Copper-Catalyzed Dehydrogenative Diels-Alder Reaction

Article abstract of DOI:10.1021/acs.orglett.8b01067

A practical and effective copper-catalyzed dehydrogenative Diels-Alder reaction of gem-diesters and ketone with dienes has been established. The active dienophiles were generated in situ via a radical-based dehydrogenation process, which reacted with a wide variety of dienes to afford various polysubstituted cyclohexene derivatives in good to excellent yields.

Full text of DOI:10.1021/acs.orglett.8b01067

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Dehydrogenative Diels−Alder Reaction
Bing Jiang,†,∥ Qiu-Ju Liang,†,∥ Yu Han,† Meng Zhao,† Yun-He Xu,*,† and Teck-Peng Loh*,†,‡,§
†Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and
Technology of China, Hefei 230026, China
‡Institute of Advanced Synthesis, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University,
Nanjing 210009, P. R. China
§Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371
S
* Supporting Information
ABSTRACT: A practical and effective copper-catalyzed
dehydrogenative Diels−Alder reaction of gem-diesters and
ketone with dienes has been established. The active
dienophiles were generated in situ via a radical-based
dehydrogenation process, which reacted with a wide variety
of dienes to afford various polysubstituted cyclohexene
derivatives in good to excellent yields.
Scheme 1. Oxidative Dehydrogenative Diels−Alder
he Diels−Alder reaction is probably one of the most
Reactions
T
powerful reactions for the construction of six-membered
rings.1 Accordingly, it has been widely used for the synthesis of
many natural products and pharmaceuticals.2 Nevertheless,
there are still limitations associated with this important
reaction.3 For example, there is still the need to prepare the
highly reactive and toxic dienophiles before the reaction.
Therefore, methods that can generate the reactive dienophiles
in situ from easily accessible and more stable compounds in the
reaction will be highly desirable. We envisage that dienophiles
generated in situ via dehydrogenation of alkanes will be useful.
It is important to note that dehydrogenation processes to yield
alkenes have been documented by the groups of Stahl,4 Dong,5
Nicolaou,6 Ishihara,7a Kuwano,8 Huang,9 Su,10 White,11
Nozaki,12 Cheng,13 Yu,14 Newhouse,15 and Kang.16 On the
other hand, Su and co-workers have elegantly utilized this
process for the amine conjugate addition.10c Moreover, a few
examples on dehydrogenative Diels−Alder reactions have
emerged as unique protocols for the one-step construction of
unsaturated six-membered carbocycles. One such case is via Pd,
Pt/C-catalyzed, or oxidative dehydrogenation to generate
reactive diene intermediates (Scheme 1), which was reported
by White,11a Porco,17a Ishihara,7b Zhang,18 and others.19
Another example developed by Porco and co-workers is an
Rh/C-catalyzed dehydrogenative reaction of cyclopentanone
derivatives to form very reactive cyclopentadienone dienophi-
les.17b Therefore, we envision that a highly efficient gem-diester
or ketone dehydrogenation process in combination with a
subsequent Diels−Alder reaction would provide an appealing,
atom-economic alternative to the traditional way by eliminating
the need for troublesome pre-preparation and isolation of α,β-
unsaturated carbonyl compounds. To realize this design, the
catalytic system must conform to the following requirements:
(a) the catalytic system selectively dehydrogenates gem-diester
or ketone over a cyclohexene product to avoid overoxidation;
(b) the catalytic system selectively takes place prior to a
Michael conjugate addition to overcome the byproduct from
the dienophile precursor and TEMPOH; (c) the oxidative
Received: April 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01067
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
dehydrogenation conditions are compatible with a Diels−Alder
cyclization donor (an accessible electron-rich diene); and (d)
the catalytic system is capable of facilitating both dehydrogen-
ation and Diels−Alder reactions. With our continued interest in
a Diels−Alder reaction to construct six-membered ring-
containing frameworks efficiently,3q,20,21 we hereby report a
copper-catalyzed dehydrogenative Diels−Alder reaction that
uses gem-diester or ketone as the direct dienophile through an
acrylate or enone intermediate generated in situ.
