Styrene as 4π-Component in Zn(II)-Catalyzed Intermolecular Diels-Alder/Ene Tandem Reaction

Article abstract of DOI:10.1021/acs.orglett.6b01511

A mild Zn-catalyzed intermolecular Diels-Alder/ene tandem reaction with styrene as a 4π-component is reported. A variety of dihydronaphthalene products could be prepared in moderate to good yields. Moreover, a combination of DFT calculations and experiments was performed to further understand the mechanism of this unique tandem reaction.

Full text of DOI:10.1021/acs.orglett.6b01511

Letter
pubs.acs.org/OrgLett
Styrene as 4π-Component in Zn(II)-Catalyzed Intermolecular Diels−
Alder/Ene Tandem Reaction
Min Zheng, Feng Wu, Kai Chen,* and Shifa Zhu*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South
China University of Technology, Guangzhou, 510640, P. R. China
S
* Supporting Information
ABSTRACT: A mild Zn-catalyzed intermolecular Diels−Alder/
ene tandem reaction with styrene as a 4π-component is reported. A
variety of dihydronaphthalene products could be prepared in
moderate to good yields. Moreover, a combination of DFT
calculations and experiments was performed to further understand
the mechanism of this unique tandem reaction.
he Diels−Alder reaction is one of the most useful
developed.4 Biju et al. has taken advantage of benzyne as an
effective dienophile to react with styrene under mild conditions
(Scheme 1b).5 As our continuing efforts to develop tandem
reactions based on alkynes,6 we desire to develop a more
general intermolecular Diels−Alder/ene-tandem reaction be-
tween styrene as a 4π-component and alkynes as a 2π-
component (Scheme1c).
T
pericyclic reactions to construct the six-membered
carbocyclic compounds.1 The Diels−Alder reaction typically
involves the 4π-electron of the conjugated diene and 2π-
electron of the dienophile. In comparison with the conjugated
diene, the Diels−Alder reaction using styrene as a 4π-
component is, however, much less developed, in which the
unfavorable dearomatization should occur.
Initially, the reaction between an electron-deficient alkyne,
ethynyl phenyl ketone 2a, and styrene was chosen as the model
reaction. No reaction occurred in the absence of a Lewis acid
catalyst (Table 1, entry 1). It is well-known that the Diels−
Alder reactions involving alkynones and 1,3-dienes could be
promoted by a Lewis acid, which can decrease the electron
density of the triple bond via coordination to the alkynone’s
carbonyl group and lead to a lower LUMO (the lowest
unoccupied molecular orbital) energy.7 The reaction of 1a and
2a was then carried out at room temperature in DCE in the
presence of different Lewis acids. We are gratified to find that
the reaction could be activated by a variety of Lewis acid
catalysts, such as In(OTf)3, ZnCl2, Fe(OTf)3, AlCl3, and BF3·
Et2O, yielding the dihydronaphthalene 3a in 18−60% yields
(entries 2−6). Among these Lewis acid catalyzed reactions, the
best result was observed in the presence of ZnCl2, and 3a was
afforded in 60% yield (entry 3). When the Brønsted acid TFA
was used as the catalyst, the product 3a was obtained in 28%
yield (entry 7). The yield of 3a dropped to less than 5% when a
1:1 ratio mixture of ZnCl2 and TFA was applied (entry 8). The
yield of 3a can be enhanced to 76% when the temperature was
increased to 60 °C (entry 9); however, further increasing the
temperature to 80 °C resulted in a lower yield (entry 10).
