Bay-Substituted Thiaza[5]helicenes: Synthesis and Implications on Structural and Spectroscopic Properties

Article abstract of DOI:10.1021/acs.joc.9b01793

A series of bay-substituted thiaza[5]helicenes was synthesized to investigate the effect of different substituents on the properties of these helicenes. These thiaza[5]helicenes with different substituents were prepared in a straightforward manner through indole- and benzo[b]thiophene synthesis, palladium-catalyzed Suzuki coupling, oxidative cyclization, and functional group interconversion reactions. We investigated the impact of these different bay area substituents compared to the unsubstituted thiaza[5]helicene on the structural parameters and studied the steady-state electronic spectroscopy of these thiaza[5]helicenes in toluene and acetonitrile. We found that different functional groups influence the solid state structure and spectroscopic properties, but a single substituent in the bay area of a thiaza[5]helicene was not enough to prevent enantiomerization at room temperature.

Full text of DOI:10.1021/acs.joc.9b01793

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Article
Bay substituted thiaza[5]helicenes: Synthesis and
implications on structural and spectroscopic properties
Mathias Daniels, Flip de Jong, Tom Vandermeeren, Luc
Van Meervelt, Mark Van der Auweraer, and Wim Dehaen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01793 • Publication Date (Web): 23 Sep 2019
Downloaded from pubs.acs.org on September 24, 2019
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Bay substituted thiaza[5]helicenes: Synthesis and
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implications on structural and spectroscopic properties
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Mathias Daniels,[a] Flip de Jong,[b] Tom Vandermeeren,[a] Luc Van Meervelt,[c] Mark Van
der Auweraer,[b] and Wim Dehaen*[a]
[a]
Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Leuven
Chem&Tech Celestijnenlaan 200F, B-3001 Leuven, Belgium wim.dehaen@kuleuven.be
[b]
Molecular Imaging and Photonics, Department of Chemistry, KU Leuven, Leuven
Chem&Tech - Celestijnenlaan 200F, B-3001 Leuven, Belgium.
[c]
Biochemistry, Molecular and Structural Biology, Department of Chemistry, KU Leuven,
Leuven Chem&Tech - Celestijnenlaan 200F, B-3001 Leuven, Belgium.
Abstract
A series of bay substituted thiaza[5]helicenes was synthesised to investigate the effect of
different substituents on the properties of these helicenes. These thiaza[5]helicenes with
different substituents were prepared in a straightforward manner through indole- and
benzo[b]thiophene synthesis, palladium catalysed Suzuki coupling, oxidative cyclization and
functional group interconversion reactions. We investigated the impact of these different bay
area substituents compared to the unsubstituted thiaza[5]helicene on the structural
parameters and studied the steady state electronic spectroscopy of these thiaza[5]helicenes
in toluene and acetonitrile. We found that different functional groups influence the solid state
structure and spectroscopic properties, but a single substituent in the bay area of a
thiaza[5]helicene was not enough to prevent enantiomerisation at room temperature.
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Introduction
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Substituents in the bay area (or fjord region) of helicenes generally increase the
enantiomerisation barrier and torsion angle in the helicene1. The effect of some bay area
substituents in pentahelicene was reported by Juríček et al. who prepared a series of
disubstituted [5]helicenes with fluorine-, methoxy- and methyl- substituents and compared the
barrier of enantiomerisation and torsion angle with literature values of mono- and
unsubstituted [5]helicenes1. This is one of few studies on the relation between substituents
and structure performed on [5]helicenes and to our knowledge no such study on
heterahelicenes was reported. Benzothieno[2,3-c]carbazoles or thiaza[5]helicenes are ideal
to investigate the influence of different functional groups on the enantiomerisation barrier and
torsion angle. We expect the unsubstituted derivative to have a very small helical pitch based
on the structure determination of indolo[2,3-c]carbazole, being virtually flat2, and benzo[1,2-
b:4,3-b']bis[1]benzothiophene having an interplanar angle of 31,7°3. Hence the functional
group is expected to have a large influence on the physical properties of thiaza[5]helicenes.
Surprisingly, only one report on the synthesis of a compound containing this scaffold is known.
In this report, Ito, Itami and coworkers used a palladium-catalysed one-step annulative -
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extension
(APEX)
reaction
between
N-methylindole
and
3,3’-diiodo-2,2’-
bibenzo[b]thiophene4. Solid state structure elucidation of this compound substantiated our
assumption that the helical pitch of thiaza[5]helicenes is small. Previously other
benzo[b]thiophene fused carbazoles have been prepared from dibenzothiophenes using a
Cadogan-reaction for the carbazole formation5–7. This reaction usually requires rather harsh
conditions and is incompatible with some functional groups. A benzo fused thiaza[5]helicene
could be prepared through oxidative cyclisation, which has been proven to be suitable for the
preparation of similar ring systems in previous work8,9. With heteroaromatic systems only mild
conditions are needed, and with reagents like DDQ (2,3-Dichloro-5,6-dicyano-1,4-
benzoquinone) of FeCl3, the desired bond formation can be accomplished efficiently10.
Results and Discussion
Synthesis of thiaza[5]helicenes
A strategy was designed that would give easy access to both unsubstituted- and bay
substituted thiaza[5]helicenes. The synthesis of the precursors includes a 2-phenylindole
producing reaction or a 2-phenylbenzo[b]thiophene preparation followed by a palladium
catalysed Suzuki coupling. These precursors can then be cyclised under oxidative conditions
to yield the desired helicene. The high functional group compatibility of these methods
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combined with functional group interconversion enabled us to prepare several analogues in
an uncomplicated manner.
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The unsubstituted indole 2a was prepared through a Fischer indole synthesis with
2’bromoacetophenone 1 and phenylhydrazine. We replaced polyphosphoric acid in an
existing procedure with methane sulfonic acid as it is less troublesome to handle11. Nitro-
substituted indole 2b was synthesised using a Makosza reaction, this lesser known indole
synthesis can be used to prepare 4-nitroindoles in a single step from ketones and 3-
nitroaniline12. The base mediated reaction has a high selectivity for the formation of 4-
nitroindole, and in our case only a trace amount of the 6-nitroindole is detected on TLC but
not isolated. Originally, reaction conditions were described using potassium tert-butoxide as
base, but we observed a slight increase in isolated yield when using the sodium salt. We also
observe a decrease in isolated yield on working at a larger scale. Alkylation of indole 2b with
bromoethane delivered compound 3b in quantitative yield using potassium carbonate in
dimethyl sulfoxide. Alkylation of indole 2a with bromoethane and potassium hydroxide in
dimethyl sulfoxide resulted in the isolation of compound 3a in 91% yield. In the alkylation
reaction of indole 2a a stronger base is needed than for indole 2b with an electron withdrawing
nitro group. When potassium carbonate was used, the desired compound 3a was observed,
but conversion is rather slow. (Scheme 1) We found that N-alkylation (even with a relatively
short alkyl chain) resulted in a significant increase in solubility.
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phenylhydrazine
CH3SO3H, 100°C
(R=H)
C2H5
KOH, C2H5Br
DMSO, RT
(R=H)
O
HN
N
R
R
3-nitroaniline
NaOt-Bu, DMSO,
RT, air
Br
Br
Br
K2CO3, C2H5Br
DMSO, RT
(R=NO2)
1
3a
3b
, R=H, 91%
, R=NO2, Quant.
2a
2b
, R=H, 78%
, R=NO2, 70%
(R=NO2)
Scheme 1: Synthesis indoles through Fischer- or Makosza reaction and alkylation
Base mediated condensation reactions of benzylthiols and ortho-halobenzaldehydes are well
known for the formation of benzo[b]thiophenes. Often, these reactions are performed on room
temperature. According to Patel et al.13, ortho-chlorobenzylthiol required higher temperatures
for the conversion to the corresponding benzo[b]thiophene. It was reported that only the
intermediate cyclisation product was formed at 50-60°C and a temperature increase to 140°C
was needed for dehydration to the corresponding benzo[b]thiophene. During initial
experiments, we detected similar intermediates, and heating at 150°C was needed to
efficiently convert these to benzo[b]thiophene 6 (scheme 2) as the steric hindrance was more
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pronounced. It appears 2-bromobenzylthiol 4 is a challenging substrate as the conditions
reported by Patel and coworkers resulted in the formation of benzo[b]thiophene 6 in only low
yield. A selection of the screened reaction conditions for the synthesis of benzo[b]thiophene 6
through a base mediated condensation reaction between 2-chlorobenzaldehyde 5 and 2-
bromobenzylthiol 4 can be found in Table S1 (SI).
