Fluorescent Dyes with Large Stokes Shifts Based on Benzo[1,2-d:4,5-d']bis([1,3]dithiole) (“S4-DBD Dyes”)

Article abstract of DOI:10.1002/ejoc.202000093

We report on a further development of [1,3]-dioxolo[4.5-f]benzodioxole (DBD) fluorescent dyes by replacement of the four oxygen atoms of the heterocyclic core by sulfur atoms. This variation causes striking changes of the photophysical properties. Whereas absorption and emission significantly shifted to longer wavelength, the fluorescence lifetimes and quantum yields are diminished compared to DBD dyes. The latter effect is presumably caused by an enhanced intersystem crossing to the triplet state due to the sulfur atoms. The very large Stokes shifts of the S⁴-DBD dyes ranging from 3000 cm^–1 to 7400 cm^–1 (67 nm to 191 nm) should be especially emphasized. By analogy with DBD dyes a broad variation of absorption and emission wavelength is possible by introducing different electron withdrawing substituents. Moreover, some derivatives for coupling with biomolecules were developed.

Full text of DOI:10.1002/ejoc.202000093

A Journal of
Accepted Article
Title: Fluorescent dyes with large Stokes shifts based on benzo[1,2-
d:4,5-d’]bis([1,3]dithiole) (“S4-DBD dyes”)
Authors: Pablo Wessig, Daniel Freyse, David Schuster, and Alexandra
Kelling
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10.1002/ejoc.202000093
European Journal of Organic Chemistry
FULL PAPER
Fluorescent dyes with large Stokes shifts based on benzo[1,2-
d:4,5-d’]bis([1,3]dithiole) (“S4-DBD dyes”)
P. Wessig*[a], D. Freyse[a], D. Schuster[a], A. Kelling[a]
[a]
Prof. Dr. P. Wessig, D. Freyse, D. Schuster, A. Kelling
Institut für Chemie
Universität Potsdam
Karl-Liebknecht-Str. 24-25, 14476 Potsdam
E-mail: wessig@uni-potsdam.de
ag-wessig.chem.uni-potsdam.de
Supporting information for this article is given via a link at the end of the document.
Abstract: We report on a further development of [1,3]-dioxolo[4.5-
f]benzodioxole (DBD) fluorescent dyes by replacement of the four
oxygen atoms of the heterocyclic core by sulfur atoms. This variation
causes striking changes of the photophysical properties. Whereas
absorption and emission significantly shifted to longer wavelength,
the fluorescence lifetimes and quantum yields are diminished
compared to DBD dyes. The latter effect is presumably caused by
an enhanced intersystem crossing to the triplet state due to the
sulfur atoms. Especially the very large Stokes shifts of the S4-DBD
dyes ranging from 3000 cm-1 to 7400 cm-1 (67 nm to 191 nm) should
be emphasized. By analogy with DBD dyes a broad variation of
absorption and emission wavelength is possible by introducing
different electron withdrawing substituents. Moreover, some
derivatives for coupling with biomolecules were developed.
shifts ∆λ ( > 100 nm), long fluorescence lifetimes τF (> 20ns) and
a large bleaching stability. Meanwhile, we developed numerous
different applications, e.g. fluorescent probes for lipophilic
environment in proteins[5a-d]
dsDNA[5f]. Moreover, DBD dyes were used in various FRET
pairs as acceptor[6a] or donor[6b-d]
powerful and versatile class of fluorescent dyes is
, , and
biological membranes[5e]
.
A
distinguished by a broad adaptability of physical and chemical
properties to a specific application. This is mainly achieved by
structural variation of the dye. Recently we demonstrated that
absorption and emission wavelength of DBD dyes 1 can be
varied over
a broad spectral range by different electron
withdrawing groups (R1CO, R2CO) in positions 4 and 8 of the
aromatic core (Fig. 1).[4c] Another option for structural variation is
the replacement of all oxygen atoms of the DBD core by sulfur
atoms. From this we expect a distinct red-shift of absorption and
emission wavelength. Herein we describe synthesis and
properties of a new class of fluorescent dyes based on
benzo[1,2-d:4,5-d’]bis([1,3]dithiole). By analogy with DBD dyes
we call these dyes S4-DBD dyes 2 (Fig. 1).
Introduction
The detection of luminescence is one of the most sensitive
techniques for monitoring molecular events. Above all, countless
applications in biology, biochemistry, and medicine have
contributed to the popularity of this method.[1,2] Depending on the
luminescence lifetime a distinction is made between the long-
lived phosphorescence and the rather short-lived fluorescence.
Besides inorganic materials (e.g. quantum dots) and
luminescent metal ions (mainly lanthanides), small fluorescent
organic molecules are utilized in luminescence applications. The
suitability of a fluorescent dye for a specific application is
influenced by an array of physical and chemical properties. Here
the absorption maxima and emission wavelength (λEX, λEM), the
fluorescence quantum yield (ΦF), the molar attenuation
coefficient (ε), the fluorescence lifetime (τF), the bleaching
stability and two combinations of these properties, the Stokes
shift (∆λ = λEM - λEX) and the brightness (εΦF) are of particular
importance. A large Stokes shift minimizes self-quenching and
scattered light in the context of biological imaging. Furthermore,
fluorescent dyes possessing large Stokes shifts play an
important role in super-resolution microscopy (e.g. STED).[3]
There is no fluorescent dye exhibiting ideal properties in all
these categories. Therefore, there is still a great need for new
fluorescent dyes.
O
R1
O
R1
4
8
4
8
R3
R4
R3
R4
S
S
S
S
O
O
O
O
2
6
R2
O
R2
O
2
1
4
3a R1 - R4 = H
R1
R2
2
R3
R4
6 S
S
S
R - R4 = Me
1
3b
1 - R4 = Pentyl
S
3c
R
8
Figure 1. Structure of DBD dyes 1, S4-DBD dyes 2 and parent scaffold 3
Results and Discussion
Synthesis of S4-DBD dyes
Benzo[1,2-d:4,5-d’]bis([1,3]dithioles) (hereinafter S4-DBD) were
first mentioned in 1969 by Klemm and Geiger, whereby atoms 2
and 6 (cf. 3 in Fig. 1) were sp2 hybridized and part of a C-C
double bond.[7] Only nearly a quarter of a century later the parent
compound 3a was prepared by reduction of the corresponding
Some years ago, we discovered a new class of fluorescent dyes
based on [1,3]-dioxolo[4.5-f]benzodioxole, which are called DBD
dyes.[4] The outstanding features of these dyes are large Stokes
1
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10.1002/ejoc.202000093
European Journal of Organic Chemistry
FULL PAPER
2,6-bisdithione,[8] obtained from the tetrathiol.[9] Bearing in mind
the well known C-H acidity of thioacetals we hypothesized that
2,2,6,6-tetrasubstituted derivatives such as 3b should be more
suitable for functionalization of position 4 and 8. Compound 3b
was first mentioned in the patent literature. Already in 1982
Odorisio et al. reported on the preparation of S4-DBD
compounds by reductive dealkylation of 1,2,4,5-tetrakis-
(ethylthio)benzene and acid-catalyzed reaction of the resulting
1,2,4,5-tetramercaptobenzene with aldehydes and ketones.[10]
An improved two-step synthesis avoiding the isolation of 1,2,4,5-
tetramercaptobenzene, which is sensitive to oxidation, was
developed by Rawal and co-workers in 2002 and is summarized
in Scheme 1.[11]
The selective preparation of 6a succeeded using 2.2 eq. n-BuLi
in diethylether. Obviously, the presumably extremely basic
dilithiated 3b (vide infra) is only formed in hexane but
immediately destroyed in ether (Scheme 2).
Next we attempted to prepare 4,8-diacyl derivatives in a similar
manner. Unfortunately, the reaction of dilithiated 3b with various
Weinreb amides, acyl chlorides, and N,N-dimethylacetamide
gave only traces of the target compounds together with small
amounts of monoacyl derivatives. Obviously, the acylation
reagents are rather deprotonated than attacked by a nucleophile
due to the strong basicity of dilithiated 3b. Furthermore, it is
known that Weinreb amides can undergo an O-N bond cleavage
if treated with strong bases.[12] This hypothesis is corroborated
by the reaction with trifluoroacetic acid derivatives. Thus 3b
provided after lithiation both with N-methoxy-N-methyl-
trifluoroacetamide and N,N-dimethyl-trifluoroacetamide 25% of
the corresponding diketone 7b besides varying amounts of
monoketone 6b (Scheme 3).
Cl
Cl
Cl
Cl
tBuS
tBuS
StBu
StBu
i
4
5
ii
S
S
S
S
3b
Scheme 1. Synthesis of compound 3b. i tert.-BuSH, Na, DMF, 55-70%, ii
HBF4-Et2O, acetone, toluene, rfx., 85%.
Starting with the commercially available 1,2,4,5-tetrachloro-
benzene
4
1,2,4,5-tetrakis(tert.-butylsulfanyl)benzene
5
is
Scheme 3. Synthesis of trifluoromethylketones 6b, 7b. i: 1) 4 eq. n-BuLi,
TMEDA, n-hexane, r.t., 3h; 2) method A: 4.5 eq. N-methoxy-N-methyl-
trifluoroacetamide. method B: 4.5 eq. N,N-dimethyl-trifluoroacetamide.
prepared with good yields by reaction with sodium tert.-butyl-
thiolate. Simultaneous removal of tert.-butyl groups and
acetalization with acetone afforded the target compound 3b.
To introduce the electron-withdrawing groups in 4 and 8 position
we first investigated the synthesis of monoaldehyde 6a and
dialdehyde 7a. The latter is formed in good yields using 4 eq. n-
BuLi in TMEDA/hexane and subsequent treatment with DMF by
analogy with the previously published procedure for oxygen
DBD dyes.[4c] In this case the monoaldehyde 6a is only formed in
traces (method A). The use of 4 eq. tert.-BuLi instead of n-BuLi
gives similar yields.
Because a single-stage introduction of the acyl groups is
seemingly difficult we investigated multistep routes. Thus,
treatment of dilithiated 3b with CO2 afforded the dicarboxylic
acid 7c together with small amounts of monocarboxylic acid 6c.
Unfortunately, this compound is slightly soluble in any solvents
and difficult to purify. Nevertheless, the 4,8-dipentanoyl-S4-DBD
dye 7e was obtained from 7c by reaction with n-BuLi, albeit with
an unsatisfactory yield of 26%. We achieved significantly better
results by treating the dialdehyde 7a with n-BuLi to give the diol
7d, followed by oxidation with Dess-Martin periodinane[13]
(Scheme 4).
To circumvent the solubility problems of 7c we investigate the
synthesis of 2,2,6,6-tetrapentylsubstituted 3c by acetalization of
5 with 6-undecanone. The corresponding dicarboxylic acid 7i
was prepared analogously to 7c but in much better yields
(Scheme 5). Compound 7i is also much easier to purify as it is
more soluble in most organic solvents in comparison to 7c.
