NaH promoted [4+3] annulation of crotonate-derived sulfur ylides with thioaurones: Synthesis of 2,5-dihydrobenzo[4,5]thieno[3,2-: B] oxepines

Article abstract of DOI:10.1039/c7cc04466f

The [4+3] annulation reaction of crotonate-derived sulfur ylides with thioaurones has, for the first time, been reported using NaH as the base. A diverse array of 2,5-dihydrobenzo[4,5]thieno[3,2-b]oxepines is obtained in good to excellent yields. The proposed mechanism is investigated and supported by DFT calculations.

Full text of DOI:10.1039/c7cc04466f

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NaH promoted [4+3] annulation of crotonate-derived sulfur ylides
and thioaurones: synthesis of 2,5-dihydrobenzo[4,5] thieno[3,2-
b]oxepine
Received 00th January 20xx,
Accepted 00th January 20xx
Youquan Zhang,a Aimin Yu,*a Jiru Jia,a Shanshan Ma,a Ke Li,a Yin Wei*b and Xiangtai Meng*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
The first [4+3] annulation reaction of crotonate-derived sulfur
ylide and thioaurone is reported using NaH as the base. A diverse
array of 2,5-dihydrobenzo[4,5]thieno[3,2-b]oxepine is obtained in
good to excellent yields. The proposed mechanism is investigated
and supported by DFT calculations.
Recently, crotonate-derived sulfur ylides are popular in organic
synthesis as sources of one carbon or three carbon synthon in
the presence of an inorganic base.1 The capability of
crotonate-derived sulfur ylides to undergo [2+1],2 [3+3],3
[3+3]/[1+2],4 [3+2]/[1+2]5 pericyclic reactions with various
substrates is used to construct three, six, bicyclic compounds,
and heterocycles. Among these pericyclic reactions, chalcone
and its derivatives are typically used. Tang reported a domino
reaction of crotonate-derived sulfur ylides with α, β-
unsaturated ketones for synthesis of cyclohexadiene epoxides
in high efficiency (Scheme 1a).4 Zhang and co-workers
introduced an alkynyl into the α position of chalcone, and
reacted it with crotonate-derived sulfur ylides to generate
bicycle[3.1.0]hexanes (Scheme 1b).5 Huang and co-workers
reported another two domino reactions of crotonate-derived
sulfur ylides, leading to alkynylated benzene derivatives and 2-
alkenyl aziridines (Scheme 1a).3,6 We have been inspired by
this work, and surveyed the entire diversity of crotonate-
derived sulfur ylides reactions described in the literature,
showing that [4+3] pericyclic reactions of crotonate-derived
sulfur ylides have not reported before. We believe that this
methodology is efficient to the synthesis of seven-membered
carbo- and heterocycles,7 which are often observed in natural
products and medicine molecules. During our ongoing
Scheme 1 Reactivity of crotonate-derived sulfur ylides in domino reactions.
investigation of domino reactions,8 based on the
aforementioned work of Tang, Zhang, and Huang, we
envisioned that adjustment of the chalcone structure might
alter the reactivity dramatically. Here, we report an [4+3]
pericyclic reaction between thioaurones and crotonate-
derived
sulfur
ylides;
pleasingly,
the
2,5-
dihydrobenzo[4,5]thieno[3,2-b]oxepine
derivatives
were
formed. To the best of our knowledge, this is the first [4+3]
pericyclic reaction of crotonate-derived sulfur ylides (Scheme
1c).
In order to test our postulate, we synthesized a series of
thioaurones
1
(see Supporting Information),9 and studied their
reactivity with crotonate-derived sulfur ylides. We commenced
our study with 1a and 2a as model substrates and the results
are summarized in Table 1. The reaction of 1a and 2a was
carried out in THF in the presence of Cs2CO3 as the base at
room temperature (entry 1). The desired [4+3] pericyclic
reaction product 3a was obtained in 17% yield. After
purification by column chromatography, 3a was characterized
a.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: aiminyu@tjut.edu.cn,
1
by H NMR, 13C NMR spectroscopy and HRMS. The structure
mengxiangtai23@mail.nankai.edu.cn
was unambiguously determined by single crystal X-ray
crystallography.10 The new observed reactivity prompted us to
optimize the reaction conditions to improve the yield. First, we
screened the solvent effects (Table 1). No product could be
isolated when DMSO was used (entry 2). When EtOH and DMF
were used, no improvement was made in the yield either
b.State Key Laboratory of Organometallic Chemistry, University of Chinese Academy
of Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. China. E-mail: weiyin@sioc.ac.cn
Electronic Supplementary Information (ESI) available: Full experimental details,
characterization and NMR spectra of all new compounds. CCDC 1545831 (3a),
1545864 (1v), 1546413 (6) and 1549207 (7). For ESI and crystallographic data in CIF
or other electronic format. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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(entries 3 and 4). Only moderate yields were observed when
With optimal conditions determined, we then focused on
CH3OH, Toluene, CH3CN, CH2Cl2, CCl4 were used as solvents exploring the substrate scope with respect to substitution on
(entries 5-9). With dioxane and CHCl3 used as solvents, the (Table 2). It was found that under optimized conditions the
reaction proceeded smoothly to produce 3a in 60% and 75% reaction tolerated thioaurones with halogen groups and a
1
1
yields, respectively (entries 10 and 11). Therefore, CHCl3 is the methyl group at C5 or C7 positions of the green benzene rings.