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CHO
S
Cs2CO3
DMF, 150°C
Cl
SH
Br
Br
, 80%
4
5
6
Scheme 2: Base mediated benzo[b]thiophene formation
Suzuki reaction between aryl bromides 3a-b and benzo[b]thiophene boronic acid 7 in a
tetrahydrofuran/water solvent mixture in combination with potassium carbonate and
tetrakis(triphenylphosphine)palladium catalyst resulted in the isolation of compound 9a in 92%
yield and compound 9b in 85% yield (Scheme 3). Compound 9c was prepared from bromide
6 in 87% through Suzuki-coupling with boronic acid 8 using the same conditions (Scheme 3).
C2H5
Pd(PPh3)4, K2CO3,
THF/H2O (4:1)
100°C
Pd(PPh3)4, K2CO3,
THF/H2O (4:1)
100°C
N
C2H5
N
Br
S
R
R
CN
(HO)2B
Br
S
(HO)2B
S
N
3a
, R=H
6
7
3b
, R=NO2
9a
9b
9c
, R=H, 92%
, R=NO2, 85%
, R=CN, 87%
8
Scheme 3: Suzuki coupling and oxidative cyclisation
In several cases, both iron trichloride and DDQ perform well as reagents for oxidative
cyclisation. When we compared both conditions before, we discovered that the DDQ/BF3 Et2O
system superior to iron trichloride, delivering the highest isolated yield and fastest reaction
speed8. When comparing these conditions for the synthesis of helicene 10b, we observed
similar results. The isolated yield of the reaction with DDQ/BF3 Et2O was 93%, while the
reaction with iron trichloride only delivered 87% of helicene 9b. In addition, complete
conversion of compound 9b was obtained after shorter reaction time, making this system the
most convenient. (scheme 4) This was also observed in the oxidative cyclisation of compound
9a and 9c, where these conditions deliver helicenes 10a and 10c in good yields. One of the
target compounds was carboxylic acid substituted thiaza[5]helicene 10d. We anticipated that
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the most straightforward approach would be to subject nitrile 10c to acidic or basic hydrolysis.
After screening different reaction conditions shown in Table S2 (SI), solubility of compound
10c in the solvent used appeared to affect the conversion, but during these reactions, no
carboxylic acid 10d was formed and only amide 10e was detected. Hydrolysis of nitrile 10c in
2-(2-methoxyethoxy)ethanol with sodium hydroxide at 150°C resulted in the most rapid
conversion. Amide 10e was isolated after 2 hours in 90% yield. In our opinion, steric hindrance
most likely prevents the further hydrolysis to carboxylic acid 10d. After a small change in the
reaction sequence, we were able to obtain carboxylic acid substituted helicene 10d. Hydrolysis
of nitrile 9c proceeded readily in 2-(2-methoxyethoxy)ethanol with sodium hydroxide at 150°C,
and carboxylic acid 9d was obtained in high yield. Oxidative cyclisation of compound 9d was
performed using the DDQ and BF3.Et2O system and resulted in the formation of helicene 10d
in excellent yield.
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C2H5
C2H5
N
S
DDQ, BF3Et2O
DCM
N
S
R
0°C
R
9a
9b
9c
9d
, R=H
, R=NO2
, R=CN
10a
10b
10c
10d
10e
, R=H, 96%
, R=NO2, 93%
, R=CN, 75%
, R=COOH, 97%
, R=CONH2,
NaOH
2-(2-Methoxyethoxy)-
ethanol
NaOH
2-(2-Methoxyethoxy)-
ethanol
, R=COOH
150°C, 90%
150°C, 90%
Scheme 4: Oxidative cyclisation and hydrolysis of nitrile
Palladium catalysed reduction of the nitro-group of helicene 10b to aminohelicene 10f
occurred in ethyl acetate with hydrazine hydrate as hydrogen source. The same reaction under
hydrogen atmosphere was also tested, and on small scale, the isolated yield was only slightly
lower. The main difference was the duration of larger scale reactions until complete
conversion. A large-scale reaction under hydrogen atmosphere proceeded significantly slower
than the reaction with hydrazine hydrate. Compound 10f is somewhat sensitive to oxygen,
and decomposed when exposed to air at ambient temperature in solution, but can be stored
in solid form without observable decomposition (scheme 5).
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O
4
5
6
7
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C2H5
C2H5
N
C2H5
O
N
S
O
N
Pd/C
11
O
NO2
NH2
N
N2H4.H2O
EtOAc, RT
O
DMF, 150°C
S
S
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10b
10f
10g
, 64%
, 58%
Scheme 5: Reduction of nitrohelicene 10b and phthalimide protection of aminohelicene 10f
Phthalimide protection of amine 10f was carried out with phthalic anhydride 11 in
dimethylformamide at high temperature (150 °C, scheme 5). Noticeable decomposition is
observed during reaction in dimethylformamide, however solvent free conditions result in even
more degradation. Considering that decomposition could be caused by polar solvents, toluene
was tested as an alternative, but no conversion of compound 10f to product 10g was
observed.
In an effort to determine the enantiomerisation barrier of bay substituted thiaza[5] helicenes
10b-f, separation of enantiomers using chiral HPLC was attempted, but could not be achieved
at room temperature. This is probably due to the limited steric hindrance in the bay area,
allowing the investigated thiaza[5]helicenes with a single bay area substituent to
enantiomerise at ambient conditions.
Solid state structure analysis
The three parameters commonly used to determine helicity are helical pitch, the interplanar
angle (figure S1, SI) and torsion angles (figure S2, SI). As in our opinion, the interplanar angle
is a good measure for helicity in small organic molecules, we compared the interplanar angle
of the substituted and unsubstituted thiaza[5]helicenes. The benzene ring fusion of
thiaza[5]helicenes 10a-g contributes to the rigidity of these helicenes, probably lowering the
the interplanar and torsion angles compared to non-fused helicenes. Single crystals of
helicenes 10a-g were subjected to X-ray analysis (molecular structures are shown in figures
1-7, crystal packing can be found in figures S4-10 (SI) and structural data can be found in
Table 1). In the solid state, the conformation of these compounds can be studied easily. As
expected, the two molecules in the asymmetric unit of unsubstituted helicene 10a have a
rather low interplanar angle (7.92(12)° and 20.70(12)°) and the interplanar angles of the
helicenes with substituents in the bay area are all convincingly larger. Helicene 10d with acid
substituent (24.5(2)° and 31.4(3)°) and helicene 10b with nitro substituent (31.08(19)°) have
similar interplanar angles. This angle is larger in both aminohelicene 10f (37.50(14)°) and
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phthalimide 10g (34.52(15)°). In the aminohelicene 10f this could be explained by steric effects
because of the stronger sp3 hybridisation character of the nitrogen in the amine, compared to
sp2 hybridisation of the nitrogen in the nitro group. More surprising is the similarity in
interplanar angles of helicene 10c with nitrile substituent (28.38(10)° and 35.73(9)°) and
helicene 10e with amide substituent (30.9(3)° and 36.1(3)°). We would expect an increase in
steric hindrance because of the presence of the extra oxygen atom, but the differences in
interplanar angles are only small. Not only differences in steric hindrance, but other
parameters, like crystal packing, influence the structure. Differences in interplanar angle
because of crystal packing are standing out when the asymmetric unit consists of more than
one molecule. This difference is largest in helicene 10a, where the interplanar angle more than
doubled from 7.92(12)° to 20.70(12)°.
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The sum of the torsion angles in the bay area of the [5]helicene is a good measure for the
distortion of the molecule. We discovered when ranking the sum of torsion angles, that the
order is very similar to this of the interplanar angles. Distortion in the unsubstituted helicene
10a is small (30.2(7)° and 15.0(6)°) and the difference between the two molecules in the
asymmetric unit is quite large. The distortion in helicene 10b with nitro substituent (40.2(11)°)
and helicene 10d with acid substituent (38.7(14)° and 42.3(16)°) is similar. The same was
observed in the case of helicene 10e with amide substituent (45.0(16)° and 41.9(17)°) and
helicene 10c with nitrile substituent (46.6(5)° and 39.3(6)°). Analogous with the interplanar
angle, distortion is notably larger in both helicene 10g with phthalimide substituent (49.8(9)°)
and helicene 10f with amino substituent (50.7(9)°).
Another measurement that is easily compared is the distance between the bay area carbon
atoms (figure S3, SI). We found that the differences in distance between helicenes were small.
