42. i 4-oxopentyl 2,2-
dimethylpropanoate, BF3 . Et2O (cat.), DCM, 12 h, r.t., 55%. ii LiOH, MeOH,
°
12 h, r.t., 83%. iii n-BuLi, TMEDA, n-hexane 0 C, 1 h, 35% (+21%
monoaldehyde). iv propargyl chloroformate, DMAP, pyridine,12 h, r.t., 89%. v
succinic anhydride, pyridine, DMAP, 62%. vi N-Hydroxysuccinimide, EDC,
DCM, 16 h, r.t., 87%. vii TsCl, DMAP, pyridine, 12 h, r.t., 50%. viii NaN3, DMF,
14 h, r.t., >99%. ix (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetyl chloride,[13]
DIPEA, DCM/DMF, 5 h, r.t., 62%.
Scheme 8. Syntheses of reactive S1-DBD dyes 45–48. i tert-butyl[(4,4-dimeth-
oxycyclohexyl)oxy]dimethylsilane,[5m] PPTSA, toluene, 2 h, rfx., 53% (2 steps
°
from 4). ii n-BuLi, TMEDA, n-hexane 0 C, 1 h, 35% (+35% monoaldehydes).
iii HF, ACN, quant. iv propargyl chloroformate, DMAP, pyridine,12 h, r.t., 88%.
v succinic anhydride, pyridine, DMAP, r.t., 14 h, 64%. vi N-Hydroxysuccini-
mide, EDC, DCM, 12 h, r.t., 85%. vii N-(2-aminoethyl)-maleimide-trifluoroace-
tate, DIPEA, DMF, r.t., 15 h, 65%.
Figure 3. X-ray structures of 7a, b and 21 with selected bond lengths.
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3.32 Å[17]), which suggests the presence of chalcogen bridges. In
the three compounds the S···O distances vary from 2.73 Å to
ring heteroatoms and the À M effect of formyl groups each
conformer can be expressed as three mesomers (A-1,2,3, B-
1,2,3, C-1,2,3). This assumption is supported by inspecting the
bond orders obtained from a Natural Bond Orbital (NBO)
analysis.[21] In Figure 4 the Wiberg bond indices (totals by
atoms) are depicted in the formulae of A-1, B-1, C-1. The indices
of those ring heteroatoms to which a formyl oxygen atom is
directed are significantly increased indicating a partial double
bond to the aromatic ring (for details see the SI). The origin of
the pronounced preference of sulfur over oxygen as donor
atoms should be the higher Lewis basicity of thioethers
compared with ethers. Additionally, there are presumably
stronger Coulomb forces (dashed lines in Figure 4) between S
and O due to larger vdW radius of S.
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°
°
2.92 Å, the CÀ S···O angles from 157 to 164 and the S···O=C
°
°
angles from 93 to 101 . The values correspond very well with
already published distances and angles for such sigma-hole
interactions between intramolecular S···O atoms.[18] Further
illustrations of the crystal structure and the intermolecular
interactions are shown in the Supporting Information.
To find out the reason for the preferred conformation of the
acyl groups we performed DFT calculations (M06-2X-D3[19]/def2-
TZVP[20]) with 1,4-S2-DBD dialdehyde (analogous to compound
34, without methyl groups). Considering conformations A, B, C
we found that A with both formyl oxygen atoms directed to
sulfur atoms is by far the most stable conformation. The other
two conformers B, C are less stable by 4.2 kcal/mol and 8.0 kcal/
mol respectively (Figure 4). Bearing in mind the +M effect of
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Photophysical properties of Sn-DBD dyes
The photophysical properties of selected Sn-DBD dyes and, for
comparison, of O4-DBD dialdehyde[6] are summarized in Table 1
(for complete data see the SI). First, we compare the
dialdehydes of S1-DBD (9a), 1,2-S2-DBD (21), and 1,4-S2-DBD
(34). The introduction of one sulfur atom results in a significant
red-shift of absorption (25 nm) and emission (9 nm) without
reduction of fluorescence lifetime τF and quantum yield ΦF. This
effect is increased by a second S atom in o-position (21), though
entailed with clear reduction of τF, ΦF. Surprisingly, the latter
effect is not observed with 1,4-S2-DBD dialdehyde 34. Perhaps
the spatial proximity of the sulfur atoms in 1,2-DBD dyes cause
a stronger spin-orbit coupling and consequently an increase of
the intersystem crossing to the triplet state than in 1,4-S2-DBD
dyes.[7b] The data of 21, 23, 25, 27 illustrate the influence of
bridge tuning. In all cases the replacement of one-atom bridge
by two-atom bridge leads to worse photophysical properties
(blue shift of λabs, λem, decreased values for τF and ΦF).
Nevertheless, the extremely high Stokes Shift (193 nm) of 23 is
remarkable. The properties of 1,2-S2-DBD ketones (29a) and
esters (29b) are in the expected range.
Figure 4. Mesomeric structures, conformers, and Wiberg bond indices (totals
by atoms) of 1,4-S2-DBD dyes.
Table 1. Photophysical data of O4-DBD dialdehyde and selected Sx-DBD dyes.[a]
[b,c]
[c]
[b,f]
Δλ[c]
τF[e]
ΦF
ɛ
[d]
No.
λabs
λem
~
Δn
[g]
9a
21
23
25
475
500
505
437
493
420
459
413
520
609
618
637
630
595
588
590
525
620
134
118
133
193
102
168
131
112
100
4.63
3.82
4.10
7.01
3.48
6.80
4.84
5.17
3.10
17.7
17.9
9.8
4.0
9.1
3.7
9,6
8.4
16.8
0.32
0.43
0.21
0.10
0.21
0.07
0.23
0.30
0.52
1.78
4.22
4.76
2.15
3.72
1.42
4.91
3.44
4.08
27
29a
29b
34
[a] solvent: actonitrile. [b] λabs and ɛ refer to the long-wave absorption. [c] λabs, λem, Δλ in nm. [d] Δ� in 103 ·cmÀ 1 [e] τF in ns. [f] ɛ in 103 ·MÀ 1 cmÀ 1. [g] O4-DBD
dialdehyde.[6]
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2,2-Dimethylbenzo[d][1,3]oxathiole-5,6-dione (4): FREMYs salt
(740 mg, 4.06 mmol, 1.0 equiv.) was added to a solution of KH2PO4
Conclusion
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°
(718 mg, 5.28 mmol, 1.3 equiv.) in 40 mL H2O at 0 C. Alcohol 3
A red-shift of absorption and emission wavelength as much as
possible without significant reduction of fluorescence lifetime
and quantum yields is the most important criterion for
evaluating the influence of structural alterations of DBD dyes.
Nevertheless, the synthetic accessibility and possibilities for
functionalization are also very important. Based on the photo-
physical criterion the 1,4-S2-DBD dyes would be the optimal
solution (e.g. 34), but the syntheses to these compounds
currently proceed with very low yields. On the other hand, there
is an efficient route to 1,2-S2-DBD dyes with tetrathiocines as
key intermediates. Moreover, we demonstrated that a variety of
reactive compounds for bioconjugation (37–42) are easily
accessible.
The “bridge tuning”, i.e. the replacement of the heterocyclic
five-membered by a six-membered ring is an interesting
variation of DBD dyes, but does not improve the photophysical
properties.
In summary, a considerable improvement of DBD dyes, both
photophysically and synthetically, could be achieved by “sulfur-
tuning”.[22]
(740 mg, 4.06 mmol, 1.0 equiv.) was dissolved in 10 mL MeOH and
added dropwise over a period of 10 min to the solution. The
mixture was stirred for 2 h at room temperature while the solution
turned into a red suspension which was filtered off. The solid was
washed several times with DCM and water. The phases of the
filtrate were separated and the water phase was extracted with
DCM (2×). The combined organic layers were washed with brine
and dried with MgSO4. After removing the solvent in vacuo, the
crude product was purified by flash silica gel column chromatog-
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raphy (DCM:MeOH 50:1) to yield 4 (680 mg, 15.34 mmol, 86%) as a
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red solid, m.p. 210 C. Rf (PE:EE/3:1): 0.23. H-NMR (400 MHz, CDCl3,
ppm) 6.40 (s, 1 H), 6.00 (s, 1 H), 1.92 (s, 6 H). 13C-NMR (101 MHz,
CDCl3, ppm) 177.7, 175.8, 167.6, 153.8, 117.4, 102.9, 102.8, 31.0. IR
(ATR, cmÀ 1): 3061, 1659, 1639, 1558, 1365, 1247, 1162, 1026, 838.
HRMS (EI): calcd. for C9H8O3S1 196.0194 [M]+, found 196.0195.
6,6-Dimethyl-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d][1,3]oxathiole (6):
Quinone 4 (650 mg, 3.31 mmol, 1.0 equiv.) was dissolved in 40 mL
anhydrous THF with a spatula-tip of PtO2. The atmosphere was
flushed three times with hydrogen and stirred under hydrogen [p
(H2)=1 atm] at room temperature till complete conversion moni-
tored by TLC (2 h). During the hydrogenation the colour of the
solution turned from red to colourless. The solvent was reduced to
10% and the atmosphere flushed with nitrogen. 20 mL dry DMF,
anhydrous K2CO3 (2.29 g, 16.56 mmol, 5.0 equiv.) and CH2BrCl
(0.30 mL, 3.98 mmol, 1.2 equiv.) were added to the residue and
Experimental Section
°
stirred for 3 h at 90 C and further 14 h at room temperature. The
reaction mixture was acidified with 2 M HCl and extracted with
ethyl acetate (2×). The combined organic layers were washed with
brine, dried with MgSO4 and concentrated under reduced pressure.
Purification of the crude product by flash silica gel column
chromatography (PE:EE 10:1) gave 6 (537 mg, 2.55 mmol, 77%) as
a colourless oil. Rf (PE:EE/20:1): 0.45. 1H-NMR (400 MHz, CDCl3,
ppm): 6.59 (s, 1 H), 6.41 (s, 1 H), 5.87 (s, 2 H), 1.81 (s, 6 H). 13C-NMR
(101 MHz, CDCl3, ppm): 149.1, 145.8, 142.5, 116.9, 102.9, 101.4, 98.5,
94.8, 30.2. IR (ATR, cmÀ 1): 2969, 2886, 1494, 1464, 1379, 1278, 1128,
1036. HRMS (EI): calcd. for C10H10O3S1 210.0351 [M]+, found:
210.0346.
General information: See the Supporting Information
5-Hydroxybenzo[d][1,3]oxathiol-2-one
(2):
1,4-Benzoquinone
(10.90 g, 100.0 mmol, 1.0 equiv.) was dissolved in 80 mL glacial
acetic acid and added dropwise to a solution of thiourea (9.21 g,
121.0 mmol, 1.2 equiv.) in 100 mL 2 M HCl at room temperature.
The reaction mixture was treated with 10 mL HCl (conc.) and stirred
for 1 h while a white precipitate was formed. The reaction was
heated for 1 h at 95 C and cooled with an ice bath. The white
precipitate was filtered of, washed with H2O and purified by silica
°
gel column chromatography (PE:EE 5:1) yielding
2 (13.9 g,
°
6,6-Dimethyl-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d][1,3]oxathiole-4,8-
dicarbaldehyde (9a): n-BuLi (2.5 M in hexane, 0.40 mL, 1.00 mmol,
2.1 equiv.) was given to a mixture of compound 6 (100 mg,
0.48 mmol, 1.0 equiv.) and dry TMEDA (0.14 mL, 0.95 mmol,
82.7 mmol, 82%) as a white solid, m.p. 158 C. Rf (PE:EE/10:1): 0.33.
1H-NMR (400 MHz, DMSO-d6): 9.77 (s, 1 H), 7.25 (d, J=8.8 Hz, 1 H),
3
7.11 (s, 1 H), 6.76 (d, 3J=8.8 Hz, 1 H) ppm. 13C-NMR (101 MHz,
DMSO-d6): 169.4, 154.9, 140.7, 123.1, 114.6, 112.5, 109.5 ppm. IR
(ATR, cmÀ 1): 3324, 1694, 1587, 1459, 1286, 1207, 1096, 1042, 857.
