Preparation of Thioanisole Biscarbanion and C-H Lithiation/Annulation Reactions for the Access of Five-Membered Heterocycles

Article abstract of DOI:10.1021/acs.orglett.8b00850

The synthesis, isolation, and X-ray structure of a thioanisole-based trilithium complex are reported. On the basis of the double-lithiation strategy, two novel synthetic methodologies have been developed under mild reaction conditions (room temperature): (1) reactions of lithiated thioanisoles with nitriles give benzoisothiazoles via a [3 + 2]-type of approach with two new bond formations and (2) formation of benzothiophenes from thioanisoles and amides through a [4 + 1] pattern forming 4 new chemical bonds.

Full text of DOI:10.1021/acs.orglett.8b00850

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Preparation of Thioanisole Biscarbanion and C−H Lithiation/
Annulation Reactions for the Access of Five-Membered Heterocycles
Ranran Zhu,†,§,∥,⊥ Zheyuan Liu,‡,§,⊥ Jie Chen,†,§,∥,⊥ Xiaoyu Xiong,†,§,∥ Yuntao Wang,†,§,∥ Lin Huang,†,§,∥
Jinshan Bai,†,§,∥ Yanfeng Dang,*,‡,§ and Jianhui Huang*,†,§,∥
†School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, China
‡Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, China
§Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, China
∥Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, Tianjin 300072, China
S
* Supporting Information
ABSTRACT: The synthesis, isolation, and X-ray structure of a thioanisole-based trilithium complex are reported. On the basis
of the double-lithiation strategy, two novel synthetic methodologies have been developed under mild reaction conditions (room
temperature): (1) reactions of lithiated thioanisoles with nitriles give benzoisothiazoles via a [3 + 2]-type of approach with two
new bond formations and (2) formation of benzothiophenes from thioanisoles and amides through a [4 + 1] pattern forming 4
new chemical bonds.
a
Scheme 2. Synthesis of Trilithium 4
arbanion as one of the most reactive species in organic
Cchemistry has continuously been the core synthon in
molecular design.1 Two major strategies are commonly used for
the generation of carbanions, including halogen−main group
metal exchange2 and hydrogen−metal exchange (deprotona-
tion).3−6
The regioselective and stereoselective deprotonations are the
main challenges in this field.7−9 Double lithiation of thioanisole
1 using nBuLi, followed by the reaction with diketone 2
provided a six-membered diol 3 in 59% yield (Scheme 1a).
a
Reaction conditions: substrate 1 (0.25 mmol), nBuLi/TMEDA (1.0
mmol), in hexane (2.0 mL) at 65 °C for 3 h.
Scheme 1. Double Lithiation/Annulation Reactions
Our research interests on the studies of synthetically useful
methodologies have previously focused on the regioselective
C−H activation reactions, in particular, modular construction
of heterocycles.10
Inspired by Xi’s development of dilithium reagents and
further applications in both organic chemistry and organo-
metallic chemistry,11 we focused on the studies of multi-
lithiation processes. Herein, we report our recent discoveries on
the preparation of bislithiated thioanisole complex 4 and two
new synthetic methodologies for the synthesis of benzoisothia-
zoles 6 and benzothiophenes 8.12,13 Novel bond formation
strategies and unprecedented cyclization approaches are
disclosed (Scheme 1b).14
Received: March 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00850
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a
Scheme 3. Synthesis of Benzaisothiazoles from
Organolithium 4
Scheme 5. Synthesis of Benzothiophenes from Trilithium 4
a
a
Reaction conditions: substrate 4 (0.20 mmol), amide (2.0 mmol) in
TBME (2.0 mL) at rt for 24 h
The ligand evaluation was also carried out; no lithiation was
observed if no ligand was added. The use of (−)-sparteine16
generated a complicated reaction mixture; the disilylated
product was only obtained in 8% yield. PMDTA17 was not
an efficient ligand either, and no desired product was isolated.
To our surprise, the white powder isolated was not bislithium
4x, instead, the white solid was trilithiated product 4, as
confirmed unambiguously by the X-ray crystallographic studies.
Interestingly, complex 4 is insensitive and can be stored at
room temperature for few days.18
a
Reaction conditions: lithium 4 (0.2 mmol), R1CN (1.0 mmol), in
TBME (2.0 mL) at rt for 24 h.
a
Scheme 4. Modular Synthesis of Benzoisothiazoles
Unlike previously known bidentate (κ2) ligand,19 TMEDA
was deprotonated during our processes.20 Single crystals were
obtained of the compound 4 isolated (Scheme 2). The distance
of Li3−C12 is comparable to those of trimeric or tetrameric
phenyllithium complexes reported previously in the litera-
ture.21,22
With the optimal conditions for the synthesis of trilithiated
thioanisole 4 available, we then investigated the possible
cyclization reactions. Encouragingly, when benzonitrile was
examined, benzoisothiazole 6a was isolated in 74% yield. We
then tested the scope and limitation of this annulation reaction.
As shown in Scheme 3, when lithium 4 was utilized, a range of
substituted benzonitriles could be coupled to give the
corresponding benzoisothiazoles 6a−m in useful to good yields.
Even reactions with very hindered aliphatic nitriles and
curved aromatic nitriles are possible; the reactions provided the
challenging benzoisothiazoles 6n−p in slightly lower yields.
The low yields for the synthesis of these products was due to
the poor solubility of the corresponding nitriles.
The direct synthesis of benzoisothiazoles under mild
conditions (room temperature) was also examined; the
preparation of benzoisothiazole 6a was straightforward. The
treatment of starting thioanisole 1 with organolithium reagent
and TMEDA in TBME and then trapping of the lithiated