Treatment of dilithiated 3b with ethyl chloroformate afforded
diester 7f apart from low quantities of monoester 6f. The dinitrile
7h was accessible from dialdehyde 7a via dioxime 7g in good
yields (Scheme 6).
Scheme 2. Synthesis of aldehydes 6a, 7a. i method A: 1. 4 eq. n-BuLi, n-
hexane, TMEDA, r.t., 3h or 4 eq. tert.-BuLi, n-hexane, TMEDA, r.t., 1h; 2. DMF.
method B: 1. 2 eq. n-BuLi, Et2O, r.t., 2 h, rfx.; 2. DMF.
2
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10.1002/ejoc.202000093
European Journal of Organic Chemistry
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coupling with biomolecules (e.g. peptides, proteins, lipids,
nucleic acids) is indispensable.
Scheme 6. Synthesis of esters 6e, 7e and dinitrile 7h. i 1) 4 eq. n-BuLi,
TMEDA, n-hexane, 3h, r.t.; 2) 6 eq. ethyl chloroformate, -70°C. ii 3 eq. NH2OH,
MeOH, 3 h, rfx. iii DMSO, Ac2O.
Scheme 4. Synthesis of acids 6c, 7c and 4,8-dipentanoyl-S4-DBD dye 7e. i 1)
4 eq. n-BuLi, TMEDA, n-hexane, r.t., 3h; 2) CO2, -20°C. ii 8 eq. n-BuLi, n-
hexane, 40°C, 26%. iii 4 eq. n-BuLi, neat TMEDA, r.t. 56%. iv Dess-Martin
periodinane, DCM, 86%.
Scheme 5. Synthesis of carboxylic acid 7i. i HBF4-Et2O, 6-undecanone,
toluene, 3 h, rfx. ii 1) 3 eq. tert..-BuLi, TMEDA, n-hexane, r.t., 1h; 2) CO2, -
20°C.
Scheme 7. Synthesis of 6d,e and 8a-d. i 4 eq. n-BuLi, THF, r.t., 10 min. ii 1) 4
eq. n-BuLi, TMEDA, r.t., 3h; 2) 5 eq. DMF. iii 1) 4 eq. n-BuLi, TMEDA, r.t., 3h;
2) 4.5 eq. N-methoxy-N-methyl-trifluoroacetamide. iv Dess-Martin periodinane,
DCM.
Next we were interested in 4,8-asymmetrically disubstituted S4-
DBD dyes 8 (including monosubstituted compounds), because
such dyes facilitate spectroscopic fine-tuning. In this context, we
defined monoaldehyde 6a as key intermediate due to its good
accessibility (cf. Scheme 2, method B). By analogy with the
preparation of diketone 7e we obtained monoketone 6e by
oxidation of alcohol 6d. Treatment of 6a with an excess n-BuLi,
followed by reaction either with DMF or the Weinreb amide of
trifluoroacetic acid gave the alcohols 8a or 8c, which were
subsequently oxidized to asymmetrical S4-DBD dyes 8b,d
(Scheme 7).
Based on our previous publications on DBD dyes two strategies
have been proven to be successful: A) functionalization of one of
the acyl groups in 4,8 position or B) functionalization of one of
the acetal moieties. First we pursued the approach A. Starting
again with monoaldehyde 6a we protected the aldehyde group
as dioxolane 9. Although compound 9 was obtained with
excellent yield it turned out to be extremely sensitive towards
traces of acids and consecutive reactions with 9 failed. Instead
of protection we now reduced the aldehyde to the primary
alcohol 10 with nearly quantitative yield. The subsequent
lithiation and carboxylation to acid 11 and oxidation to formyl-
For applications of fluorescent dyes, above all in the field of the
biosciences, the presence of functional groups capable for
3
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10.1002/ejoc.202000093
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acid 8a were successful but the yield for these two steps was
and maleimide 22 (reactive towards thiol groups). Furthermore
the azide 24 was prepared from 18 via the tosylate 23 (Scheme
10).
unacceptably low (15%, Scheme 8).
Scheme 8. Synthesis of 9-11 and 8e. i 1.1eq. ethylene glycol, cat. TsOH,
toluene, rfx, 3 h, 99%. ii NaBH4, THF, 0°C, 30 min, 99%. iii 1. 3eq. n-BuLi,
TMEDA, n-hexane, r.t., 3 h; 2. CO2, 25%. iv (COCl)2, DMSO, Et3N, DCM, -
78°C, 61%.
Therefore we discarded approach A and focused on approach B
– the functionalization of one of the acetal moieties. First we
were looking for a way to selectively introduce two different
acetals. Already thirty years ago, the preparation of bis-
dithiocarbonate 12 and the selective opening of one of the
dithiolane rings upon treatment with alcoholates were
described.[14] We applied this procedure to compound 5 and
performed the abovementioned ring opening with LiOMe giving
the intermediate 13. Compound 14 was obtained after treatment
with acetone in the presence of HBF4 and BF3. Repeating these
steps with 25[15] which was synthesized in one step from
commercially available 5-hydroxy-pentan-2-one, afforded
Scheme 9. Synthesis of 17. i 1. Na, pyridin, rfx. 3 h; 2. COCl2, 55%. ii 2 eq.
LiOMe, THF, 1 h. iii 4 eq. HBF4/Et2O, acetone, rfx., 4 h, 46%. iv 1. 2 eq. LiOMe,
THF, 1h; 2. 3.5 eq. HBF4/Et2O, 2 eq. BF3/Et2O, 5-pivaloyloxy-pentan-2-one 25,
rfx, 4 h, 55%. v HBF4/Et2O, toluene, rfx., 1 d, 60%. vi 1. 2 eq. HBF4/Et2O,
toluene, rfx, 3 h; 2. 2 eq. BF3/Et2O, 1eq. 25, r.t., 2h; 3. 1.5 eq. acetone, r.t., 2h,
4. NaOH, MeOH, rfx, 3 h, 30-34%. vii NaOH, MeOH, rfx, 3 h, 89%.
unsymmetrically
substituted
S4-DBD
compound
15.
Unfortunately, none of the three steps proceeded with
significantly more than 50% yield. Alternatively, we investigated
the direct route via the benzene-1,2,4,5-tetrathiol 16.[16] This
compound could be obtained from 5 and should be directly used
due to its high oxidation sensitivity. It should be noted that 16
has been prepared for the first time by this way. 15 could be
obtained from 16 directly only with erratic yields, probably due
the oxygen-sensitive nature of 16. So we studied the direct
synthesis of 17 by preparing 16 in situ. Deprotection of 5 with
HBF4-Et2O under inert conditions was followed by addition BF3-
Et2O and successive treatment with 25 and acetone. 15 was
afforded as an inseparable mixture with 3b. Therefore the raw
product was subjected to NaOH/MeOH to saponify the ester.
The resulting polarity difference facilitated the separation of the
desired alcohol 17 and the by-product 3b. The overall yield from
5 was 30-34% and consequently this route should be preferred
(Scheme 9).
The syntheses of bioreactive S4-DBD dyes should be
exemplarily demonstrated with S4-DBD dialdehyde chromophore
due to its outstanding photophysical properties (vide infra). First,
alcohol 17 was converted to dialdehyde 18 by treatment with an
excess n-BuLi followed by reaction with DMF. The subsequent
reaction of 18 with succinic anhydride afforded carboxylic acid
19, which was used for the preparation of three bioreactive S4-
DBD dyes: N-propargyl-amide 20 (for CuAAC with azides), N-
hydroxy-succinimide ester 21 (reactive towards NH2 groups),
Scheme 10. Syntheses of bioreactive S4-DBD dyes 19-22, 24. i 1. 6 eq. n-
BuLi, TMEDA, r.t. 2 h; 2.7 eq. DMF, r.t. 1 h, 38%. ii 5 eq. succinic anhydride,
10 eq. pyridine, cat. DMAP, r.t., 16 h, 87% iii 4 eq. propargylamine, 1.5 eq.
DCC, cat. N-hydroxysuccinimide (HOSu), DCM, r.t., 5h, 74%. iv 1.1eq. HOSu,
1.1 eq. DCC, cat. DMAP, DCM, r.t., 16h, 83%.
v 21, 1.5 eq. N-(2-
4
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The photophysical properties of S4-DBD dyes in ethanol are
summarized in table 1 (for other solvents see the SI). The
absorption wavelength of compounds 6 with one electron
withdrawing group range from 390 to 444 nm and the
corresponding emission wavelength from 469 to 606 nm. If a
second acceptor is introduced (7, 8) both absorption and
emission wavelength are considerably red-shifted. A special
behavior is observed with carboxylic acids 7c, 7i, and 8e. In
these cases the absorption wavelength shows a remarkable
concentration dependency, which is exemplarily depicted in fig.
3 for compound 8e. Similar phenomena are known for other
carboxylic acids[18] and arise from intermolecular hydrogen
bonds between carboxyl groups.
aminoethyl)maleimide trifluoroacetate 32, 2 eq. DIPEA, DCM, r.t., 16h, 85%. vi
2eq. TsCl, 4eq. pyridine, cat. DMAP, DCM, rfx., 3 h, 64%. vii 2 eq. NaN3, DMF,
r.t., 16h, 92%.
The X-ray crystal structure of 7a is depicted in fig. 2. The most
striking difference between this structure and the previously
published structure of DBD dyes[4a] lies in the strongly folded
dithiole rings, whereas the dioxole rings in DBD dyes are
virtually planar. The angle between the π-plane (green) and the
parallel planes defined by the sulfur atoms and the acetal C-
atom (red) amounts to about 31°.
Figure 2. X-ray crystal structure of 7a (π-plane: green, S-C-S planes: red).
Consequently, two of the four methyl groups are nearly
perpendicular on the π-plane (angles between the normal of the
π-plane and Me-C bonds are only 4.9°). However, the activation
barrier of the ring flip should be very low based on NMR (only
one signal for the methyl groups at 1.93 ppm) and molecular
modeling (EA = 1.6 kcal/mol, see the SI).
Figure 3. Concentration dependency of absorption wavelength of λabs of 8e.
