Synthesis of Benzothiophene-Fused Oxa[6.6.5]tricyclic Skeletons through a Cinchonidine- or NaOH-Promoted Quadruple Domino Sequence

Article abstract of DOI:10.1002/chem.201900890

Two base-promoted quadruple domino reactions between thioaurones and allylic phosphonium salts have been developed to synthesize benzothiophene-fused oxa[6.6.5]tricyclic skeletons in moderate to good yields with excellent stereoselectivity and broad functional-group tolerance. This is a simple and useful protocol for the rapid construction of the umbrella-like oxa[6.6.5]tricyclic skeleton.

Full text of DOI:10.1002/chem.201900890

A Journal of
Accepted Article
Title: Synthesis of Benzothiophene-Fused Oxa-[6.6.5]-Tricyclic
Skeletons via a Cinchonidine- or NaOH-Promoted Quadruple
Domino Sequence
Authors: Ke Li, Liang Wang, Aimin Yu, Lingli Zhu, Lei Zhang, Yingchun
Gu, and Xiangtai Meng
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To be cited as: Chem. Eur. J. 10.1002/chem.201900890
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Synthesis of Benzothiophene-Fused Oxa-[6.6.5]-Tricyclic
Skeletons via a Cinchonidine- or NaOH-Promoted Quadruple
Domino Sequence
Ke Li,[a] Liang Wang,*[a] Aimin Yu,[a] Lingli Zhu,[a] Lei Zhang,[b] Yingchun Gu[b] and Xiangtai Meng*[a]
Abstract: Two base-promoted quadruple domino reactions between
thioaurones and allylic phosphonium salts have been developed to
synthesize benzothiophene-fused oxa-[6.6.5]-tricyclic skeletons in
moderate to good yields with excellent stereoselectivity and broad
functional group tolerance. This is a simple and useful protocol for the
rapid construction of the umbrella-like oxa-[6.6.5]-tricyclic skeleton.
Figure 1. Examples of compounds containing an oxa-[6.6.5]-tricyclic skeleton.
Introduction
two domino reactions for the construction of cyclic and fused
bicyclic compounds (Scheme 1, a and b).[6] Furthermore,
The umbrella-like oxa-[6.6.5]-tricyclic skeleton is
a highly
benzothiophene-fused heterocyclic compounds are important
structural skeletons in biologically active compounds and material
chemistry.[7] During our ongoing efforts to develop domino
reactions,[8] we envisaged that the reaction of a thioaurone
bearing an α, β-unsaturated aldehyde with a phosphine ylide
might form a benzothiophene-fused oxa-[6.6.5]-tricyclic skeleton
via a multiple domino process (Scheme 1, c). To the best of our
knowledge, a highly stereoselective synthesis of such an
umbrella-like oxa-[6.6.5]-tricyclic skeleton in one step from acyclic
starting materials has not been reported.
privileged motif that is featured in many natural products as well
as pharmaceuticals displaying a broad spectrum of biological
activities, including insecticidal, phytotoxic, and cancer chemo-
preventative properties (Figure 1).[1] Therefore, the development
of an efficient methodology for the construction of the umbrella-
like oxa-[6.6.5]-tricyclic skeleton is required.[2] However, the
preparation of this motif remains challenging due to the large
number of potential stereoisomers and dearth of synthetic
strategies for its preparation. The current synthetic methodologies
for accessing this motif require many steps. The traditional
approaches involve either the installation of each ring individually
or the simultaneous addition of two rings to a monocyclic starting
material.[3] These approaches often suffer from poor
stereoselectivity and long reaction routes. The ideal preparation
of this skeleton would utilize a domino process from readily
available starting materials.
Domino reactions facilitate the generation of complex 3D
architectures from simple starting materials in
a single
operation.[4] By minimizing the number of isolated reaction
intermediates, domino reactions enhance the selectivity and
reduce the time and cost of the targeted chemical synthesis.
