3-Thiolated pyrroles/pyrrolines: controllable synthesis and usage for the construction of thiolated fluorophores

Article abstract of DOI:10.1039/d0cc07988j

Thiolation/cyclization of homopropargylic tosylamides allowed the selective synthesis of 3-thiolated pyrroles and pyrrolines controlled by solvents. Moreover, the desired 3-thiolated pyrroles were readily transformed to organic fluorophores benzothienopyrrole and bisthiolated boron dipyrromethene (S-BODIPY).

Full text of DOI:10.1039/d0cc07988j

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3-Thiolated pyrroles/pyrrolines: controllable
synthesis and usage for the construction
of thiolated fluorophores†
Cite this: Chem. Commun., 2021,
57, 1943
Received 8th December 2020,
Accepted 18th January 2021
Jun Tian,‡a Kang-Ning Yuan,‡a Wen Liu,b Hong-Hong Chang,a Xing Li
and
a
ac
Wen-Chao Gao
*
DOI: 10.1039/d0cc07988j
rsc.li/chemcomm
Thiolation/cyclization of homopropargylic tosylamides allowed the pyrrolines with thiols (Scheme 1c).6 Considering the importance
selective synthesis of 3-thiolated pyrroles and pyrrolines controlled and structural similarity of these two N-heterocycles, the develop-
by solvents. Moreover, the desired 3-thiolated pyrroles were readily ment of synthetic methods from common precursors is convenient
transformed to organic fluorophores benzothienopyrrole and and thus valuable.
bisthiolated boron dipyrromethene (S-BODIPY).
The mutual conversion of pyrroles with pyrrolines could be
achieved through oxidation or hydrogentation,7 while the
As two important N-heterocycles, pyrrole and pyrroline rings sulfur-incorporation usually affected this conversion due to
are privileged structural subunits present in many drugs, oxidation tendency and catalyst poisoning of sulfur.8 Encour-
natural products and organo-functional materials.1 In particular, aged by the thiolation/cyclization of alkynes induced by
when the heterocycles incorporated a thio group, excellent physical, N-thiosuccinimides,9 we speculated that the cyclization of
chemical, and biological properties were usually exhibited homopropargylic tosylamides would make the construction of
(Scheme 1a).2 Although the functionalization and modification of thiolated N-heterocycles possible, and the control of reaction
pyrroles and pyrrolines have been well studied,3 the construction of
thiolated pyrroles and pyrrolines is of great interest but less
explored. The electrophilic thiolation of pyrroles is a straight-
forward way to obtain 3-thiolated pyrroles, while the controlled
incorporation of a monothio group is still a problem due to the
high reactivity of the pyrrole ring.4 A worthwhile endeavour was
thus turned to the thiolation/cyclization of alkyne derivatives
triggered by thio-radicals or thio-electrophiles,5 which led to the
construction of thiolated pyrroles with high regioselectivity and
efficiency. For example, Yan and co-workers disclosed a tandem
thiolation/cyclization of homopropargylic amines with thiosulfo-
nates to access 3-thiolated pyrroles, and thiosulfonates were
employed as both oxidants and electrophiles (Scheme 1b).5b As
for the synthesis of 3-thiolated pyrrolines, methods are mainly
focused on the copper-catalysed C–S cross coupling of 3-halo
a College of Biomedical Engineering, Taiyuan University of Technology,
Taiyuan 030024, China. E-mail: gaowenchao@tyut.edu.cn
b School of Basic Medical Sciences, Shanxi Medical University, Taiyuan 030001,
China
c Shanghai Key Laboratory of Green Chemistry and Chemical Process,
East China Normal University, Shanghai, 200062, China
† Electronic supplementary information (ESI) available. CCDC 2036448–2036449.
For ESI and crystallographic data in CIF or other electronic format see DOI:
Scheme 1 Significance and synthetic strategies of 3-thiolated pyrroles
10.1039/d0cc07988j
and pyrrolines.
‡ Jun Tian and Kang-Ning Yuan contributed equally.