Photophysical properties of S4-DBD dyes
Table 1. Photophysical data of S4-DBD dyes 6-8 (in EtOH)
R1
R2
λABS
λEM
∆λ
∆ꢀꢁ
τF
ΦF
ε
[nm]
[nm]
[nm]
[103 cm-1]
[ns]
[%]
[103 M-1cm-1]
6a
6b
6c
6e
6f
CHO
-
444
442
390
405
396
526
606
616
469
556
482
665
537
612
550
510
531
639
632
162
174
79
6.02
2.2
2.8
<1
4.5
1.1
0.4
3.5
1.1
8.4
3.0
6.2
13.7
0.9
7.2
7.5
2.6
5.39
COCF3
COOH
COBu
COOEt
CHO
-
6.39
4.32
6.71
4.51
3.97
5.13
7.41
5.07
2.97
4.48
5.95
5.19
1.21
3.27
3.16
3.69
1.58
4.73
3.01
4.64
4.11
4.79
4.60
2.11
-
-
151
86
1.5
<1
-
7a
7c
7e
7f
-
139
116
191
120
67
3.4
2.6
3.5
2.9
1.3
3.3
3.0
2.8
COOH
COBu
COOEt
CN
-
421[a]
421
-
-
430
7h
7i
-
443
COOH
COBu
COOH
-
429[b]
463
102
176
156
8b
8e
CHO
CHO
476[c]
5
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European Journal of Organic Chemistry
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[a] c = 1.3 mM; [b] c = 1.7 mM; [c] c = 0.24 mM (absorption wavelength of 7c, 7i, and 8e depends on concentration).
A series of dyes exhibits red emission above 600 nm. Especially
to be emphasized are the partly very large Stokes shifts ∆ꢀꢁ
reaching values of 4000 – 7400 cm-1. Compared with their
oxygen analogs the absorption maxima are almost always red-
shifted by 20 nm on average (except 7e, for details see the SI)
with a maximum of 47 nm (7a). The shift of emission wavelength
is even greater and reaches values of 20 – 30 nm. The
fluorescence lifetimes τF of S4-DBD dyes are significantly lower
than those of DBD dyes and amount to 1 – 3 ns. The
fluorescence quantum yields exhibit single-digit values (except
7f), which is substantially below the values of DBD dyes. The
reason for the lower τF and ΦF values of S4-DBD dyes could be
an increased intersystem crossing (ISC) efficiency to give the
triplet state. This process, which is caused by enhanced spin-
orbit coupling with the sulfur atoms,[19] competes with the
fluorescence. To prove this hypothesis
a
triplet-triplet
annihilation / upconversion (TTA-UC) experiment was carried
out with compound 7a and 9,10-Diphenylanthracene (DPA) as
annihilator.[20] The individual photophysical steps are
represented by equations 1-5. After excitation at 540 nm (eq. 1)
7a undergoes an ISC to the triplet state (eq. 2). Then the triplet
energy is transferred to DPA (eq. 3). Between two triplet excited
DPA molecules triplet-triplet annihilation takes place giving a
ground state and a singlet excited DPA molecule (eq. 4). Finally,
the DPA fluorescence of DPA at 410-430 nm is observed (eq. 5).
It should be noted that a direct excitation of DPA at 540 nm can
be ruled out so that the DPA fluorescence must originate from
TTA-UC.
Figure 4. Comparison of 41 dyes from ref. [3] with some S4-DBD dyes.
Conclusion
We have developed a new class of fluorescent dyes based on
benzo[1,2-d:4,5-d’]bis([1,3]dithiole) and called them S4-DBD
dyes.[17] Starting with the commercially available 1,2,4,5-
tetrachlorobenzene 4 the parent heterocycle 3b (bearing four
methyl groups in positions 2 and 6) could be prepared in two
steps and with good yields on a gram-scale level. Lithiation in
positions 4 and 8, followed by reaction with various electrophilic
reagents provides access to a broad range of fluorescent S4-
DBD dyes. Compared with the previously developed DBD dyes
a
considerable bathochromic shift of the absorption and
emission wavelength is observed. However, the fluorescence
lifetimes and quantum yields of S4-DBD dyes are significantly
lower. We assume that a slightly accelerated intersystem
crossing to the triplet state, caused by enhanced spin-orbit
coupling with the sulfur atoms is the reason for this
phenomenon.[18] An outstanding feature of S4-DBD dyes is that
they posses very large Stokes shifts. They could therefore be
predestined for super-resolution microscopy. Finally, a series of
S4-DBD dye derivatives were developed, which enable the
coupling with biomolecules. Thus, carboxylic acid 19, OSu-ester
21 (for amines), alkyne 20, azide 24 (for CuACC), and
maleimide 22 were synthesized. We are currently developing
promising biochemical applications of S4-DBD dyes.
Fluorescent dyes with large Stokes shifts decrease the crosstalk
between excitation and emission as well as the self-quenching
due to back-scattering from biological tissues. Moreover, such
dyes have particular significance in super-resolution microscopy
(e.g. STED). Recently Hell and co-workers published a review
about dyes with large Stokes shifts suitable for STED.[3] To
evaluate the S4-DBD dyes concerning the absorption and
emission wavelength we compared them with 41 dyes (only one-
component systems) from reference [3]. The results for the most
outstanding dyes 6e, 7a,e,f and 8b are depicted in figure 4 (the
blue dashed curves mark different Stokes shifts ∆ ꢀꢁ) and furnish
evidence for the competitiveness of S4-DBD dyes.
Experimental Section
General Information. See the Supporting information
1,2,4,5-Tetrakis(tert.-butylthio)benzene (5). To an ice-cooled solution
of dry DMF (600 mL) and 2-methylpropane-2-thiol (159 g, 1.76 mol, 5
eq.) in an 1 L Schlenk flask, were added small pieces of sodium (39.60 g,
1.72 mol, 4.9 eq.) after which the mixture was stirred overnight. To the
brown-yellow suspension was added 1,2,4,5–tetrachlorobenzene 4 (76 g,
208 mmol) and the mixture was refluxed for 8 h. After cooling to room
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000093
European Journal of Organic Chemistry
FULL PAPER
temperature the reaction mixture was poured on ice. The precipitate was
collected, washed thoroughly with water, methanol and small amounts of
cold petrol ether and dried under reduced pressure to yield 5 (90.23 g,
60 %) as creamy-white powder. m.p.: 144 – 145 °C. Rf (PE:EE/15:1):
0.68; 1H-NMR (300 MHz, CDCl3, ppm): 1.35 (s, 36 H), 7.94 (s, 2 H); 13C-
NMR (75 MHz, CDCl3, ppm): 31.3, 48.1, 139.3, 144.7; HRMS (EI):
calculated for C22H38S4 [M]+: 430.1856, found: 430.1853.
ether for 10 min and cooled down to 0 °C. The precipitate was collected,
washed thoroughly with petroleum ether and dissolved in a small amount
of DCM. Precipitation with petroleum ether followed by drying in vacuum,
yielded 7a (620 mg, 52 %) as a blackish red solid. m.p.: >240 °C
(decomposition). Rf (PE:EE/15:1): 0.29; 1H-NMR (300 MHz, CDCl3, ppm):
1.93 (s, 12 H), 10.19 (s, 2 H); 13C-NMR (75 MHz, CDCl3, ppm): 31.9,
65.6, 126.9, 141.8, 188.8; HRMS (EI) calculated for C14H14O2S4 [M]+:
341.9877, found: 341.9882; IR (cm-1): 3327, 2954, 2841, 1669, 1448,
1361, 1225, 1165, 1153, 856.
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole) (3b). To a 250
mL flask containing a suspension of 5 (10 g, 23.21 mmol), acetone (13.7
mL, 185.71 mmol,
8
eq.) and toluene (100 mL) was added
2,2,2-Trifluoro-1-(2,2,6,6-tetramethylbenzo[1,2-d:4,5-
tetrafluoroboric acid diethyl ether complex (6.4 mL, 46.43 mmol, 2 eq.)
and the mixture was refluxed for 3 h. After cooling to room temperature,
the blackish mixture was washed with saturated NaHCO3 solution and
the aqueous phase was extracted with DCM twice. The combined
organic layers were dried over MgSO4 and the solvent was removed in
vacuum. The crude yellow-brown product was purified by recrystallization
from petrol ether to yield 3b (5.60 g, 85 %) as a white solid. m.p.: 146 –
147 °C. Rf (PE:EE/15:1): 0.68; 1H-NMR (300 MHz, CDCl3, ppm): 1.89 (s,
12 H), 7.03 (s, 2 H); 13C-NMR (75 MHz, CDCl3, ppm): 31.3, 65.7, 116.8,
135.7; HRMS (EI): calculated for C12H14S4 [M]+: 285.9978, found:
285.9976.
d']bis([1,3]dithiole)-4-yl)ethan-1-one
(6b)
and
1,1'-(2,2,6,6-
tetramethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-4,8-diyl)bis(2,2,2-
trifluoroethan-1-one) (7b). A 50 mL three-necked flask was charged
with 3b (200 mg, 698 µmol), dry n-hexane (10 mL) and TMEDA (211 µl,
1.40 mmol, 2 eq.). To the suspension was added dropwise n-BuLi-
solution in pentane (1.86 mL, 2.79 mmol, 4 eq.) and the mixture was
stirred at room temperature for 3 h. Then the mixture was cooled to 0 °C
and 2,2,2-trifluoro-N-methoxy-N-methylacetamide (338 µl, 2.79 mmol, 4.5
eq.) was added dropwise. The reaction was allowed to stir 1 h at room
temperature and then water was added. The yellow slurry was acidified
with 1 M hydrochloric which turned blood-red. The aqueous layer was
extracted with DCM 3 times and the combined organic layers were dried
over MgSO4. After concentration in vacuum, the crude product was
purified by flash column chromatography (PE:EE) to yield 7b (82 mg,
25 %) as black-red solid. m.p.: 150 – 152 °C and 6b (80 mg, 30 %) as a
red-orange solid. m.p.: 93 – 97 °C.
2,2,6,6-Tetrapentylbenzo[1,2-d:4,5-d']bis([1,3]dithiole) (3c). To 100
mL flask containing a suspension of 5 (4 g, 9.29 mmol), undecan-6-one
(4.74 g, 27.86 mmol,
3 eq.) and toluene (50 mL) was added
tetrafluoroboric acid diethyl ether complex (2.55 mL, 18.57 mmol, 2 eq.)
and the mixture was refluxed for 3 h. After cooling to room temperature,
the blackish mixture was washed with saturated NaHCO3 solution and
the aqueous layer was extracted with DCM 3 times. The combined
organic layers were dried over MgSO4 and the solvent was removed in
vacuo. The crude product was purified by flash column chromatography
(PE) to yield 3c (3.71 g, 78 %) as colorless white crystals. m.p.: 72 –
76 °C. Rf (PE): 0.39; 1H-NMR (300 MHz, CDCl3, ppm): 0.79 – 0.99 (m, 12
H), 1.25 – 1.38 (m, 16 H), 1.40 – 1.55 (m, 8 H), 1.96 – 2.14 (m, 8 H), 6.94
(s, 2 H); 13C-NMR (75 MHz, CDCl3, ppm): 14.0, 22.5, 25.7, 31.8, 41.0,
74.8, 116.0, 135.1; HRMS (EI): calculated for C28H46S4 [M]+: 510.2482,
found: 510.2486. IR (cm-1): 3340, 2955, 2923, 2858, 1452, 1381, 1363,
1248, 1164 1150.