HRMS: calcd. for C7H4O3S1 167.9881 [M]+, found 167.9886.
°
2.0 equiv.) in 6 mL anhydrous hexane and stirred for 1 h at 0 C. Dry
DMF (0.10 mL, 1.19 mmol, 2.5 equiv.) was added and stirred for 1 h
°
at 0 C. The reaction mixture was quenched with 1 M HCl. After
2,2-Dimethylbenzo[d][1,3]oxathiol-5-ol (3): NaOH (0.71 mg,
17.84 mmol, 3.0 equiv.) was added to a mixture of 2 (1.00 g,
5.95 mmol, 1.0 equiv.) in 40 mL H2O/MeOH (1:1) and stirred for 2 h
phase separation the water layer was extracted with ethyl acetate
(2×). The combined organic layers were washed with brine, dried
with MgSO4, evaporated and purified with flash silica gel column
°
at 60 C under a nitrogen atmosphere. The reaction was acidified
chromatography (PE:EE 5:1) to afford 9a (54 mg, 0.22 mmol, 45%)
with 1 M HCl to pH=2 and extracted with ethyl acetate (2×). The
solvent was removed under reduced pressure and the remaining
white solid dissolved in acetone (0.80 mL, 6.0 mmol, 1.1 equiv.),
80 mL anhydrous toluene and a catalytic amount of p-toluenesul-
fonic acid. The mixture was refluxed in a DEAN-STARK apparatus for
20 h, cooled to room temperature, washed with saturated NaHCO3
solution and dried with MgSO4. After the solvent was removed
under reduced pressure, the crude product was purified by flash
silica gel column chromatography (PE:EE 10:1) to afford 3 (740 mg,
4.61 mmol, 69%) as a colourless oil. Rf (PE:EE/5:1): 0.53. 1H-NMR
(400 MHz, CDCl3, ppm): 6.63 (s, 1 H), 6.61 (s, 1 H), 1.82 (s, 6 H). 13C-
NMR (101 MHz, CDCl3, ppm): 150.6, 149.4, 128.1, 112.0, 110.8, 109.9,
98.1, 30.2. IR (ATR, cmÀ 1): 3381, 2973, 1474, 1367, 1327, 1215, 1173,
1117. HRMS (EI): calcd. for C9H10O2S1 182.0396 [M]+, found 182.0399.
1
°
as a red solid, m.p. 188 C. Rf (PE:EE/ 5:1): 0.20. H-NMR (400 MHz,
CDCl3, ppm): 10.18 (s, 2 H), 6.20 (s, 2 H), 1.86 (s, 6 H). 13C-NMR
(101 MHz, CDCl3, ppm): 186.3, 185.5, 151.0, 145.6, 145.4, 118.7,
116.0, 110.1, 104.4, 100.8, 30.7. IR (ATR, cmÀ 1): 2962, 2908, 1664,
1438, 1408, 1258, 1057, 1018, 925. HRMS (EI): calcd. for C12H10O5S1
266.0249 [M]+, found: 266.0253.
Additionally 7a was isolated in 9% and 8a with a yield of 25%,
both as a yellow solid.
6,6-Dimethyl-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d][1,3]oxathiole-8-
carbaldehyde (7a): M.p. 132 C, Rf (PE:EE/5:1) 0.55. 1H-NMR
°
(400 MHz, CDCl3, ppm): 10.16 (s, 1 H), 6.59 (s, 1 H), 6.04 (s, 2 H), 1.80
(s, 6 H). 13C-NMR (101 MHz, CDCl3, ppm): 185.8, 150.0, 146.2, 145.1,
117.3, 113.5, 102.8, 99.4, 98.6, 30.5. IR (ATR, cmÀ 1): 3086, 2974, 2901,
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2849, 1676, 1459, 1378, 1346, 1290, 1215, 1153, 1053. HRMS (EI):
Compound 7c was additionally added in a yield of 4% as well as
8c in 25%.
1
2
3
4
5
6
7
8
calcd. for C11H10O4S1 238.0300 [M]+, found: 238.0293.
6,6-Dimethyl-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d][1,3]oxathiole-4-
Ethyl 6,6-dimethyl-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d][1,3]oxa-
carbaldehyde (8a): M.p. 135 C, Rf (PE:EE/5:1): 0.38. 1H-NMR
thiole-8-carboxylate (7c): Rf (PE:EE/10:1): 0.45. H-NMR (400 MHz,
1
°
(400 MHz, CDCl3, ppm): 10.14 (s, 1 H), 6.79 (s, 1 H), 6.05 (s, 2 H), 1.88
(s, 6 H). 13C-NMR (101 MHz, CDCl3, ppm): 186.5, 150.1, 146.1, 143.2,
118.2, 108.2, 108.1, 103.1, 100.6, 30.4. IR (ATR, cmÀ 1): 3081, 2974,
2924, 2868, 1682, 1617, 1453, 1366, 1273, 1170, 1067, 1031. HRMS
(EI): calcd. for C11H10O4S1 238.0300 [M]+, found: 238.0305.
CDCl3, ppm): 6.55 (s, 1 H), 6.02 (s, 2 H), 4.40 (q, 3J=7.2 Hz, 2 H), 1.80
3
(s, 6 H), 1.40 (t, J=7.1 Hz, 3 H). 13C-NMR (101 MHz, CDCl3, ppm):
164.3, 149.4, 146.5, 143.2, 120.3, 102.3, 98.1, 97.2, 65.3, 61.7, 30.4,
14.5. IR (ATR, cmÀ 1): 2925, 2833, 1652, 1593, 1368, 1243, 1172, 1050,
934. HRMS (EI): calcd. for C13H14O5S1 282.0562 [M]+, found: 282.0564.
9
1,1’-(6,6-Dimethyl-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d][1,3]oxa-
Ethyl
6,6-dimethyl-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d][1,3]oxa-
1
thiole-4,8-diyl)bis(butan-1-one) (9b): Compound
6
(100 mg,
thiole-4-carboxylate (8c): Rf (PE:EE/10:1): 0.68. H-NMR (400 MHz,
CDCl3, ppm): 6.73 (s, 1 H), 6.00 (s, 2 H), 4.39 (q, 3J=7.1 Hz, 2 H), 1.86
(s, 6 H), 1.37 (s, 3 H). 13C-NMR (101 MHz, CDCl3, ppm): 166.4, 149.2,
146.3, 142.5, 115.9, 101.4, 98.0, 94.8, 69.4, 64.9, 30.5, 30.2, 14.3. IR
(ATR, cmÀ 1): 2956, 2928, 2871, 1764, 1464, 1367, 1243, 1172, 1117,
1050. HRMS (EI): calcd. for C13H14O5S1 282.0562 [M]+, found:
282.0569.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
0.48 mmol, 1.0 equiv.) was dissolved with TMEDA (0.15 mL,
0.95 mmol, 2.0 equiv.) in 3 mL dry n-hexane and cooled to 0 C.
After adding n-BuLi (2.5 M in hexane, 0.40 mL, 1.00 mmol,
°
°
2.1 equiv.) the mixture was stirred for 1 h at 0 C. N-methoxy-N-
methyl butanamide (156 mg, 1.19 mmol, 2.5 equiv.) was added and
°
stirred for another hour at 0 C. The mixture was quenched with
1 M HCl. The phases were separated and the water layer extracted
with ethyl acetate (2×20 mL). The combined organic layers were
dried with MgSO4 and concentrated in vacuo. After purification by
flash silica gel column chromatography (PE:EE 10:1) compound 9b
[1,3]Dioxolo[8,9][1,2,5,6]benzotetrathiocino[3,4-f][1,3]benzodiox-
ole (11): In a 100 mL flask disulfur dichloride (1.4 mL, 17.6 mmol,
1.0 equiv.) was added to a solution of 1,3-benzodioxole (2 mL,
17.60 mmol, 1.0 equiv.) in 40 mL glacial acetic acid and stirred for
18 h at room temperature. The yellow solid was collected by
filtration, washed with diethyl ether (100 mL) and dried in vacuo to
yield 11 (2.69 g, 7.30 mmol, 84%) as a yellow solid which was used
(50 mg, 0.14 mmol, 30%) was isolated as an orange solid, m.p.
1
°
146 C. Rf (PE:EE/10:1): 0.35. H-NMR (400 MHz, CDCl3, ppm): 6.11 (s,
2 H), 2.91 (m, 4 H), 1.80 (s, 6 H), 1.76–1.62 (m, 4 H), 0.96 (s, 6 H). 13C-
NMR (101 MHz, CDCl3, ppm): 198.5, 196.9, 147.8, 144.9, 142.9, 120.8,
115.8, 112.1, 102.7, 97.6, 46.0, 45.0, 30.4, 17.6, 17.2, 14.0, 13.9. IR
(ATR, cmÀ 1): 2960, 2930, 2872, 1687, 1662, 1427, 1365, 1261, 1077.
HRMS (EI): calcd. for C18H22O5S1 350.1188 [M]+, found: 280.1185.
°
without further purification in the next step, m.p. 107–107.5 C. Rf
1
(DCM:MeOH/50:1): 0.60. H-NMR (400 MHz, CDCl3, ppm): 7.24 (s, 4
H), 5.97 (s, 4 H). 13C-NMR (101 MHz, CDCl3, ppm): 148.6, 131.9, 111.2,
101.6. IR (ATR, cmÀ 1): 2882, 1498, 1456, 1230, 1032, 923. HRMS (EI):
calcd. for C14H8O4S4 367.9305 [M]+, found: 367.9307.
Additionally 7b was isolated in 13% and 8b in 26%.
1-(6,6-Dimethyl-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d][1,3]oxathiol-8-
Benzo[d][1,3]dioxole-5,6-dithiol (12): Compound 11 (3.30 g,
8.96 mmol, 1.0 equiv.) was suspended in 60 mL dry DMF. After
adding NaBH4 (1.69 g, 44.78 mmol, 5.0 equiv.) the solution was
yl)butan-1-one (7b): M.p. 147 C, Rf (PE:EE/10:1): 0.63. 1H-NMR
°
(400 MHz, CDCl3, ppm): 6.56 (s, 1 H), 6.02 (s, 2 H), 2.93 (t, 3J=7.3 Hz,
2 H), 1.77 (s, 6 H), 1.76–1.70 (m, 2 H), 0.98 (s, 3 H). 13C-NMR
(101 MHz, CDCl3, ppm): 197.2, 149.9, 146.1, 142.6, 119.4, 114.6,
103.0, 101.9, 98.2, 96.9, 44.8, 31.1, 30.4, 17.3, 14.0. IR (ATR, cmÀ 1):
2955, 2929, 1676, 1613, 1445, 1365, 1270, 1231, 1165, 1045, 958.
HRMS (EI): calcd. for C14H16O4S1 280.0769 [M]+, found 280.0764.
°
heated for 2 h at 100 C. The light brown solution was cooled with
an ice bath, quenched with 50 mL water and extracted with DCM
(1×20 mL). The organic phase was put aside and not further used.
The water layer was acidified with 1 M HCl to pH=2 and extracted
with DCM (2×30 mL). The solvent of the combined organic layers
was removed. Toluene (2×50 mL) was given to the crude product
and removed in vacuo to remove DMF and water residues.
Compound 12 (3.34 g, 8.96 mmol, quant.) was isolated as a light
greenish oil and used without further purification in the next step.
1H-NMR (400 MHz, CDCl3, ppm): 6.87 (s, 2 H), 5.93 (s, 2 H), 3.69 (s, 2
H). 13C-NMR (101 MHz, CDCl3, ppm): 147.2, 123.1, 111.7, 101.6. IR
(ATR, cmÀ 1)=2893, 2785, 2539, 1499, 1458, 1227, 1032, 925. HRMS
(EI): calcd. for C7H6O2S2 185.9809 [M]+, found: 185.9812.
