Copper(I)/DDQ-Mediated Double-Dehydrogenative Diels-Alder Reaction of Aryl Butenes with 1,4-Diketones and Indolones

Article abstract of DOI:10.1021/acs.orglett.0c02486

A copper(I)/DDQ-mediated double-dehydrogenative Diels-Alder (DDDA) reaction of simple butenes with 1,4-diketones and indolones has been established for the first time. This strategy is based on a tandem double-dehydrogenation/Diels-Alder reaction from nonprefunctionalized starting materials, in which both a diene and dienophile were in situ generated via activation of fourfold inert C(sp3)-H bonds in one catalytic system.

Full text of DOI:10.1021/acs.orglett.0c02486

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Letter
Copper(I)/DDQ-Mediated Double-Dehydrogenative Diels−Alder
Reaction of Aryl Butenes with 1,4-Diketones and Indolones
Wen-Lei Xu,‡ Wei Hu,‡ Wei-Ming Zhao, Min Wang, Jie Chen,* and Ling Zhou*
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ABSTRACT: A copper(I)/DDQ-mediated double-dehydrogen-
ative Diels−Alder (DDDA) reaction of simple butenes with 1,4-
diketones and indolones has been established for the first time. This
strategy is based on a tandem double-dehydrogenation/Diels−
Alder reaction from nonprefunctionalized starting materials, in
which both a diene and dienophile were in situ generated via
activation of fourfold inert C(sp3)−H bonds in one catalytic system.
ross-dehyrogenative coupling (CDC) reactions allow
Cmolecular complexity and diversity to be created by the
functionalization of C(sp3)−H, representing efficient method-
ologies for constructing C−C and C−heteroatom bonds in a
single operation.1 The Diels−Alder (DA) reaction remains
arguably one of the most atom-economic strategy for the
construction of cyclohexene derivatives,2 which has extensive
applications in natural product synthesis, clinical drug
discovery, and functional molecule design.3 However,
prefunctionalization of a diene and dienophile component is
extraordinarily tedious before the reaction, which contains
great opportunities for simplifying the DA process. Con-
sequently, diverse dehydrogenative Diels−Alder (DHDA)
reactions have been emerged,4 including oxidative generation
of dienes by White,4b Porco,4c Zhou,4d,j,k Zhang,4e Yao,4f
Antonchick,4g and Li4i (Scheme 1, eq 1), and a Cu(II)-
catalyzed oxidative generation of a dienophile approach by Xu
and Loh4h (Scheme 1, eq 2). Despite the progress in these
DHDA reactions, either the dienophile or diene still needs to
be preprepared. A question raised is whether both diene and
dienophile can be generated in one process, and then react
with each other to complete the DA reaction. It would be
appealing if these two oxidation processes could be performed
in one pot. Thus, a double-dehydrogenation/Diels−Alder
(DDDA) reaction in a single operation would provide a step-
economic, eco-friendly alternative to the traditional method by
eliminating the need for tedious preparation of the diene and
dienophile (Scheme 1, eq 3). To the best of our knowledge,
the DDDA reaction from readily available starting materials via
activation of fourfold inert C(sp3)−H bonds has not been
reported to date. This is because there are great challenges still
imbedded in this unparalleled DDDA reaction, including the
following: (1) discovery of compatible reaction partners to
match LUMO with HOMO; (2) establishment of a new
catalytic system to abstract hydrogen from both electron-rich
C−H bonds and electron-deficient ones; (3) the compatibility
of the oxidative double-dehydrogenative reaction and the
Diels−Alder reaction.