Among reported domino reactions, allylic ylides have been
identified as versatile reactants for the preparation of carbocyclic
and heterocyclic compounds.[5] For example, Tang has reported
[a]
[b]
K. Li, L. Wang, A. Yu, L. Zhu, X. Meng
Tianjin Key Laboratory of Organic Solar Cells and Photochemical
Conversion, School of Chemistry & Chemical Engineering, Tianjin
University of Technology, Tianjin 300384, P. R. China.
E-mail: xtmeng@tjut.edu.cn; wangliang@tjut.edu.cn
L. Zhang, Y. Gu
Tianjin Engineering Technology Center of Chemical Wastewater
Source Reduction and Recycling, School of Science, Tianjin
Chengjian University, Tianjin 300384, P. R. China.
Scheme 1. Various reaction modes of allylic phosphine ylides.
Results and Discussion
Towards this aim, we designed and synthesized a series of
thioaurones
1
to screen domino reactions with allylic
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
phosphonium salts 2a (Table 1). To our delight, the treatment of
1a (0.3 mmol) with 2a (1.2 mmol) in the presence of NaOH (1.5
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mmol) in CHCl3 at room temperature afforded desired products
3a and 3a in 20% yield with 1.8:1 dr (the stereochemistry was
unambiguously confirmed by X-ray crystallographic analysis)
(entry 1).[9] In this domino reaction, multiple events occurred in
improvement was observed in the stereoselectivity relative to
what was obtained with NaOH (2.8:1 dr). No improvement in the
yield or stereoselectivity was obtained by using KOtBu or weak
bases, such as Na2CO3, K2CO3, and Cs2CO3 (entries 4-7). Similar
to the results obtained with NaOMe, the use of piperidine gave a
slight decrease in yield with a modest improvement in the
stereoselectivity (17% yield and 6:1 dr; entry 8). To further
improve the reaction yield and stereoselectivity, tertiary amines
were screened as potential bases for the reaction. For example,
Table 1. Optimization of the domino reaction for accessing 3a.[a]
i
i
the use of PrN2H, DABCO, Et3N, DBU, and PrN2Et resulted in
moderate yields and stereoselectivities (entries 9-14). The results
of this screening revealed cinchonidine to be the most effective
base, as desired product 3a was obtained in 60% yield with 32:1
dr (entry 15).[10] Other solvents, including CH2Cl2, THF, EtOH,
CH3CN, toluene, DMSO, and DMF, were found to be less efficient
than CHCl3 (entries 16-22). Additionally, either decreasing or
increasing the reaction temperature resulted in unsatisfactory
yields and drs of 3a (entries 23-24). Finally, the amount of
cinchonidine was also examined. Decreasing the amount of
cinchonidine did not improve the yield of 3a (entries 25-27).
Yield/%
Entry
Solvent
Base
Time/min
(dr 3a:3a)[b]
1
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
THF
NaOH
30
20 (1.8:1)
55 (22:1)
11 (2.8:1)
29 (5.3:1)
43 (14:1)
41 (3.5:1)
20 (2.9:1)
17 (6.0:1)
56 (3.9:1)
16 (29:1)
25 (23:1)
41 (6.5:1)
42 (3.9:1)
46 (5.4:1)
60 (32:1)
37 (8.2:1)
42 (1.4:1)
26 (49:1)
37 (7.0:1)
40 (2.5:1)
26 (3.0:1)
32 (2.1:1)
2
EtONa
25
3
MeONa
30
4
tBuOK
12 h
90
5
Na2CO3
6
K2CO3
30
7
Cs2CO3
40
8
piperidine
iPr2NH
30
Table 2. Substrate scope for product 3.[a]
9
60
10
11
12
13
14
15
16
17
18
19
20
21
22
23[c]
DMAP
60
DABCO
30
Et3N
30
DBU
30
iPr2NEt
30
Cinchonidine
Cinchonidine
Cinchonidine
Cinchonidine
Cinchonidine
Cinchonidine
Cinchonidine
Cinchonidine
Cinchonidine
Cinchonidine
Cinchonidine
Cinchonidine
Cinchonidine
16 h
24 h
30
EtOH
30
CH3CN
toluene
DMSO
DMF
30
30
30
30
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
20 h
30
38 (30:1)
55 (3.3:1)
24[d]
25[e]
16 h
16 h
16 h
52 (32:1)
50 (32:1)
32 (32:1)
26[f]
27[g]
[a] Unless otherwise stated, reactions were performed with 1a (0.3 mmol),
2a (1.2 mmol), base (1.5 mmol), and solvent (2 mL) at room temperature.