1-(6,6-Dimethyl-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d][1,3]oxathiol-4-
yl)butan-1-one (8b): M.p. 147 C, Rf (PE:EE/10:1): 0.48. 1H-NMR
°
(400 MHz, CDCl3, ppm): 6.71 (s, 1 H), 5.99 (s, 2 H), 2.87 (t, 3J=7.3 Hz,
2 H), 1.86 (s, 6 H), 1.73–1.68 (m, 2 H), 0.97 (s, 3 H). 13C-NMR
(101 MHz, CDCl3, ppm): 198.4, 147.3, 145.0, 143.0, 118.5, 110.2,
106.0, 102.3, 99.3, 45.9, 30.3, 17.7, 14.0. IR (ATR, cmÀ 1): 2957, 2931,
2870, 1677, 1613, 1443, 1365, 1275, 1230, 1176, 1048. HRMS (EI):
calcd. for C14H16O4S1 280.0769 [M]+, found: 280.0766.
2,3,10,11-Tetrahydro[1,4]dioxino[2’,3’:8,9][1,2,5,6]benzotetra-
thio-cino[3,4-g][1,4]benzodioxine (14): 1,4-Benzodioxan (2.0 mL,
15.86 mmol, 1.0 equiv.) and disulfur dichloride (1.27 mL,
15.86 mmol, 1.0 equiv.) were added to 40 mL glacial acetic acid and
stirred for 24 h at room temperature. The precipitate was filtered of,
washed with 100 mL diethyl ether and dried in vacuo. 2.45 g
(6.18 mmol, 78%) of 14 were isolated as a beige solid and used
without further purification in the next step, m.p. 189–190. Rf
Diethyl 6,6-dimethyl-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d][1,3]oxa-
thiole-4,8-dicarboxylate (9c): To
a solution of compound 6
(140 mg, 0.66 mmol, 11.0 equiv.) and TMEDA (0.21 mL, 1.33 mmol,
2.0 equiv.) in dry hexane (5 mL) n-BuLi (2.5 M in hexane, 0.56 mL,
°
1.40 mmol, 2.1 equiv.) was given and stirred for 1 h at 0 C. Then
ethyl chloroformate (0.18 mL, 1.66 mmol, 2.5 equiv.) was added and
°
stirred again for 1 h at 0 C. The reaction was quenched with
saturated NH4Cl-solution and extracted with ethyl acetate (3×
30 mL). The combined organic layers were washed with brine, dried
with MgSO4, evaporated and purified by flash silica gel column
chromatography (PE:EE 10:1) to yield 9c (73 mg, 0.21 mmol, 30%)
1
(DCM:MeOH 50:1): 0.65. H-NMR (400 MHz, CDCl3, ppm): 7.26 (s, 4
H), 4.24 (s, 8 H). 13C-NMR (101 MHz, CDCl3, ppm): 144.1, 125.3, 117.9,
64.5. IR (ATR, cmÀ 1): 2980, 2921, 2882, 1560, 1466, 1295, 1275, 1250,
1062, 893. HRMS (EI): calcd. for C16H12O4S4 395.9618 [M]+, found:
395.9621.
1
as a yellowish oil. Rf (PE:EE/10:1): 0.30. H-NMR (400 MHz, CDCl3,
ppm): 6.11 (s, 2 H), 4.43–4.36 (m, 4 H), 1.83 (s, 6 H), 1.39–1.36 (m, 6
H). 13C-NMR (101 MHz, CDCl3, ppm): 163.9, 162.6, 148.3, 146.1, 143.2,
121.9, 109.9, 104.9, 103.1, 98.0, 62.1, 61.6, 30.5, 14.4, 14.3. IR (ATR,
cmÀ 1): 2962, 2931, 1769, 1720, 1434, 1368, 1261, 1174, 1070,
1022 cmÀ 1. HRMS (EI): calcd. for C16H18O7S1 354.0773 [M]+, found:
354.0765.
2,3-Dihydrobenzo[b][1,4]dioxine-6,7-dithiol (15): 14 (1.00 g,
2.52 mmol, 1.0 equiv.) was suspended in dry DMF (15 mL) and
NaBH4 (0.48 g, 12.6 mmol, 5.0 equiv.) was added. The mixture was
heated for 2 h at 100 C while the colour of the solution turned
from brownish to yellow. The reaction was cooled to 0 C with an
°
°
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ice bath and quenched with 20 mL water and 20 mL DCM was
and acidified (pH=2) with 2 M HCl. Ethyl acetate was added and
the phases were separated. The water layer was extracted with
ethyl acetate (2×30 mL) and the combined organic layers washed
with brine, dried with MgSO4, concentrated under reduced pressure
and purified by flash silica gel column chromatography (PE:EE
1
2
3
4
5
6
7
8
9
added. The organic phase was put apart and wasn't used further.
The water layer was acidified with 1 M HCl (pH=2) and extracted
with DCM (2×30 mL). The combined organic layers were concen-
trated in vacuo. The residue was dissolved in dry toluene and
concentrated again under reduced pressure to yield 15 (1.01 g,
2.52 mmol, quant.) without further purification as a colourless oil
and used without further purification in the next step. 1H-NMR
(400 MHz, CDCl3, ppm): 6.18 (s, 2 H), 3.47 (s, 2 H), 3.46 (s, 4 H). 13C-
NMR (101 MHz, CDCl3, ppm): 142.6, 122.7, 119.9, 64.2. IR (ATR,
cmÀ 1): 2930, 2890, 2538, 1487, 1325, 1190, 1058, 865 cmÀ 1. HRMS
(E): calcd. for C8H8O2S2 199.9966 [M]+, found: 199.9962.
10:1) yielding 19 (540 mg, 1.21 mmol, 48%) as a white solid, m.p.
1
°
121 C. Rf (PE:EE/5:1): 0.35. H-NMR (400 MHz, CDCl3, ppm): 6.76 (s,
2 H), 4.21 (s, 4 H), 3.19 (s, 4 H). 13C-NMR (101 MHz, CDCl3, ppm):
142.0, 124.3, 117.5, 64.5, 29.9. IR (ATR, cmÀ 1): 2959, 2885, 1484,
1453, 1358, 1253, 1233, 1030. HRMS (EI): calcd. for C10H10O2S2
226.0112 [M]+, found: 226.0113.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
6,6-Dimethyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d][1,3]dioxole-4,8-
dicarbaldehyde (21): n-BuLi (2.5 M in hexane, 0.19 mL, 0.46 mmol,
2.1 equiv.) was given to a solution of 16 (50 mg, 0.22 mmol,
1.0 equiv.) and TMEDA (0.07 mL, 0.44 mmol, 2.0 equiv.) in dry
hexane at room temperature and stirred for 1 h. Anhydrous DMF
(0.04 mL, 0.55 mmol, 2.5 equiv.) was given to the reaction mixture
and stirred for another 30 min. The reaction was quenched with
1 M HCl. After phase separation the water layer was extracted with
ethyl acetate (2×20 mL). The combined organic layers were washed
with brine, dried with MgSO4 and concentrated under reduced
pressure. Purification of the residue by flash silica gel column
chromatography (PE:EE 3:1) gave 21 (36 mg, 0.13 mmol, 58%) as a
6,6-Dimethyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d][1,3]dioxole (16):
The Dithiol 12 (2.0 g, 10.74 mmol, 1.0 equiv.) and acetone (1.20 mL,
16.1 mmol, 1.5 equiv.) were dissolved in 100 mL dry DCM. Boron
trifluoride etherate complex (48%-solution, 4.25 ml, 16.1 mmol,
1.5 equiv.) was added and stirred over night at room temperature.
The reaction was quenched with saturated NaHCO3 solution
(20 mL). After phase separation the water layer was extracted with
DCM (2×30 mL)). The combined organic layer were washed with
brine and dried with MgSO4. The solvent was removed in vacuo
and the crude product purified by flash silica gel column
chromatography (PE:EE, 10:1) to yield 16 (1.33 g, 5.88 mmol, 50%)
as a white solid, m.p. 72–73 C. Rf (PE:EE/10:1): 0.60, 1H-NMR
red solid, m.p. 230 C (decomp.). Rf (PE:EE/3:1): 0.33. 1H-NMR
°
°
(400 MHz, CDCl3, ppm): 6.70 (s, 2 H), 5.91 (s, 2 H), 1.88 (s, 6 H). 13C-
NMR (101 MHz, CDCl3, ppm): 146.3, 129.8, 104.2, 101.5, 66.4, 31.1. IR
(ATR, cmÀ 1): 2959, 2921, 2855, 1502, 1455, 1255, 1148, 1034. HRMS
(EI): calcd. for C10H10O2S2 226.0122 [M]+, found: 226.0119.
(400 MHz, CDCl3, ppm): 10.26 (s, 2 H), 6.27 (s, 2 H), 1.86 (s, 6 H). 13C-
NMR (101 MHz, CDCl3, ppm): 185.7, 149.8, 132.2, 117.2, 104.6, 64.9,
32.2. IR (ATR, cmÀ 1): 2970, 2924, 2881, 1669, 1450, 1390, 1251, 1215,
1103, 1024. HRMS (EI): calcd. for C12H1004 S2 282.0008 [M]+, found:
282.0007.
6,7-Dihydro-[1,4]dithiino[2’,3’:4,5]benzo[1,2-d][1,3]dioxole (17):
12 (1.00 g, 5.37 mmol, 1.0 equiv.), 1,2-dibromoethane (0.97 mL,
11.28 mmol, 2.1 equiv.) and dry K2CO3 (2.23 g, 16.11 mmol,
3.0 equiv.) were dissolved in dry DMF. The mixture was stirred for
Additionally 20 was isolated as a yellow solid with a yield of 18%.
6,6-Dimethyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d][1,3]dioxole-4-
carbaldehyde (20): M.p. 128 C, Rf (PE:EE/3:1): 0.51. 1H-NMR
°
°
3 h at 90 C and 12 h at room temperature. The black solution was
(400 MHz, CDCl3, ppm): 10.18 (s, 1 H), 6.90 (s, 1 H), 6.09 (s, 2 H), 1.87
(s, 6 H). 13C-NMR (101 MHz, CDCl3, ppm): 185.8, 146.6, 131.6, 115.5,
108.7, 103.1, 65.5, 31.6. IR (ATR, cmÀ 1): 2956, 2925, 2857, 1672, 1456,
1378, 1251, 1097, 1045. HRMS (EI): calcd. for C11H10O3S2 254.0071
[M]+, found: 254.0074.
acidified (pH=4) with 1 M HCl and extracted with diethyl ether (3×
50 mL). The combined organic layers were washed with brine and
concentrated in vacuo. Purification by flash silica gel column
chromatography (PE:EE 10:1) gave 17 (0.57 g, 2.69 mmol, 50%) as
a white solid, m.p. 101–103 C. Rf (PE:EA/10:1): 0.43. 1H-NMR
°
(400 MHz, CDCl3, ppm): 6.73 (s, 2 H), 5.90 (s, 2 H), 3.17 (s, 4 H). 13C-
NMR (101 MHz, CDCl3, ppm): 146.3, 125.3, 109.6, 101.3, 30.5. IR (ATR,
cmÀ 1): 2965, 2922, 2892, 1496, 1461, 1223, 1032, 929. HRMS (EI):
calcd. for C9H8O2S2 211.9966 [M]+, found: 211.9967.