7b Rf (PE:EE/5:1): 0.11. 1H-NMR (300 MHz, CDCl3, ppm): 1.91(s); 13C-
NMR (75 MHz, CDCl3, ppm): 30.6, 67.9, 113.7, 117.6, 125.8, 138.2,
183.3, 184.0; HRMS (EI) calculated for C16H12F6O2S4 [M]+: 477.9624,
found: 477.9633; IR (cm-1): 2940, 1704, 1455, 1368, 1218, 1157, 1054,
957, 833, 728.
6b Rf (PE:EE/5:1): 0.71.1H-NMR (300 MHz, CDCl3, ppm): 1.89(s, 12 H),
7.21 (s, 1 H); 13C-NMR (75 MHz, CDCl3, ppm): 30.8, 66.1, 113.6, 117.4,
119.6, 123.5, 136.5, 138.3, 183.6, 184.1; HRMS (EI) calculated for
C
14H13F3OS4 [M]+: 381.9801, found: 381.9811; IR (cm-1): 2962, 2923,
1688, 1367, 1258, 1202, 1186, 1170, 1142, 989.
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-4-
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-4-carboxylic
acid (6c) and 2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-
4,8-dicarboxylic acid (7c). A 50 mL three-necked flask was charged
with 3b (400 mg, 1.4 mmol), dry n-hexane (20 mL) and TMEDA (464 µl,
3.1 mmol, 2 eq.). To the suspension was added dropwise n-BuLi solution
in pentane (3.72 mL, 5.6 mmol, 4 eq.). The mixture was stirred at room
temperature for 3 h and cooled down to -20 °C. Dry CO2-gas was
bubbled through the mixture for 30 min and the mixture was allowed to
reach room temperature. To the slurry was added water until a yellow
solution was formed. The mixture was washed with DCM 3 times and the
aqueous layer was acidified with concentrated hydrochloric acid. The
precipitate was allowed to settle overnight in a refrigerator. The orange
precipitate was collected, washed thoroughly with water and extracted
carbaldehyde (6a). A 100 mL three-necked flask was charged with 3b
(1.5 g, 5.24) and dry Et2O (50 mL). n-BuLi (1.6 M in pentane, 7.2 mL,
11.5 mmol, 2.2 eq.) was added and the mixture was gently refluxed for 2
h. After cooling to room temperature dry DMF (1.6 mL, 20.94 mmol, 4
eq.) was added and the reaction is stirred for 1 h at that temperature. To
the white-beige slurry water was added and the color changes
immediately to dark orange. The aqueous layer was extracted with DCM
3 times and the combined organic layers were dried over MgSO4. After
concentrated in vacuum, the crude product was purified by flash column
chromatography (PE/EE) to yield 6a (1.24 g, 70 %) as a yellow solid.
m.p.: 148 °C. Rf (PE:EE/15:1): 0.38; 1H-NMR (300 MHz, CDCl3, ppm):
1.90 (s, 12 H), 7.19 (s, 1 H), 10.07 (s, 1 H); 13C-NMR (75 MHz, CDCl3,
ppm): 31.6, 65.8, 120.2, 137.8, 139.6, 188.6; HRMS (EI): calculated for
C13H14OS4 [M]+: 313.9928, found: 313.9938; IR (cm-1): 2968, 2845, 1673,
1519, 1413, 1362, 1260, 1201, 947, 878.
extensively with DCM. This filtrate contains mostly 6c.
A second
extraction with warm THF gives a filtrate with contains mostly 7c. Both
filtrates were separately concentrated in vacuum and separately purified
by flash column chromatography (DCM:MeOH:TFA) to yield 7c (246 mg,
47 %) as an orange solid. m.p.: >300 °C) and 6c (68 mg, 15 %) as a
greenish solid. m.p.: >288 °C (decomposition).
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']bis[1,3]dithiole-4,8-
dicarbaldehyde (7a). A 50 mL three-necked flask was charged with 3b
(1 g, 3.49 mmol), dry n-hexane (20 mL) and TMEDA (1 mL, 7.0 mmol, 2
eq.). To the suspension was added dropwise n-BuLi solution in pentane
(8.2 mL, 14.0 mmol, 4 eq.). The mixture was stirred at room temperature
for 3 h and cooled down to 0 °C. Dry DMF (1.2 mL, 15.7 mmol, 4.5 eq.)
was added and the reaction was allowed to stir for 1 h at room
temperature. To the white slurry was added water, which immediately
turned to dark red. The aqueous layer was extracted with DCM 3 times
and the combined organic layers were dried over MgSO4. After
concentration in vacuum, the crude product was refluxed in petrol ether
7c. Rf (DCM:MeOH:TFA/100:1:0.4): 0.19; 1H-NMR (300 MHz, DMSO-d6,
ppm): 1.75 (s); 13C-NMR (75 MHz, DMSO-d6, ppm): 30.7, 60.7, 123.5,
138.9, 167.1; HRMS (EI) calculated for C14H14O4S4 [M]+: 373.9775,
found: 373.9784; IR (cm-1): 2917, 1665, 1415, 1366, 1341, 1249, 1208,
1108, 814, 721.
6c. Rf (DCM:MeOH:TFA/100:1:0.4): 0.21; 1H-NMR (300 MHz, DMSO-d6,
ppm): 1.79 (s, 12 H), 7.41 (s, 1 H); 13C-NMR (75 MHz, DMSO-d6, ppm):
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000093
European Journal of Organic Chemistry
FULL PAPER
31.0, 62.7, 119.0, 121.4, 136.0, 138.6, 166.7; HRMS (EI) calculated for
C13H14O2S4 [M]+: 329.9871, found: 39.9878; IR (cm-1): 2957, 2919, 1663,
1419, 1365, 1253, 1148, 1084, 1021, 986.
(PE/EE) to yield 7e (124 mg, 26 %) as a yellow-orange solid. Method B.
In a 50 mL flask, 7d (100 mg, 0.218 mmol) was dissolved in DCM (15
mL). DMP (240 mg, 0.567 mmol, 2.6 eq.) was added and the mixture
was stirred at room temperature for 30 min. To the reaction was added a
solution of sodium thiosulfate and sodium hydrogen carbonate in water
and the aqueous layers was extracted with DCM 3 times. The combined
organic layer were dried over MgSO4 and concentrated in vacuum.
Purification by flash column chromatography (PE/EE) afforded 7e (85 mg,
86 %) as yellow-orange solid. m.p.: 85-90 °C; Rf (PE:EE/15:1): 0.47; 1H-
NMR (300 MHz, CDCl3, ppm): 0.93 (t, J = 7.3 Hz, 6 H), 1.31 – 1.48 (m, 4
H), 1.63 – 1.76 (m, 4 H), 1.84 (s, 12 H), 2.90 (t, J = 7.3 Hz, 4 H); 13C-
NMR (75 MHz, CDCl3, ppm): 13.8, 22.3, 26.5, 30.7, 41.9, 63.9, 131.6,
136.9, 203.0; HRMS (EI) calculated for C22H30O2S4 [M]+: 454.1129,
found: 454.1115; IR (cm-1): 2958, 1657, 1454, 1369, 1215, 1172, 1034,
991, 787, 708.
1-(2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-4-
yl)pentan-1-ol (6d). A 50 mL three-necked flask was charged with 6a
(300 mg, 0.954 mmol) and dry THF (6 mL). n-BuLi-solution in pentane
(827 µl, 1.24 mmol, 1.3 eq) was added dropwise and the resulting brown
slurry was allowed to stir for 10 min at room temperature. Water was
added and the aqueous layer was extracted with DCM 3 times. The
combined organic layers were dried over MgSO4 and concentrated in
vacuum. The crude product was purified by flash column
chromatography (DCM:MeOH) to yield 6d (231 mg, 65 %) as
a
colourless viscous oil. Rf (PE:EE/15:1): 0.24 1H-NMR (300 MHz, CDCl3,
ppm): 0.90 (t, J = 7.0 Hz, 3 H), 1.22 – 1.53 (m, 4 H), 1.65 – 1.83 (m, 2 H),
1.85(s, 6 H), 1.89 (s, 6 H), 2.16 (br s, 1 H), 4.71 – 4.76 (m, 1 H), 7.00 (s,
1 H); 13C-NMR (75 MHz, CDCl3, ppm):14.0, 22.4, 28.0, 29.4, 32.7, 33.9,
64.6, 74.8, 115.8, 133.4, 134.2, 137.0; HRMS (EI) calculated for
C17H24OS4 [M]+: 372.0710, found: 372.0701; IR (cm-1): 3341, 2956, 2925,
2861, 1453, 1384, 1365, 1167, 1150, 1033.
Ethyl
2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-4-
carboxylate (6f) and Diethyl 2,2,6,6-tetramethylbenzo[1,2-d:4,5-
d']bis([1,3]dithiole)-4,8-dicarboxylate (7f). A 50 mL three-necked flask
was charged with 3b (200 mg, 698 µmol), dry n-hexane (20 mL) and
TMEDA (210 µl, 1.40 mmol, 2 eq.). To the suspension was added
dropwise n-BuLi solution in pentane (1.86 mL, 2.79 mmol, 4 eq.). The
mixture was stirred at room temperature for 3 h and cooled down to -
70 °C. Ethyl chloroformate (400 µl, 4.19 mmol, 6 eq.) was added and the
reaction was allowed to reach room temperature overnight. Water was
added, the aqueous layer was extracted with DCM 3 times and the
combined organic layers were dried over MgSO4. After concentration in
vacuum, the crude product was purified by flash column chromatography
(PE:EE) to yield 7f (189 mg, 63 %) as yellow solid. m.p.: 178 – 180 °C
and 6f (32 mg, 12 %) as a yellow-greenish waxy solid.
1-(2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-4-
yl)pentan-1-one (6e). In a 50 mL flask, 6d (200 mg, 0.531 mmol) was
dissolved in DCM (25 mL). Dess-Martin periodinane (DMP, 450 mg, 1.06
mmol, 2 eq.) was added and the mixture was stirred at room temperature
for 30 min. To the reaction was added a solution of sodium thiosulfate
and sodium hydrogen carbonate in water and the aqueous layer was
extracted with DCM 3 times. The combined organic layer were dried over
MgSO4 and concentrated in vacuo. Purification by flash column
chromatography (PE:EE) afforded 6e (175 mg, 88 %) as yellow solid (81
– 83 °C). Rf(PE:EE/10:1): 0.55; 1H-NMR (300 MHz, CDCl3, ppm): 0.93 (t,
J = 7.4 Hz, 3 H), 1.31 – 1.46 (m, 2 H), 1.65 – 1.77 (m, 2 H), 1.86 (s, 12 H),
2.93 (t, J = 7.3 Hz, 2 H), 7.15 (s, 1 H); 13C-NMR (75 MHz, CDCl3, ppm):
13.9, 22.3, 26.6, 31.0, 41.9, 64.2, 118.7, 130.1, 136.5, 137.3, 201.8;
HRMS (EI) calculated for C17H22OS4 [M]+: 370.0554, found: 370.0555; IR
(cm-1): 2952, 2923, 2864. 1659, 1449, 1361, 1256, 1196,1169, 1147.