Scheme 1. DHDA and DDDA Reactions
Recently, we have reported several DDQ-mediated DHDA
reactions from prenyl derivatives via in situ generated diene
intermediates.4d,j,k With our continued interest in exploring
efficient cycloaddition reactions and oxidative dehydrogen-
ations,5 we envisioned that the DDDA reaction would be
realized by combination of our previously reported DHDA
strategy with a metal-catalyzed dehydrogenative generation of
dienophile. Among the metal-catalyzed dehydrogenative
strategies, copper-catalyzed dehydrogenations have exhibited
Received: July 29, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02486
© XXXX American Chemical Society
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their powerful ability to convert alkanes to alkenes.6 From the
mechanistic point of view, copper(II) species should
coordinate to a carbonyl substrate during the desaturation of
the dienophile precursor.6e,i However, electron-rich dienes
generally used in the DA reaction usually do not contain a
carbonyl group. As a result, a catalytic oxidant system, which
has been developed in those dehydrogenative approaches, may
be not applicable to the DDDA reaction. Thus, to realize our
hypothesis, a new catalytic system for double-dehydrogenation
of dienophile and diene precursors should be established.
Herein, we describe a copper(I)/DDQ-mediated DDDA
reaction of butenes with 1,4-diketones and indolones via
activation of fourfold inert C(sp3)−H bonds (Scheme 1, eq 3).
We initially investigated the DDDA reaction of prenyl
benzene 1a wth 1,4-bis(4-chlorophenyl)butane-1,4-dione 2a in
the presence of CuI as a catalyst, DDQ as an oxidant, and
several common N-containing bidentate ligands (Table 1,
entries 1−4). The target product 3a was obtained in the
presence of CuI (15 mol %), L1 ligand (30 mol %), and DDQ
(2.6 equiv) in chlorobenzene at 115 °C for 96 h, which is
constant with our hypothesis. Of the ligands examined (entries
1−4), 4,4′-di-tert-butyl-2,2′-bipyridine (L4) gave the best result
(entry 4) for the copper-catalyzed DDDA reaction. Di-tert-
butyl peroxide, generally used in many reported metal-
catalyzed oxidative dehydrogenation reactions, returned only
a trace amount of the desired product (entry 6). Subsequently,
a variety of copper catalysts and solvents were evaluated
sequentially (entries 7−15). When the DDDA reaction was
performed by employing DDQ as the oxidant, CuI as the
catalyst, and 4,4′-di-tert-butyl-2,2′-bipyridine (L4) as the ligand
in trifluoromethylbenzene, the expected product 3a could be
isolated in 91% yield (entry 15). Reducing the loading of
catalyst and ligand to 10 mol % and 20 mol % led to a lower
yield (entry 16). Surprisingly, in the absence of a copper
catalyst, product 3a was obtained in 19% yield (entry 17),
while no desired product was detected when the reaction was
conducted in the absence of L4 (entry 18). These results
suggest that the ligand plays a critical role in the oxidation of
1,4-diketone 2a to a 1,4-enedione intermediate. As expected, in
the absence of oxidant no reaction resulted (entry 19). These
control experiments revealed that all reaction components in
the DDDA reaction were indispensable. Notably, although
poor diastereoselectivities of 3a were observed, both of them
are endo-selectivity, resulting from the stereospecificity of the
DA reaction.
With the optimal catalytic conditions determined, we then
evaluated the substrate scope in terms of substituted but-2-
enes by employing 1,4-bis(4-chlorophenyl)butane-1,4-dione
2a as the dienophile precursor. As shown in Scheme 2, the
reaction could be amenable to a wide range of butene 1 with
diverse substituents, furnishing cyclohexene derivatives 3 in
good to excellent yields and excellent endo selectivities. Prenyl
benzene substrates bearing varieties of functional groups such
as halogens, alkoxy, and alkyl at the ortho-, meta-, and para-
position of the phenyl ring were subjected to this new DDDA
reaction, and the corresponding products, in most cases, were
obtained in excellent yields (3a−m, 83−91%; 3n−o, 73% and
62%). Excellent yields were also gained with either thienyl- or
naphthalenyl-substituted prenyl substrates (3p−q, 88% and
81%). Moreover, diphenyl substituted but-2-ene 1r returned
the expected product 3r in 90% yield. In addition, several 1,4-
diketones were further explored, and the reactions proceeded
smoothly to generate the desired products in excellent yields
(3am−ac, 82−93%).