6,7-Dihydro-[1,4]dithiino[2’,3’:4,5]benzo[1,2-d][1,3]dioxole-4,9-di-
carbaldehyde (23): A mixture of 17 (70 mg, 0.33 mmol, 1.0 equiv.)
and TMEDA (0.1 mL, 0.69 mmol, 2.1 equiv.) in 10 mL dry hexane
°
was cooled to 0 C and treated with n-BuLi (1.6 M in hexane,
0.52 mL, 0.82 mmol, 2.5 equiv.). After 1 h dry DMF (0.07 mL,
2,2-Dimethyl-6,7-dihydro-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-b][1,4]-
dioxine (18): Dithiol 15 (1.54 g, 7.69 mmol, 1.0 equiv.) was dissolved
in 50 mL dry DCM. Acetone (0.85 mL, 11.5 mmol, 1.5 equiv.) and
BF3*OEt2-Komplex (48%-solution, 2.97 mL, 11.53 mmol, 1.5 equiv.)
were added and stirred for 14 h at room temperature. The mixture
was quenched by adding saturated NaHCO3 solution (20 mL) to the
reaction. The phases were separated and the water layer extracted
with DCM (2×30 mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. Purification of the crude by flash
silica gel column chromatography (PE:EE 20:1) gave 18 (1.00 g,
°
0.82 mmol, 2.5 equiv.) was added at 0 C to the mixture and stirred
°
for a further hour at 0 C. 1 M HCl (5 mL) was added, phases
separated and the water-layer extracted with ethyl acetate (2×
10 mL). The combined organic layers were dried with MgSO4,
concentrated in vacuo and purified by flash silica gel column
chromatography to yield 23 (28 mg, 0.11 mmol, 32%) as an orange
solid, m.p. 231 C. Rf (PE:EE/3:1): 0.18. 1H-NMR (400 MHz, CDCl3,
°
ppm): 10.51 (s, 2 H), 6.27 (s, 2 H), 3.25 (s, 4 H). 13C-NMR (101 MHz,
CDCl3, ppm): 187.8, 148.8, 131.7, 121.0, 104.5, 31.9. IR (ATR, cmÀ 1):
2920, 1676, 1566, 1443, 1388, 1271, 1190, 1019. HRMS (EI): calcd. for
C11H8O4S2 267.9864 [M]+, found: 267.9863.
°
4.16 mmol, 54%) as a white solid, m.p. 92–93 C. Rf (PE:EA/10:1):
1
0.65. H-NMR (400 MHz, CDCl3, ppm): 6.72 (s, 2 H), 4.20 (s, 4 H), 1.88
(s, 6 H). 13C-NMR (101 MHz, CDCl3, ppm): 141.9, 130.5, 111.9, 111.6,
66.0, 64.5, 31.3. IR (ATR, cmÀ 1): 2961, 2855, 1624, 1558, 1340, 1285,
1131, 1024. HRMS (EI): calcd. for C11H12O2S2 [M]+ 240.0279, found:
240.0282
Additionally 22 was isolated in a yield of 19% as a yellow solid.
6,7-Dihydro-[1,4]dithiino[2’,3’:4,5]benzo[1,2-d][1,3]dioxole-4-car-
1
°
baldehyde (22): M.p. 126 C. Rf (PE:EE/3:1): 0.43. H-NMR (400 MHz,
CDCl3, ppm): 10.36 (s, 1 H), 6.89 (s, 1 H), 6.06 (s, 2 H), 3.23–3.12 (m, 4
H). 13C-NMR (101 MHz, CDCl3, ppm): 187.4, 149.1, 146.4, 128.3, 126.9,
118.2, 114.0, 102.9, 30.6, 30.4. IR (ATR, cmÀ 1): 2901, 1676, 1593,
1450, 1223, 1203, 1054, 922. HRMS (EI): calcd. for C10H8O3S2
239.9915 [M]+, found: 239.9913.
2,3,7,8-Tetrahydro-[1,4]dithiino[2’,3’:4,5]benzo[1,2-b][1,4]dioxine
(19): Compound 15 (1.00 g, 2.52 mmol, 1.0 equiv.), dry K2CO3
(2.07 g, 14.98 mmol, 5.0 equiv.) and 1,2-dibromoethane (0.90 mL,
10.49 mmol, 2.1 equiv.) were dissolved in 50 mL dry DMF. The
°
suspension was stirred for 3 h at 90 C and further 16 h at room
temperature. The dark gray solution was cooled with an ice bath
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doi.org/10.1002/ejoc.202001418
°
2,2-Dimethyl-6,7-dihydro-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-b][1,4]
dioxine-4,9-dicarbaldehyde (25): A suspension of 18 (100 mg,
0.42 mmol, 1.0 equiv.) and TMEDA (0.13 mL, 0.83 mmol, 2.0 equiv.)
in dry hexane was treated with n-BuLi (2.5 M in hexane, 0.35 mL,
0.87 mmol, 2.1 equiv.) at room temperature and stirred for 1 h. Dry
DMF (0.08 mL, 1.04 mmol, 2.5 equiv.) was given to the reaction and
stirred again for 1 h at room temperature. The reaction was
quenched with 1 M HCl and the phases separated. The water layer
was extracted three times with ethyl acetate and the combined
organic layers dried over MgSO4. The solvent was removed in vacuo
and the crude product purified by flash silca gel column
chromatography (PE:EE 3:1) to yield 25 (43 mg,0.15 mmol, 35%) as
an orange solid, m.p. 145 C. Rf (PE:EE/10:1): 0.40. 1H-NMR
(400 MHz, CDCl3, ppm): 6.19 (s, 2 H), 2.95 (t, 3J=7.1 Hz, 4 H), 1.73 (s,
1
2
3
4
5
6
7
8
9
3
10 H, CH2), 0.97 (t, J=7.4 Hz, 6 H). 13C-NMR (101 MHz, CDCl3, ppm):
197.8, 146.7, 133.7, 118.3, 102.5, 60.2, 45.3, 31.4, 17.4, 13.9. IR (ATR,
cmÀ 1): 2960, 2872, 1666, 1423, 1389, 1253, 1218, 1150, 1046, 967.
HRMS (EI): calcd. for C18H22O4S2 366.0960 [M]+, found: 366.0961.
Furthermore 28a was isolated as a yellow solid in a yield of 20%.
1-(6,6-Dimethyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d][1,3]dioxol-4-
yl)butan-1-one (28a): M.p. 92 C. Rf (PE:EE/10:1): 0.63. 1H-NMR
°
3
(400 MHz, CDCl3, ppm): 6.86 (s, 1 H), 6.05 (s, 2H), 2.93 (t, J=7.3 Hz,
3
3
2 H), 1.82 (s, 6 H), 1.73 (q, J=7.3 Hz, 2 H), 0.97 (t, J=7.4 Hz, 3 H).
13C-NMR (101 MHz, CDCl3, ppm): 197.5, 146.8, 146.2, 132.0, 131.5,
116.7, 107.5, 102.1, 63.3, 44.9, 31.4, 17.4, 13.9. IR (ATR, cmÀ 1): 2954,
2926, 2868, 1659, 1588, 1443, 1391, 1239, 1210, 1034. HRMS (EI):
calcd. for C14H16O3S2 296.0541 [M]+, found: 296.0543.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
a red solid, m.p. 192 C. Rf (PE:EE/3:1): 0.25, 1H-NMR (400 MHz,
°
CDCl3, ppm): 10.64 (s, 2 H), 4.43 (s, 4 H), 1.82 (s, 6 H). 13C-NMR
(101 MHz, CDCl3, ppm): 187.9, 144.1, 134.7, 122.4, 64.6, 63.0, 32.6. IR
(ATR, cmÀ 1): 2957, 2925, 2879, 1663, 1569, 1429, 1366, 1294, 1224,
1097. HRMS (EI): calcd. for C13H12O4S2 296.0177 [M]+, found:
296.0172.
Diethyl 6,6-dimethyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d][1,3]diox-
ole-4,8-dicarboxylate (29b): To a suspension of compound 16
(150 mg, 0.66 mmol, 1.0 equiv.) and TMEDA (0.20 mL, 1.33 mmol,
2.0 equiv.) in dry hexane (10 mL), n-BuLi (0.90 mL, 1.6 M in hexane,
1.39 mmol, 2.1 equiv.) was added at room temperature. The mixture
was stirred for 1 h and ethyl chloroformate (0.16 mL, 1.66 mmol,
2.5 equiv.) was added. After 1 h the reaction was quenched with
1 M HCl (10 mL) and the phases were separated. The water layer
was extracted with ethyl acetate (2×20 mL), dried over MgSO4 and
concentrated in vacuo. The residue was purified by flash silica gel
column chromatography (PE:EA 10:1) to yield 29b (100 mg,
Additionally 24 was isolated as a yellow solid in a yield of 15%.
2,2-Dimethyl-6,7-dihydro-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-b][1,4]
°
dioxine-4-carbaldehyde (24): M.p. 130–132 C. Rf (PE:EE/3:1): 0.52.
1H-NMR (400 MHz, CDCl3, ppm): 10.40 (s, 1 H), 6.95 (s, 1 H), 4.36–
4.27 (m, 4 H), 1.85 (s, 6 H). 13C-NMR (101 MHz, CDCl3, ppm): 187.8,
145.0, 141.3, 131.7, 120.4, 117.0, 64.8, 64.5, 64.2, 31.9. IR (ATR, cmÀ 1):
2957, 2922, 2870, 1664, 1559, 1439, 1294, 1213, 1064. HRMS (EI):
calcd. for C12H12O3S2 268.0228 [M]+, found: 268.0231.
°
2,3,7,8-Tetrahydro-[1,4]dithiino[2’,3’:4,5]benzo[1,2-b][1,4]diox-
ine-5,10-dicarbaldehyde (27): 19 (100 mg, 0.44 mmol, 1.0 equiv.)
was suspended in a mixture of TMEDA, dry hexane (20 mL) and dry
THF (2 mL). n-BuLi (2.5 M in hexane, 0.38 mL, 0.93 mmol, 2.1 equiv.)
0.27 mmol, 41%) as a yellow solid, m.p. 141–143 C. Rf (PE:EE/10:1):
0.38, 1H-NMR (400 MHz, CDCl3, ppm): 6.15 (s, 2 H), 4.41 (q, 3J=
7.1 Hz, 4 H), 1.82 (s, 6 H), 1.40 (t, 3J=7.1 Hz, 6 H). 13C-NMR (101 MHz,
CDCl3, ppm): 164.2, 147.6, 133.5, 111.9, 103.2, 62.2, 61.3, 31.4, 14.4.
IR (ATR, cmÀ 1): 2959, 2926, 1768, 1701, 1433, 1367, 1244, 1148,
1027, 952. HRMS (EI): calcd. for C16H18O6S2 370.0554 [M]+, found:
370.0059.
°
was added and stirred for 1 h at 0 C. Anhydrous DMF (0.1 mL,
1.1 mmol, 2.5 equiv.) was added and stirred for further 30 min. The
reaction was quenched with 1 M HCl (10 mL) and the phases were
separated. The water layer was extracted with ethyl acetate (2×
20 mL). The combined organic layers were dried over MgSO4,
concentrated in vacuo and purified by flash silica gel column
chromatography (PE:EE 5:1) to yield 27 (24 mg,0.08 mmol, 19%) as
a red solid, m.p. 235 (decomp.). Rf (PE:EE/1:1): 0.42. 1H-NMR
(400 MHz, CDCl3, ppm): 10.47 (s, 2 H), 4.40 (s, 4 H), 3.20 (s, 4 H). 13C-
NMR (101 MHz, CDCl3, ppm): 189.0, 143.7, 129.5, 126.4, 64.5, 29.8. IR
(ATR, cmÀ 1): 2924, 2875, 1670, 1560, 1466, 1377, 1289, 1248, 1063.
HRMS (EI): calcd. for C12H10O4S2 282.0021 [M]+, found: 282.0015.
Additionally 28b was isolated as a light-yellow solid in a yield of
12%.
Ethyl 6,6-dimethyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d][1,3]dioxole-
4-carboxylate (28b): M.p. 68 C. Rf (PE:EE/10:1): 0.50. 1H-NMR
°
3
(400 MHz, CDCl3, ppm): 6.84 (s, 1 H), 6.05 (s, 2 H), 4.42–4.27 (q, J=
7.1 Hz, 2 H), 1.86 (s, 6 H), 1.40 (s, 3 H). 13C-NMR (101 MHz, CDCl3,
ppm): 164.5, 147.3, 146.7, 130.6, 117.5, 107.2, 102.5, 63.7, 61.9, 31.4,
14.5. IR (ATR, cmÀ 1): 2958, 2923, 2854, 1769, 1451, 1258, 1105, 1025,
797. HRMS (EI): calcd. for C13H14O4S2 298.0334 [M]+, found: 298.0338.
Additionally 26 was isolated as a yellow solid with a yield of 21%.