[b] Isolated yields, the product ratio was estimated by 1H NMR spectroscopy
of the crude product. [c] The reaction was conducted at 0 °C. [d] The
reaction was conducted as reflux. [e] 3.0 equiv. of cinchonidine was used.
[f] 2.0 equiv. of cinchonidine was used. [g] 1.0 equiv. of cinchonidine was
used.
sequence. (1)
A benzothiophene-fused oxa-[6.6.5]-tricyclic
skeleton was formed via a quadruple domino reaction. (2) Two
carbon-carbon single bonds, one carbon-carbon double bond and
one carbon-oxygen single bond were formed. (3) Three new rings,
three vicinal tertiary centers and one quaternary center were
constructed in a single operation. These interesting results
prompted us to optimize the reaction conditions. Using NaOEt in
place of NaOH as the base increased the yield of 3a to 55% with
22:1 dr (entry 2). However, the yield decreased to 11% when
NaOMe was employed as the base, and only a modest
[a] Reaction conditions: 1 (0.3 mmol), 2a (1.2 mmol), cinchonidine (1.5
mmol), CHCl3 (2 mL) at room temperature. Yields of isolated products. dr >
20:1 (the product ratio was estimated from the crude 1H NMR spectrum).
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Next, the substrate scope of this domino reaction was evaluated
(Table 2). First, we explored substitution at R2 with R1 with chloride
at the C5 position. The reaction was tolerant of substituents at the
C5 position of 1 (R2), such that all reactions proceeded smoothly
and generated corresponding products 3a-3e in moderate to good
yields with excellent drs. Electron-donating or electron-
withdrawing substituents at R2 generally resulted in a lower
reaction yield. However, substrates 1 bearing chloro- or fluoro- at
C4 (R2) afforded desired products 3f and 3g in yields of 59% and
49%, respectively. Furthermore, substrate 1 with a fluoro
substituent at the C6 (R2) position afforded 3h in 53% yield. Next,
we extended the scope of the domino reaction with respect to
substitution at R1. C5 (R1) bromo-, fluoro-, or methyl-substituted
substrates were examined, and they produced corresponding
products 3i-3k in 50%-63% yields. The substrate possessing a
bromine at the C6 (R1) position produced 3l in a yield of 43%. The
substrate with a methyl substituent at C7 (R1) reacted with 2a to
yield 3m in only 28% yield. A benzo-fused derivative gave desired
product 3n in a yield of 65%. We also tested the substrate scope
Given these results, the domino reaction was extended to
thioaurones 4. The optimization of reaction conditions established
that the best conditions were as follows: thioaurone 4 (1.0 equiv.),
allylic phosphonium salt 2a (4.0 equiv.), and NaOH (5.0 equiv.) in
CHCl3 at reflux (see SI, Table S1). Corresponding products 5a
and 5a were obtained in 70% yield with 5:1 dr, and their
stereochemistry was unambiguously confirmed by X-ray
crystallographic analysis.[9] Evaluation of the substrate scope of
substituted thioaurones 4 demonstrated successful domino
processes with good yields and excellent diastereoselectivities
(Table 3). Substitution at R2 was explored with R1 maintained as
the C5 chloro derivative. For example, when R2 has a proton or a
methyl group at the C5 position, corresponding products 5a and
5b were obtained in yields of 70% and 54%, respectively. When
a methoxy group, a strong electron donor, was installed at the C5
(R2) position, the reaction afforded desired product 5c in 47%
yield. C5 (R2) chloro- or fluoro-substituted substrates likewise
reacted efficiently to furnish desired products 5d and 5e in yields
of 54% and 67%, respectively. Furthermore, chloro- or fluoro-
groups were successfully introduced into 4 at the C4 (R2) position,
giving desired products 5f and 5g in 60% and 57% yield,
respectively. However, installation of a fluoro substituent at the
C6 (R2) position afforded product 5h in only 47% yield.