Similar to the other measurements, the bay area carbon atoms of unsubstituted helicene 10a
are closest together (3.343(3) and 3.309(4) Å) and these from amino substituted helicene 10f
(3.545(4) Å) are furthest apart. When ranking the other helicenes, the distance in compound
with phthalimide substituent 10g (3.473(3) Å) is slightly larger than the distance in helicene
10c with nitrile substituent (3.506(3) and 3.430(3) Å) and helicene 10b with nitro substituent
(3.466(5) Å). The distances in helicene 10d with acid substituent (3.394(7) and 3.497(8) Å)
and helicene 10e with amide substituent (3.375(7) and 3.405(7) Å) are smallest, not counting
the unsubstituted helicene.
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Figure 1: The molecular structures of 10a, showing the atom-labelling scheme for the heteroatoms.
Displacement ellipsoids are drawn at the 50% probability level.
Figure 2: The molecular structure of 10b, showing the atom-labelling scheme for the heteroatoms.
Displacement ellipsoids are drawn at the 50% probability level.
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Figure 3: The molecular structures of 10c, showing the atom-labelling scheme for the heteroatoms.
Displacement ellipsoids are drawn at the 50% probability level.
Figure 4: The molecular structures of 10d, showing the atom-labelling scheme for the heteroatoms.
Displacement ellipsoids are drawn at the 50% probability level.
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Figure 5: The molecular structures of 10e, showing the atom-labelling scheme for the heteroatoms.
Displacement ellipsoids are drawn at the 50% probability level.
Figure 6: The molecular structure of 10f, showing the atom-labelling scheme for the heteroatoms.
Displacement ellipsoids are drawn at the 50% probability level.
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Figure 7: The molecular structure of 10g, showing the atom-labelling scheme for the heteroatoms.
Displacement ellipsoids are drawn at the 50% probability level.
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Table 1: Solid state structural data of compounds
5
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Molecule
R
10a
H
10b
NO2
10c
CN
10d
COOH
Pna21
10e
CONH2
Pca21
10f
NH2
P21/c
na
10g
C6H4(CO)2
N
Space group
P-1
na
P21/c
P21/n
na
I2/a
10
11
12
13
14
15
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19
20
21
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Angle
ring
and
and
32.1(2)
38.3(2)
46.2(2)
52.84(11)
substituent 1 (°)a
Angle ring
36.8(3)
24.5(2)
46.6(2)
36.1(3)
substituent 2(°)a
Interplanar angle
(°)b
1
2
20.70(12) 31.08(19)
7.92(12)
35.73(9)
37.50(14)
34.52(15)
Interplanar angle
(°)b
28.38(10)
31.4(3)
30.9(3)
torsion angle 1(°)c
torsion angle 2(°)c
torsion angle 3(°)c
distortion 1 (°)d
10.0(4)
10.2(4)
10.0(4)
18.5(7)
17.7(6)
4.0(6)
18.9(3)
19.6(3)
8.1(3)
10.5(9)
15.4(8)
12.8(8)
16.7(10)
22.8(9)
5.5(9)
16.5(5)
23.5(5)
10.7(5)
18.7(6)
19.5(5)
11.6(5)
30.2(7)
4.8(4)
40.2(11)
46.6(5)
19.5(4)
38.7(14)
12.8(10)
45.0(16)
14.2(10)
50.7(9)
49.8(9)
torsion angle 1(°)c
torsion angle 2(°)c
torsion angle 3(°)c
distortion 2 (°)d
2.5(3)
7.7(4)
14.7(3)
5.1(3)
20.9(9)
8.6(8)
20.5(10)
7.2(10)
15.0(6)
39.3(6)
42.3(16)
3.394(7)
41.9(17)
3.375(7)
distance 1 (Å)e
3.343(3)
3.466(5)
3.506(3)
3.545(4)
3.473(3)
distance 2 (Å) e
3.309(4)
3.430(3)
3.497(8)
3.405(7)
a. Dihedral angle between the substituent and the ring of the helicene
b. Angle between the two terminal benzene rings of the helicene (figure S1, SI)
c. Torsion angle between four adjacent carbon atoms (figure S2, SI)
d. Sum of torsion angles between four adjacent carbon atoms
e. Distance between the carbon atoms in the bay area (figure S3, SI)
Spectroscopy
The absorption and emission spectra of compounds 10a, 10b, 10c, 10d, 10e, 10f and 10g
were recorded in toluene and acetonitrile (ACN) and are presented in Figures 8 and 9. The
corresponding figures of merit are shown in Table 2. The absorption spectrum of the
unsubstituted compound 10a in toluene features a vibrationally resolved S0 → S1 transition at
397 nm with a vibrational spacing of 1360 cm-1 and an extinction coefficient at the maximum
of 9100 M-1·cm-1. The absorption spectra of the remaining compounds are red shifted with
respect to 10a, but retain to some extent the vibrational structure, with the exception of the
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NO2-substituted compound 10b (which also features a significantly lower extinction
coefficient). The broadening of the individual vibronic bands suggests an increased coupling
with low frequency vibrations such as torsion of the substituent and/or a vibration
corresponding to a change in ‘distortion’. The latter effect would be related to the increased
‘distortion’ in the substituted helicenes. For the acceptor substituents (10b to 10e) the red shift
parallels the electron withdrawing character of the substituent. However, also for the electron
donor substituted helicenes the red shift increases from 10f to 10e in parallel with the strength
of the electron donor. This general red shift can be attributed to an extension of the conjugation
of the helicene, which apparently behaves neither as an outspoken electron acceptor nor as
an outspoken electron donor. This is no surprise considering the meta orientation of the
substituent versus the carbazole nitrogen. For compound 10b the more extensive red shift
and complete loss of vibrational structure of the absorption spectrum suggests a charge
transfer character of the excitation as the ‘distortion’ of 10b is quite similar (Table 1) to that of
the other substituted helicenes. In ACN, the absorption spectra shift about 5 nm to shorter
wavelengths while retaining the vibrational structure. This can be attributed to the smaller
polarizability of ACN14,15 and suggests a very small or absent dipole moment in the ground
state. The emission spectrum of 10a in toluene features a small Stokes’ shift (620 cm-1) and
is a mirror image of the absorption spectrum.
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Figure 8: Normalised UV-vis absorption spectra in dilute solution (about 10-5 M). The absorption
spectra were normalised to the maximum of the first maximum of the S0→S1 transition.
In the emission spectrum in toluene of 10c and 10e a vibronic shoulder still can be
distinguished, while the emission spectrum of the other molecules consists of just one broad
band, due to increased coupling with low frequency vibrations. This effect is also reflected in
the Stokes’ shift and FWHM of the emission spectra which increase from 10a over 10e and
10c to 10d and 10b. The width of the emission spectra (FWHMem) is quite large in comparison
to the Stokes shift14–16
.
휈
It is possible to estimate the FWHM (FWHMem) of the emission band from the Stokes shift ∆ ,
using equation 1 and 217,18
.
2
-1
휈
(FWHM) = 8 (ln 2) ∆ kT (in cm )
(Equation 1)
(Equation 2)
At 298 K this expression becomes:
-4
2
–1
휈
∆ = 8.9514 x 10 (FWHM) (in cm )
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In toluene the values of FWHMem evaluated from the Stokes shift using this expression amount
to 33 % to 50 % of the experimental values for compounds 10a and 10c to 10f. Only for 10b
and 10g, compounds with a much larger Stokes shift, the calculated values of the FWHMem
amount to about 70 % of the experimental ones. This discrepancy could be due to coupling
with a vibration for which the potential energy surface is much steeper in the ground state than
in the excited state. Furthermore one must take into account that equation 1 and 2 assume
that only vibrations for which hvib < kT contribute to the spectral features. According to the
vibrational progression seen in the absorption spectra also high frequency vibrations
contribute to the spectral features which could lead to a larger FWHMem than predicted by
equation 1 and 2.
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One should note that in contrast to the absorption spectra, the red shift of the emission
maximum of 10d compared to 10a is more outspoken than that of 10c while also the FWHM
of the emission spectrum is larger. The properties of the emission spectrum of 10d cannot be
attributed to differences in planarity as the difference in ‘distortion angle’ between 10c or 10e
and 10d is smaller than the experimental error and smaller than the differences between the
two different molecules in the unit cell. It is also unlikely that this effect is due to a more
outspoken charge transfer character of the excited state as the CN moiety is a stronger
electron acceptor than the carboxylic acid. Therefore, the deviating results obtained for 10d,
are attributed to electron-phonon coupling with the rotation of the carboxylic acid. The latter is
suggested by the different dihedral angles between the COOH moiety and the neighbouring
ring in 10d and 10e. While this angle amounts to 38.3(2)°and 36.8(3)° in 10d, it is 46.2(2)°and
46.6(2)° in 10e. This means a stronger electronic coupling between the carboxyl group and
the -system in 10d compared to 10e and hence a steeper potential energy surface for the
rotation of the carboxyl moiety in 10d. As resonance forms where the electrons of the ring are
delocalized over the carboxyl moiety (leading to an excited state dipole, cfr. infra ) contribute
more to the excited state than to the ground state, one can expect the carboxyl moiety to
become more coplanar with the neighbouring ring in the excited state. This shift in equilibrium
geometry leads to band broadening and an increased Stokes shift. Due to more extensive
conjugation in 10d, leading to a steeper potential surface, it can be more important in 10d.