2,3,7,8-Tetrahydro-[1,4]dithiino[2’,3’:4,5]benzo[1,2-b][1,4]diox-
6,6-Dimethyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d][1,3]dioxole-4,8-
dicarboxylic acid (30): Ester 29b (30 mg, 0.08 mmol, 1.0 equiv.) has
been dissolved with NaOH (130 mg, 3.2 mmol, 40 equiv.) in a
ine-5-carbaldehyde (26): M.p. 129 C. Rf (PE:EE/1:1): 0.6., 1H-NMR
°
(400 MHz, CDCl3, ppm): 10.42 (s, 1 H), 6.91 (s, 1 H), 4.34–4.32 (m, 2
H), 4.28–4.25 (m, 2 H), 3.28–3.25 (m, 2 H), 3.13–3.10 (m, 2 H). 13C-
NMR (101 MHz, CDCl3, ppm): 188.9, 145.8, 140.7, 128.6, 124.0, 123.2,
122.4, 64.8, 64.1 29.4, 29.2. IR (ATR, cmÀ 1): 2925, 2879, 1641, 1560,
1466, 1377, 1289, 1248, 1063. HRMS (EI): calcd. for C11H10O3S2
254.0066 [M]+, found: 254.0069.
°
mixture of 8 mL ACN/H2O (1:1) and stirred at 60 C for 4 h. The
mixture was treated with 20 mL water and extracted with ethyl
acetate (10 mL). The water layer was acidified (pH=2) with 1 M HCl
and extracted with ethyl acetate (2×20 mL), dried over MgSO4 and
evaporated. Compound 30 (25 mg, 0.08 mmol, quant.) was isolated
°
as a yellow solid, m.p. 235 C (decomp.). Rf (DCM:MeOH/10:1): 0.30.
1,1’-(6,6-Dimethyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d][1,3]dioxole-
1H-NMR (400 MHz, DMSO-d6, ppm): 6.17 (s, 2 H,), 1.73 (s, 6 H). 13C-
NMR (101 MHz, DMSO-d6, ppm): 164.9, 147.2, 131.7, 111.8, 103.1,
60.6, 30.8. IR (ATR, cmÀ 1): 3414, 2917, 1866, 1688, 1438, 1265, 1249,
1069, 1017. HRMS (EI): calcd. for C12H10O6S2 313.9919 [M]+, found:
313.9914.
4,8-diyl)bis(butan-1-one) (29a):
A mixture of 16 (100 mg,
0.44 mmol, 1.0 equiv.) and TMEDA (0.14 mL, 0.88 mmol, 2.0 equiv.)
in dry hexane (4 mL) was stirred at room temperature and n-BuLi
(2.5 M in hexane, 0.37 mL, 0.93 mmol, 2.1 equiv.) was added. The
solution was stirred for 1 h at room temperature till N-methoxy-N-
methyl butanamide (145 mg, 1.10 mmol, 2.5 equiv.) was added and
stirred for further 2 h at the same temperature. 1 M HCl (10 mL)
was added and the phases were separated. The water-layer was
extracted with ethylacetate (2×20 mL) and the combined organic
layers dried over MgSO4, evaporated and purified by flash silica gel
column chromatography to yield 29a (45 mg, 0.16 mmol, 36%) as
O-(2,2-Dimethylbenzo[d][1,3]oxathiol-5-yl)
dimeth-
ylcarbamothioate (31): Compound 3 (1.30 g, 7.13 mmol, 1.0 equiv.),
N,N-diisopropylethylamine (1.82 mL, 10.70 mmol, 1.5 equiv.) and
dimethylthiocarbamoyl chloride (1.32 g, 10.70 mmol, 1.5 eq) were
dissolved in 8 mL dry DMF and stirred for 18 h at room temper-
ature. Water (20 mL) and ethyl acetate (20 mL) was added and the
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phases separated. The water layer was extracted twice (20 mL) and
3-(6-Methyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d][1,3]dioxol-6-yl)
propyl pivalate (35a): Boron trifluoride etherate complex (48%
solution, 6.80 mL, 25.8 mmol, 1.5 equiv.) was given to a solution of
compound 12 (3.20 g, 17.2 mmol, 1.0 equiv.) and 4-oxopentyl 2,2-
dimethylpropanoate (4.80 g, 25.8 mmol, 1.5 equiv.) in dry DCM and
stirred for 20 h at room temperature. The mixture was quenched
with saturated NaHCO3 solution. After phase separation the water-
layer was extracted with DCM (2×20 mL). The combined organic
layers were washed with brine, dried with MgSO4 and concentrated
in vacuo. The product was purified by flash silica gel column
chromatography (PE:EE 10:1) to yield 35a (3.3 g, 9.3 mmol, 55%)
1
2
3
4
5
6
7
8
9
the combined organic layers dried over MgSO4. The solvent was
removed in vacuo and the residue purified by flash silica gel
column chromatography (PE:EE 5:1) to yield 31 (1.44 g, 5.35 mmol,
75%) as a colourless oil which was used without further purification
in the next step. Rf (PE:EE/3:1): 0.70. 1H-NMR (400 MHz, CDCl3,
ppm): 6.80 (m, 1 H), 6.75–6.72 (m, 1 H), 6.64–6.62 (m, 1 H), 3.44 (s, 3
H), 3.30 (s, 3 H), 1.84 (s, 6 H). 13C-NMR (101 MHz, CDCl3, ppm): 188.1,
152.9, 148.7, 127.8, 119.6, 116.9, 110.7, 110.2, 98.6, 43.4, 38.8, 30.6,
30.3. IR (ATR, cmÀ 1): 3341, 2975, 2936, 1532, 1468, 1393, 1285, 1172,
1194, 1117, 956, 851. HRMS (EI): calcd. for C12H15O2N1S2 269.0539
[M]+, found: 269.0543.
1
as a colourless oil. Rf (PE:EE/10:1): 0.43. H-NMR (400 MHz, CDCl3,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
ppm): 6.67 (s, 2 H), 5.91 (s, 2 H), 4.07 (t, 3J=6.3 Hz, 2 H), 2.08 (s, 2 H),
1.85 (s, 5 H, CH2), 1.18 (s, 9 H). 13C-NMR (101 MHz, CDCl3, ppm):
178.6, 146.3, 129.6, 104.1, 101.6, 70.2, 63.9, 39.9, 38.9, 28.9, 27.3,
25.9. IR (ATR, cmÀ 1): 2986, 2935, 2830, 1722, 1659, 1592, 1369, 1280,
1191, 1123, 1040, 956. HRMS (EI): calcd. for C17H22O4S2 354.0960
[M]+, found: 354.0956.
6,6-Dimethylbenzo[1,2-d:4,5-d’]bis([1,3]oxathiole)-2-one (32): 31
(200 mg, 0.74 mmol, 1.0 equiv.), benzoquinone (88 mg, 0.82 mmol,
1.1 equiv.), Pd(OAc)2 (9 mg, 0.04 mmol, 0.05 equiv.) and p-toluene-
sulfonic acid (14 mg, 0.07 mmol, 0.1 equiv.) were dissolved in 4 mL
glacial acetic acid and 4 mL dry toluene. The suspension was
°
heated for 18 h at 120 C. All volatile compounds were removed in
vacuo. The crude was purified by flash silica gel column chromatog-
raphy (PE:EE 5:1) to yield 32 (40 mg, 0.17 mmol, 23%) as a white
solid which was used without further purification in the next step.
3-(6-Methyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d][1,3]dioxol-6-yl)
propan-1-ol (35b): 35a (3.60 g, 10.16 mmol, 1.0 equiv.) was
suspended with lithium hydroxide monohydrate (1.28 g,
30.47 mmol, 3.0 equiv.) in 100 mL MeOH and stirred for 18 h at
room temperature. The solvent was removed and the crude
product solved in 50 mL 1 M HCl. The mixture was extracted with
ethyl acetate (2×) and the combined organic layer washed with
brine, dried with MgSO4, evaporated and purified with flash silica
gel column chromatography (PE:EE 2:1) to yield 35b (2.53 g,
9.4 mmol, 92%) as a colourless oil. Rf (PE:EE/3:1): 0.18. 1H-NMR
(400 MHz, CDCl3, ppm): 6.67 (s, 2 H), 5.90 (s, 2 H), 3.65 (t, 3J=6.4 Hz,
2 H), 2.19–2.08 (m, 2 H), 1.85 (s, 3 H), 1.77 (s, 2 H). 13C-NMR
(101 MHz, CDCl3, ppm): 146.2, 129.4, 104.1, 101.5, 70.4, 62.6, 39.8,
29.7, 29.1. IR (ATR, cmÀ 1): 2959, 2916, 1728, 1500, 1462, 1241, 1095,
1034, 934. HRMS (EI): calcd. for C12H14O3S2 270.0384 [M]+, found:
270.0382.
108–110 C. Rf (PE:EE/5:1): 0.68. 1H-NMR (300 MHz, CDCl3, ppm):
°
7.04 (s, 1 H), 6.78 (s, 1 H), 1.85 (s, 6 H). 13C-NMR (101 MHz, CDCl3,
ppm): 169.1, 152.6, 142.9, 125.4, 118.9, 106.4, 104.1, 99.2, 30.4. IR
(ATR, cmÀ 1): 3382, 2957, 2923, 2852, 1751, 1451, 1370, 1261, 1090,
1032. HRMS (EI): calcd. for C10H8O3S2 239.9915 [M]+, found:
239.9920.
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d’]bis([1,3]oxathiole) (33): 32
(70 mg, 0.29 mmol, 1.0 equiv.) and NaOH (117 mg, 2.91 mmol,
10.0 equiv.) has been dissolved in a mixture of 20 mL MeOH/H2O
°
(1:1) and stirred for 2 h at 60 C. The colourless solution was
acidified with 1 M HCl and extracted with ethyl acetate (2×20 mL).
The combined organic layers were evaporated and dissolved in
40 mL dry toluene,
a spatula-tip of PPTSA and 2,2-dimeth-
oxypropane (15 μL, 0.1 mmol, 0.4 equiv.). The mixture was distilled
(1 mL/min) with a LIEBIG condenser while every 15 minutes 2,2-
dimethoxypropane (15 μL, 0.1 mmol, 0.4 equiv.) and 15 mL dry
toluene have been added. After 2 h the mixture was washed with
saturated NaHCO3 solution. The water layer was extracted with
ethyl acetate (2×20 mL) and the combined organic layers dried
over MgSO4, evaporated and purified by flash silica gel column
chromatography (PE:EA 20:1) to yield 33 (15 mg, 0.06 mmol, 21%)
6-(3-Hydroxypropyl)-6-methyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d]
[1,3]dioxole-4,8-dicarbaldehyde (36): 35b (100 mg, 0.37 mmol,
1.0 equiv.) and TMEDA (0.12 mL, 0.78 mmol, 2.1 equiv.) were
°
dissolved in 5 mL dry hexane and cooled to 0 C. n-BuLi (1.6 M in
hexane, 0.81 mL, 1.29 mmol, 3.5 equiv.) was added and stirred for
°
1 h at 0 C. At the same temperature anhydrous DMF (0.07 mL,
0.92 mmol, 2.5 equiv.) was added. After 1 h the reaction mixture
was quenched with 1 M HCl (10 mL). After phase separation the
water layer was extracted with ethyl acetate (2×). The combined
organic layers were dried with MgSO4 and concentrated under
reduced pressure. Purification of the residue by flash silica gel
column chromatography (PE:EE 1:1) gave 36 (42 mg, 0.13 mmol,
35%) as a red oil. Rf (PE:EE/1:1): 0.25. 1H-NMR (400 MHz, CDCl3,
as a white solid, m.p. 137–138 C. Rf (PE:EE/20:1): 0.47. 1H-NMR
°
(300 MHz, CDCl3, ppm): 6.56 (s, 2 H), 1.81 (s, 12 H). 13C-NMR
(101 MHz, CDCl3, ppm): 150.1, 129.1, 125.6, 105.0, 98.4, 30.3. IR (ATR,
cmÀ 1): 2959, 2923, 2853, 1463, 1367, 1281, 1175, 1104, 956. HRMS
(EI): calcd. for C12H14O2S2 254.0435 [M]+, found: 254.0431.