Subsequently, the substrate scope with respect to diaryl-
substituted 1,4-diketones was investigated with the use of
diphenyl substituted butenes. Notably, but-1-ene-1,4-diyldi-
benzene (1s) and but-2-ene-1,4-diyldibenzene (1t) were all
compatible and afforded the same desired product 4a in 81%
and 85% yields, respectively. As summarized in Scheme 2, a
series of diaryl-substituted 1,4-diketones bearing electronically
diverse functionalities at any position on the phenyl ring
smoothly underwent the DDDA reaction with also exclusive
endo selectivity (4b−m, 51−92%, from 1t). Nevertheless, 1,4-
diketones with different substituents at the ortho-positon of
the phenyl ring exhibited lower reactivity probably due to
steric hindrance, and only moderate yields were furnished (4j−
l, 51−67%). Additionally, thienyl- and naphthyl-substituted
1,4-diketones were well-tolerated, and high yields were
observed (4n−p, 73−84%, from 1t). The structure of product
4p was further assigned by X-ray analysis (CCDC 1961346).
To further enlarge the generality of the DDDA reaction, we
performed this protocol with benzoylmethyl indolones. As
shown in Scheme 2, an array of indolones derived from N-
methyl isatins reacted effectively with prenyl benzene 1a under
the optimal catalytic conditions, leading to the desired
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
catalyst
CuI
CuI
CuI
CuI
solvent
ligand oxidant yield (%)
dr
1
2
3
4
5
6
7
8
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
L1
L2
L3
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
−
DDQ
DDQ
DDQ
DDQ
26
73
37
89
n.d.
trace
77
80
24
1:1.2
1:1.1
1:1.2
1:1.3
−
d
CuI
CuI
BQ
e
DTBP
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
−
−
CuBr
CuCl
CuCl2
CuBr2
CuSO4
Cu(OAc)2
CuI
CuI
CuI
CuI
−
1:1.3
1:1.3
1:1.2
1:1.1
−
9
10
11
12
13
14
15
21
trace
trace
75
72
91
78
19
n.d.
n.d.
−
PhBr
1:1.2
1:1.3
1:1.3
1:1.2
1:1.1
−
PhCH3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
f
16
17
18
19
CuI
CuI
L4
−
a
Reactions were carried out with 1a (0.20 mmol), 2a (0.10 mmol),
DDQ (0.26 mmol), CuI (15 mol %), L (30 mol %) at 115 °C in
b
c
solvent (2.0 mL) under N2 for 96 h. Isolated yield. The dr value was
d
e
1
determined by H NMR. BQ = p-benzoquinone. DTBP = di-tert-
butyl peroxide. CuI (10 mol %) and L4 (20 mol %) were used.
f
B
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a
Scheme 2. Scope of the DDDA Reaction
a
Reactions were carried out with 1 (0.20 mmol), 2 (0.10 mmol), DDQ (0.26 mmol; 0.29 mmol for product 4), CuI (15 mol %), L4 (30 mol %) at
1
115 °C in PhCF3 (2.0 mL) under N2 for 96 h (120 h for product 4). Isolated yield. The dr value was determined by H NMR.
spirocyclic oxindoles in good to excellent yields (6a−g, 83−
94%). Furthermore, Ts- and Bn-protected indolones also
proved to be compatible substrates and returned the
corresponding products 6h and 6i in excellent yields.
Interestingly, butene 1t was also compatible, and a fair yield
(69%) of the desired product 6ta could be observed with
exclusive diastereoselectivity. The structure of pruduct 6ta was
also confirmed by X-ray crystallography (CCDC 1961351).