The emission spectrum of 10f, which has the strongest electron donating substituent, shows
a Stokes shift and a FWHMem comparable to the compounds 10c and 10e suggesting a similar
electron-phonon coupling in spite of a significantly larger ‘distortion angle’ in the ground state.
The spectral data of 10f in toluene indicate that for extending the conjugation the helicene
moiety can act as electron acceptor and as electron donor.
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The emission of 10b shows a much larger Stokes shift and a more extensive red shift versus
10a compared to compounds 10c to 10f while its FWHMem is much large than observed for
10a, 10c, 10e and 10f. This suggests the formation of an intramolecular charge transfer (ICT)
state with an electronic structure differing significantly from that of the Franck Condon excited
state rather than to a change in geometry. Actually, the ground state geometry as reflected in
the ‘distortion angle’ is within experimental error the same for 10b to 10e. The formation of an
ICT state could also explain why the fluorescence quantum yield of 10b is about one order of
magnitude smaller than that of 10a and 10c to 10e. In analogy to 10b, 10g shows a much
larger red shift versus 10a accompanied by a much larger Stokes shift and a larger FWHMem
compared to 10c to 10f. A more extensive conjugation can be excluded as the phthalimide
moiety is a weaker -donor than the NH2 moiety. The formation of an intramolecular charge
transfer state (ICT) where the phthalimide acts as an electron acceptor is again a more likely
explanation. This can also explain why in toluene the fluorescence quantum yield of 10g is an
order of magnitude smaller than that of 10 and 10c to 10e.
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Going to ACN, the relative intensity of the vibronic bands in the emission spectrum of 10a is
changed and the emission band is slightly red shifted and broadened while also the Stokes
shift becomes larger, indicating an increased dipole moment in the excited state.
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Figure 9: Normalised UV-vis emission spectra in dilute solution (about 10-5 M). The emission spectra
were obtained for an excitation wavelength of 365 nm in acetonitrile (ACN) and toluene.
For the other molecules the emission spectrum in ACN is a structureless band characterized
by a significant red shift of the emission maximum, and hence also an increase of the Stokes
shift compared to toluene. This suggests a dipolar character of the excited state which is most
outspoken for 10b and 10f. Quite surprisingly for the other electron acceptor substituted
helicenes the dipolar character of the excited state as derived from the solvent dependence
of the Stokes shift19,20 does not follow the electron withdrawing character of the substituent
which increases in the order 10e < 10d < 10c < 10b. Although except for 10b the FWHMem is
increased in ACN, this increase is limited to 380 to 700 cm-1 and is not correlated with the
increase of the Stokes shift. For all compounds the fluorescence quantum yield is smaller in
acetonitrile. Although except for 10g, where no fluorescence is observed in ACN, this
difference is small, it is systematic, and in agreement with a dipolar character of the excited
state. In contrast to the other compounds, the emission spectrum of 10d in ACN has a small
shoulder at the blue edge. In order to elucidate the origin of this shoulder the absorption and
emission spectra of 10d were determined in function of the concentration from 1.3x10-6 M to
3.8 10-5 M (Figure S11, SI).
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While at the lowest concentrations the absorption spectrum shows a vibrational fine structure,
this structure disappears upon increasing the concentration. The species prevailing at low
concentration has a 0-0 transition which is situated close to 405 nm. Hence its absorption
spectrum is significantly blue shifted compared to that observed at higher concentration and
resembles that of 10a and 10g. At the lowest concentrations the emission spectrum shows a
vibrational fine structure with a maximum of the 0-0 band at 415 nm, i.e. close to that of 10a.
This corresponds to a Stokes shift of only 600 cm-1, which is close to the value found for 10a.
Upon increasing the concentration this band disappears at the profit of a structureless band
with maximum at 489 nm. This behaviour is reflected in the excitation spectra of the 415 nm
emission, which up to 1.3x10-5 M shows the same vibrational fine structure as the absorption
spectra at low concentration. On the other hand, the excitation spectra of the long wavelength
emission show at all concentrations a more red shifted and structureless band with maximum
between 415 to 420 nm. Our hypothesis is that these concentration effects originate from
dissociation of the carboxylic acid moiety at low concentrations. We were able to confirm this
by recording spectra under basic and acidic conditions (Figure S11, SI). The spectra at low
concentration correspond to the spectra of the deprotonated species we obtained after
addition of 10 equivalents of base (KOH) and the spectra at high concentration correlate well
with the spectra obtained after addition of 10 equivalents of acid (HCl) to a solution with a low
concentration of 10d. For the deprotonated form, the vibrational fine structure is visible, while
for the protonated form, a broad red shifted band is discerned. Deprotonation will decrease
the electron accepting character of the carboxy substituent and hence the delocalization of
the electron cloud of the helicene moiety over the substituent. One should note that for all
other molecules, a good agreement between the excitation spectra taken at different emission
wavelengths and the absorption spectra was observed (Figure S12, SI), in toluene as well as
in ACN, indicating that only one species is directly populated by excitation.
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While for 10d at a concentration of 3.8·10-5 M, where the contribution of the broad band is
dominating, a fluorescence quantum yield of 5.5 % was recovered, no reliable fluorescence
quantum yield could be obtained for the deprotonated species as at low concentration it was
not possible to determine the absorbance with sufficient accuracy.
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Table 2: Absorption and fluorescence emission maxima (of the first vibronic band of the S0→S1
transition), Stokes shift, full width at half maximum of the emission (FWHMem), extinction coefficient (ε)
and fluorescence quantum yield (φ) of the investigated compounds in solution. aA concentration of 3.8
10-5 M was used.
9
흀풆풎
/nm
흂
(
풂풃풔 ― 흂풆풎
/cm-1
FWHMem
/cm-1
)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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59
60
-1
-1
흀
풂풃풔 /nm
휺
흋
(%)
Molecule
/M cm
10a
10b
10c
10d
10e
10f
397
444
420
413
410
417
407
393
440
414
407
406
411
402
407
610
449
475
432
451
610
412
702
471
489
460
489
/
620 ± 50
6130 ± 50
1540 ± 50
3160 ± 50
1240 ± 50
1810 ± 50
8180 ± 50
1170 ± 50
8480 ± 50
2920 ± 50
4120 ± 50
2890 ± 50
3880 ± 50
/
2540 ± 50
3770 ± 50
3230 ± 50
3610 ± 50
3220 ± 50
2880 ± 50
4080 ± 50
2920 ± 50
3300 ± 50
9100 ± 900
4600 ± 500
6300 ± 600
6400 ± 600
7400 ± 700
8000 ± 800
7700 ± 800
8700 ± 900
4400 ± 400
9.1 ± 0.9
<0.5
8.6 ± 0.9
5.8 ± 0.6
8.9 ± 0.9
2.8 ± 0.3
<0.5
10g
10a
10b
10c
10da
10e
10f
7.5 ± 0.8
<0.5
3590 ± 50 10800 ± 1100
6.3 ± 0.6
5.5 ± 0.6
6.7 ± 0.7
2.1 ± 0.2
0
4160 ± 50
3900 ± 50
3580 ± 50
/
7700 ± 800
6700 ± 700
7600 ± 800
7300 ± 700
10g
Conclusion
We discussed a straightforward manner to prepare several functionalised thiaza[5]helicenes
through oxidative cyclisation of easily obtainable intermediates prepared from readily available
starting materials. From oxidative cyclisation experiments, we found that DDQ is a suitable
reagent for preparation of thiaza[5]helicenes with good functional group tolerance. We
compared the hydrolysis of the nitrile on the thiaza[5]helicene and the precursor and found
that both the amide and carboxylic acid substituted thiaza[5]helicene could be obtained readily
from the same precursor by changing the reaction sequence. We also showed the possibility
to reduce the nitro substituent to the amine and the conversion of the amine to the phthalimide.