3
ppm): 10.24 (s, 2 H), 6.26 (s, 2 H), 3.65 (t, J=6.3 Hz, 2 H), 2.05 (s, 2
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d’]bis([1,3]oxathiole)-4,8-di-
carbaldehyde (34): n-BuLi (60 μL, 2.5 M in hexane, 0.12 mmol,
2.1 equiv.) was added to a solution of 33 (15 mg, 0.06 mmol,
1.0 equiv.) and TMEDA (20 μL, 0.12 mmol, 2.1 equiv.) in 5 mL dry
hexane at room temperature and stirred for 1 h. Dry DMF (12 μL,
0.15 mmol, 2.5 equiv.) was added and stirred for further 30 min. The
reaction was quenched with 1 M HCl and the two phases were
separated. The water layer was extracted with ethyl acetate (2×
20 mL). The combined organic layers were washed with brine, dried
over MgSO4 and concentrated under reduced pressure. Purification
by flash silica gel column chromatography (PE:EE 10:1) gave 34
H), 1.85 (s, 5 H). 13C-NMR (101 MHz, CDCl3, ppm): 185.6, 149.7, 132.2,
117.1, 104.6, 69.1, 62.6, 40.7, 31.1, 29.5. IR (ATR, cmÀ 1): 3357, 2951,
2928, 2856, 2865, 1677, 1440, 1378, 1254, 1036. HRMS (EI): calcd. for
C14H14O5S2 326.0283 [M]+, found: 326.0281.
The monoaldehyde was additionally isolated as a yellow solid in a
yield of 21%:
6-(3-Hydroxypropyl)-6-methyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d]
[1,3]dioxole-4-carbaldehyde: Rf (PE:EA/1:1): 0.45. 1H-NMR
(400 MHz, CDCl3, ppm): 10.18 (s, 1 H), 6.86 (s, 1 H), 6.09 (s, 2 H), 3.68
3
(t, J=6.3 Hz, 2 H), 2.16–2.11 (m, 2 H), 1.87 (s, 3 H), 1.82 (s, 2 H). 13C
°
(5 mg, 0.02 mmol, 27%) as a red solid, m.p. 210 C. Rf (PE:EE/5:1)
NMR (101 MHz, CDCl3, ppm): 185.7, 149.6, 146.5, 131.2, 129.8, 115.1,
108.5, 103.1, 69.6, 62.6, 40.3, 30.2, 29.6. IR (ATR, cmÀ 1): 3357, 2925,
2859, 1676, 1444, 1378, 1250, 1045. HRMS (EI): calcd. for C13H14O4S2
298.0334 [M]+, found: 298.0329.
1
0.55. H-NMR (300 MHz, CDCl3, ppm): 10.28 (s, 2 H), 1.89 (s, 12 H).
13C-NMR (101 MHz, CDCl3, ppm): 187.5, 153.4, 124.6, 117.4, 100.7,
30.9, 29.9. IR (ATR, cmÀ 1): 2938, 2866, 1696, 1651, 1528, 1432, 1358,
1302, 1280, 1119, 1074, 1014. HRMS (EI): calcd. for C14H14O4S2
310.0334 [M]+, found: 310.0339.
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3-(4,8-Diformyl-6-methyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d][1,3]-
cmÀ 1) 3412, 2925, 2872, 1680, 1455, 1392, 1331, 1208, 1107, 1008.
HRMS (EI): calcd. for C21H20O7S3 480.0371 [M]+, found: 480.0368.
1
2
3
4
5
6
7
8
9
dioxol-6-yl)propyl prop-2-yn-1-yl carbonate (37): To a solution of
36 (40 mg, 0.12 mmol, 1.0 equiv.) and dry pyridine (9 μL,
0.12 mmol, 1.0 equiv.) in 5 mL anhydrous DCM, propargyl chlor-
oformate (12 μL, 0.12 mmol, 1.5 equiv.) was added and stirred at
6-(3-Azidopropyl)-6-methyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d]
[1,3]-dioxole-4,8-dicarbaldehyde (41): Compound 40 (20 mg,
0.04 mmol, 1.0 equiv.) was dissolved in 5 mL dry DMF. After NaN3
(4 mg, 0.06 mmol, 1.5 equiv.) was added the reaction was stirred
over night at room temperature. The solvent was removed in vacuo
and the resulting residue solved in DCM. The organic layers were
washed with H2O and brine (2×), dried over MgSO4 and concen-
trated under reduced pressure. After purification with flash silica
gel column chromatography (PE:EE 5:1) 41 (14 mg, 0.04 mmol,
°
0 C. After complete conversion of the reaction, monitored by TLC
(5 h), the solvent was removed. The crude product was purified by
flash silica gel column chromatography (PE:EE 3:1) to yield 37
1
(45 mg, 0.11 mmol, 89%) as a red oil. Rf (PE:EE/1:1): 0.70. H-NMR
(400 MHz, CDCl3, ppm): 10.25 (s, 2 H), 6.27 (s, 2 H), 4.71 (d, 3J=
3
2.4 Hz, 2 H), 4.18 (t, J=6.3 Hz, 2 H), 2.52 (s, 1 H, CH), 2.11–2.01 (m,
2 H), 1.97–1.89 (m, 2 H), 1.86 (s, 3 H) 13C-NMR (500 MHz, CDCl3,
ppm): 185.5, 154.6, 149.8, 132.1, 117.2, 104.6, 101.8, 68.6, 68.2, 55.4,
54.0, 40.9, 30.9, 25.6. IR (ATR, cmÀ 1): 3275, 2949, 2924, 2854, 1749,
1676, 1448, 1388, 1244, 1100, 1027, 865. HRMS (EI): calcd. for
C18H16O7S2 408.0337 [M]+, found: 408.0334.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
°
quant.) was obtained as a red solid, m.p. 90–91 C. Rf (PE:EE/3:1):
0.45. 1H-NMR (400 MHz, CDCl3, ppm): 10.26 (s, 2 H) 6.27 (s, 2 H), 3.31
3
(t, J=6.7 Hz, 2 H), 2.07–2.03 (m, 2 H), 1.87–1.82 (m, 5 H), 1.25 (s, 2
H). 13C-NMR (500 MHz, CDCl3, ppm): 185.5, 149.9, 132.0, 117.1, 104.6,
68.7, 51.4, 41.6, 31.1, 25.9. IR (ATR, cmÀ 1): 2959, 2918, 2847, 2094,
1690, 1447, 1386, 1243, 1100, 1028. HRMS (EI): calcd. for
C14H13O4N3S2 351.0347 [M]+, found: 351.0344.
3-(((3-(4,8-Diformyl-6-methyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d]
[1,3]dioxol-6-yl)propoxy)carbonyl)oxy)propanoic acid (38): 36
(100 mg, 0.31 mmol, 1.0 equiv.), succinic anhydride (306 mg,
3.06 mmol, 10.0 equiv.), anhydrous pyridine (0.12 mL, 1.53 mmol.
5.0 equiv.) and a spatula-tip of DMAP were dissolved in 5 mL dry
DCM and stirred for 18 h at room temperature. The reaction was
quenched with H2O. After phase separation the organic layer was
washed with 1 M HCl (2×), dried with MgSO4 and concentrated
under reduced pressure. Purification with flash silica gel column
chromatography (DCM: MeOH 25:1) afforded 38 (80 mg,
3-(4,8-Diformyl-6-methyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d][1,3]-
dioxol-6-yl)propyl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetate
(42): Oxalyl chloride (55 μL, 0.64 mmol, 5.0 equiv.) was added to a
stirred solution of 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetic acid
(20 mg, 0.13 mmol, 1.0 equiv.) in 5 mL dry DCM at room temper-
ature. After 12 h all volatile compounds have been removed. The
residue was dissolved in 5 mL dry DCM and added to a solution of
alcohol 36 (34 mg, 0.10 mmol, 1.0 equiv.), DIPEA (35 μL, 0.21 mmol,
2.0 equiv.) and two drops of DMF in 10 mL dry DCM. After 5 h the
mixture was diluted with water (10 mL) and the phases were
separated. The water layer was extracted with DCM (2×30 mL) and
the combined organic layers washed (2×50 mL) with saturated
NaHCO3-solution, dried over MgSO4 and concentrated in vacuo.
After purification by flash silica gel column chromatography 42
(30 mg, 0.06 mmol, 62%) was isolated as a red oil. Rf (PE:EE/1:1):
0.19 mmol, 62%) as
a
red oil. Rf (PE:EA/1:1): 0.10. 1H-NMR
(400 MHz, CDCl3, ppm): 10.27 (m, 2 H), 6.26 (s, 2 H), 4.12–4.07 (m, 2
3
H), 2.63 (dd, J=12.1, 4.2 Hz, 4 H), 2.08–1.99 (m, 2 H), 1.89–1.82 (m,
5 H, CH2). 13C-NMR (101 MHz, CDCl3, ppm): 185.6, 172.2, 149.8,
131.9, 117.0, 104.6, 68.7, 64.4, 40.9, 31.0, 29.0, 25.6. IR (ATR, cmÀ 1):
3343, 2959, 2920, 2859, 1726, 1446, 1389, 1245, 1159, 1028. HRMS
(EI): calcd. for C18H18O8S2 426.0443 [M]+, found: 426.0440.
1
2,5-Dioxopyrrolidin-1-yl 3-(((3-(4,8-diformyl-6-methyl-[1,3]dithio-
lo-[4’,5’:4,5]benzo[1,2-d][1,3]dioxol-6-yl)propoxy)carbonyl)oxy)-
propanoate (39): Compound 38 (33 mg, 0.08 mmol, 1.0 equiv.) was
dissolved with EDC (21 μL, 0.12 mmol, 1.5 equiv.) and N-hydrox-
ysuccinimide (14 mg, 0.12 mmol, 1.5 equiv.) in 3 mL anhydrous
DCM and stirred for 18 h. The mixture was washed with brine (2×),
saturated NaHCO3-solution and dried over MgSO4. After purification
with silica gel column chromatography (PE:EE 1:1) 39 (35 mg, 0.67,
87%) was isolated as a red oil. Rf (PE:EE 1:1): 0.20. 1H-NMR
0.48. H-NMR (400 MHz, CDCl3, ppm): 10.27 (s, 2 H), 6.80 (s, 2 H),
6.28 (s, 2 H), 4.26 (s, 2 H), 4.15 (t, 3J=6.2 Hz, 2 H), 2.04–2.00 (m, 2 H),
1.87 (s, 5 H). 13C-NMR (101 MHz, CDCl3, ppm) δ=185.5, 169.9, 167.2,
149.8, 134.7, 132.0, 117.1, 104.6, 68.7, 65.4, 40.8, 38.8, 31.3, 25.5. IR
(ATR, cmÀ 1): 2956, 2929, 2856, 1471, 1101, 1066, 1047, 867. HRMS
(EI): calcd. for C20H17O8S1 463.0396 [M]+, found: 463.0395.
Tert-butyl((6’,6’-dimethylspiro[cyclohexane-1,2’-[1,3]dioxolo-
[4’,5’:4,5]benzo[1,2-d][1,3]oxathiol]-4-yl)oxy)dimethylsilane (43):
Compound 4 (400 mg, 2.04 mmol, 1.0 equiv.) and PtO2 (5 mg,
0.02 mmol, 0.01 equiv.) were dissolved in 40 mL dry THF. The
atmosphere was flushed with hydrogen (3×) and the reaction
stirred under hydrogen [p(H2)=1 atm] at room temperature till
complete conversion followed by TLC. The colour of the solution
turned from red to colourless. The solvent was removed under
reduced pressure. The crude, tert-butyl[(4,4-dimethoxycyclohexyl)
oxy]dimethylsilane (123 mg, 0.45 mmol, 0.2 equiv.) and PPTSA
(15 mg, 0.02 mmol, 0.05 equiv.) were dissolved in 40 mL dry
toluene. The flask was equipped with a LIEBIG condenser and the
mixture heated till the solvent was distilled (1 mL/min). Every 15
3
(400 MHz, CDCl3, ppm): 10.24 (s, 2H), 6.27 (s, 2H), 4.13 (t, J=6.2 Hz,
3
3
2 H), 2.93 (t, J=6.9 Hz, 2 H), 2.85 (s, 4 H), 2.72 (t, J=6.9 Hz, 2 H),
2.06–2.01 (m, 2 H), 1.91–1.84 (m, 5 H, CH2). 13C-NMR (101 MHz,
CDCl3, ppm): 185.6, 171.0, 169.1, 167.8, 149.8, 132.0, 117.1, 104.6,
68.7, 64.7, 40.9, 30.9, 28.9, 26.5, 25.7, 25.5. IR (ATR, cmÀ 1): 2952,
2920, 2861, 1732, 1677, 1448, 1390, 1252, 1202, 1058, 1027, 863.