7f. Rf (PE:EE/15:1): 0.30. 1H-NMR (300 MHz, CDCl3, ppm): 1.45 (t, J =
7.2 Hz, 6 H), 1.80 (s, 12 H), 4.43 (q, J = 7.2 Hz, 4 H); 13C-NMR (75 MHz,
CDCl3, ppm): 14.2, 31.1, 61.0, 62.5, 122.7, 140.1, 165.9; HRMS (EI)
calculated for C18H22O4S4 [M]+: 430.0401, found: 430.0403; IR (cm-1):
2975, 1693, 1449, 1343, 1241, 1218, 1095, 1013, 861, 784.
1,1'-(2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-4,8-
diyl)bis(pentan-1-ol) (7d). A 50 mL three-necked flask was charged with
7a (200 mg, 0.58 mmol) and dry TMEDA (10 mL). To the dark-red
suspension was added dropwise n-BuLi solution in pentane (1.5 mL, 2.34
mmol, 4 eq.) and was stirred for 30 min at room temperature. Water was
added and the aqueous layer was extracted with DCM 3 times. The
combined organic layers were dried over MgSO4 and concentrated in
vacuum. The crude product was purified by flash column
chromatography (DCM:MeOH) to yield the two diasteromers of 7d (150
mg, 56 % %) as a beige solid. m.p.: 171 – 207 °C. Rf (DCM:MeOH/50:1):
0.6; 0.45). 1H-NMR (300 MHz, CDCl3, ppm): 0.90 (t, J = 7.0 Hz, 6 H),
1.25 – 1.42 (m, 6 H), 1.43 – 1.57 (m, 2 H), 1.69 – 1.95 (m, 16 H), 2.87 (br
s, 2H), 4.68 – 4.73 (m, 1 H), 4.79 – 4.83 (m, 1 H); 13C-NMR (75 MHz,
CDCl3, ppm): 14.0, 22.5, 28.1, 30.7, 33.6, 34.0, 63.2, 63.7, 74.7, 74.8,
133.6, 134.7; HRMS (EI) calculated for C22H34O2S4 [M]+: 458.1442,
found: 458.1439; IR (cm-1): 3340, 2955, 2923, 2858, 1452, 1381, 1363,
1248, 1164, 1150.
6f. Rf (PE:EE/15:1): 0.43. 1H-NMR (300 MHz, CDCl3, ppm): 1.44 (t, J =
7.2 Hz, 3 H), 1.85 (s, 12 H), 4.41 (q, J = 7.2 Hz, 2 H), 7.15 (s, 1 H); 13C-
NMR (75 MHz, CDCl3, ppm): 14.3, 31.3, 62.3, 63.1, 119.3, 120.5, 136.6,
139.4, 165.6; HRMS (EI) calculated for C15H18O2S4 [M]+: 358.0190,
found: 358.0180; IR (cm-1): 2958, 1692, 1454, 1388, 1378, 1361, 1254,
1148, 1080, 1015.
1Z,1'Z)-2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-4,8-
dicarbaldehyde dioxime (7g). 7a (200 mg, 0.58 mmol) was refluxed in a
100 mL flask with methanol (40 mL), sodium acetate trihydrate (238 mg,
175 mmol, 3 eq.) and hydroxylamine hydrochloride (122 mg, 175 mmol, 3
eq.) for 3 h. The mixture was cooled down to 0 °C and 40 mL water was
added. The precipitate was collected and washed with water. After drying
in vacuum, 7g (161 mg, 74 %) was obtained as a yellow-orange solid.
m.p.: 265-269 °C (turning brown) which was used in the next step without
further purification. Rf (DCM): 0.42. 1H-NMR (300 MHz, DMSO-d6, ppm):
1.82 (s, 12 H), 8.06 (s, 2 H), 11.92(s, 2H); 13C-NMR (75 MHz, DMSO-d6,
ppm): 30.8, 62.8, 121.7, 135.0, 145.6; HRMS (EI) calculated for
C14H16O2N2S4 [M]+: 372.0095, found: 372.0087; IR (cm-1): 3267, 2964,
1365, 1287, 1247, 1168, 1152, 976, 908, 688.
1,1'-(2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-4,8-
diyl)bis(pentan-1-one) (7e). Method A. A 50 mL three-necked flask was
charged with 3b (300 mg, 1.05 mmol), dry n-hexane (20 mL) and TMEDA
((316 µl, 2.1 mmol, 2 eq.). To the suspension was added dropwise n-BuLi
solution in pentane (2.62 mL, 4.19 mmol, 4 eq.). The mixture was stirred
at room temperature for 1 h and cooled down to -20 °C. Dry CO2-Gas
was bubbled through the mixture for 1.5 h and after that was stirred for
30 min at room temperature. To the slurry was added n-BuLi-solution in
pentane (5.24 mL, 8.38 mmol, 8 eq.) and the resulting mixture was
heated for 14 h at 45 °C. After cooling to room temperature, water was
added, the aqueous layer was extracted with DCM 3 times and the
combined organic layers were dried over MgSO4. After concentration in
vacuum, the crude product was purified by flash column chromatography
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-4,8-
dicarbonitrile (7h). A 50 mL Schlenk flask was charged with 7g (100 mg,
0.27 mmol), K2CO3 (223 mg, 1.61 mmol, 3 eq.) and dry DMSO (15 mL).
After adding acetic anhydride (152 µm, 0.161 mmol, 3 eq.), the mixture
was stirred for 3 h at 90 °C. 30 mL water was added and the mixture was
cooled down to ca. 0 °C. The precipitate was collected, washed with
water 3 times and dried in vacuo. The crude product was purified by flash
column chromatography (PE/EE) to yield 7h (72 mg, 80 %) as a yellow
solid. m.p >300 °C. Rf (PE:EE/10:1): 0.37. 1H-NMR (300 MHz, CDCl3,
ppm): 1.98 (s, 12 H); 13C-NMR (151 MHz, CDCl3, ppm): 31.8, 67.8, 103.3,
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000093
European Journal of Organic Chemistry
FULL PAPER
114.7, 141.1; HRMS (EI) calculated for C14H12N2S4 [M]+: 335.9878,
found: 335.9880; IR (cm-1): 2981, 2222, 1451, 1439, 1368, 1237, 1166,
1153, 1109, 723.
aqueous layer was extracted with DCM 3 times. The combined organic
layer were dried over MgSO4 and concentrated under reduced pressure.
Purification by flash column chromatography (PE:EE) yields 8c (141 mg,
43 %) as a orange solid. m.p.: 112 – 115 °C. Rf (PE:EE/5:1): 0.22. 1H-
NMR (300 MHz, CDCl3, ppm): 0.91 (t, J = 7.1 Hz, 3 H), 1.26 – 1.58 (m, 4
H), 1.66 – 1.97 (m, 14 H), 2.42 (br s, 1 H), 4.68 – 4.79 (m, 1 H); 13C-NMR
(75 MHz, CDCl3, ppm):13.9, 22.4, 27.9, 29.2, 31.9, 33.5, 65.3, 74.8,
113.5, 117.4, 122.7, 135.9, 137.0, 137.4, 184.6 HRMS (EI): calculated for
C19H23F3O2S4 [M]+: 468.0533, found: 468.0527.
2,2,6,6-Tetrapentylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-4,8-
dicarboxylic acid (7i). A 100 mL three-necked flask was charged with
3c (1.35 g, 2.64 mmol), dry n-hexane (30 mL) and TMEDA (800 µl, 5.28
mmol, 2 eq.). To the solution was added dropwise tert.-BuLi solution in
pentane (5.28 mL, 7.93 mmol, 3 eq.). The mixture was stirred at room
temperature for 1 h and cooled down to -20 °C. Dry CO2 gas was
bubbled through the mixture for 30 min and the mixture was allowed to
reach room temperature. To the slurry was added water and a yellow
precipitate was formed. After acidification with concentrated hydrochloric
acid, the mixture was extracted with DCM 8 times and concentrated in
vacuo. The crude product was refluxed with toluene and filtered after
cooling to 0 °C. The solid was washed with acetone until the filtrate
became colourless. The filtrate was concentrated in vacuo and purified
by flash column chromatography (DCM:MeOH:TFA) to yield 7i (1.13 g,
1-(2,2,6,6-Tetramethyl-8-(2,2,2-trifluoroacetyl)benzo[1,2-d:4,5-
d']bis([1,3]dithiole)-4-yl)pentan-1-one (8d). In a 50 mL flask, 8c (73 mg,
0.156 mmol) was dissolved in DCM (10 mL). DMP (132 mg, 0.312 mmol,
2 eq.) was added and the mixture was stirred at room temperature for 1.5
h. To the reaction was added a solution of sodium thiosulfate and sodium
hydrogen carbonate in water and the aqueous layer was extracted with
DCM 3 times. The combined organic layer were washed with 1M
hydrochloric acid, dried over MgSO4 and concentrated in vacuo.
Purification by flash column chromatography (DCM) afforded 8d (57 mg,
78 %) as orange solid. m.p.: 65 – 67 °C. Rf (PE:EE/5:1): 0.58. 1H-NMR
(300 MHz, CDCl3, ppm): 0.94 (t, J = 7.4 Hz, 3 H), 1.33 – 1.47 (m, 2 H),
1.64 – 1.77 (m, 2 H), 1.87 (s, 12 H), 2.94 (t, J = 7.25 Hz, 2 H); 13C-NMR
(75 MHz, CDCl3, ppm): 13.8, 22.3, 26.4, 30.5, 41.7, 65.7, 115.64 (q, J =
292 Hz), 124.7, 132.0, 136.7, 137.9, 184.2, 184.6, 202.1; HRMS (EI)
calculated for C19H21O2F3S4 [M]+: 466.0371, found: 466.0383; IR (cm-
1):2953, 2922, 1699, 1657, 1227, 1199, 1171, 1078, 979.
71
%)
as
an
dark-red
solid.
m.p.:
>300
°C.
Rf
(DCM:MeOH:TFA/100:1:0.4): 0.19. 1H-NMR (300 MHz, DMSO-d6, ppm):
0.69 – 0.93 (br m, 12 H), 1.10 – 1.53 (br m, 24 H), 1.78 – 1.97 (br m, 8
H); 13C-NMR (75 MHz, DMSO-d6, ppm): 13.8, 21.9, 24.9, 31.2, 40.6, 69.2,
122.6, 138.7, 166.9; HRMS (EI) calculated for C30H46O4S4 [M]+: 598.2279,
found: 598.2276; IR (cm-1): 2955, 2926, 2856, 2504, 1666, 1417, 1341
1254, 1202, 727.