Through comparison of the prepared thiaza[5]helicenes, we determined that functional groups
of similar size have a small influence on structural parameters, but do influence some
spectroscopic properties significantly. Generally, the maximum and features of the absorption
and emission spectra correlate with the strength of the electron accepting and donating
character of the substituent indicating that the helicene moiety can act as well as electron
donating and as electron accepting moiety. On the other hand, the ‘distortion angle’ has only
a limited influence of the spectral properties.
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Experimental Section
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9
All reagents and solvents were purchased from commercial sources and used as received
unless noted otherwise. Reactions were carried out in standard glassware with Teflon-coated
magnetic stirring bars on a magnetic stirrer under nitrogen atmosphere. Heating was
performed in an aluminium reaction block with temperature sensor. Moisture sensitive
reactions were carried out in oven dried (200°C overnight) glassware. NMR spectra were
measured on a Bruker Avance 300, a Bruker Ascend 400 or a Bruker Avance 600 apparatus.
Shift values are expressed in ppm relative to tetramethylsilane (1H, 0) or solvent signal
(13C{1H}, CDCl3:77.16, DMSO-d6: 39.52). Melting points were determined on a Mettler-Toledo
DSC822 instrument, using a heating rate of 0.5 °C.min−1 under helium atmosphere. HRMS
spectra were acquired on a quadrupole orthogonal acceleration time-of-flight mass
spectrometer (Synapt G2 HDMS, Waters, Milford, MA). Samples were infused at 3µL/min and
spectra were obtained in positive (or: negative) ionisation mode with a resolution of 15000
(FWHM) using leucine enkephalin as lock mass.
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For the preparation of the solutions, commercially available acetonitrile and toluene of
spectroscopic or HPLC grade was used as received. The solutions of 10d in toluene and ACN
were prepared using a stock solution in DMSO. The final DMSO content was kept below 1 %.
The UV-Visible absorption spectra were recorded on a Lambda 40 spectrophotometer with
blocked beam and blank corrections. For the emission experiments a Horiba Jobin-Yvon
Fluorolog FL3-22 fluorimeter was used with corrections for the wavelength dependence of the
excitation beam intensity, the wavelength dependent sensitivity of the detector and the optical
path. Fluorescence quantum yields were measured on the same set-up using an integrating
sphere and homemade cylindrical quartz cuvettes21,22. When recording the Rayleigh scatter,
a neutral density filter of 0.3 % was used.
General procedure for the Suzuki coupling
Bromide (1 eq), boronic acid (1.1-2 eq), K2CO3 (2 eq) and Pd(PPh3)4 (5-10 mol%) were
combined in a screw cap reaction tube. THF (8 ml/mmol of bromide) and water (2 ml/ mmol of
bromide) were added, the tube was purged with nitrogen and the reaction was heated at
100 °C overnight. After TLC indicated complete conversion of starting material, water (50 ml)
was added, the phases were separated and the aqueous layer was extracted twice with DCM.
The combined organic layers were washed with brine, dried over MgSO4 and concentrated.
The crude reaction mixture was purified by flash column chromatography.
General procedure for the oxidative cyclisation using DDQ and BF3.Et2O
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Starting material (1 eq) was dissolved into dry DCM to form a 0.01 M solution, cooled to 0 °C
and BF3.Et2O (10 eq) was added dropwise. DDQ (1.5 eq) was added in small portions and the
reaction was warmed slowly to room temperature and stirred for 1 h. After complete
conversion of starting material on TLC, the reaction was poured into saturated aqueous
NaHCO3 and shaken vigorously with frequent venting. The phases were separated and the
aqueous phase was extracted twice with DCM. The combined organic layers were washed
with saturated aqueous NaHCO3, brine and dried over MgSO4. The crude reaction mixture
was purified by column chromatography.
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2-(2-Bromophenyl)-1H-indole 2a
Prepared according to a slightly modified literature procedure11. Phenylhydrazine (2.5 ml, 25
mmol) and 2'-bromoacetophenone (3.37 ml, 25 mmol) were mixed and heated to 100 °C for
1 h. Then methanesulfonic acid (20 ml, 313 mmol) was added and the mixture was heated to
100°C for 1h. After TLC showed complete conversion, the mixture was poured into ice water
(300 ml) and extracted with diethyl ether (3*300 ml). The combined organic layers were
washed with brine (300 ml), dried with over MgSO4 and concentrated. The crude product was
dissolved in n-heptane (150 ml) while heating at 50 °C. The mixture was filtered while hot and
concentrated. Compound 2a (5.34 g, 19.6 mmol, 78 % yield) was obtained as an off-white
solid. Analytical data were in accordance with literature11.
2-(2-Bromophenyl)-4-nitro-1H-indole 2b
2’-Bromoacetophenone (19 ml, 140 mmol) and 3-nitroaniline (13.8 g, 100 mmol) were
dissolved in DMSO (150 ml) and cooled in an ice water bath to 18-20 °C. NaOt-Bu (23 g,
240 mmol) in 150 ml DMSO was added and the mixture was stirred under air for 1 h. After
TLC indicated complete conversion of starting material, the mixture was poured into saturated
aqueous NH4Cl solution (1 l) and filtered. After recrystallisation from methanol, 22 g of
compound 2b (70 mmol, 70% yield) was obtained as an orange solid Tm: 206.3-206.4 °C,
+
HRMS: calculated for C14H10BrN2O2 [M+H]+: 316.9921 found: 316.9912
1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 7.9 Hz,
1H), 7.83 (d, J = 7.9 Hz, 1H), 7.71 (dd, J = 7.6, 1.7 Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.45 –
7.29 (m, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 141.2, 139.1, 138.5, 133.7, 132.4, 131.8,
130.6, 128.1, 121.7, 121.5, 121.0, 119.2, 117.4, 102.4.
2-(2-Bromophenyl)-1-ethyl-1H-indole 3a
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2-(2-Bromophenyl)indole (1 g, 3.67 mmol) was dissolved in DMSO (10 ml), KOH (250 mg,
4.4 mmol) and bromoethane (330µl, 4.4 mmol) were added and the reaction was stirred at
room temperature under nitrogen atmosphere overnight. The reaction mixture was poured into
water (100 ml) and extracted with diethyl ether (100 ml). The organic phase was washed with
water (100 ml) and brine (100 ml), dried over MgSO4 and concentrated. The crude material
was purified by kugelrohr distillation. Ethyl-2-bromophenylindole 3a (1 g, 3.34 mmol, 91%
yield) was isolated as a slightly yellow oil that solidified over time at room temperature. Tm=
80.5-82.2 °C, HRMS (API+): calculated for C16H15NBr+ [M+H]+: 300.0383; found: 300.0385
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1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.45 – 7.36 (m,
3H), 7.31 (ddd, J = 8.2, 6.4, 2.7 Hz, 1H), 7.28 – 7.21 (m, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.48 (s,
1H), 4.02 (q, J = 7.7 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 139.0,
136.1, 134.6, 133.0, 132.9, 130.3, 128.2, 127.3, 125.3, 121.8, 121.0, 119.8, 109.9, 102.7,
38.9, 15.4.
2-(2-Bromophenyl)-1-ethyl-4-nitro-1H-indole 3b
2-(2-Bromophenyl)-4-nitro-1H-indole 2b (14 g, 44.1mmol) was dissolved in 200 ml DMSO
stirring at room temperature. K2CO3 (6.7 g, 48.6 mmol) and bromoethane (3.6 ml, 48.6 mmol)
were added and the reaction mixture was stirred at room temperature under nitrogen
atmosphere until TLC indicated complete conversion of starting material (overnight). The
reaction mixture was diluted with ether (500 ml), washed with water (3*1 l) and brine (500 ml),
dried over MgSO4 and concentrated. Compound 3b (15.2 g, 44.1mmol, 100% yield) was
obtained as a red oil that slowly solidified at room temperature to form a yellow to orange solid
+
Tm: 83.4-85.0 °C, HRMS (ES+): calculated for C16H14BrN2O2 [M+H]+: 345.0234; found:
345.0226
1H NMR (400 MHz, CDCl3) δ 8.15 (dd, J = 8.0, 0.8 Hz, 1H), 7.73 (dt, J = 3.1, 0.8 Hz, 1H), 7.71
(dt, J = 3.4, 0.9 Hz, 1H), 7.48 – 7.42 (m, 2H), 7.40 – 7.34 (m, 1H), 7.30 (t, J = 8.1 Hz, 1H),
7.23 (d, 0.5Hz, 1H), 4.10 (s, br, 2H), 1.22 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 143.6, 140.4, 138.3, 133.13, 133.09, 132.5, 131.0, 127.6, 124.6, 122.3, 120.6, 117.8, 116.7,
103.3, 39.5, 15.4.