To validate the synthetic practicability of the reaction, the
selective manipulations of these products were further
instantiated (Scheme 3). Compounds 3a and 4a can be
further converted to dihydroisobenzofuran 7 and 8.7 Further
aromatization of 7 and 8 gave the corresponding 1,2-
phenylenebis(phenylmethanone) 9 and 10 in high yields,
which are key intermediates in material chemistry.8 For
example, 10 is an important precursor of 1,4-diphenylph-
thalazine 11, which is a promising ligand in near-infrared-
(NIR-) emitting materials.9
To gain insight into the DDDA reaction mechanism, a series
of control experiments were performed. As outlined in Scheme
4, to test our double-dehydrogenative hypothesis, we carried
out two parallel DHDA reactions by employing 1,4-enedione
2aa and 1,3-butadiene 1tt as possible intermediates,
respectively. In the first case, prenyl benzene 1a was treated
with the intermediate 2aa in the absence of CuI and ligand,
and the product 3a was generated in extremely excellent yield
(Scheme 4, eq 4). In the second case, when the amount of
DDQ was reduced from 2.6 equiv in the standard reaction
conditions to 1.5 equiv, the DHDA reaction of 2a with
intermediate 1tt also proceeded smoothly to afford the product
4a in 83% yield (Scheme 4, eq 5). In addition, HRMS analysis
of the crude model reaction captured the masses of key
intermediates G and 2aa. These outcomes indicated that the
DDDA reaction includes the following reaction sequence: first,
double-dehydrogenation of butenes and 1,4-diketones to give
1,3-butadienes and 1,4-enediones; then, Diels−Alder reaction
of 1,3-butadienes and 1,4-enediones to yield the final product.
Moreover, a radical trapping experiment was also conducted in
the presence of TEMPO as a radical scavenger, and even no
desired product was generated in the DDDA reaction of 1a
and 2a (Scheme 4, eq 6). To a certain degree, these results
suggest that this strategy involved a radical process.
Scheme 3. Synthesis of Compounds 9−11
Based on the mechanistic studies mentioned above and
previous literature, a plausible mechanism was proposed for
the unprecedented reaction (Scheme 4).4j,6i,10 First, CuI is
oxidized to the copper(II) species A by DDQ,11 which
C
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Finally, the Diels−Alder reaction takes place to afford the
corresponding product 3.
Scheme 4. Control Experiments and Proposed Mechanism
In summary, we have established a novel copper-catalyzed
DDDA reaction from simple nonprefunctionalized alkene and
saturated ketones via direct functionalization of four C−H
bonds in one reaction. This protocol avoids the need for extra
steps for preparation of dienes and dienophiles and, therefore,
represents a straightforward and step-economical concept. This
unprecedented reaction shows broad substrate scope and
excellent functional group tolerance. Mechanistic studies
disclosed that the Cu(I)/DDQ-mediated tandem double-
dehydrogenation/Diels−Alder reaction represented an unpar-
alleled radical-based process. This work will not only
contribute to the field of copper-based catalyst system and
Diels−Alder reaction but also serve as a powerful approach in
the synthesis of cyclohexene-derived diketones and spirocyclic
oxindoles.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02486.
Experimental detail, X-ray crystal structures of 4p and
6ta, spectroscopic and analytical data for new com-
pounds (PDF)
Accession Codes
CCDC 1961346 and 1961351 contain 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.