species with benzonitrile as the electrophile gave the desired
product 6a in 72% yield. Reactions of other sulfides and nitriles
were also successful; the desired products were obtained in
good to useful yields. The reaction is more practical (instead of
65 °C lithiation), and the yields are similar compared to the
procedures using separated lithium salt 4 (Scheme 4).
Lithium complex 4 was not only reacted with nitriles but also
with amides via a [4 + 1]-type cyclization to give a
benzothiopene skeleton. The treatment of trilithium salt 4
with DMF 7a and amide 7b resulted in benzothiophene 8a and
8b in 78% and 63% yields, respectively (Scheme 5).
a
Reaction conditions: substrate 1 (0.20 mmol), nBuLi (1.0 mmol),
TMEDA (0.60 mmol) in TBME (2.0 mL) at rt for 0.5 h, then RCN
(1.0 mmol), at rt for 24 h.
We initiated our studies by investigating the formation of
dianions on substituted arene at both the lateral and ortho-
positions. Attempts on the lithiation of thioanisole 115 with 2.0
equiv of organolithium reagent (nBuli, sBuli, or tBuLi) in
ethereal solvent (Et2O or THF) at low temperature (−78 °C)
were not fruitful; no dianion was observed. Interestingly, when
a solution of arene 1 was treated with 1.0 equiv of nBuLi with
an equal molar amount of TMEDA in hexane at 65 °C,
followed by trapping the reaction mixture with TMSCl as the
eletrophile, a mixture of of silane 1-b and bissilane 1-c was
detected, and the corresponding silanes 1-b and 1-c were
isolated in 81% and 9% yields, respectively (Supporting
Information, Scheme 1).
Similar to the benzoisothiazole synthesis, the synthesis of
benzothiophene from thioanisoles is also investigated. Pleas-
ingly, the reaction of thioanisoles with a number of amides
provided the corresponding benzothiophenes 8a−h in useful to
B
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a
Table 1. Modular Synthesis of Benzothiophenes
Scheme 6. Control Experiments
a
Scheme 7. D-Labeled Experiments
a
Reaction conditions: thioether 1-D (0.2 mmol), TMEDA (3.0 equiv),
nBuLi (5.0 equiv), TBME (2 mL), under standard conditions, then
benzonitrile (5.0 equiv) at rt for 24 h.
Scheme 8. Proposed Mechanism
with bisisopropyl and piperidine ring protected amides (Table
1, entries 1−3). The four C−C bonds were formed within a
single chemical step; the synthesis of these molecules via
multilithiation bond formation provided a new pathway for
molecular design.
To elucidate the reaction mechanism, we have attempted to
isolate the possible reaction intermediate(s). Interestingly, as
shown in Scheme 6, when lithium 4 was treated with 3.0 equiv
of tBuCN, isothiazole 6o and ketone 9h were isolated in 23%
and 50% yields. Under similar conditions, and after being at
room temperature for 24 h, the reaction mixture was then
heated at 50 °C; isothiazole 6o was isolated in 40% yield
instead. These two experiments implied that both carbanions
may react with nitrile electrophile and the sp3C carbanion
reacted first. Upon quenching with NH4Cl(aq), the corre-
sponding product 9i was isolated. Further heating of the
reaction mixture resulted in the formation of isothiazole 6o in a
nearly doubled yield.
a
Reaction conditions: thioether 1 (0.2 mmol), TMEDA (3.0 equiv),
nBuLi (5.0 equiv), TBME (1 mL), rt, 3 h, then at 0 °C for 0.5 h, amide
was added in one portion, rt, 24 h.
The D-labeled thioanisole 1-D was treated with nBuLi/
TMEDA under our standard reaction conditions, then
benzonitrile was introduced, and the desired benzoisothiazole
6a was isolated in 65% yield with no D association.
good yields. Dimethylamine-substituted amides seem more
reactive and provided higher yields than reactions using amides
C
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Interestingly, we have also isolated the corresponding side
product 10 with 60% of D association (Scheme 7). These
results indicate that the methyl group may have been
deprotonated multiple times before being cleaved to form the
benzoisothiazole ring system.
University of York, UK) are also acknowledged. Special thanks
to Dr. Jun Xu (Tianjin University) for assistance with the X-ray
crystallographic studies.
REFERENCES
■
Density functional theory (DFT) calculations were also
performed to explore the detailed reaction mechanism using
the B3LYP-D3 method and the SMD solvation model. We
chose the reactions of substrate 1 with phenylacetonitrile and
DMF as representatives for the mechanistic investigation.
Scheme 8 illustrates our proposed reaction pathways, which can
be characterized by the following key steps, namely,
deprotonations by the lithium reagent leading to the bislithium
complex IN1, two successive electrophilic additions by the
nitrile or DMF substrate, and an N−S or a C−C bond-forming
reaction providing the final product 6a or 8a. The most favored
reaction pathways for these reactions are presented (see the
SI).
In summary, we have reported the synthesis and isolation of
an interesting lithiated species (4). In addition, we have also
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00850.
General information, experimental procedures, spectral
data, and energies and Cartesian coordinates (PDF)
Accession Codes
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CCDC 1495213 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yanfengdang@tju.edu.cn.
*E-mail: jhuang@tju.edu.cn.
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ORCID
Yanfeng Dang: 0000-0002-9297-9759
Jianhui Huang: 0000-0001-7281-663X
Author Contributions
⊥R.Z., Z.L., and J.C. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the “973” Program (2015CB856500)
and the NSFC (Grant No. 21672159) are gratefully acknowl-
edged. Valuable discussions with Professor Peter O’Brien (The
D
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