by employing diethyl 2-methylmalonate as dienophile precursor
(Scheme 2). We found that a wide variety of readily available
a
Scheme 2. Substrate Scope of Dienes
First, we evaluated the model reaction with 2,3-dimethylbuta-
1,3-diene and the dienophile precursor diethyl 2-methylmalo-
nate, and the results are summarized in Table 1. Pleasingly, the
Table 1. Development of the Tandem Dehydrogenation/
a
Diels−Alder Reaction
a
Reaction conditions: 2 (0.3 mmol), diethyl 2-methylmalonate 1a (0.6
mmol), Cu(OAc)2 (0.03 mmol), L4 (0.03 mmol), TEMPO (1.6
equiv), (trifluoromethyl)benzene (2 mL), air atmosphere, 24 h.
dienes with alkyl substituents tethering various functionalities at
the C-2 and/or C-3 positions could provide the corresponding
cyclohexene derivatives in moderate to excellent yields (3a−i).
The dienes with reactive halide substituents, in particular, the
iodide group, could also be tolerated in the reaction to give the
corresponding products in moderate to excellent yields,
respectively. Moreover, the volatile 2,3-dimethylbuta-1,3-diene
also smoothly underwent cyclization reaction to generate the
desired product 3j in 92% yield. We also observed that myrcene
with an additional double bond could be well-tolerated, while a
mixture product 3k/3k′ in total 83% yield and with moderate
regioselectivity (p/m = 84:16) was obtained. On the other
hand, when the diene derived from irisone reacted with diethyl
2-methylmalonate, an exclusive isomer product 3l in 76% yield
was isolated. Furthermore, other five-membered and seven-
membered dienes bearing nitro, acetyl, cyano, or Ts-protected
amine groups were subjected to this transformation. All of the
desired bridged products were obtained in moderate to high
yields (3m−p). Subsequently, we also evaluated the dienes with
respect to different aryl substituents (3q−ac). A variety of
substrates with electronically diverse functionalities on the
phenyl ring were tolerated to afford the corresponding products
in 61−95% yields. It is worth mentioning that the dienes with
an aryl group at the C-1 position showed highly reactive
efficiency and excellent regioselectivities (3q,x−ac). Finally, a
gram-scale dehydrogenative Diels−Alder reaction for the
synthesis of cyclized product 3a was proven to be feasible in
a slightly decreased yield.
a
Reaction conditions: 2,3-dimethylbuta-1,3-diene 2j (0.3 mmol),
diethyl 2-methylmalonate 1a (0.9 mmol), Cu(OAc)2 (0.03 mmol),
L (0.03 mmol), TEMPO, solvent (2 mL), 24 h. Yield was determined
by H NMR spectroscopic analysis using mesitylene as an internal
standard. Diethyl 2-methylmalonate (2.0 equiv) was used. ODCB:
b
1
c
d
1,2-dichlorobenzene. 3j′ and 3j′′ could be detected in less than 1%
1
yield by crude H NMR spectroscopic analysis.
dehydrogenative Diels−Alder reaction product 3j was obtained
in a promising yield (65%) in the presence of 10 mol % of
Cu(OAc)2 as catalyst and TEMPO (1.0 equiv) as oxidant in
chlorobenzene (PhCl) at 120 °C being stirred for 24 h under
argon atmosphere (Table 1, entry 1). Therefore, a series of
solvents, catalysts, and ligands were examined sequentially. It
was found that the yield of the product could be improved up
to 93% by employing the Cu(OAc)2/di(pyridin-2-yl)-
methanone catalytic system upon increasing the loading of
TEMPO (1.6 equiv) in (trifluoromethyl)benzene (PhCF3)
under air atmosphere (Table 1, entry 14). The dehydrogen-
ation efficiency was not affected, even if we reduced the
dienophile precursor to 2 equiv (Table 1, entry 15). Control
experiments indicated that all components in this catalytic
system were essential to afford the cyclohexene derivative 3j in
an excellent yield.
After determining the optimized reaction conditions, we
further investigated the substrate scope and limitation of dienes
B
DOI: 10.1021/acs.orglett.8b01067
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Letter
To show the generality of this transformation, we next tested
potential application of the current Cu(II)-catalyzed dehydro-
genation Diels−Alder strategy to other gem-diesters and
ketones (Scheme 3). We found that various readily available
aromatization product and normal adduct could be obtained in
82% yield (3ar/3ar′). In addition, gem-diketone was also
effective in affording the spiro product 3at in 68% yield.