AUTHOR INFORMATION
Corresponding Authors
■
Jie Chen − Key Laboratory of Synthetic and Natural Functional
Molecule of the Ministry of Education, Department of Chemistry
& Materials Science, National Demonstration Center for
Experimental Chemistry Education, Northwest University, Xi’an
710127, P. R. China; orcid.org/0000-0001-6745-5534;
Email: chmchenj@nwu.edu.cn
Ling Zhou − Key Laboratory of Synthetic and Natural
Functional Molecule of the Ministry of Education, Department
of Chemistry & Materials Science, National Demonstration
Center for Experimental Chemistry Education, Northwest
University, Xi’an 710127, P. R. China; orcid.org/0000-
0002-6805-2961; Email: zhoul@nwu.edu.cn
Authors
Wen-Lei Xu − Key Laboratory of Synthetic and Natural
Functional Molecule of the Ministry of Education, Department
of Chemistry & Materials Science, National Demonstration
Center for Experimental Chemistry Education, Northwest
University, Xi’an 710127, P. R. China
Wei Hu − Key Laboratory of Synthetic and Natural Functional
Molecule of the Ministry of Education, Department of Chemistry
& Materials Science, National Demonstration Center for
Experimental Chemistry Education, Northwest University, Xi’an
710127, P. R. China
coordinates with 2 to generate a LCu(II)-enolate species B or
an organocopper complex C (C′).6e Then, based on the radical
property, organocopper complex C (C′) gives rise to the
Cu(III) intermediate D and a Cu(I) species in the presence of
the Cu(II) species.6f,11 Subsequently, the generated D
undergoes oxidative elimination to generate intermediate
dienophiles E and another Cu(I) species.12 Then the resulting
Cu(I) species is oxidized to the Cu(II) species by DDQ, and
the process repeats. Moreover, prenyl benzene 1a was
synchronously oxidized by DDQ to generate intermediate
diene F, where a thermal reversible DA process was involved.4j
Wei-Ming Zhao − Key Laboratory of Synthetic and Natural
Functional Molecule of the Ministry of Education, Department
D
https://dx.doi.org/10.1021/acs.orglett.0c02486
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
of Chemistry & Materials Science, National Demonstration
Center for Experimental Chemistry Education, Northwest
University, Xi’an 710127, P. R. China
Min Wang − Key Laboratory of Synthetic and Natural
Functional Molecule of the Ministry of Education, Department
of Chemistry & Materials Science, National Demonstration
Center for Experimental Chemistry Education, Northwest
University, Xi’an 710127, P. R. China
pubs.acs.org/OrgLett
Letter
5630−5647. (g) Wessig, P.; Mu
̈
ller, G. The Dehydro-Diels−Alder
Reaction. Chem. Rev. 2008, 108, 2051−2063. (h) Reymond, S.;
Cossy, J. Copper-Catalyzed Diels−Alder Reactions. Chem. Rev. 2008,
108, 5359−5406. (i) Mehta, G.; Uma, R. Stereoelectronic Control in
Diels−Alder Reaction of Dissymmetric 1,3-Dienes. Acc. Chem. Res.
2000, 33, 278−286. (j) Jorgensen, K. A. Catalytic asymmetric hetero-
Diels−Alder reactions of carbonyl compounds and imines. Angew.
Chem., Int. Ed. 2000, 39, 3558−3588. (k) Klunder, A. J. H.; Zhu, J.;
Zwanenburg, B. The Concept of Transient Chirality in the
Stereoselective Synthesis of Functionalized Cycloalkenes Applying
the Retro-Diels−Alder Methodology. Chem. Rev. 1999, 99, 1163−
1190. (l) Corey, E. J.; Guzman-Perez, A. The Catalytic Enantiose-
lective Construction of Molecules with Quaternary Carbon Stereo-
centers. Angew. Chem., Int. Ed. 1998, 37, 388−401. (m) Kagan, H. B.;
Riant, O. Catalytic asymmetric Diels Alder reactions. Chem. Rev.
1992, 92, 1007−1019. (n) Craig, D. Stereochemical aspects of the
intramolecular Diels−Alder reaction. Chem. Soc. Rev. 1987, 16, 187−
238. (o) Brieger, G.; Bennett, J. N. The intramolecular Diels−Alder
reaction. Chem. Rev. 1980, 80, 63−97.
Complete contact information is available at:
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Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(3) (a) Yang, B.; Gao, S. Recent advances in the application of Diels-
Alder reactions involving o-quinodimethanes, aza-o-quinone methides
and o-quinone methides in natural product total synthesis. Chem. Soc.