Neither increasing nor decreasing the amount of styrene 1a can
improve the reaction yield (entries 11−12). Other solvents
such as MeCN and THF were also investigated in this model
reaction. An inferior result was observed in MeCN, and no
Since 1963, intramolecular didehydro-Diels−Alder
(IMDDA) reactions of styrene-ynes to construct naphthalenes
and other polycyclic aromatic hydrocarbons have attracted
much attention. However, the IMDDA reaction required harsh
reaction conditions (e.g., high temperature or microwave-
assisted conditions), which often resulted in the polymerization
of styrene.2 In 2015, Brummond et al. reported the mechanistic
study of the thermal IMDDA reaction of styrene-ynes, and they
found that the naphthalene product was formed via the loss of
hydrogen gas from the initially formed cycloadduct A (Scheme
1a).3 As a more straightforward and convenient way to prepare
the naphthalene derivatives, the intermolecular Diels−Alder
reaction of styrene (4π-component) with an alkyne (2π-
component) was much more challenging and highly under-
Scheme 1. Diels−Alder Reactions Involving Styrene and
Alkyne
Received: May 25, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01511
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Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scopes
entry
cat. (10%)
1a (equiv) temp (°C)
solvent
3a (%)
1
none
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
2.5
2.0
2.0
rt−60
rt
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeCN
THF
n.r.
33
60
22
38
18
28
<5
2
In(OTf)3
ZnCl2
3
rt
4
Fe(OTf)3
AlCl3
rt
5
rt
6
BF3·Et2O
TFA
rt
7
rt
b
8
ZnCl2/TFA
ZnCl2
rt
c
9
60
80
60
60
60
60
76
10
11
12
13
14
ZnCl2
55
41
74
63
n.r.
ZnCl2
ZnCl2
ZnCl2
ZnCl2
a
The reaction was conducted in a sealed Schlenk tube with 1a (0.50
mmol), 2a (0.25 mmol) in DCE (2 mL), 12 h, under N2. The yield
1
was determined by H NMR using CH3NO2 as an internal standard.
b
c
Bz: benzoyl. 10 mol % ZnCl2 and 10 mol % TFA were used. Isolated
yield.
reaction occurred in THF at all, which may result from the
coordination between zinc and solvent (entries 13 and 14).8
With the optimized reaction conditions in hand (Table 1,
entry 9), the substrate scope was then explored (Scheme 2). It
was found that the catalytic system could be successfully
applied to a wide scope of alkynones 2. For example, in
addition to phenyl alkynone 2a, other terminal aryl alkynones
with different substituents at the phenyl group can serve as
effective substrates as well, yielding the products 3a−m in
moderate to good yields (46−84%). It seems that the reactions
are not very sensitive to the electronic effects of the alkynone
substrates. Both the alkynones with electron-donating and
-withdrawing groups functioned well under the catalytic
conditions. The functional groups of methoxyl, hydroxyl, and
nitro were well tolerated (3c, 3d, 3h, 3k). Besides aryl
alkynones, the alkenyl- and alkynyl-substituted alkynones can
also be used as effective substrates, affording the desired
products 3n and 3o in 72% and 36% yields, respectively. Alkyl
alkynone transferred to the corresponding dihydronaphatha-
lene 3p in 41% yield. Further substrate screening showed that
the internal alkynone was not an effective substrate for this
reaction. Methyl propiolate was ineffective for this trans-
formation as well (3q). An internal alkyne showed much lower
reactivity, probably due to the steric hindrance. The extremely
electron-poor dimethyl acetylenedicarboxylate (DMAD), which
is typically an excellent dienophile for the traditional [4 + 2]
reactions,9 however, is not effective in our reaction. The
reaction cannot occur until the temperature was enhanced to
150 °C (3r, 47%). The electron-deficient alkenes, such as
methyl acrylate, dimethyl maleate, or phenyl vinyl-ketone, were
not effective dienophiles for this transformation.
a
The reaction was conducted in a sealed Schlenk tube with 1a (0.50
mmol), 2a (0.25 mmol), ZnCl2 (10 mol %) in DCE (2 mL) at 60 °C
b
under N2 for 12 h. Isolated yields are given. Bz: benzoyl. ZnI2 as
catalyst, rt, 24 h. 150 °C in toluene, 12 h.
c
derivatives with both electron-donating and -withdrawing
substituents on phenyl ring could be converted into the
dihydronaphthalenes 3s−3ab smoothly, with the yields ranging
from 43% to 75%. It is noted that the reactions occurred well
even when bulkier α- or β-substituted styrenes were applied as
the substrates (3ac−af). It was found that α- or β-
methylstyrene (3ac, 3ae) was a better 4π-component than α-
or β-phenyl styrene (3ad, 3af).