8-(1-Hydroxypentyl)-2,2,6,6-tetramethylbenzo[1,2-d:4,5-
d']bis([1,3]dithiole)-4-carbaldehyde (8a). In a 50 mL three-necked flask
6a (220 mg, 0.7 mmol) was dissolved in dry TMEDA (10 mL), cooled to
0 °C and then n-BuLi solution in pentane (1.75 mL, 2.8 mmol, 4 eq.) was
added dropwise. After stirring for 3 h at room temperature, dry DMF (270
µl, 3.5 mmol, 5 eq.) was added and the resulting slurry was stirred for
another 30 min at room temperature. Water was added and the aqueous
layer was extracted with DCM 3 times. The combined organic layer were
dried over MgSO4 and concentrated under reduced pressure. Purification
by flash column chromatography (PE/EE) yields 8a (129 mg, 46 %) as a
yellow solid. m.p.: 145 - 147 °C. Rf (PE:EE/5:1): 0.39 1H-NMR (300 MHz,
CDCl3, ppm): 0.91 (t, J = 7.1 Hz, 3 H), 1.23 – 1.58 (m, 4 H), 1.68 – 2.01
(m, 14 H), 2.34 (br s, 1H), 4.75 – 4.82 (m, 1 H), 10.08 (s, 1 H); 13C-NMR
(75 MHz, CDCl3, ppm):13.9, 22.4, 27.9, 29.8, 32.8, 33.4, 64.3, 74.7,
124.8, 135.6, 138.4, 141.3, 188.6; HRMS (EI): calculated for C18H24O2S4
[M]+: 400.0659, found: 400.0652. IR (cm-1):3325, 2952, 2926, 2858, 1670,
1366, 1250, 1168, 1036, 1000.
8-Formyl-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-4-
carboxylic acid (8e). In a 50 mL three-necked flask, dry DMSO (80 µl,
1.12 mmol, 4.5 eq.) was dissolved in dry DCM (10 mL) followed by
cooling to -78 °C. Oxalyl chloride (86 µl, 0.999 mmol, 4 eq.) was added
dropwise and the mixture was stirred at that temperature for 30 min. To
the reaction was added a solution of 11 (90 mg, 0.250 mmol) in dry
DMSO (10 mL) and was allowed to stir additional 30 min at that
temperature. Triethylamine (350 µl, 2.50 mmol, 10 eq.) was added and
the mixture was stirred at room temperature for 30 min. 1M hydrochloric
acid was added, the aqueous layer was extracted with ethyl acetate 3
times, the combined organic layers were dried over MgSO4.
Concentration under reduced pressure was followed by flash column
chromatography (DCM:AcOH). 8e (55 mg, 61 %) was obtained as a dark
red solid. m.p. >300 °C. Rf (DCM:AcOH/50:1): 0.24; 1H-NMR (300 MHz,
DMSO-d6, ppm): 1.82 (s, 12 H), 10.04 (s, 1 H); 13C-NMR (75 MHz,
DMSO-d6, ppm): 32.0, 63.9, 126.7, 140.8, 141.2, 167.4, 190.0; HRMS
(EI) calculated for C14H14O3S4 [M]+: 357.9826, found: 357.9834; IR (cm-
1): 3384, 2921, 2855, 2255, 1847, 1556, 1216, 985.
2,2,6,6-Tetramethyl-8-pentanoylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-
4-carbaldehyde (8b). In a 50 mL flask, 8a (113 mg, 0.282 mmol) was
dissolved in DCM (25 mL). DMP (240 mg, 0.564 mmol, 2 eq.) was added
and the mixture was stirred at room temperature for 10 min. To the
(2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-4-
yl)methanol (10). 6a (340 mg, 1.08 mmol) was dissolved in a 100 mL
flask containing THF (20 mL) und cooled down with an ice-bath. NaBH4
(82 mg, 2.16 mmol, 2 eq.) was dissolved in water (10 mL) and added
dropwise to the solution which decolorized quickly. After stirring for 30
min at room temperature, 1M hydrochloric acid was carefully added until
residue NaBH4 was completely quenched. The mixture was extracted
with DCM 3 times, the combined organic layer were dried over MgSO4
and concentrated in vacuo, yielding 10 (339 mg, 99 %) as a white-yellow
solid which was used without further purification. m.p.: 130°C. Rf
(PE:EE/5:1): 0.37; 1H-NMR (300 MHz, CDCl3, ppm): 1.89 (s, 12 H), 4.56
(s, 2 H), 7.01 (s, 1 H); 13C-NMR (75 MHz, CDCl3, ppm): 31.3, 65.1, 116.3,
129.4, 135.8, 136.5; HRMS (EI): calculated for C13H16OS4 [M]+: 316.0079,
found: 316.0086; IR (cm-1): 3451, 2860, 2958, 2916, 1403, 1364, 1149,
1123, 1041, 964.
reaction was added
a solution of sodium thiosulfate and sodium
hydrogen carbonate in water and the aqueous layer was extracted with
DCM once. The combined organic layer were dried over MgSO4 and
concentrated in vacuo. Purification by flash column chromatography
(PE:EE) afforded 8b (109 mg, 97 %) as orange solid. m.p.: 108 - 109 °C.
Rf (PE:EE/15:1): 0.48. 1H-NMR (300 MHz, CDCl3, ppm): 0.92 (t, J = 7.3
Hz, 3 H), 1.31 – 1.45 (m, 2 H), 1.63 – 1.75 (m, 2 H), 1.88 (s, 12 H), 2.92
(t, J = 7.3 Hz, 2 H), 10.12 (s, 1 H); 13C-NMR (75 MHz, CDCl3, ppm): 13.8,
22.3, 26.4, 31.3, 41.9, 64.9, 125.7, 133.1, 136.7, 141.5, 188.6, 203.0;
HRMS (EI) calculated for C18H22O2S4 [M]+: 398.0503, found: 398.0499;
IR (cm-1):2952, 2926, 1672, 1657, 1367, 1352, 1221, 1167, 1151, 945.
2,2,2-Trifluoro-1-(8-(1-hydroxypentyl)-2,2,6,6-tetramethylbenzo[1,2-
d:4,5-d']bis([1,3]dithiole)-4-yl)ethan-1-one (8c). In a 50 mL three-
necked flask 3 (220 mg, 0.7 mmol) was dissolved in dry TMEDA (10 mL),
cooled to 0 °C and then n-BuLi solution in pentane (1.75 mL, 2.8 mmol, 4
eq.) was added dropwise. After stirring for 3 h at room temperature,
2,2,2-trifluoro-N-methoxy-N-methylacetamide (364 µl, 3.15 mmol, 4.5 eq)
8-(Hydroxymethyl)-2,2,6,6-tetramethylbenzo[1,2-d:4,5-
d']bis([1,3]dithiole)-4-carboxylic acid (11). A 100 mL three-necked
flask was charged with 10 (300 mg, 948 µmol) and dry TMEDA (20 mL).
To the solution was added dropwise n-BuLi solution in pentane (2.53 mL,
3.79 mmol, 4 eq.). The mixture was stirred at room temperature for 1 h
and cooled down to -20 °C. Dry CO2-Gas was bubbled through the
was added and the resulting slurry was stirred for
1 h at room
temperature. Water und 1M hydrochloric acid were added and the
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000093
European Journal of Organic Chemistry
FULL PAPER
mixture for 30 min and the mixture was allowed to reach room
temperature. To the slurry was added water and cooled down to 0 °C.
Concentrated hydrochloric acid was carefully added and the resulting
orange precipitate was extracted with ethyl acetate. Drying over MgSO4,
removal of the solvent in vacuo, followed by flash column
chromatography (DCM:AcOH), yielding 11 (109 mg, 25 %) as a yellow-
orange solid. m.p.: >300 °C. Rf (DCM:AcOH/50:1): 0.19. 1H-NMR (300
MHz, DMSO-d6, ppm): 1.78 (s, 12 H), 4.33 (s, 2 H); 13C-NMR (75 MHz,
DMSO-d6, ppm): 30.9, 61.7, 63.2, 132.9, 136.1, 139. 1, 166.8; HRMS (EI)
calculated for C14H16O3S4 [M]+: 359.9982, found: 359.9972; IR (cm-1):
2958, 2915, 2852, 1702, 1670, 1365, 1261, 1230, 1157, 1152.
carefully and the organic layer was separated. The aqueous layer was
washed quickly with DCM once and then acidified with concentrated
hydrochloric acid. The white precipitated was collected, washed with
water and dissolved in DCM. The insoluble residue was discarded. All
steps were carried out as quickly as possible. After concentration and
drying in vacuum, 16 (998 mg, 60 %) was obtained as a very oxygen
sensitive white solid, which was directly used without further purification.
1
m.p.: 119 - 123 °C. H-NMR (300 MHz, CDCl3, ppm): 3.70 (s, 4 H), 7.41
(s, 2 H); 13C-NMR (75 MHz, CDCl3, ppm): 129.9, 132.8; HRMS (EI)
calculated for C6H6S4 [M]+: 205.9352, found: 205,9344; IR (cm-1): 2976,
2958, 2916, 1724, 1425, 1284, 1258, 1157, 1134, 1093.
Benzo[1,2-d:4,5-d']bis([1,3]dithiole)-2,6-dione (12). In a 1 l three-
necked flask 5 (30 g, 69.64 mmol) was suspended in dry pyridine (500
mL). After heating to 100 °C sodium (8.65 g, 376.06 mmol, 5.4 eq.) in
pieces was added to the mixture which turned reddish. Heating was
continued for 3 h after which the mixture was cooled down to -5 °C. 20 %
phosgene solution in toluene (110 mL, 208.92 mmol, 3 eq.) was added
very carefully over a dropping funnel and the resulting slurry was stirred
for 30 min at that temperature. After the carefully addition of 100 mL ice-
cold water the mixture was poured on 400 mL of ice water. The
precipitate was collected and washed thoroughly with water and
methanol. After recrystallization with toluene, 12 (9.87 g, 55 %) was
obtained as beige needles. m.p.: >300 °C. IR (cm-1):3004, 2970, 2947,
1738, 1634, 1432, 1366, 1229, 1217, 1206.