Rev. 2018, 47, 7926−7953. (b) Oliveira, B. L.; Guo, Z.; Bernardes, G.
J. L. Inverse electron demand Diels−Alder reactions in chemical
biology. Chem. Soc. Rev. 2017, 46, 4895−4950. (c) Nawrat, C. C.;
Moody, C. J. Quinones as Dienophiles in the Diels-Alder Reaction:
History and Applications in Total Synthesis. Angew. Chem., Int. Ed.
2014, 53, 2056−2077. (d) Juhl, M.; Tanner, D. Recent applications of
intramolecular Diels−Alder reactions to natural product synthesis.
Chem. Soc. Rev. 2009, 38, 2983−2992. (e) Takao, K.; Munakata, R.;
Tadano, K. Recent advances in natural product synthesis by using
intramolecular Diels-Alder reactions. Chem. Rev. 2005, 105, 4779−
4807. (f) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.;
Vassilikogiannakis, G. The Diels−Alder reaction in total synthesis.
Angew. Chem., Int. Ed. 2002, 41, 1668−1698.
(4) (a) Li, W.; Zhou, L.; Zhang, J. Recent Progress in
Dehydro(genative) Diels-Alder Reaction. Chem. - Eur. J. 2016, 22,
1558−1571. (b) Stang, E. M.; White, M. C. Molecular complexity via
C-H activation: a dehydrogenative Diels-Alder reaction. J. Am. Chem.
Soc. 2011, 133, 14892−14895. (c) Qi, C.; Cong, H.; Cahill, K. J.;
Muller, P.; Johnson, R. P.; Porco, J. A., Jr. Biomimetic dehydrogen-
ative Diels-Alder cycloadditions: total syntheses of brosimones A and
B. Angew. Chem., Int. Ed. 2013, 52, 8345−8346. (d) Feng, H.-X.;
Wang, Y.-Y.; Chen, J.; Zhou, L. A Dehydrogenative Diels-Alder
Reaction of Prenyl Derivatives with 2,3-Dichloro-5,6-dicyanobenzo-
quinone. Adv. Synth. Catal. 2015, 357, 940−944. (e) Zhou, L.; Xu, B.;
Zhang, J. Metal-Free Dehydrogenative Diels-Alder Reactions of 2-
Methyl-3-Alkylindoles with Dienophiles: Rapid Access to Tetrahy-
drocarbazoles, Carbazoles, and Heteroacenes. Angew. Chem., Int. Ed.
2015, 54, 9092−9096. (f) Kuo, C.-W.; Konala, A.; Lin, L.; Chiang, T.-
T.; Huang, C.-Y.; Yang, T.-H.; Kavala, V.; Yao, C.-F. Synthesis of
benzo[a]carbazole derivatives from 3-ethylindoles by exploiting the
dual character of benzoquinone as an oxidizing agent and dienophile.
Chem. Commun. 2016, 52, 7870−7873. (g) Manna, S.; Antonchick, A.
P. A Metal-Free Oxidative Dehydrogenative Diels-Alder Reaction for
Selective Functionalization of Alkylbenzenes. Chem. - Eur. J. 2017, 23,
7825−7829. (h) Jiang, B.; Liang, Q. J.; Han, Y.; Zhao, M.; Xu, Y. H.;
Loh, T. P. Copper-Catalyzed Dehydrogenative Diels-Alder Reaction.
Org. Lett. 2018, 20, 3215−3219. (i) Wu, X.; Zhu, H. J.; Zhao, S. B.;
Chen, S. S.; Luo, Y. F.; Li, Y. G. An Asymmetric Dehydrogenative
Diels-Alder Reaction for the Synthesis of Chiral Tetrahydrocarbazole
Derivatives. Org. Lett. 2018, 20, 32−35. (j) Xu, W. L.; Zhang, H.; Hu,
Y. L.; Yang, H.; Chen, J.; Zhou, L. Metal-Free Dehydrogenative Diels-
Alder Reactions of Prenyl Derivatives with Dienophiles via a Thermal
Reversible Process. Org. Lett. 2018, 20, 5774−5778. (k) Xu, W. L.;
Tang, L.; Ge, C. Y.; Chen, J.; Zhou, L. Synthesis of Tetrahy-
droisoindolinones via a Metal-Free Dehydrogenative Diels-Alder
Reaction. Adv. Synth. Catal. 2019, 361, 2268−2273.