best choice for this domino reaction. Next, a variety of bases The bromo-substituted substrates were effective, which may
were examined in CHCl3. Na2CO3 and K2CO3 exhibited offer an opportunity for further derivatization (3a-3c, 3y). For
moderate reactivity, giving 3a 53% and 39% yields, respectively the red aromatic ring, both electron-withdrawing and
(entries 12 and 13). No improvements were observed with electron-donating groups were tolerated at the different
t
stronger bases NaOH, EtONa, BuOK (entries 14-16). To our positions, and the corresponding products were obtained in
delight, with NaH used as base, 3a was obtained in 85% yield good yields. For example, when a strong electron-deficient
(entry 17). Slightly lower yields were observed when using group was placed on the red benzene ring, the reaction
organic bases, such as DABCO, DBU, DMAP, piperidine or performed much better than others (3e: 96%, 3i: 91%, 3n
:
iPr2EtN as bases (entries 18-22). Moderate yield was obtained 94%). However, when a strong electron-donating group was
when Et3N was used (entry 23). Furthermore, lowering the installed on the red benzene ring, 3b and 3x were obtained in
o
temperature to 0 or -10 C, the yield of 3a decreased even if 78% and 87% yields, respectively. The efficiency of the domino
the reaction time was prolonged (entries 24 and 25). Neither reaction was not significantly affected by steric hindrance (3l
-
decreasing nor increasing the amount of NaH, the yield of 3o). As expected, the reaction of 1-naphthyl, 2-thienyl, and 2-
desired product 3a could not be improved (entries 26-28).
Py substituted
3p 3q and 3r in 74-85% yields. C5 fluoro- or methyl-
substituted (green benzene rings) substrates also tolerated,
and produced the desired products in 72-87% yields (3s 3x). In
1 also worked well, giving the desired products
,
Table 1 Optimization of reaction conditionsa
-
the case of the substrate containing a cinnamyl group, the
product 3y produced 69% yield. A benzo-fused derivative also
gave the desired product 3z in 86% yield. C7 chloro-substituted
(green benzene ring) substrate smoothly reacted with 2a to
give 3aa in 66% yield. It turned out that increasing the size of
the ester group in sulfonium salt 2b did not affect the
efficiency of the reaction (3ab).
Entry
1
Solvent
THF
Base
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
NaOH
EtONa
tBuOK
NaH
Time/min
90
90
12
2
Yield/%b
17
0
2
DMSO
EtOH
3
16
20
35
45
31
54
46
60
75
53
39
61
38
46
85
12
41
38
31
49
66
69
71
55
36
79
4
DMF
5
CH3OH
Toluene
CH3CN
CH2Cl2
CCl4
22
4
Table 2 Substrate scope of the domino reactiona
6
7
5
8
12
6.5 h
90
34
5 h
50
14
2 h
40
1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24c
25d
26e
27f
28g
Dioxane
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DABCO
DBU
34
4
DMAP
piperidine
iPr2EtN
Et3N
29
11
46
90
5
NaH
NaH
10
2
NaH
NaH
15
1
NaH
a Unless otherwise noted, reactions of 1a (0.16 mmol) and 2a (0.19 mmol)
were carried out in the presence of base (2.5 equiv) in 2 mL of solvent at
b
room temperature, reaction time was based on full consumption of 1a
.
a Reaction conducted on a 0.3 mmol scale of
/NaH is 1:1.2:2.5), unless otherwise noted, reaction time is 1 min.
1 in 4 mL of CHCl3 (molar ratio
b
Isolated yields. c The reaction was performed at 0 oC. d The reaction was of
1/2
performed at -10 oC. e 2.0 equiv of NaH was used. f 1.5 equiv of NaH was Yields of isolated product. Reaction time is 5 min. Reaction time is 15
c
d
used. g 3.0 equiv NaH was used.
min. e Reaction time is 1 h.