Subsequently, we used dimethyl 2-allylmalonate as the
precursor via a dienoate intermediate, but unfortunately, only
16% yield of the desired product (3au) was obtained, possibly
due to its low conversion of the starting materials under the
optimized reaction conditions. Pleasingly, the corresponding
tetrasubstituted cyclohexene derivatives were also formed in
moderate to good yields when the ethane-1,1,2-tricarbonyl or
1,2-dicarbonyl compounds were applied to react with diethyl
3,4-dimethylenehexanedioat (3av−ay).
Scheme 3. Substrate Scope of Dienophile Precursors
On the basis of the previous reports,10c,d a plausible
mechanism was proposed as shown in Scheme 4. First,
Scheme 4. Proposed Possible Mechanism
Cu(OAc)2 reacts with gem-diester to form an organocopper
species B or a chelate copper−enolate complex C. Thus, a
radical intermediate D could be generated via a homolysis
process, along with formation of a Cu(I) complex. Following
this, the radical intermediate D would be captured by TEMPO
to form α-TEMPO-substituted intermediate E, which then
undergoes a fast TEMPOH elimination to furnish the
dienophile G in the presence of another TEMPO (F). Finally,
the α,β-unsaturated carbonyl compounds generated in situ will
react with various dienes under the Cu(II)/L4 catalytic system
to afford the cyclohexene derivatives J as well as a trace amount
of undesired Michael addition byproducts H and I.
In conclusion, we have demonstrated a new strategy for a
copper-catalyzed dehydrogenative Diels−Alder reaction of
easily available gem-diesters and ketones with a wide variety
of dienes. This strategy avoids the need of additional steps for
the preparation of unstable α,β-unsaturated carbonyl com-
pounds. This work also opens a new method of constructing
the cyclohexene derivatives in a highly efficient fashion. This
work also features high efficiency in dehydrogenation, atomic
economy, and good functional compatibility. Further in-depth
application studies of this oxidative radical dehydrogenation
Diels−Alder reaction in organic synthesis are underway in our
laboratory.
a
Reaction conditions: diethyl 3,4-dimethylenehexanedioate 2a (0.3
mmol), 1 (0.6 mmol), Cu(OAc)2 (0.03 mmol), L4 (0.03 mmol),
TEMPO (1.6 equiv), (trifluoromethyl)benzene (2 mL), air atmos-
phere, 24 h.
gem-diesters bearing primary or secondary alkyl substituents on
the oxygen atom all provided the corresponding cyclohexene
derivatives successfully. Despite some functionalities existing in
the gem-diesters that were prone to being oxidized, the
established oxidative conditions enabled these gem-diesters to
participate in this transformation smoothly and afford the
desired products in moderate to high yields (3ah−al). To
access the enantioselective cyclohexene products, the use of
chiral auxiliaries is one of many powerful and efficient strategies
to produce the desired stereoisomer.22 Herein, we attempted to
introduce the chiral (−)-menthol to dienophile precursor in
order to realize the stereoselective transformation. An excellent
isolated yield of the desired products 3am could be observed
with poor diastereoselectivity, most probably due to the need
for high temperature. When a geraniol-derived gem-diester was
subjected to this reaction, the corresponding product 3an with
multiple double bonds was isolated in 69% yield. Additionally,
the substrate bearing a phosphate group was also compatible
and yielded the desired product 3ao. Moreover, this catalytic
protocol is not only limited to gem-diesters but also applicable
to a variety of ketones. The cyclic adducts were also obtained in
good yields under the optimal reaction conditions (3ap−as).
We noted that when 1-(3-nitrophenyl)propan-1-one was used
to react with diethyl 3,4-dimethylenehexanedioate, a mixture of
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.8b01067.
C
DOI: 10.1021/acs.orglett.8b01067
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Organic Letters
Letter
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Detailed experimental procedures and spectral data
(PDF) for all new compounds (1H NMR, 13C NMR,
1
19F NMR, H−1H COSY NMR HR-MS) (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xyh0709@ustc.edu.cn.
*E-mail: teckpeng@ntu.edu.sg.
ORCID
Yun-He Xu: 0000-0001-8817-0626
Teck-Peng Loh: 0000-0002-2936-337X
Author Contributions
∥B.J. and Q.-J.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support of the National
Natural Science Foundation of China (21672198), the State
Key Program of the National Natural Science Foundation of
China (21432009), the State Key Laboratory of Elemento-
Organic Chemistry Nankai University (201620), and the
Collaborative Innovation Center of Chemistry for Energy
Materials (2011-iChEM).
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Chem., Int. Ed. 2017, 56, 3956.
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