Modification of R1 via bromo- or methyl-substitution at the C5
position also resulted in products 5i and 5j in good yields (60%
and 49%, respectively). Lastly, we explored the reactivity of a
naphthalene-containing substrate, which generated product 5k in
55% yield. All the dr values were from 5:1 to 6:1.
i
of the allylic phosphonium salt. Pr- or Ph-substituted substrates
reacted with 1a to afford corresponding products 3o and 3p in
50% and 24% yields, respectively. When there was a methyl
substituent at the β position of the allylic phosphonium salt,
desired product 3q (confirmed by X-ray crystallography) was
obtained in 27% yield.[9] To extend the utility of our domino
reaction, substrate 1r, where the sulfur heteroatom has been
replaced with an oxygen atom, was also tested; however, desired
product 3r was obtained in only 16% yield.
Table 3. Substrate scope for product 5.[a]
Scheme 2. Control experiment.
To elucidate the reaction mechanism, we performed the domino
reaction of 1a and 2a in the presence of 20.0 equivalents of D2O.
1
Product 3a-D was obtained in 53% yield. The H NMR spectrum
of 3a-D indicated that 70% of the deuterium incorporation
occurred on the double bond, and 30% of the incorporation was
observed at the CH2 site (Scheme 2).[11] On the basis of the above
results in conjunction with previous reports,
a possible
mechanism is proposed in Scheme 3. Initial deprotonation of
allylic phosphonium salt 2a yields intermediate A. Intermediate B,
the resonance structure of intermediate A, is transformed into
intermediate C via a Michael addition. Intermediate D, a
resonance form of C, undergoes an O-Michael addition to form
intermediate E. Subsequently, proton transfer to E produces
intermediate F. Next, intermediate F undergoes an intramolecular
Michael addition to afford intermediate G and then forms ylide H
via another proton transfer process. Finally, ylide H undergoes a
Wittig reaction to form product 3.[12] The stereoselective formation
of product 3 was also discussed. First, O-Michael addition of D
produces E with two hydrogens (in the 2 and 4 positions) on the
same face of the ring, which is kinetically more stable.[13] In terms
[a] Reaction conditions: 1 (0.3 mmol), 2 (1.2 mmol), NaOH (1.5 mmol),
CHCl3 (2 mL) at reflux. Yields of isolated products, dr determined from the
crude 1H NMR spectrum.
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of intermediate G, the hydrogen adjacent to the aldehyde and the
hydrogen adjacent to the oxygen are on the same face of the ring,
which will facilitate the subsequent Witting reaction. The
mechanism of the formation of 5 was similar to that of 3.
Scheme 4. Transformations of 3a
.
Scheme 3. Proposed mechanisms.
Derivatization of the reactive umbrella-like oxa-[6.6.5]-tricyclic
skeleton to generate further value-added products was
subsequently investigated (Scheme 4). The reaction of 3a with
1.05 equiv. of m-CPBA in CH2Cl2 at room temperature for 24 h
provided sulfoxide derivative 6 in 54% yield (Scheme 4a).
Similarly, sulfone derivative 7 was obtained in the presence of 2.2
equiv. of m-CPBA in CH2Cl2 at room temperature over the course
of 1 h (Scheme 4b).[14] Conversely, the reduction of 3a using
DIBAL-H (DIBAL-H = diisobutylaluminum hydride) in toluene was
achieved at -78 °C, and desired product 8 was obtained in 70%
yield (Scheme 4c).[15] Furthermore, the oxidation of 3a with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in a mixture of
DCE/H2O or DCE/MeOH (DCE = 1,2-dichloroethane) at room
temperature afforded products 9 or 10 in 45% or 79% yields,
respectively (Scheme 4d and 4e).[16] Similar oxidation and
reduction reactions were observed for 5a, and corresponding
products 11, 12, and 13 were obtained in yields of 67%-75%
Scheme 5. Transformations of 5a
.