3-(2,6,6-Trimethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-2-yl)propan-1-
ol (17). In a 250 mL Schlenk flask 5 (10 g, 23.21 mmol) was refluxed with
degassed toluene (150 mL) and tetrafluoroboric acid diethyl ether
complex (6.37 mL, 46.43 mmol, 2 eq.) for 3 h. After cooling to room
temperature, boron trifluoride diethyl ether complex (5.73 mL, 46.43
mmol, 2 eq.) was added followed by the addition of 25 (4.32 g, 23.21
mmol). The mixture was stirred at room temperature for 2h after which
acetone (2.56 mL, 34.82 mmol, 1.5 eq.) was added and stirring at room
temperature was continued for
2 h. Saturated sodium hydrogen
carbonate solution was added and the aqueous layer was extracted with
DCM 3 times. The combined organic layers were concentrated under
reduced pressure after which the beige solid was refluxed with methanol
(100 mL) and NaOH (7.58 g, 189.46 mmol, 8 eq.) for 3 h. After removal
of the solvent in vacuum, water was added and the mixture was
extracted with DCM 3 times. The combined organic layers were dried
over MgSO4 and concentrated under reduced pressure. Purification by
flash column chromatography (PE:EE) yields 17 (2.50 g, 32 %) as a
white solid. m.p.: 142 – 146 °C. Rf (PE:EE/1:1): 0.53. 1H-NMR (300 MHz,
CDCl3, ppm): 1.72 – 1.93 (m, 11 H), 2.17 – 2.19 (m, 2 H), 3.65 (t, J = 6.3
Hz, 2 H), 6.99 (s, 2 H); 13C-NMR (75 MHz, CDCl3, ppm): 29.4, 29.5, 31.2,
31.3, 39.9, 62.4, 65.7, 69.7, 116.5, 135.4, 135.6; HRMS (EI) calculated
for C14H18OS4 [M]+: 330.0241, found: 330.0242; IR (cm-1): 2379, 1964,
2921, 1448, 1422, 1363, 1256, 1091, 1065, 849.
6,6-Dimethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-2-one (14). 12 (900
mg, 69.64 mmol) was suspended in dry THF (150 mL) in a 250 mL three-
necked flask. Lithium methanolate in methanol (3.17 mL, 6.97 mmol, 2
eq.) was added dropwise after which the slurry completely turned to a
brown solution. Continuous stirring for 1 h at room temperature is
followed first by slow addition of tetrafluoroboric acid diethyl ether
complex (1.05 mL, 7.66 mmol, 2.2 eq.), then boron trifluoride diethyl
ether complex (946 µl, 7.66 mmol, 2.2 eq.) and finally acetone (1.54 mL,
20.90 mmol, 6 eq.). The mixture is stirred at room temperature for 30 min
and under refluxed for 4 h. Saturated sodium hydrogen carbonate
solution is added and the aqueous layer was extracted with DCM 3 times
followed by drying over MgSO4 and concentration in vacuum. Purification
by flash column chromatography (PE:EE) yields 14 (433 mg, 46 %) as a
reddish solid. m.p.: 152 – 154 °C. Rf (PE:EE/10:1): 0.5. 1H-NMR (300
MHz, CDCl3, ppm): 1.93 (s, 6 H), 7.30 (s, 2 H); 13C-NMR (75 MHz, CDCl3,
ppm): 31.3, 66.0, 116.5, 129.0, 138.6, 189.6; HRMS (EI) calculated for
C10H8OS4 [M]+: 271.9453, found: 271.9449; IR (cm-1): 2969, 1737, 1641,
1447, 1425, 1366, 1332, 1217, 1094, 855.
2-(3-Hydroxypropyl)-2,6,6-trimethylbenzo[1,2-d:4,5-
d']bis([1,3]dithiole)-4,8-dicarbaldehyde (18). A 50 mL three-necked
flask was charged with 17 (230 mg, 0.696 mmol and dry TMEDA (10 mL).
To the solution was added dropwise n-BuLi solution in pentane (2.32 mL,
5.57 mmol, 8 eq.). The mixture was stirred at room temperature for 2 h
and cooled down to 0 °C. Dry DMF (535 µl, 6.96 mmol, 10 eq.) was
added and the reaction was allowed to stir for 30 min at room
temperature. Water was added after which a color change to dark red
followed. The aqueous layer was extracted with DCM 3 times and the
combined organic layers were dried over MgSO4. After concentration in
vacuum, the crude product was purified by flash column chromatography
(PE:EE) yielding 18 (102 mg, 38 %) as a blackish red solid. m.p.: 170 –
172 °C. Rf (PE:EE/1:1): 0.39. 1H-NMR (300 MHz, CDCl3, ppm): 1.77 –
1.96 (m, 11 H), 2.11 – 2.22 (m, 2 H), 3.69 (t, J = 6.2 Hz, 2 H), 10.17 (s, 2
H); 13C-NMR (75 MHz, CDCl3, ppm): 29.4, 30.5, 31.8, 31.9, 40.4, 62.3,
65.6, 69.7, 126.7, 141.7, 188.8; HRMS (EI) calculated for C16H18O3S4
[M]+: 386.0139, found: 386.0129; IR (cm-1): 3364, 2919, 2850, 1671,
1358, 1225, 1171, 1151, 1055, 856.
3-(2,6,6-Trimethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-2-yl)propyl
pivalate (15). In a 100 mL three-necked flask 14 (200 mg, 0.734 mmol)
was dissolved in dry THF (25 mL) and lithium methanolate in methanol
(834 µl, 1.84 mmol, 2.5 eq.) was added dropwise. The solution turned
cloudy and was stirred for 1 h at room temperature. Tetrafluoroboric acid
diethyl ether complex (352 µl, 2.57 mmol, 3.5 eq.), then boron trifluoride
diethyl ether complex (181 µl, 1.47 mmol, 2 eq.) and 25 (205 mg, 1.10
mmol, 1.5 eq.) were added. The mixture was allowed stir at room
temperature for 16 h after which saturated sodium hydrogen carbonate
solution was added and the aqueous layer was extracted with DCM 3
times. The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. Purification by flash column
chromatography (PE:EE) yields 15 (166 mg, 55 %) as a white waxy solid.
m.p.: 86 – 88 °C. Rf (PE:EE/15:1): 0.43. 1H-NMR (300 MHz, CDCl3,
ppm): 1.19 (s, 9 H), 1.82 – 1.92 (m, 11 H), 2.05 – 2.18 (m, 2 H) 4.09 (t, J
= 6.2 Hz, 2 H), 7.01 (s, 2 H); 13C-NMR (75 MHz, CDCl3, ppm): 25.8, 27.2,
29.1, 31.2, 31.4, 38.8, 40.0, 63.7, 65.8, 69.5, 116.7, 135.3, 135.8, 178.4;
HRMS (EI) calculated for C19H26O2S4 [M]+: 414.0810, found: 414.0807.
4-(3-(4,8-Diformyl-2,6,6-trimethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-
2-yl)propoxy)-4-oxobutanoic acid (19). In a 25 mL Schlenk flask 18 (55
mg, 0.142 mmol), dry pyridine (115µl, 1.42 mmol, 10 eq.) and a spatula-
tip of DMAP were dissolved in dry DCM (10 mL). Upon adding succinic
anhydride (71 mg, 0.711 mmol, 5 eq.) the mixture was stirred at room
temperature for 16 h. Water was added and the mixture was extracted
twice with DCM. The combined organic layers were washed twice with
saturated sodium hydrogen carbonate solution and than twice with 1 M
hydrochloric acid and dried over MgSO4. Concentration in vacuum yields
19 (60 mg, 87 %) as a blackish red solid, which was pure enough for
further use. m.p.: 80 – 82 °C. Rf (DCM:MeOH:TFA/50:1:0.1): 0.19 1H-
NMR (300 MHz, CDCl3, ppm): 1.86 – 1.96 (m, 11 H), 2.04 – 2.18 (m, 2 H),
2.54 – 2.74 (m, 4 H), 4.03 – 4.22 (m, 2 H), 10.17 (s, 2 H); 13C-NMR (75
Benzene-1,2,4,5-tetrathiol (16). 5 (3.5 g, 8.12 mmol) was refluxed with
degassed toluene (60 mL) and tetrafluoroboric acid diethyl ether complex
(2.23 mL, 16.25 mmol, 2 eq.) in a 250 mL Schlenk flask for 1 d. After
cooling to room temperature, degassed 12% NaOH (30 mL) was added
10
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000093
European Journal of Organic Chemistry
FULL PAPER
MHz, CDCl3, ppm): 25.6, 28.8, 30.5, 31.8, 31.8, 40.4, 64.1, 65.8, 69.3,
126.7, 141.5, 141.8, 172.0, 177.6, 188.7; HRMS (EI) calculated for
C20H22O6S4 [M]+: 486.0294, found: 486.0289; IR (cm-1): 2959, 2923,
2851, 1731, 1711, 1674, 1358, 1227, 1166, 858.
tip of DMAP were dissolved in dry DCM (10 mL). Upon adding tosyl
chloride (99 mg, 0.517 mmol, 2 eq.) the mixture was refluxed for 3 h.
After cooling to room temperature water and 1 M hydrochloric acid were
added to the mixture, following by extraction twice with DCM. The
combined organic layers were washed with saturated sodium hydrogen
carbonate solution twice, dried over MgSO4 and concentrated in vacuum.
Purification by flash column chromatography (PE:EE) yields 23 (89 mg,
64 %) as a blackish red solid. m.p.: 133 – 134 °C. Rf (PE:EE/2:1): 0.58;
1H-NMR (300 MHz, CDCl3, ppm): 1.80 – 1.97 (m, 11 H), 2.01 – 2.11 (m,
2 H), 2.45 (s, 3 H), 4.06 (t, J = 5.8 Hz, 2 H), 7.35 (d, J = 7.9 Hz, 2 H),
7.77 (d, J = 8.3 Hz, 2 H), 10.15 (s, 2 H); 13C-NMR (75 MHz, CDCl3, ppm):
21.6, 25.8, 30.5, 31.8, 31.8, 40.1, 65.9, 68.9, 69.7, 126.7, 127.9, 129.9,
132.9, 141.3, 141.9, 144.9, 188.6; HRMS (EI) calculated for C23H24O5S5
[M]+: 540.0227, found: 540.0238; IR (cm-1): 2922, 1674, 1355, 1228,
1173,917, 858, 814, 733, 553.
3-(4,8-Diformyl-2,6,6-trimethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-2-
yl)propyl 4-oxo-4-(prop-2-yn-1-ylamino)butanoate (20). In a 25 mL
Schlenk flask 19 (35 mg, 0.072 mmol), propargylamine (20 µl, 0.316
mmol, 4.4 eq.) and a spatula-tip of N-hydroxysuccinimide were dissolved
in dry DCM (10 mL). Upon adding DCC (22 mg, 0.108 mmol, 1.5 eq.) the
mixture was stirred at room temperature for 5 h. The mixture was
concentrated to half in a N2 stream and cooled to ca -20 °C before
filtering. The filter was washed with cold DCM and the filtrate was
washed with 1 M hydrochloric acid, dried over MgSO4 and concentrated
in vacuum. Purification by flash column chromatography (DCM:MeOH)
yields 20 (28 mg, 74 %) as a blackish red solid. m.p.: 57 – 59 °C. Rf
(DCM:MeOH/50:1): 0.21; 1H-NMR (500 MHz, CDCl3, ppm): 1.88 - 198 (m,
11 H), 2.06 – 2.15 (m, 2 H), 2.24 (t, J = 2.5 Hz, 1 H), 2.50 (t, J = 6.6 Hz, 2
H), 2.68 (t, J = 6.6 Hz, 2 H), 4.05 (dd, J = 2.5 Hz, J = 2.2 Hz, 2 H), 4.12 (t,
J = 6.3 Hz, 2 H), 4.71 (t, J = 2.2 Hz, 1 H), 10.19 (s, 2 H); 13C-NMR (126
MHz, CDCl3, ppm): 25.7, 29.3, 29.3, 30.7, 30.8, 31.8, 31.9, 40.5, 64.1,
65.8, 69.3, 71.6, 79.5, 126.7, 141.5, 141.9, 188.7; HRMS (EI) calculated
for C23H25O5NS4 [M]+: 523.0616, found: 523.0605; IR (cm-1): 3003, 2970,
2950, 1738, 1672, 1448, 1366, 1229, 1217, 1172.