■
We thank the National Natural Science Foundation of China
(NSFC 21672170), Natural Science Basic Research Plan in
Shaanxi Province of China (2018JC-020), and China
Postdoctoral Science Foundation (2018M643705) for financial
support.
REFERENCES
■
(1) For selected reviews, see: (a) Li, C.-J. Cross-Dehydrogenative
Coupling (CDC): Exploring C−C Bond Formations beyond
Functional Group Transformations. Acc. Chem. Res. 2009, 42, 335−
344. (b) Scheuermann, C. J. Beyond Traditional Cross Couplings:
The Scope of the Cross Dehydrogenative Coupling Reaction. Chem. -
Asian J. 2010, 5, 436−451. (c) Yoo, W.-J.; Li, C.-J. Cross-
Dehydrogenative Coupling Reactions of sp(3)-Hybridized C−H
Bonds. In C−H Activation; Yu, J. Q., Shi, Z., Eds.; 2010; Vol. 292,
pp 281−302. (d) Kuhl, N.; Hopkinson, M. N.; Glorius, F. Selective
Rhodium(III)-Catalyzed Cross-Dehydrogenative Coupling of Furan
and Thiophene Derivatives. Angew. Chem., Int. Ed. 2012, 51, 8230−
8234. (e) Matcha, K.; Antonchick, A. P. Metal-Free Cross-
Dehydrogenative Coupling of Heterocycles with Aldehydes. Angew.
Chem., Int. Ed. 2013, 52, 2082−2086. (f) Girard, S. A.; Knauber, T.;
Li, C.-J. The Cross-Dehydrogenative Coupling of Csp3−H Bonds: A
Versatile Strategy for C−C Bond Formations. Angew. Chem., Int. Ed.
2014, 53, 74−100. (g) Lv, L.; Li, Z. Fe-Catalyzed Cross-Dehydrogen-
ative Coupling Reactions. Top. Curr. Chem. 2017, 374 (38), 225.
(h) Hosseinian, A.; Ahmadi, S.; Nasab, F. A. H.; Mohammadi, R.;
Vessally, E. Cross-Dehydrogenative C−H/S−H Coupling Reactions.
Top. Curr. Chem. 2018, 376, 39. (i) San Segundo, M.; Correa, A.
Cross-Dehydrogenative Coupling Reactions for the Functionalization
of alpha-Amino Acid Derivatives and Peptides. Synthesis 2018, 50,
2853−2866. (j) Huang, C.-Y.; Kang, H.; Li, J.; Li, C.-J. En Route to
Intermolecular Cross-Dehydrogenative Coupling Reactions. J. Org.
Chem. 2019, 84, 12705−12721.
(2) For selected reviews, see: (a) Bhojgude, S. S.; Bhunia, A.; Biju, A.
T. Employing Arynes in Diels-Alder Reactions and Transition-Metal-
Free Multicomponent Coupling and Arylation Reactions. Acc. Chem.
Res. 2016, 49, 1658−1670. (b) Jiang, X.; Wang, R. Recent
Developments in Catalytic Asymmetric Inverse-Electron-Demand
Diels-Alder Reaction. Chem. Rev. 2013, 113, 5515−5546. (c) Funel,
J.-A.; Abele, S. Industrial Applications of the Diels-Alder Reaction.
Angew. Chem., Int. Ed. 2013, 52, 3822−3863. (d) Foster, R. A. A.;
Willis, M. C. Tandem inverse-electron-demand hetero-/retro-Diels−
Alder reactions for aromatic nitrogen heterocycle synthesis. Chem.