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solvents would discriminate the oxidation state of thiolated improve the yield of 3a to 75%. Other solvents were also
products, which led to the synthesis of 3-thiosubstituted pyrroles or examined for this transformation, while none of them could
pyrrolines selectively (Scheme 1d). Recently, nitromethane give a better yield of 3a than CH3NO2 (entries 14–17). To our
(CH3NO2), a common solvent, has emerged as a useful carbon delight, when CH3CN was employed as the solvent in the
donor or nitrogen source to access useful molecules,10 and the presence of 0.3 equiv. of AlCl3, the 3-thiolated pyrrole 3a was
generated HCHO, HNO and other N-containing species through the not detected at all, and 3-thiolated pyrroline 4a was afforded
Nef process played an important role in these transformations.11 in 80% yield (entry 17). Thus, by switching reaction solvents,
These oxidative species would enable CH3NO2 as a potential oxidant 3-thiolated pyrrole 3a and 3-thiolated pyrroline 4a could be
for the dehydrogenative aromatization of pyrrolines. Herein, with selectively produced.
our continuous interest in thioelectrophiles,12 we wish to report a
With the optimized conditions in hand, a series of N-thio-
switchable strategy for the synthesis of 3-thiosubstituted pyrroles or succinimides and homopropargylic tosylamides were investi-
pyrrolines through AlCl3-subcatalysed electrophilic thiolation/cycli- gated (Scheme 2). N-Arylthio succinimides with various sub-
zation of homopropargylic tosylamides, and the selectivity of pro- stituents, such as methyl, methoxy, azide, bromide, and nitro
ducts was controlled by the use of CH3NO2 or MeCN as the solvent. groups, could be well tolerated in this reaction, and gave the
To get the optimal reaction conditions, homopropargylic corresponding products in moderate to good yields (3a–f, 4a–f).
tosylamide 1a and N-phenylthio succinimide 2a were employed The electrophile with 2-thionaphthalene could also promote
as model substrates for the thiolation/cyclization, and both 1a this reaction, and the desired products were obtained in
and 2a could be readily prepared from commercially available moderate yields (3g and 4g). Furthermore, several N-alkylthio
compounds. At first, several catalysts that can activate N-thio- succinimides including ethylthio, benzylthio and 3-(ethoxy-3-
succinimides were screened with CH3NO2 as the solvent at oxopropyl)thio groups were also evaluated, and both the 3-thio-
60 1C (Table 1, entries 1–4), and it was found that 3-thiolated lated pyrrole and pyrroline products could be produced
pyrrole 3a was obtained when using AlCl3 as the catalyst (entry smoothly (3h–j, 4h–j). Notably, the cyclization promoted by
4). Increasing the amount of AlCl3 could improve the yield of 3a the electrophile derived from L-cysteine also proceeded
(entries 4–6), and further test indicated that 0.4 equiv. of AlCl3 (3k and 4k), providing an elaborate access to late-stage mod-
was a better choice (entry 5).13 The attempt with higher ification of amino acids. The variation of substituents on the
temperature did not give a better result (entry 7). It is known 2-aryl ring was tested as well, and both the electron-donating
that acidic conditions benefited the production of oxidative (–OMe) and -withdrawing groups (–Cl, and –CN) were suitable
species through the Nef process in CH3NO2,11 and we investi- for the cyclization, and the desired 3-thiolated products were
gated several acids as additives for this reaction (entries 8–13). produced in good yields (3l–n, 4l–n). The functional groups at
Notably, the use of 1.0 equiv. of HCl as the additive could the a-position of tosylamides were not limited to the aromatic
systems, and products bearing an n-butyl or a cyclohexyl group
could also be afforded in moderate yields (3o, 3p, 4o, and 4p).
Table 1 Optimization of reaction conditionsa
Additionally, this cyclization also proceeded to afford
3-thiolated-4,5-unsubstituted products (3q, 3r, 4q, and 4r),
which left flexible positions for further derivation.
Having successfully achieved the selective synthesis of
3-thiolated pyrroles, further synthetic derivation of 3-thiolated
pyrrole 3a was also explored (Scheme 3). For example, the tosyl
group could be readily removed by hydrolysis to access 5 or
migrated to the 4-position to afford full substituted pyrrole 6.
Furthermore, in the presence of NBS, the bromination of 3a
was also successfully achieved to give 7, which would facilitate
the linkage of arenes with pyrroles through the cross coupling
reaction.