2-(3-Azidopropyl)-2,6,6-trimethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-
4,8-dicarbaldehyde (24). In 50 mL flask 23 (40 mg, 0.74 mmol) and
NaN3 (7 mg, 0.111 mmol, 1.5 eq.) were dissolved in dry DMF (7 mL) and
stirred at room temperature for 16 h. DCM was added and the mixture
was washed twice with saturated sodium hydrogen carbonate solution,
once with
1 M hydrochloric acid and dried over MgSO4. After
concentration vacuum 24 (28 mg, 92 %) was obtained as blackish red
viscous oil. Rf (PE:EE/5:1): 0.36; 1H-NMR (300 MHz, CDCl3, ppm): 1.73 –
1.98 (m, 11 H), 2.05 – 2.18 (m, 2 H), 3.34 (t, J = 6.6 Hz, 2 H), 10.17 (s, 2
H); 13C-NMR (75 MHz, CDCl3, ppm): 25.8, 30.4, 31.8, 41.1, 51.0, 65.8,
69.2, 126.7, 141.3, 141.9, 188.7; HRMS (EI) calculated for C16H17O2N3S4
[M]+: 411.0204, found: 411.0210; IR (cm-1): 2958, 2933, 2851, 2093,
1675, 1358, 1228, 1172, 1151, 858.
3-(4,8-Diformyl-2,6,6-trimethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-2-
yl)propyl (2,5-dioxopyrrolidin-1-yl) succinate (21). In a 25 mL Schlenk
flask 19 (55 mg, 0.142 mmol), N-hydroxysuccinimide (19 mg, 0.090 mmol,
1.1 eq.) and a spatula-tip of DMAP were dissolved in dry DCM (10 mL).
Upon adding DCC (11 mg, 0.090 mmol, 1.1 eq.) the mixture was stirred
at room temperature for 16 h. The mixture was concentrated to half in a
N2 stream and cooled to ca -20 °C before filtering. The filter was washed
with cold DCM and the filtrate was concentrated in vacuum. Purification
by flash column chromatography (PE:EE) yields 21 (40 mg, 83 %) as a
blackish red solid. m.p.: 66 – 68 °C. Rf (PE:EE/1:1): 0.39. 1H-NMR (500
MHz, CDCl3, ppm): 1.90 - 195 (m, 11 H), 2.08 – 2.14 (m, 2 H), 2.74 (t, J =
6.9 Hz, 2 H), 2.85 (br s, 4 H), 2.94 (t, J = 6.9 Hz, 2 H), 4.16 (t, J = 6.3 Hz,
2 H), 10.18 (s, 2 H); 13C-NMR (126 MHz, CDCl3, ppm): 25.6, 25.6, 26.3,
28.8, 30.4, 31.8, 31.9, 40.5 64.4, 65.7, 69.3, 126.7, 141.6, 141.8, 167.6,
168.8, 170.7, 188.7; HRMS (EI) calculated for C24H25O8NS4 [M]+:
583.0463, found: 583.0443; IR (cm-1): 2926, 2853, 1737, 1675, 1362,
1229, 1205, 1175, 1090, 1070.
4-Oxopentyl pivalate (25). In
a 250 mL three-necked flask 5-
hydroxypentan-2-one (10 g, 97.91 mmol) was dissolved in dry DCM (140
mL) and dry pyridine (20 mL, 2.45 mmol, 2.5 eq.). After addition of a
spatula tip of DMAP, the mixture was cooled down to 0 °C. Pivaloyl
chloride (24 mL, 195.8 mmol, 2 eq.) was added dropwise and the
reaction was allowed to stir for 16 h at room temperature. Water was
added to the mixture and the organic layer was washed twice with 20 %
ammonia solution, twice with 1 M hydrochloric acid and dried over
MgSO4. Concentration in vacuo yields 25 (13.92 g, 80 %) as colorless to
slightly yellow liquid which was directly used in the next step without
further purification. Rf (PE:EE/15:1): 0.16; 1H-NMR (300 MHz, CDCl3,
ppm): 1.14 (s, 9 H), 1.81 – 1.92 (m, 2 H), 2.11 (s, 3 H), 2.47 (t, J = 7.3 Hz,
2 H), 3.93 – 4.07 (m, 2 H); 13C-NMR (75 MHz, CDCl3, ppm): 22.7, 27.1,
29.8, 38.61, 39.7, 63.3, 178.3, 207.5; HRMS (ESI): calculated for
C10H19O3 [M+H+]: 187.1334; found: 187.1323.
3-(4,8-Diformyl-2,6,6-trimethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-2-
yl)propyl 4-((2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)amino)-4-
oxobutanoate (22). In a 25 mL Schlenk flask 19 (30 mg, 0.061 mmol)
and N-hydroxysuccinimide (9 mg, 0.074 mmol, 1.2 eq.) were dissolved in
dry DCM (8 mL). Upon adding EDCl (14 mg, 0.074 mmol, 1.2 eq.) the
mixture was stirred at room temperature for 5 h (monitoring by TLC). To
the mixture were added 32 (19 mg, 0.074 mmol, 1.2 eq.) and DIPEA (21
µl, 0.123 mmol, 2 eq.), followed by stirring at room temperature for 16 h.
Saturated sodium hydrogen carbonate solution was added and the
aqueous layer was extracted once with DCM. The combined organic
layers were washed with 1 M hydrochloric acid, dried over MgSO4 and
concentrated in vacuum. Purification by flash column chromatography
(DCM:MeOH) yields 22 (32 mg, 85 %) as blackish red solid. m.p.: 96 –
99 °C. Rf (DCM:MeOH/25:1): 0.30; 1H-NMR (300 MHz, CDCl3, ppm):
1.86 - 197 (m, 11 H), 2.07 – 2.17 (m, 2 H), 2.42 (t, J = 6.8 Hz, 2 H), 2.61
(t, J = 6.8 Hz, 2 H), 3.36 – 3.53 (m, 2 H), 3.63 – 3.74 (m, 2 H), 4.10 (t, J =
6.2 Hz, 2 H), 6.03 (br s, 1 H), 6.71 (s, 2 H), 10.18 (s, 2 H); 13C-NMR (126
MHz, CDCl3, ppm):25.7, 29.3, 30.7, 30.8, 31.8, 31.9, 37.6, 38.9, 40.4,
64.0, 65.8, 69.4, 126.7, 134.2, 141.5, 141.8, 170.8, 171.7, 172.8, 188.7;
HRMS (EI) calculated for C26H28O7N2S4 [M]+: 608.0774, found: 608.0772;
IR (cm-1): 1705, 1673, 1535, 1438, 1406, 1361, 1227, 1171, 728, 696.
tert.-Butyl (2-aminoethyl)carbamate (30). A 500 mL three-necked flask
was charged with ethane-1,2-diamine (30 mL, 458.19 mmol, 10 eq.) and
dry DCM (150 mL). Upon cooling with an ice bath, di-tert.-butyl
dicarbonate (10 g, 45.82 mmol) in DCM (100 mL) was added dropwise.
Stirring at room temperature for 16 h was followed by washing the
organic layer with water 3 times. The organic layer was dried over
MgSO4 and concentrated in vacuo. 30 (3.55g, 48 %) was obtained as
colorless oil. 1H-NMR (300 MHz, CDCl3, ppm): 1.21 (s, 2 H), 1.41 (s, 9 H),
2.69 – 2.81 (m, 2 H), 3.03 – 3.24 (m, 2 H), 5.02 (br s, 1 H); 13C-NMR (75
MHz, CDCl3, ppm):28.3, 41.8, 43.4, 79.1, 156.1.
tert.-Butyl (2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)carbamate
(31). In a 100 mL flask a mixture of maleic anhydride (1.60 g, 16.32
mmol), triethylamine (2.71 mL, 19.58 mmol, 1.2 eq.) and ethanol (40 mL)
was cooled down to 0 °C. 30 (3.14 g, 19.58 mmol, 1.2 eq.) was added
dropwise and stirring continued for 4 h. The solvent was removed in
vacuum completely and acetic anhydride (45 mL) and sodium acetate
(1.47 g, 17.95 mmol, 1.1 eq.) was added. The mixture was heated at
70 °C for 3 h before cooling with an ice bath. Saturated sodium hydrogen
carbonate solution was carefully added, followed by stirring for 15 min,
after which the mixture was extracted with DCM 3 times. The combined
organic layer were washed with 1 M hydrochloric acid twice, dried over
3-(4,8-Diformyl-2,6,6-trimethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-2-
yl)propyl 4-methylbenzenesulfonate (23). In a 25 mL Schlenk flask 18
(100 mg, 0.259 mmol), pyridine (84 µl, 1.03 mmol, 4 eq.) and a spatula-
11
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10.1002/ejoc.202000093
European Journal of Organic Chemistry
FULL PAPER
MgSO4 and concentrated in vacuum. Purification by flash column
chromatography (PE:EE), yields 31 (3.36 g, 86 %) as a white solid. Rf
(PE:EE/1:1): 0.50. 1H-NMR (300 MHz, CDCl3, ppm): 1.38 (s, 9 H), 2.23 –
2.37 (m, 2 H), 3.59 – 3.70 (m, 2 H), 4.82 (br s, 1 H), 6.70 (s, 2 H); 13C-
NMR (75 MHz, CDCl3, ppm): 28.2, 37.9, 39.3, 79.4, 134.1, 170.8; HRMS
(EI) calculated for C11H16O4N2 [M]+: 240.1105, found: 240.1101.
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1H-NMR (300 MHz, DMSO-d6, ppm): 2.99 (t, J = 5.8 Hz, 2 H), 3.66 (t, J =
5.9 Hz, 2 H), 7.05 (s, 2 H), 8.04 (br s, 3 H); 13C-NMR (75 MHz, DMSO-d6,
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Keywords: fluorescence dyes • sulfur • heterocycles • Stokes
shift • photophysics
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10.1002/ejoc.202000093
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Replacing oxygen by sulfur atoms substantially changes the photophysical behavior of DBD dyes. While fluorescence quantum yields
and lifetimes are decreased, absorption and emission wavelength markedly red-shifted. Especially to be emphasized the very large
Stokes shifts. A series of S4-DBD dyes with different electron withdrawing groups were prepared enabling a broad range of emission
wavelength.
Key topic: fluorescence dyes
13
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