(Scheme 5 ). Gratifyingly, both domino reactions are amenable to Conclusions
scale-up. For example, 500 mg of 1a and 4a were converted to
3a and 5a in 41% and 55% yields, respectively.
In summary, we have successfully developed two novel and
efficient base-promoted quadruple domino reactions for the
synthesis of benzothiophene-fused oxa-[6.6.5]-tricyclic skeletons
from readily available starting materials. The reactions are highly
functional-group tolerant and provide access to structures that are
not easily accessible via traditional synthetic strategies. Further
work on applications and extensions of the scope of this protocol,
as well as a more detailed investigation of the reaction
mechanism, are currently underway.
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Q. Liu, Angew. Chem. Int. Ed. 2009, 48, 2868-2872; Angew. Chem. 2009,
121, 2912-2916.
Experimental Section
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Wang, S.-F. Zhu, L.-W. Ye, C.-Y. Zhou, X.-L. Sun, Y. Tang, Q.-L. Zhou,
Adv. Synth. Catal. 2010, 352, 1914-1919; c) J.-B. Zhu, P. Wang, S. Liao,
Y. Tang, Chem. Commun. 2013, 49, 4570-4572; d) P. Wang, S. Liao, S.
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General procedure for the synthesis of 3: Under an Ar atmosphere, to
a CHCl3 (2 mL) solution of ylide 2 (1.2 mmol) was added cinchonidine (1.5
mmol). The resulting mixture was stirred for 45 min at room temperature.
Substrate 1 (0.3 mmol) was added, and the resulting mixture was stirred
for 4-72 h at room temperature. After the reaction was completed
(monitored by TLC), the solvent was removed under vacuum, and the
residue was purified by column chromatography (SiO2, ethyl
acetate:petroleum ether = 1:5) to afford pure product 3.
[6]
[7]
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a) L.-W. Ye, S.-B. Wang, Q.-G. Wang, X.-L. Sun, Y. Tang, Y.-G. Zhou,
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Allard, M. Forster, B. Souharce, H. Thiem, U. Scherf, Angew. Chem. Int.
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This work was financially supported by the National Natural
Science Foundation of China (Grant No. 21403154), the Natural
Science Foundation of Tianjin (Grant No. 13JCYBJC38700), and
the Tianjin Municipal Education Commission (Grant No.
20120502, 20180KJ137). X. M. is grateful for the support from the
131 Talents Program of Tianjin and Training Project of Innovation
Team of Colleges and Universities in Tianjin (TD13-5020).
[9]
CCDC-1860280 (3a), 1860281 (3a), 1860282 (3q), 1860283 (5a),
1860284 (5a), 1860285 (8), 1860286 (9), 1860287 (12) and 1860288
(13) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Keywords: Domino reaction • Oxa-[6.6.5]-tricyclic skeleton •
Thioaurone • Phosphine ylide • Base-promoted reaction
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Entry for the Table of Contents
FULL PAPER
Ke Li, Liang Wang, Aimin Yu, Lingli Zhu,
Lei Zhang, Yingchun Gu, Xiangtai
Meng*
Page No. – Page No.
Synthesis of Benzothiophene-Fused
Oxa-[6.6.5]-Tricyclic Skeletons via a
Cinchonidine- or NaOH-Promoted
Quadruple Domino Sequence
Two base-promoted quadruple domino reactions between thioaurones and allylic
phosphonium salts have been developed to synthesize benzothiophene-fused oxa-
[6.6.5]-tricyclic skeletons in moderate to good yields with excellent stereoselectivity
and broad functional group tolerance. This is a simple and useful protocol for the
rapid construction of the umbrella-like oxa-[6.6.5]-tricyclic skeleton.
This article is protected by copyright. All rights reserved.