Benzothienopyrroles, that contain both sulfur and nitrogen,
are important objectives in polymeric materials possessing
good electronic properties.14 With the use of obtained
3-thiolated pyrrole 3e, the highly conjugated benzothienopyr-
role 8 could be prepared in 40% yield after detosylation and
intramolecular C–C bond formation (Scheme 4a). Moreover, the
Entry
Solvent
Cat. (equiv)
Add. (equiv)
Yieldb (%)
1
2
3
4
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
DMF
CuCl (0.2)
Cu(OAc)2 (0.2)
BF3ÁEt2O (0.2)
AlCl3 (0.2)
AlCl3 (0.4)
AlCl3 (0.6)
AlCl3 (0.4)
AlCl3 (0.4)
AlCl3 (0.4)
AlCl3 (0.4)
AlCl3 (0.4)
AlCl3 (0.4)
AlCl3 (0.4)
AlCl3 (0.4)
AlCl3 (0.4)
AlCl3 (0.4)
AlCl3 (0.3)
—
—
—
—
—
—
—
0
0
0
47
67
67
61
21
64
70
75
61
67
0
5
6
7c
8
TfOH (0.4)
TFA (0.4)
HCl (0.4)
HCl (1.0)
pTsOH (1.0)
TMSCl (1.0)
HCl (1.0)
HCl (1.0)
HCl (1.0)
—
9
10
11
12
13
14
15d
16e
17f
THF
CH3CN
CH3CN
Trace
14
0
pyrrole ring is also
a key unit in fluorescent boron-
dipyrromethenes (BODIPY) that have been used as versatile
photosensitizers for imaging, sensing, polymerization, and
photodynamic therapy applications.15 The optoelectronic properties
of BODIPY could be tuned by incorporating appropriate substituents
onto the BODIPY framework.16 Detosylation of 3-thiolated pyrrole 3r
a
Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), catalyst
b
(0.02 mmol), in CH3NO2 (1.5 mL) at 60 1C for 1–6 h. Isolated yield.
c
e
d
The reaction was carried out at 80 1C. 4a was isolated in 47% yield.
4a was isolated in 74% yield. 4a was isolated in 80% yield.
f
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Scheme 2 Scope of the selective synthesis of 3-thiolated pyrroles and pyrrolines. Conditions A: 1 (0.1 mmol), 2 (0.15 mmol), AlCl3 (0.04 mmol), in
CH3NO2 (1.5 mL) at 60 1C for 1–6 h; conditions B: 1 (0.1 mmol), 2 (0.15 mmol), AlCl3 (0.03 mmol), in CH3CN (1.5 mL) at 60 1C for 2–6 h. a The reaction was
run without HCl.
Scheme 3 Further derivation of 3-thiolated pyrrole 3a.
followed by condensation with 4-bromobenzaldehyde and dehydro-
genation gave the bis-thiolated dipyrromethane, which was com-
plexed with boron trifluoride etherate to afford the bisthiolated
BODIPY in 61% yield (Scheme 4b). This new kind of BODIPY dye
with diphenylthio groups exhibited an intense bathochromic
fluorescence with lmax at around 710 nm, and a Stokes shift in
Scheme 4 Synthesis of bisthiolated organic fluorescent molecules.
the range of 132–151 nm.13
To understand the mechanism, several control experiments
were conducted (Scheme 5a). In the absence of thioelectro- CH3NO2 solvent via dehydrogenative aromatization, which
philes or AlCl3, the cyclization of 1a did not occur. These results demonstrated that some oxidative species were generated in
indicated that the reaction was initiated from the activation of nitromethane catalysed by AlCl3. On the basis of these results
N-thiosuccinimides with AlCl3. In addition, 3-thiolated pyrro- and literature reports,9–11 a possible mechanism is proposed in
line 4a could be transformed to 3-thiolated pyrrole 3a in the Scheme 5b. The oxidative species such as hyponitrous acid
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In summary, we have developed AlCl3-subcatalysed electrophi-
lic thiolation/cyclization of homopropargylic tosylamides for the
synthesis of 3-thiolated pyrroles and pyrrolines, which were
selectively produced by the use of nitromethane or acetonitrile
as the solvent. This protocol featured simple and mild reaction
conditions, a broad substrate scope, good regioselectivity and
controllable products. More importantly, 3-thiolated pyrroles were
applied to the synthesis of organo-optoelectronic benzothienopyr-
roles and bisthiolated BODIPY, providing new avenues for the
preparation of S-containing material molecules. Efforts to exploit
this strategy for other applications are underway.
This work was supported by the National Natural Science
Foundation of China (No. 21901179), the Key R&D Program of
Shanxi Province (International cooperation) (No. 201803D421093),
the Natural Science Foundation of Shanxi Province (No.
201901D211052), the Scientific Activities of Selected Returned Over-
seas Professionals of Shanxi Province (No. 20200002) and the
Research Project of Shanxi Scholarship Council (No. HGKY2019029
and 2020-053).
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There are no conflicts to declare.
1946 | Chem. Commun., 2021, 57, 1943À1946
This journal is The Royal Society of Chemistry 2021