HRMS (EI): calcd. for C22H21O10N1S2 523.0601 [M]+, found: 523.0603.
3-(4,8-Diformyl-6-methyl-[1,3]dithiolo[4’,5’:4,5]benzo[1,2-d][1,3]-
dioxol-6-yl)propyl 4-methylbenzenesulfonate (40): Alcohol 36
(40 mg, 0.13 mmol, 1.0 equiv.) was solved with pyridine (0.02 mL,
0.19 mmol, 1.5 eq), p-TsCl (28 mg, 0.15 mmol, 1.2 equiv.) and a
spatula-tip of DMAP in 5 mL dry DCM and stirred for 20 h at room
temperature. The mixture was quenched with 10 mL water and
extracted with DCM (2×). The combined organic layers were
washed with Brine, dried with MgSO4, evaporated and purified by
flash silica gel column chromatography (PE:EE 3:1) to yield 36
(29 mg, 0.06 mmol, 50%) as a red oil which was used without
further purification in the next step. Rf (PE:EE/1:1): 0.55. 1H-NMR
minutes
tert-butyl[(4,4-dimethoxycyclohexyl)oxy]dimethylsilane
(123 mg, 0.45 mmol, 0.2 equiv.) and 15 mL dry toluene were added.
After 2 h the mixture was cooled to room temperature and washed
with saturated NaHCO3-solution. The water-layer was extracted with
ethyl acetate (2×20 mL) and the combined organic layers were
dried over MgSO4, evaporated and purified by flash silica gel
column chromatography (PE:EE 20:1) to yield 43 (440 mg,
1
1.08 mmol, 53%) as a colourless oil. Rf (PE:EE/10:1): 0.82. H-NMR
3
(400 MHz, CDCl3, ppm): 10.23 (s, 2 H), 7.75 (d, J=8.2 Hz, 2 H), 7.34
(400 MHz, CDCl3, ppm): 6.51 (s, 1 H), 6.33 (s, 1 H), 3.93 (s, 1 H), 1.81
(s, 8 H), 0.90 (s, 9 H), 0.06 (s, 6 H). 13C-NMR (101 MHz, CDCl3, ppm):
148.6, 145.6, 142.5, 129.2, 119.0, 115.7, 102.7, 94.3, 68.1, 66.5, 31.2,
30.5, 30.2, 26.0, 18.2, À 4.7. IR (ATR, cmÀ 1): 2952, 2929, 2924, 2854,
3
(d, J=8.1 Hz, 2 H), 6.27 (s, 2 H), 4.02 (s, 2 H), 2.44 (s, 3 H), 2.30 (s, 5
H), 2.25 (s, 2 H). 13C-NMR (101 MHz, CDCl3, ppm): 185.5, 149.9, 145.4,
143.6, 130.0, 128.6, 125.9, 104.6, 68.3, 53.6, 40.5, 31.0, 21.4. IR (ATR,
Eur. J. Org. Chem. 2021, 499–511
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°
1749, 1676, 1448, 1388, 1244, 1100, 1027, 865. HRMS (EI): calcd. for
C21H32O4S1Si1 408.1791 [M]+, found: 408.1798.
0.14 mmol, 2.0 equiv.) were dissolved in 5 mL dry DCM at 0 C and
stirred for 16 h while the reaction reached room temperature. All
volatile compounds were removed in vacuo. The crude was purified
by flash silica gel column chromatography (PE:EE 3:1) to yield 45
1
2
3
4
5
6
7
8
9
4-((Tert-butyldimethylsilyl)oxy)-6’,6’-dimethylspiro[cyclohexane-
1,2’-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d][1,3]oxathiole]-4’,8’-dicar-
baldehyde (44a): n-BuLi (0.41 mL, 2.5 M in hexane, 1.03 mmol,
2.1 equiv.) was added to a mixture of TMEDA (0.15 mL, 0.98 mmol,
2.0 equiv.) and 43 (200 mg, 0.49 mmol, 1.0 equiv.) dissolved in 8 mL
dry hexane. The reaction was stirred for 1 h at room temperature.
Dry DMF (0.10 mL, 1.22 mmol, 2.5 equiv.) was added and stirred for
further 30 minutes. The reaction was quenched with saturated
NH4Cl-solution and the phases were separated. The water layer was
extracted with ethyl acetate (2×20 mL) and the combined organic
layers washed with brine, dried over MgSO4 and evaporated. After
purification by flash silica gel column chromatography (PE:EE 10:1)
44a (80 mg, 0.17 mmol, 35%) was isolated as a red oil. Rf (PE:EE/
10:1): 0.35. 1H-NMR (400 MHz, CDCl3, ppm): 10.23 (s, 1 H), 10.18 (s, 1
H), 3.96 (s, 1 H), 1.96–1.79 (m, 14 H), 0.91 (s, 9 H), 0.08 (s, 6 H). 13C-
NMR (101 MHz, CDCl3, ppm): 186.3, 186.0, 150.0, 145.9, 123.9, 116.0,
110.4, 100.2, 66.3, 31.2, 31.0, 30.9, 30.8, 25.9, 18.2, À 4.7. IR (ATR,
cmÀ 1): 2952, 2929, 2855, 1680, 1458, 1375, 1265, 1089, 1055, 1020.
HRMS (EI): calcd. for C23H32O6S1Si1 464.1689 [M]+, found: 464.1683.
1
(27 mg, 0.06 mmol, 88%) as a red oil. Rf (PE:EE/3:1): 0.52. H-NMR
(400 MHz, CDCl3, ppm): 10.21 (s, 1 H), 10.18 (s, 1 H), 4.97–4.86 (m, 1
H), 4.74 (s, 2 H), 2.55 (t, 4J=2.4 Hz, 1 H), 2.22–1.97 (m, 8 H), 1.87 (s, 6
H). 13C-NMR (101 MHz, CDCl3, ppm): 186.2, 185.7, 154.0, 145.4, 145.3,
122.5, 117.6, 116.1, 110.4, 100.4, 77.0, 75.9, 73.3, 72.8, 55.4, 31.0,
30.8, 30.7, 27.5, 27.3. IR (ATR, cmÀ 1): 2924, 2853, 1745, 1676, 1456,
1374, 1250, 1216, 1085. HRMS (EI): calcd. for C21H20O8S1 432.0873
[M]+, found: 432.0878.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
4-((4’,8’-Diformyl-6’,6’-dimethylspiro[cyclohexane-1,2’-[1,3]dioxo-
lo-[4’,5’:4,5]benzo[1,2-d][1,3]oxathiol]-4-yl)oxy)-4-oxobutanoic
acid (46): A suspension of 44b (100 mg, 0.29 mmol, 1.0 equiv.),
succinic anhydride (285 mg, 2.85 mmol, 10.0 equiv.), dry pyridine
(0.12 mL, 1.43 mmol, 5.0 equiv.) and a spatula-tip of DMAP in 10 mL
dry DCM was stirred for 14 h at room temperature. Water (10 mL)
was added and the phases were separated. The organic layer was
washed with saturated NaHCO3-solution (2×20 mL), 1 M HCl (2×
20 mL), dried over MgSO4 and concentrated under reduced
pressure. Purification via flash silica gel column chromatography
gave 46 (81 mg, 0.18 mmol, 64%) as a red oil. Rf (PE:EE/1:1): 0.15.
1H-NMR (400 MHz, CDCl3, ppm): 10.22 (s, 1 H), 10.17 (s, 1 H), 5.01 (s,
Additionally 20% of [1,3]dioxolo[4’,5’:4,5]benzo[1,2-d][1,3]oxa-
thiole]-8’-carbaldehyde and 15% of 4-((tert-butyldimethylsilyl)oxy)-
6’,6’-dimethylspiro[cyclohexane-1,2’-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-
d][1,3]oxathiole]-4’-carbaldehyde were collected:
1 H), 2.66 (t, J=6.0 Hz, 4 H), 2.22–1.95 (m, 8 H), 1.85 (s, 6 H). 13C-
3
NMR (101 MHz, CDCl3, ppm): 186.4, 186.3, 185.7, 171.8, 150.4, 145.5,
145.3, 123.0, 117.5, 116.1, 110.4, 100.4, 69.3, 68.7, 31.3, 30.8, 29.4,
27.5, 27.3. IR (ATR, cmÀ 1): 3362, 2967, 2866, 1710, 1678, 1266, 1206,
1170, 1085, 1010, 730. HRMS (EI): calcd. for C21H22O9S1 450.0985
[M]+, found: 450.0982.
4-((Tert-butyldimethylsilyl)oxy)-6’,6’-dimethylspiro[cyclohexane-
1,2’-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d][1,3]oxathiole]-8’-carbalde-
hyde: Rf (PE:EE/10:1): 0.42. 1H-NMR (400 MHz, CDCl3, ppm): 10.19 (s,
1 H), 6.52 (s, 1 H), 3.96 (s, 1 H), 1.80 (s, 14 H), 0.88 (s, 9 H), 0.06 (s, 6
H). 13C-NMR (101 MHz, CDCl3, ppm): 186.3, 149.4, 146.0, 145.6, 121.6,
113.5, 99.5, 98.2, 66.11, 31.2, 30.5, 29.9, 27.3, 25.8, 18.4, À 4.7. IR
(ATR, cmÀ 1): 2951, 2929, 2855, 1679, 1462, 1375, 1278, 1096, 1053,
1017. HRMS (EI): calcd. for C22H32O5S1Si1 436.1740 [M]+, found:
436.1733.
4’,8’-Diformyl-6’,6’-dimethylspiro[cyclohexane-1,2’-[1,3]dioxolo-
[4’,5’:4,5]benzo[1,2-d][1,3]oxathiol]-4-yl (2,5-dioxopyrrolidin-1-yl)
succinate (47): 46 (50 mg, 0.11 mmol, 1.0 equiv.), EDC (30 mL,
0.17 mmol, 1.5 equiv.) and N-hydroxysuccinimide (20 mg,
0.17 mmol, 1.5 equiv.) was dissolved in 5 mL dry DCM and stirred
for 16 h at room temperature. DCM (10 mL) was added and the
organic mixture was washed with brine (2×20 mL), saturated
NaHCO3-solution (1×20 mL), Brine (1×20 mL) and dried over
MgSO4. Purification by flash silica gel column chromatography
obtained 47 (52 mg, 0.09 mmol, 85%) as a red solid, m.p. 164–165.
4-((Tert-butyldimethylsilyl)oxy)-6’,6’-dimethylspiro[cyclohexane-
1,2’-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d][1,3]oxathiole]-4’-carbalde-
1
hyde: Rf (PE:EA 10:1): 0.55. H-NMR (400 MHz, CDCl3, ppm): 10.13
(s, 1 H), 6.70 (s, 1 H), 3.91 (s, 1 H), 1.91–1.82 (m, 14 H), 0.90 (s, 9 H),
0.07 (s, 6 H). 13C-NMR (101 MHz, CDCl3, ppm): 185.5, 143.0, 141.9,
138.7, 121.5, 116.9, 108.0, 100.2, 94.8, 31.3, 31.0, 30.7, 30.4, 25.9,
18.2, À 4.7. IR (ATR, cmÀ 1): 2952, 2929, 2856, 1717, 1468, 1376, 1292,
1251, 1101, 1006. HRMS (EI): calcd. for C22H32O5S1Si1 436.1740 [M]+,
found: 436.1735.