2-(2-Bromophenyl)benzo[b]thiophene 6
2-Chlorobenzaldehyde (1.13 ml, 10 mmol), 2-bromobenzylthiol (1.33 ml, 10 mmol) and
Cs2CO3 (6.52 g, 20.00 mmol) were combined in DMF (25 ml), the reaction vessel was purged
with nitrogen and the reaction was heated at 150 °C until TLC indicated complete conversion
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of starting material (41 h) The reaction mixture was concentrated, coated on silica an purified
by column chromatography (silica, PE). 2-(2-bromophenyl)benzo[b]thiophene 6 (2.3 g, 8mmol,
80% yield) was isolated as a white solid. Analytical data were in accordance with literature23.
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2-(2-(Benzo[b]thiophen-2-yl)phenyl)-1-ethyl-1H-indole 9a
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Synthesis according to general procedure for Suzuki coupling with 2-(2-bromophenyl)-1-ethyl-
1H-indole (600 mg, 2 mmol), benzo[b]thiophen-2-ylboronic acid (534 mg, 3 mmol), K2CO3
(553 mg, 4 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), THF (8 ml) and water (2 ml). The crude
reaction mixture was purified by flash column chromatography (silica, PE:DCM 95:5). 2-(2-
(benzo[b]thiophen-2-yl)phenyl)-1-ethyl-1H-indole 9a (651 mg, 1.84 mmol, 92 % yield) was
obtained as a slightly yellow solid. Tm=146.3-147.9 °C, HRMS (API+): calculated for C24H20NS+
[M+H]+: 354.1311; found: 354.1308
1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.8 Hz, 1H), 7.69 – 7.61 (m, 2H), 7.56 – 7.39 (m,
4H), 7.30 – 7.10 (m, 5H), 7.01 (s, 1H), 6.57 (s, 1H), 3.78 (q, J = 7.2 Hz, 2H), 0.99 (t, J = 7.2
Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 142.8, 140.4, 140.0, 139.1, 136.3, 134.8, 133.0,
131.4, 130.0, 129.3, 128.5, 128.0, 124.3, 124.2, 123.9, 122.9, 122.2, 121.5, 120.9, 119.6,
110.1, 103.5, 38.6, 15.0.
2-(2-(Benzo[b]thiophen-2-yl)phenyl)-1-ethyl-4-nitro-1H-indole 9b
Synthesis according to general procedure for Suzuki coupling with 2-(2-bromophenyl)-1-ethyl-
4-nitro-1H-indole 2b (2.8 g, 8 mmol), benzo[b]thiophene-2-boronic acid (1.75 g, 9.7 mmol),
K2CO3 (2.3 g, 16 mmol) and Pd(PPh3)4 (500 mg, 0.4 mmol) in THF (20 ml) and water (5 ml).
After column chromatography (silica, PE:DCM, 1:1), compound 9b (2.75 g, 6.9 mmol, 85%
yield) was obtained as a yellow solid Tm: 187.5-188.7 °C, HRMS (ES+): calculated for
C24H19N2O2S+ [M+H]+: 399.1162; found: 399.1156
1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.69 – 7.61 (m,
1H), 7.61 – 7.43 (m, 5H), 7.39 (s, 1H), 7.28 – 7.16 (m, 3H), 7.01 (s, 1H), 3.81 (q, J = 7.2 Hz,
2H), 0.99 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 144.1, 142.1, 140.4, 140.3,
139.9, 138.4, 134.7, 132.7, 130.3, 130.1, 130.0, 128.4, 124.6, 124.4, 123.9, 123.2, 122.6,
122.2, 120.4, 117.8, 116.7, 104.2, 39.2, 15.1.
2-(2-(Benzo[b]thiophen-2-yl)phenyl)-1-ethyl-1H-indole-4-carbonitrile 9c
A solution of LDA (freshly prepared from n-butyllithium (9.6 ml, 24 mmol) and diisopropylamine
(4 ml, 28 mmol)) in anhydrous THF (50ml) in an oven dried two neck flask under nitrogen
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atmosphere was added to 1-ethyl-1H-indole-4-carbonitrile (3.40 g, 20 mmol, prepared
according to literature procedure24,25) in anhydrous THF (50 ml) stirring at -78 °C in an oven
dried two neck flask under nitrogen atmosphere. The reaction was stirred at this temperature
for 1 hour, triisopropyl borate (5.6 ml, 24 mmol) was added and the reaction was slowly
warmed to room temperature. After 1 hour at room temperature, the reaction was quenched
with 1M aqueous HCl (200 ml) and extracted with diethyl ether (200 ml). The organic phase
was dried over MgSO4 and concentrated under reduced pressure. This material was used in
the next reaction without further purification.
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Synthesis according to general procedure for Suzuki coupling with 2-(2-
bromophenyl)benzo[b]thiophene 6 (3.7 g 13 mmol), (4-cyano-1-ethyl-1H-indol-2-yl)boronic
acid (20 mmol), K2CO3 (5.4 g, 39 mmol), Pd(PPh3)4 (750 mg, 0.65 mmol) in THF (8 ml) and
water (2 ml). After column chromatography (silica, PE:DCM, 8:2 gradient to 1:1) and
crystallisation from DCM:PE, 4.3 g of compound 9c (11.3 mmol, 87% yield) was obtained as
colourless crystals. Tm=190.8-191.0 °C, HRMS (API+): calculated for C25H19N2S+ [M+H]+:
379.1263; found: 379.1260
1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 1H), 7.68 – 7.63 (m, 1H), 7.60 – 7.52 (m,
2H), 7.51 – 7.42 (m, 4H), 7.27 – 7.17 (m, 3H), 6.99 (s, 1H), 6.83 (s, 1H), 3.78 (q, J = 7.2 Hz,
2H), 0.98 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 142.1, 142.0, 140.2, 139.9,
135.8, 134.6, 132.7, 130.2, 130.1, 129.8, 129.6, 128.2, 125.1, 124.4, 124.3, 123.8, 123.0,
122.1, 121.0, 119.0, 114.6, 102.9, 102.4, 38.9, 14.9.
2-(2-(Benzo[b]thiophen-2-yl)phenyl)-1-ethyl-1H-indole-4-carboxylic acid 9d
Sodium hydroxide (1 g, 25 mmol) was added to a solution of 2-(2-(benzo[b]thiophen-2-
yl)phenyl)-1-ethyl-1H-indole-4-carbonitrile (946 mg, 2.5 mmol) in diethylene glycol
monomethyl ether (25 ml) and heated to 150 °C under nitrogen atmosphere. After TLC
indicated complete conversion of starting material, the reaction was diluted with water
(200 ml), acidified with aqueous HCl (36%) and extracted with ethyl acetate (300 ml). The
organic layer was washed with water (2*300 ml), brine (300 ml), dried over MgSO4 and
concentrated. After recrystallisation from ethanol, 890 mg of 2-(2-(benzo[b]thiophen-2-
yl)phenyl)-1-ethyl-1H-indole-4-carboxylic acid 9d (2.2 mmol, 90 % yield) was obtained as a
white solid. Tm=263.5-263.8 °C, HRMS (ES+): calculated for C25H20NO2S+ [M+H]+: 398.1209;
found: 398.1210
1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.5 Hz,
1H), 7.74 (d, J = 7.8 Hz, 1H), 7.72 – 7.61 (m, 3H), 7.59 – 7.53 (m, 2H), 7.36 (s, 1H), 7.31 –
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7.19 (m, 3H), 7.08 (s, 1H), 3.84 (s, br, 2H), 0.91 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 168.3, 142.0, 140.5, 139.8, 139.3, 136.7, 134.0, 132.5, 130.2, 129.9, 129.8,
128.5, 127.3, 124.5, 124.5, 123.7, 123.0, 122.9, 122.2, 121.7, 120.7, 115.0, 104.3, 38.2, 14.9.