After having established the intermolecular two-component
Diels−Alder/ene-tandem reaction as a reliable and efficient
synthetic process to synthesize diverse dihydro-naphthalenes,
we are especially interested in investigating the possibility of the
three-component tandem reaction, in which two different
alkynes were used instead of the same alkyne in the above-
mentioned tandem reaction. We desire that one alkyne can take
part in the Diels−Alder process while the other alkyne
participates in the subsequent ene reaction. Between these
two steps, the Diels−Alder reaction was believed to be the rate-
determining process for the tandem reaction. As mentioned
above, the internal alkynone DMAD showed much lower
reactivity toward the initial Diels−Alder reaction than the
In addition to styrene, the styrene derivatives 1 with different
substituents can be successfully employed in the reaction (3s−
3af). Similarly, these reactions were not sensitive to the
electronic effects of the styrene substrates. The styrene
B
DOI: 10.1021/acs.orglett.6b01511
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Letter
terminal alkynones, whereas DMAD can be a better dienophile
in the following ene reaction based on the traditional
observations.7,10 To verify our hypothesis, the three-component
tandem reaction of alkynone 2a, DMAD, and styrene was then
carried out. To our delight, the desired dihydronaphthalene
product 4a could be obtained in 33% yield (Scheme 3).
Alder reaction via TS1, and the reaction is highly exergonic
(−74.1 kcal/mol).
To testify the proposed reaction mechanism, a series of
control experiments have been carried out. In order to observe
or characterize the proposed dearomatization intermediate I, 2-
vinylnaphthylene 1b (with increasing aromatic content) was
then used as the 4π-component diene. The desired
intermediate Ia could be successfully isolated in 70% yield
when alkynone 2p was used as the dienophile. The reaction was
accompanied by another inseparable oxidation product 6 in
17% yield. The intermediate Ia could subsequently react with
phenyl alkynone 2a, affording the target three-component
tandem reaction product 4b in 65% yield (Scheme 5).
a
Scheme 3. Three-Component Reaction
Scheme 5. Control Experiments
a
The reaction was conducted with 1a (0.50 mmol), 2a (0.25 mmol),
DMAD (1.25 mmol), ZnCl2 (10 mol %) in DCE (2 mL), 60 °C under
N2, and 12 h. Bz: benzoyl.
With the dihydronaphthalene derivatives in hand, we also
explored their further transformations. As shown in Scheme 4,
a
Scheme 4. Oxidation of Dihydronaphthalene
Furthermore, to gain additional insight into the hydrogen
transfer process of the ene reaction, a deuterium labeling study
was also performed. As shown in Scheme 6, the reaction of
Scheme 6. Deuterium Labeling Experiment
a
The reaction was conducted with 3 (1 mmol), DDQ (2 mmol) in
toluene under 110 °C for 12 h. Yields of the isolated products are
given.
deuterated styrene with DMAD under the same conditions in
Scheme 2 provided the product 3r-d8 in 43% yield with 100%
D-transfer from C-3 to C-9, which indicated that the ene
reaction is a concerted process. All these control reaction
results from Schemes 5 and 6 were perfectly consistent with the
reaction mechanism proposed in Figure 1.
In conclusion, a mild Zn-catalyzed intermolecular Diels−
Alder/ene tandem reaction with styrene as a 4π-component is
reported. The reaction was initiated by a Diels−Alder reaction
between 4π-component styrene and a dienophile alkynone,
followed by an ene reaction with another dienophile, leading to
the dihydronaphthalene products in moderate to good yields.