1
Rf (PE:EE/1:1): 0.43. H-NMR (400 MHz, CDCl3, ppm): 10.24 (s, 2 H),
10.18 (s, 1 H), 5.04 (s, 1 H), 3.00–2.76 (m, 8 H), 2.10–1.88 (m, 8 H),
1.86 (s, 6 H). 13C-NMR (101 MHz, CDCl3, ppm): 186.2, 185.9, 170.4,
169.0, 167.8, 150.4, 145.5, 145.4, 122.7, 117.5, 116.0, 110.4, 100.4,
69.9, 69.3, 31.5, 30.7, 29.8, 29.1, 27.5, 26.5, 25.8. IR (ATR, cmÀ 1): 2923,
2852, 1726, 1675, 1457, 1372, 1268, 1203, 1084. HRMS (EI): calcd. for
C25H25O11N1S1 547.1148 [M]+, found: 547.1152.
4-Hydroxy-6’,6’-dimethylspiro[cyclohexane-1,2’-[1,3]dioxolo-
[4’,5’:4,5]benzo[1,2-d][1,3]oxathiole]-4’,8’-dicarbaldehyde (44b):
44a (100 mg, 0.22 mmol, 1.0 equiv.) and HF (10 mL, 0.23 mmol,
1.1 equiv.) were dissolved in a mixture of 4 mL ACN/THF (3:1) and
stirred for 14 h at room temperature. The reaction was quenched
with saturated NaHCO3-solution. The red solution was extracted
with DCM (3×20 mL) and the combined organic layers dried over
MgSO4 and concentrated in vacuo. Purification by flash silica gel
4’,8’-Diformyl-6’,6’-dimethylspiro[cyclohexane-1,2’-[1,3]dioxolo-
[4’,5’:4,5]benzo[1,2-d][1,3]oxathiol]-4-yl 4-((2-(2,5-dioxo-2,5-dihy-
dro-1H-pyrrol-1-yl)ethyl)amino)-4-oxobutanoate (48): Compound
47 (50 mg, 0.09 mmol, 1.0 equiv.), DIPEA (32 μL, 0.18 mmol,
2.0 equiv.) and (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethan-1-aminio
trifluoroacetate (35 mg, 0.14 mmol, 1.5 equiv.) were dissolved in
5 mL dry DMF and stirred for 14 h at room temperature. All volatile
compounds were removed in vacuo and the residue purified by
flash silica gel column chromatography (DCM:MeOH 50:1) to yield
°
column chromatography (PE:EE 1:1) gave 44b (75 mg, 0.22 mmol,
1
°
quant.) as a red solid, m.p. 156–157 C. Rf (PE:EE/1:1): 0.18. H-NMR
(400 MHz, CDCl3, ppm): 10.23 (s, 1 H), 10.18 (s, 1 H), 3.98 (s, 1 H),
2.05–1.99 (m, 6 H), 1.87–1.82 (m, 8 H). 13C-NMR (101 MHz, CDCl3,
ppm): 186.4, 185.9, 150.3, 145.7, 145.6, 123.3, 117.2, 116.1, 110.4,
100.3, 66.8, 31.6, 31.0, 30.8. IR (ATR, cmÀ 1): 3428, 2932, 2862, 1676,
1456, 1369, 1261, 1136, 1087, 1013. HRMS (EI): calcd. for C17H18O6S1
350.0824 [M]+, found: 350.0826.
48 (34 mg, 0.06 mmol, 65%) as
a red solid, m.p. 92 C. Rf
(DCM:MeOH/25:1): 0.20. 1H-NMR (300 MHz, CDCl3, ppm): 10.22 (s, 1
3
H), 10.18 (s, 1 H), 6.73–6.71 (m, 2 H), 4.14 (q, J=7.1 Hz, 1H), 3.50–
3.33 (m, 4 H), 2.66–2.43 (m, 4 H), 2.24–1.93 (m, 8 H), 1.87 (s, 6 H).
13C-NMR (101 MHz, CDCl3, ppm): 186.3, 185.8, 173.1, 172.4, 171.8,
171.0, 150.4, 145.5, 145.4, 134.4, 134.3, 122.8, 117.5, 116.1, 110.4,
100.4, 60.8, 51.9, 39.6, 38.3, 36.0, 34.9, 30.8, 29.8, 27.5, 14.3. IR (ATR,
cmÀ 1): 2926, 2854, 1702, 1438, 1369, 1265, 1203, 1084. HRMS (ESI):
calcd. for C27H29N2O10S1 573.1543 [M+H]+, found: 573.1537.
4’,8’-Diformyl-6’,6’-dimethylspiro[cyclohexane-1,2’-[1,3]dioxolo-
[4’,5’:4,5]benzo[1,2-d][1,3]oxathiol]-4-yl ethynyl carbonate (45):
Alcohol 44b (25 mg, 0.07 mmol, 1.0 equiv.), dry pyridine (18 μL,
0.14 mmol, 2.0 equiv.) and propargyl chloroformate (20 mL,
Eur. J. Org. Chem. 2021, 499–511
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510
© 2020 The Authors. European Journal of Organic Chemistry published
by Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202001418
o) D. Büchner, L. John, M. Mertens, P. Wessig D Büchner, L. John, M.
Acknowledgements
1
2
3
4
5
6
7
8
9
Mertens, P. Wessig, Chem. Eur. J. 2018, 24, 16183–16190.
[6] P. Wessig, L. John, M. Mertens, Eur. J. Org. Chem. 2018, 1674–1681.
[7] a) P. Wessig, D. Freyse, D. Schuster, A. Kelling, Eur. J. Org. Chem. 2020,
1732–1744; b) T. Haubitz, L. John, D. Freyse, P. Wessig, M. U. Kumke, J.
Phys. Chem. A 2020, 124, 4345–4353; c) DE 10 2017 122 275 A1.d) K.
Kopp, O. Schiemann, N. Fleck, Molecules 2020, 25, 3666–3677
[8] A. N. Kovregin, A. Yu Sizov, A. F. Ermolov, Russ. Chem. Bull. 2001, 50,
1255–1258.
Open access funding enabled and organized by Projekt DEAL.
Conflict of Interest
[9] R. P. Hanzlik, P. E. Weller, J. Desai, J. Zheng, L. R. Hall, D. E. Slaughter, J.
The authors declare no conflict of interest.
Org. Chem. 1990, 55, 2736–42.
[10] M. J. Begley, P. V. Fish, G. Pattenden, S. T. Hodgson, J. Chem. Soc. Perkin
Trans. 1 1990, 2263–2271.
[11] K. W. Stender, N. Woelki, G. Klar, Phosphorus Sulfur Silicon Relat. Elem.
1989, 42, 111–114.
Keywords: Fluorescent dyes · Heterocycles · Photophysics ·
Stokes shift · Sulfur
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
[12] a) A. Alberola, D. Eisler, R. J. Less, E. Navarro-Moratalla, J. M. Rawson,
Chem. Commun. 2010, 46, 6114–6116; b) J. D. Wrixon, J. J. Hayward, O.
Raza, J. M. Rawson, Dalton Trans. 2014, 43, 2134–2139; c) C. R. M.
Asquith, M. L. Meli, L. S. Konstantinova, T. Laitinen, A. Poso, O. A. Rakitin,
R. Hofmann-Lehmann, K. Allenspach, S. T. Hilton, Bioorg. Med. Chem.
Lett. 2015, 25, 1352–1355.
[13] M. Gascon-Moya, A. Pejoan, M. Izquierdo-Serra, S. Pittolo, G. Cabre, J.
Hernando, R. Alibes, P. Gorostiza, F. Busque, J. Org. Chem. 2015, 80,
9915–9925.
[14] a) H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. Int. Ed. 2001 40,
2004–2021; b) C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem.
2002, 67, 3057–3064.
[15] a) Y. Zhao, Y. Xie, C. Xia, H. Huang, Adv. Synth. Catal. 2014, 356, 2471–
2476; b) W. Li, Y. Zhao, S. Mai, Q. Song, Org. Lett. 2018, 20, 1162–1166;
c) T. Wang, X. Yu, H. Zhang, S. Wu, W. Guo, J. Wang, Appl. Organomet.
Chem. 2019, 33, e4939.
[1] a) J. R. Lakowicz, Priniciples of Fluorescence spectroscopy, 3rd Ed., Spring-
er, New York 2006; b) B. Valeur, M. N. Berberan-Santos, Molecular
Fluorescence – Principles and Applications, 2nd Ed., Wiley-VCH, Weinheim
2013.
[2] J. C. Stockert, A. Blázquet-Castro, Fluorescence Microscopy in Life
Sciences, Bentham Books 2017.
[3] T. W. J. Gadella, FLIM Techniques (Laboratory Techniques in Biochemistry
and Molecular Biology, Vol. 33), (Ed.) FRET, Elsevier, Amsderdam 2011.
[4] a) M. V. Sednev, V. N. Belov, S. W. Hell, Methods Appl. Fluoresc. 2015, 3,
042004; b) B. Huang, M. Bates, X. Zhuang, Annu. Rev. Biochem. 2009, 78,
993–1016.
[5] a) P. Wessig, R. Wawrzinek, K. Möllnitz, E. Feldbusch, U. Schilde,
Tetrahedron Lett. 2011, 52,6192–6195; b) EP 2399913 B1, US 8664410
B2; c) R. Wawrzinek, P. Wessig, K. Möllnitz, J. Nikolaus, R. Schwarzer, P.
Müller, A. Herrmann, Bioorg. Med. Chem. Lett. 2012, 5367–5371; d) R.
Wawrzinek, J. Ziomkowska, J. Heuveling, M. Mertens, A. Herrmann, E.
Schneider, P. Wessig, Chem. Eur. J. 2013, 19, 17349–17357; e) J.
Heuveling, V. Frochaux, J. Ziomkowska, R. Wawrzinek, P. Wessig, A.
Herrmann, E. Schneider, Biochim. Biophys. Acta Biomembr. 2014,
1838,106–116; f) D. Bader, D. T. Klier, C. Hettrich, F. F. Bier, P. Wessig,
Anal. Methods 2016, 9, 1235; g) T. Schwarze, M. Mertens, P. Müller, J.
Riemer, P. Wessig, H.-J. Holdt, Chem. Eur. J. 2017, 23, 17186–17190; h) T.
Schwarze, J. Riemer, H. Müller, L. John, H.-J. Holdt, P. Wessig, Chem. Eur.
J. 2019, 25, 12412–12422; i) C. Meyners, R. Wawrzinek, A. Krämer, S.
Hinz, P. Wessig, F.-J. Meyer-Almes, Anal. Bioanal. Chem. 2014, 4889–
4897; j) C. Meyners, M. Mertens, P. Wessig, F.-J. Meyer-Almes, Chem. Eur.
J. 2017, 23, 3107–3116; k) R. Wawrzinek, P. Wessig Dyes, Pigments 2015,
123, 39–43; l) P. Wessig, N. Behrends, M. U. Kumke, U. Eisold, T. Meiling,
C. Hille, RSC Adv. 2016, 6, 33510–33513; m) P. Wessig, N. Behrends, M. U.
Kumke, U. Eisold, Eur. J. Org. Chem. 2016, 4476–4486; n) U. Eisold, N.
Behrends, P. Wessig, M. U. Kumke, J. Phys. Chem. 2016, 120, 9935–9943;
[16] T. Steiner, Angew. Chem. Int. Ed. 2002, 41, 48–76; Angew. Chem. 2002,
114, 50–80.
[17] A. Bondi, J. Phys. Chem. 1964, 68, 441–451.
[18] V. d P. N Nziko, S. Scheiner, J. Org. Chem. 2015, 80, 2356–2363.
[19] a) Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215–241; b) S.
Grimme, J. Antony, S. Ehrlich, H. Krieg, J. Chem. Phys. 2010, 132, 154104.
[20] a) F. Weigend, R. Ahlrichs, Phys. Chem. Chem. Phys. 2005, 7, 3297–3305;
b) F. Weigend, Phys. Chem. Chem. Phys. 2006, 8, 1057–1065.
[21] A. E. Reed, L. A. Curtiss, F. Weinhold, Chem. Rev. 1988, 88, 899–926.
[22] Patent application has been made for S1-DBD and S2-DBD dyes: appl.
number 102020114139.4.
Manuscript received: October 27, 2020
Revised manuscript received: November 27, 2020
Accepted manuscript online: December 5, 2020
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© 2020 The Authors. European Journal of Organic Chemistry published
by Wiley-VCH GmbH