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10-Ethyl-10H-benzo[a]benzo[4,5]thieno[2,3-c]carbazole 10a
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Synthesis according to general procedure for the oxidative cyclisation using DDQ and
BF3.Et2O with 2-(2-(benzo[b]thiophen-2-yl)phenyl)-1-ethyl-1H-indole 9a (400 mg, 1.13 mmol),
DDQ (385 mg, 1.7 mmol), BF3OEt2 (1.4 ml, 11.3 mmol) and DCM (100 ml). The crude reaction
mixture was purified by column chromatography (SiO2, DCM) 10-ethyl-10H-
benzo[a]benzo[4,5]thieno[2,3-c]carbazole 10a (381 mg, 1.08 mmol, 96 % yield) was obtained
as a light yellow solid. A crystal of compound 10a was obtained by vapor diffusion of pentane
into a solution of the compound in CHCl3 at room temperature. Tm= 157.3-158.5 °C, HRMS
(API+): calculated for C24H18NS+ [M+H]+: 352.1154; found: 352.1146
1H NMR (400 MHz, CDCl3) δ 9.12 (d, J = 8.2 Hz, 1H), 8.90 (d, J = 8.1 Hz, 1H), 8.60 (dd, J =
7.6, 2.2 Hz, 1H), 8.29 (dd, J = 7.2, 2.4 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.71 – 7.48 (m, 6H),
7.39 (t, J = 7.6 Hz, 1H), 4.91 (q, J = 7.2 Hz, 2H), 1.74 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 140.2, 139.5, 137.3, 134.6, 131.7, 129.0, 128.5, 126.2, 126.1, 125.73, 125.66,
125.2, 124.7, 124.0, 123.2, 123.1, 123.0, 122.4, 121.9, 119.5, 115.4, 109.4, 41.2, 15.3.
10-Ethyl-14-nitro-10H-benzo[a]benzo[4,5]thieno[2,3-c]carbazole 10b
Synthesis according to general procedure for the oxidative cyclisation using DDQ and
BF3.Et2O with 2-(2-(benzo[b]thiophen-2-yl)phenyl)-1-ethyl-4-nitro-1H-indole 9b (4.8 g,
12mmol), DDQ (4.1 g, 18 mmol), BF3OEt2 (15.3 ml, 120 mmol) in DCM (1l). After flash
chromatography (silica, DCM), compound 10b (4.44g, 11.2mmol, 93% yield) was obtained as
a dark red solid, A crystal of compound 10b was obtained by vapor diffusion of pentane into a
solution of the compound in CHCl3 at room temperature. Tm= 224.7-226.6 °C, HRMS (ES+):
calculated for C24H17N2O2S+ [M+H]+: 397.1005; found: 397.0995
1H NMR (400 MHz, CDCl3) δ 8.56 – 8.49 (m, 1H), 8.33 – 8.27 (m, 1H), 8.11 (d, J = 7.8 Hz,
1H), 7.98 – 7.94 (m, 1H), 7.93 – 7.87 (m, 2H), 7.71 – 7.62 (m, 2H), 7.56 (t, J = 8.0 Hz, 1H),
7.46 – 7.35 (m, 2H), 5.00 – 4.86 (m, 1H), 1.73 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 143.8, 141.0, 137.9, 137.6, 135.9, 130.8, 128.4, 127.6, 127.3, 125.8, 125.5,
123.9, 123.8, 123.4, 123.1, 120.8, 117.4, 116.8, 112.9, 110.8, 41.2, 14.9.
10-Ethyl-10H-benzo[a]benzo[4,5]thieno[2,3-c]carbazole-14-carbonitrile 10c
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Synthesis according to general procedure for the oxidative cyclisation using DDQ and
BF3.Et2O with 2-(2-(benzo[b]thiophen-2-yl)phenyl)-1-ethyl-1H-indole-4-carbonitrile 2.28 (1.13
g, 3 mmol), DDQ (1 g, 4.5 mmol), BF3OEt2 (3.8 ml, 30 mmol) in DCM (300 ml). After flash
chromatography (silica, PE:DCM, 6:4), 1.11 g of 10-ethyl-10H-benzo[a]benzo[4,5]thieno[2,3-
c]carbazole-14-carbonitrile 10c (2.95 mmol, 98 % yield) was obtained as a yellow solid. A
crystal of compound 10c was obtained by vapor diffusion of hexane into a solution of the
compound in CHCl3 at room temperature. Tm= 242.5-242.9 °C, HRMS (ES+): calculated for
C25H17N2S+ [M+H]+: 377.1107; found: 377.1105
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1H NMR (400 MHz, CDCl3) δ 8.66 – 8.58 (m, 1H), 8.51 – 8.44 (m, 1H), 8.26 – 8.19 (m, 1H),
7.98 – 7.92 (m, 1H), 7.81 (dd, J = 8.4, 0.9 Hz, 1H), 7.72 (dd, J = 7.3, 0.9 Hz, 1H), 7.67 – 7.58
(m, 2H), 7.55 – 7.44 (m, 3H), 4.84 (q, J = 7.2 Hz, 2H), 1.68 (t, J = 7.2 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 140.0, 139.3, 137.1, 136.0, 132.6, 129.5, 127.8, 127.38, 127.37, 126.8,
126.5, 126.3, 126.1, 124.0, 123.0, 122.6, 122.4, 122.1, 121.3, 120.2, 113.9, 112.8, 105.5,
41.4, 15.2.
10-Ethyl-10H-benzo[a]benzo[4,5]thieno[2,3-c]carbazole-14-carboxylic acid 10d
Synthesis according to general procedure for the oxidative cyclisation using DDQ and
BF3.Et2O with 2-(2-(benzo[b]thiophen-2-yl)phenyl)-1-ethyl-1H-indole-4-carboxylic acid
(199 mg, 0.5 mmol), DDQ (170 mg, 0.750 mmol),BF3.OEt2 (0.634 ml, 5.00 mmol) in DCM (50
ml) After flash chromatography (silica, DCM:MeOH, 95:5), 193 mg of 10-ethyl-10H-
benzo[a]benzo[4,5]thieno[2,3-c]carbazole-14-carboxylic acid 10d (0.49 mmol, 97 % yield) was
obtained as a yellow solid. A crystal of compound 10d was obtained by vapor diffusion of
hexane into a solution of the compound in DCM:methanol 99:1 at room temperature.
Tm>300 °C, HRMS (ES+): calculated for C25H18NO2S+ [M+H]+: 396.1053; found: 396.1050
1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.74 (d, J = 7.8 Hz, 1H), 8.32 (d, J = 7.9 Hz,
1H), 8.27 (d, J = 7.3 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.85 (dd, J =
7.3, 1.8 Hz, 1H), 7.82 – 7.71 (m, 2H), 7.65 – 7.58 (m, 1H), 7.51 – 7.36 (m, 2H), 5.03 (q, J =
7.5 Hz, 2H), 1.59 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 169., 140.2, 138.10,
137.6, 134.7, 129.9, 128.9, 127.9, 126.9, 126.7, 125.6, 125.3, 124.6, 124.0, 123.4, 123.3,
122.8, 122.0, 121.0, 118.8, 113.9, 113.4, 40.7, 15.0z.
10-Ethyl-10H-benzo[a]benzo[4,5]thieno[2,3-c]carbazole-14-carboxamide 10e
Sodium hydroxide (400 mg, 10 mmol) was added to a solution of 10-ethyl-10H-
benzo[a]benzo[4,5]thieno[2,3-c]carbazole-14-carbonitrile 10c (376 mg, 1 mmol) in diethylene
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glycol monomethyl ether (5 ml) and heated to 150 °C under nitrogen atmosphere. After TLC
indicated complete conversion of starting material (2.5 h), the reaction was diluted with water
(100 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with water
(2*100 ml), brine (300 ml), dried over MgSO4 and concentrated. After flash chromatography
(silica, DCM), 357 mg of 10-ethyl-10H-benzo[a]benzo[4,5]thieno[2,3-c]carbazole-14-
carboxamide 10e (0.9 mmol, 90 % yield) was obtained as a yellow solid. A crystal of compound
10e was obtained by vapor diffusion of pentane into a solution of the compound in THF at
room temperature. Tm= 244.9-245.8 °C, HRMS (ES+): calculated for C25H19N2OS+ [M+H]+:
395.1213; found: 395.1205
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1H NMR (300 MHz, CDCl3) δ 8.59 – 8.46 (m, 2H), 8.33 – 8.24 (m, 1H), 7.97 – 7.89 (m, 2H),
7.79 (dd, J = 8.5, 1.1 Hz, 1H), 7.72 – 7.55 (m, 3H), 7.50 – 7.38 (m, 2H), 5.78 (s, br, 1H), 5.15
(s, br, 1H), 4.92 (q, J = 7.6 Hz, 2H), 1.76 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ
170.8, 141.0, 138.5, 138.3, 136.0, 132.1, 130.2, 129.3, 128.5, 126.5, 126.2, 126.1, 125.8,
124.7, 123.7, 123.1, 122.6, 122.5, 122.0, 118.5, 113.2, 112.5, 41.7, 15.2.