The reaction pathway was rationalized by DFT calculations,
and the key intermediate was isolated when 2-vinyl-
naphthalene was used as the 4π-component. This study could
not only help the understanding of the Diels−Alder reaction
with styrene as 4π-component but also provide a general and
efficient protocol to synthesize dihydronaphthalene derivatives.
Further studies on additional application of this Diels−Alder/
ene cascade reaction and Diels−Alder reactions with styrene
involved as a 4π-component are underway in our laboratory.
the dihydronaphthalene products could be oxidized smoothly
into the naphthalenes in excellent yields (5a−f, 85−98%) by
DDQ as the oxidant. The structure of 5a has been determined
by the single crystal X-ray analysis.
To understand the ZnCl2-catalyzed tandem Diels−Alder/ene
reaction, a DFT calculation was then carried out (see
Supporting Information for the calculation detail).11 The ene
reaction is mechanistically similar to the Diels−Alder reaction
since both reactions can proceed through a concerted cyclic
transition state involving six electrons.7,12 The coordination of
zinc to the carbonyl oxygen of alkynone 2a can decrease the
LUMO energy of dienophile, which would accelerate the
Diels−Alder and ene reactions. The free energy barrier for the
Diels−Alder reaction was about 23.5 kcal/mol. Due to the
disruption of aromaticity, the hydrogen at the 1-position of
intermediate I could be easily released to a proton acceptor
such as 2a. Then, an ene reaction could take place through a
cyclization transition state involving six electrons, requiring an
activation free energy of 17.8 kcal/mol. The potential energy
surface revealed that the rate-determining step is the Diels−
C
DOI: 10.1021/acs.orglett.6b01511
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Figure 1. DFT-computed free energy profile.11
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.6b01511.
Typical experimental procedure, characterization for all
products, and DFT calculation details (PDF)
Crystallographic data (CIF)
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L. M.; Orfanopoulos, M. J. Org. Chem. 1981, 46, 2200.
(8) (a) Wang, H.; Kehr, G.; Frohlich, R.; Erker, G. Angew. Chem., Int.
̈
AUTHOR INFORMATION
Corresponding Authors
■
Ed. 2007, 46, 4905. (b) Mikhalitsyna, E. A.; Tyurin, V. S.; Nefedov, S.
E.; Syrbu, S. A.; Semeikin, A. S.; Koifman, O. I.; Beletskaya, I. P. Eur. J.
Inorg. Chem. 2012, 2012, 5979.
(9) (a) Datta, S. C.; Franck, R. W.; Tripathy, R.; Quigley, G. J.;
Huang, L.; Chen, S.; Sihaed, A. J. Am. Chem. Soc. 1990, 112, 8472.
(b) Wender, P. A.; Jeffreys, M. S.; Raub, A. G. J. Am. Chem. Soc. 2015,
137, 9088. (c) Mackay, W. D.; Johnson, J. S. Org. Lett. 2016, 18, 536.
(10) Fernandez, I.; Bickelhaupt, F. M. J. Comput. Chem. 2012, 33,
509.
(11) DFT calculations were performed with the Gaussian 09
program. The relative Gibbs free energies were given at the
[SMD(DCE), M062X/(6-311++G(d,p), SDD)]//B3LYP/(6-
31G(d), Lanl2DZ) theoretical level. See Supporting Information for
calculation details.
*E-mail: cekchen@scut.edu.cn.
*E-mail: zhusf@scut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Ministry of Science and Technology of the
People’s Republic of China (2016YFA0602900), the NSFC
(21372086, 21422204), Guangdong Natural Science Founda-
tion (2014A030313229, 2016A030310433), China Postdoc-
toral Science Foundation (2015M582378, 2016T90777), and
the Fundamental Research Funds for the Central Universities,
SCUT for financial support of this research. Prof. Li Zhang
from SYSU is specially acknowledged for her help in language
polishing.
(12) Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1969, 8, 556.
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