2 | J. Name., 2012, 00, 1-3
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Scheme 2 Large-scale experiment and transformations.
To test the practicality of this new methodology (Scheme 2),
a gram-scale reaction was carried out. The desired product 3d
was obtained in 83% yield when the reaction was scaled up to
Scheme 4 Proposed mechanism.
1.0
Furthermore, the ortho-NO2 substituted product 3n could
easily be reduced to the amino derivative in 58% yield in the
g (1d) under the optimized reaction conditions.
the IEFPCM method with radii and nonelectrostatic terms for
SMD salvation model in chloroform (ε = 4.7113).14 Solution-
phase single point energy calculations at mPW1K/6-
311++G(d,p) level based on the gas phase optimized
structures. The reaction free energy profile for this annulations
reaction is depicted in Scheme 5. Initially, the substrate 1’ is
4
presence of Pd/C in EtOH, and intramolecular cyclization
reaction occurred in the presence of 4-methylbenzenesulfonic
acid to give
3d with 2.2 equivalents m-CPBA at room temperature in CH2Cl2
furnished compound in 70% yield. In contrast, compound
was obtained in the presence of 1.05 equivalent of m-CPBA.
The structure of and were confirmed by single crystal X-ray
crystallography.10
5 in 14% yield. Moreover, treatment of compound
associated with an allylic ylide
A to give reactant complex Int 1.
6
7
Passing through the transition state TS1 which is located 21.2
kcal/mol above the Int1, the reaction undergoes Michael
addition to arrive at a zwitterionic intermediate Int2. The
intermediate Int2 can undergo proton transfer to yield
intermediate Int3 by passing through transition state TS2 that
is 12.8 kcal/mol above the intermediate Int2; subsequently,
the intermediate Int3 also undergoes another proton transfer
to give the intermediate Int4 via transition state TS3, which is
located 11.2 kcal/mol above the intermediate Int3. We also
investigated the transition state TS2’ which represents the
transition state from Int2 to Int4 via direct 1,3-H shift process.
However, transition state TS2’ stands very high energy
(Scheme 5), thus, we ruled out the direct 1,3-H shift process
from Int2 to Int4. In the presence of CD3OD, the OH moiety in
intermediate Int3 probably undergoes H/D exchange with
CD3OD, which may account for the experimental observation
that 60% of deuterium incorporation was found at both
protons adjacent to the oxygen atom (see Scheme 3). The
intermediate Int4 undergoes an intramolecular SN2
nucleophilic substitution to give product complex Int5 with an
6
7
To gain insight into the reaction mechanism, we performed
the domino reaction with 1d and 2a in the presence of 20.0
equivalent of CD3OD. The deuterated product D-3d was
formed in 82% yield. 1H NMR analysis of D-3d showed that
60% of deuterium incorporation was observed at both H-2
sites adjacent to the oxygen atom (Scheme 3).11
According to our experimental results and previous
literature,12 the possible mechanism for this domino reaction
has been proposed in Scheme 4. The crotonate-derived
sulfonium salt 2a was treated with NaH to give an allylic ylide
A
, which resonated to
to 1a would lead to intermediate
subsequently transforms into intermediate
transfer processes, and then undergoes an intramolecular
SN2 nucleophilic substitution to furnish the product 3a
B
. Following this, Michael addition of
B
C
.
Intermediate
C
F
via two proton
F
.
In order to thoroughly understand the details of our
reaction mechanism, we performed DFT calculations on the
suggested reaction pathways for this [4+3] annulations
reaction shown in Scheme 5 (for computational details, see
Supporting Information). All of calculations were performed
with the Gaussian 09 software package.13 The geometries of all
minima and transition states have been optimized at the
mPW1K/6-31G(d) level. The solvent effect was estimated by
energy barrier of 6.1 kcal/mol via transition state TS4
.
Subsequently, the product complex Int5 was separated to
generate the annulation product 3’. DFT calculations provide
theoretical evidence for the suggested reaction mechanism.
Conclusions
We have developed a novel NaH promoted domino reaction
between thioaurones and crotonate-derived sulfonium salts.
To the best of our knowledge, this is the first example of using
a crotonate-derived sulfonium salt as a three-carbon synthon
Scheme 3 Control experiment.
in
a
[4+3] annulation reaction.
A
variety of 2,5-
dihydrobenzo[4,5]thieno[3,2-b]oxepines were obtained in
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Scheme 5 Solvation Gibbs free energy profile for the annulation reaction.
5
6
7
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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). X. M. is grateful for the
support from the 131 Talents Program of Tianjin. Y. W. is
grateful for the support from the National Natural Science
Foundation of China (Grant No. 21372250). Thanks Dr.
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