10-Ethyl-10H-benzo[a]benzo[4,5]thieno[2,3-c]carbazol-14-amine 10f
10-Ethyl-14-nitro-10H-benzo[a]benzo[4,5]thieno[2,3-c]carbazole 10b (2 g, 5 mmol) was
dissolved in ethyl acetate (50 ml). Pd(10%) on carbon (200 mg, 0.19 mmol Pd) and hydrazine
hydrate (0.49 ml, 10 mmol) were added and the reaction mixture was stirred at room
temperature under nitrogen atmosphere until TLC indicated complete conversion of starting
material. The reaction mixture was concentrated and purified through flash column
chromatography (silica, PE: EtOAc, 7:3). Compound 10f (1.07 g, 2.9 mmol, 58% yield) was
obtained as a yellow solid. A crystal of compound 10f was obtained by slow evaporation of a
solution of the compound in PE:EtOAc at room temperature. Tm= 180.2-181.0 °C, HRMS
(ES+): calculated for C24H19N2S+ [M+H]+: 367.1263; found: 367.1256
1H NMR (400 MHz, CDCl3) δ 8.54 (dd, J = 7.9, 1.5 Hz, 1H), 8.42 (dd, J = 7.4, 1.6 Hz, 1H), 8.25
(dd, J = 7.6, 1.8 Hz, 1H), 7.95 (dd, J = 7.3, 1.6 Hz, 1H), 7.66 – 7.51 (m, 2H), 7.50 – 7.31 (m,
3H), 7.01 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 4.94 – 4.69 (m, 2H), 4.17 (s, br, 2H),
1.68 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 142.4, 140.0, 137.0, 133.8, 131.1,
127.8, 127.7, 127.2, 126.3, 126.0, 125.9, 125.6, 125.1, 123.1, 122.5, 122.3, 121.5, 113.1,
110.9, 105.5, 98.5, 41.4, 15.0.
2-(10-Ethyl-10H-benzo[a]benzo[4,5]thieno[2,3-c]carbazol-14-yl)isoindoline-1,3-dione 10g
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10-Ethyl-10H-benzo[a]benzo[4,5]thieno[2,3-c]carbazol-14-amine 10f (183 mg, 0.5 mmol) and
phthalic anhydride (111 mg, 0.750 mmol) were dissolved in DMF (2 ml) and heated at 150 °C
under a nitrogen atmosphere for 70 hours. After complete conversion of starting material, the
reaction mixture was poured into water (20 ml) and extracted with diethyl ether (20 ml). The
organic phase was washed with water (20 ml), brine (20 ml), dried over Na2SO4 and
concentrated under reduced pressure. The crude product was purified by flash column
chromatography (silica, PE/DCM 1/1) and crystalised from PE/DCM. 2-(10-Ethyl-10H-
benzo[a]benzo[4,5]thieno[2,3-c]carbazol-14-yl)isoindoline-1,3-dione 10g (160 mg, 0.32 mmol,
64% yield) was obtained as a yellow solid. A crystal of compound 10g was obtained by vapor
diffusion of hexane into a solution of the compound in DCE at room temperature. Tm= 267.8-
268.0 °C, HRMS (API+): calculated for C32H21N2O2S+ [M+H]+: 497.1318; found: 497.1318
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1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J = 9.3 Hz, 1H), 8.23 (dd, J = 7.6, 1.9 Hz, 1H), 8.05
(d, J = 8.3 Hz, 1H), 7.87 – 7.56 (m, 9H), 7.45 (d, J = 7.6 Hz, 1H), 6.97 – 6.88 (m, 1H), 6.88 –
6.80 (m, 1H), 5.08 (q, J = 7.3 Hz, 2H), 1.64 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, DMSO-
d6) δ 165.8, 141.1, 137.8, 136.1, 134.1, 133.9, 131.3, 129.6, 127.5, 127.4, 126.5, 126.3,
125.2, 124.9, 124.8, 124.3, 123.7, 123.1, 122.7, 122.5, 122.0, 120.9, 120.0, 118.0, 112.3,
109.6, 40.7, 14.5.
Single Crystal X-Ray Diffraction
X-ray intensity data were collected at 294 K on an Agilent SuperNova diffractometer with Eos
CCD detector using Mo-Kα radiation (λ = 0.71073 Å). The images were interpreted and
integrated with CrysAlisPRO26 and the implemented absorption correction was applied. The
structures were solved using Olex227 with the ShelXS28 structure solution program or in the
case of 10g the ShelXT29 structure solution program and refined with the ShelXL30 refinement
package using full-matrix least-squares minimisation on F2. Non-hydrogen atoms were refined
anisotropically and hydrogen atoms in the riding mode with isotropic temperature factors fixed
at 1.2 times Ueq of the parent atoms (1.5 times Ueq for methyl groups). For 10g, the asymmetric
unit also contains a half molecule of dichloroethane (the complete molecule is generated by a
twofold rotation axis). The Cl atom shows disorder over two positions, with site-occupancy
factors of 0.634(5) and 0.366(5). Restraints on bond distances and temperature factors of the
solvent molecule were necessary during refinement.
CCDC 1919582-1919587contain the supplementary crystallographic data for this paper.
These data are provided free of charge by the Cambridge Crystallographic Data Centre.
Crystal structure determination of compound 10a
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Crystal Data for C24H17NS (M = 351.44 g/mol): triclinic, space group P-1 (no. 2), a =
11.04919(18) Å, b = 12.5553(3) Å, c = 13.5552(3) Å, α = 73.9262(19)°, β = 79.3366(16)°, γ =
79.3046(16)°, V = 1757.67(6) Å3, Z = 4, T = 294.1(2) K, μ(MoKα) = 0.191 mm-1, Dcalc =
1.328 g/cm3, 72352 reflections measured (4.848° ≤ 2Θ ≤ 52.744°), 7170 unique (Rint = 0.0269,
Rsigma = 0.0145) which were used in all calculations. The final R1 was 0.0501 (I > 2σ(I))
and wR2 was 0.1421 (all data).
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Crystal structure determination of compound 10b
Crystal Data for C24H16N2O2S (M = 396.45 g/mol): monoclinic, space group P21/c (no. 14), a =
18.3659(12) Å, b = 11.7207(9) Å, c = 8.8736(7) Å, β = 102.469(7)°, V = 1865.1(2) Å3, Z =
4, T = 294.13(16) K, μ(MoKα) = 0.198 mm-1, Dcalc = 1.412 g/cm3, 19199 reflections measured
(5.72° ≤ 2Θ ≤ 52.744°), 3814 unique (Rint = 0.0774, Rsigma = 0.0830) which were used in all
calculations. The final R1 was 0.0650 (I > 2σ(I)) and wR2 was 0.1589 (all data).
Crystal structure determination of compound 10c
Crystal Data for C25H16N2S (M = 376.46 g/mol): monoclinic, space group P21/n (no. 14), a =
12.1121(3) Å, b = 14.1893(3) Å, c = 21.9733(6) Å, β = 104.932(3)°, V = 3648.89(16) Å3, Z =
8, T = 293.9(3) K, μ(MoKα) = 0.190 mm-1, Dcalc = 1.371 g/cm3, 38167 reflections measured
(5.242° ≤ 2Θ ≤ 52.746°), 7453 unique (Rint = 0.0306, Rsigma = 0.0248) which were used in all
calculations. The final R1 was 0.0417 (I > 2σ(I)) and wR2 was 0.1106 (all data).
Crystal structure determination of compound 10d
Crystal Data for C25H17NO2S (M = 395.45 g/mol): orthorhombic, space group Pca21 (no.
29), a = 15.0652(3) Å, b = 12.5113(3) Å, c = 19.6794(5) Å, V = 3709.27(15) Å3, Z = 8, T =
293.60(19) K, μ(MoKα) = 0.197 mm-1, Dcalc = 1.416 g/cm3, 20366 reflections measured
(5.266° ≤ 2Θ ≤ 52.744°), 7367 unique (Rint = 0.0428, Rsigma = 0.0438) which were used in all
calculations. The final R1 was 0.0521 (I > 2σ(I)) and wR2 was 0.1307 (all data).
Crystal structure determination of compound 10e
Crystal Data for C25H18N2OS (M = 394.47 g/mol): orthorhombic, space group Pna21 (no.
33), a = 22.6911(13) Å, b = 20.5795(9) Å, c = 8.1911(4) Å, V = 3825.0(3) Å3, Z = 8, T =
293.9(4) K, μ(MoKα) = 0.189 mm-1, Dcalc = 1.370 g/cm3, 21414 reflections measured (5.344°
≤ 2Θ ≤ 52.728°), 7467 unique (Rint = 0.0361, Rsigma = 0.0509) which were used in all
calculations. The final R1 was 0.0603 (I > 2σ(I)) and wR2 was 0.1553 (all data).
Crystal structure determination of compound 10f
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