Soc. Rev. 2013, 42, 63−76. (e) Li, J.-L.; Liu, T.-Y.; Chen, Y.-C.
Aminocatalytic Asymmetric Diels−Alder Reactions via HOMO
Activation. Acc. Chem. Res. 2012, 45, 1491−1500. (f) Bodnar, B. S.;
Miller, M. J. The Nitrosocarbonyl Hetero-Diels-Alder Reaction as a
Useful Tool for Organic Syntheses. Angew. Chem., Int. Ed. 2011, 50,
E
https://dx.doi.org/10.1021/acs.orglett.0c02486
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(5) (a) Zhao, M.; Liu, J.-L.; Liu, H.-F.; Chen, J.; Zhou, L.
Construction of Bisbenzopyrone via N-Heterocyclic Carbene
Catalyzed Intramolecular Hydroacylation-Stetter Reaction Cascade.
Org. Lett. 2018, 20, 2676−2679. (b) Feng, W.; Yang, H.; Wang, Z.;
Gou, B.-B.; Chen, J.; Zhou, L. Enantioselective [3 + 2] Formal
Cycloaddition of 1-Styrylnaphthols with Quinones Catalyzed by a
Chiral Phosphoric Acid. Org. Lett. 2018, 20, 2929−2933. (c) Hu, Y.-
L.; Wang, Z.; Yang, H.; Chen, J.; Wu, Z.-B.; Lei, Y.; Zhou, L.
Conversion of two stereocenters to one or two chiral axes:
atroposelective synthesis of 2,3-diarylbenzoindoles. Chemical Science
2019, 10, 6777−6784. (d) Sun, H.-R.; Zhao, Q.; Yang, H.; Yang, S.;
Gou, B.-B.; Chen, J.; Zhou, L. Chiral Phosphoric-Acid-Catalyzed
Cascade Prins Cyclization. Org. Lett. 2019, 21, 7143−7148. (e) Yang,
H.; Sun, H.-R.; Xue, R.-D.; Wu, Z.-B.; Gou, B.-B.; Lei, Y.; Chen, J.;
Zhou, L. Selectfluor-Mediated Stereoselective [1 + 1 + 4 + 4]
Dimerization of Styrylnaphthols. Org. Lett. 2019, 21, 9829−9835.
(6) (a) Xu, K.; Fang, Y.; Yan, Z.; Zha, Z.; Wang, Z. A highly tunable
stereoselective dimerization of methyl ketone: efficient synthesis of E-
and Z-1,4-enediones. Org. Lett. 2013, 15, 2148−2151. (b) Rout, S. K.;
Guin, S.; Ali, W.; Gogoi, A.; Patel, B. K. Copper-Catalyzed
Esterification of Alkylbenzenes with Cyclic Ethers and Cycloalkanes
via C(sp3)-H Activation Following Cross-Dehydrogenative Coupling.
Org. Lett. 2014, 16, 3086−3089. (c) Tran, B. L.; Driess, M.; Hartwig,
J. F. Copper-Catalyzed Oxidative Dehydrogenative Carboxylation of
Unactivated Alkanes to Allylic Esters via Alkenes. J. Am. Chem. Soc.
2014, 136, 17292−17301. (d) Zhao, J.; Fang, H.; Han, J.; Pan, Y. Cu-
Catalyzed C(sp3)−H Bond Activation Reaction for Direct Prepara-
tion of Cycloallyl Esters from Cycloalkanes and Aromatic Aldehydes.
Org. Lett. 2014, 16, 2530−2533. (e) Jie, X.; Shang, Y.; Zhang, X.; Su,
W. Cu-Catalyzed Sequential Dehydrogenation-Conjugate Addition
for beta-Functionalization of Saturated Ketones: Scope and
Mechanism. J. Am. Chem. Soc. 2016, 138, 5623−5633. (f) Manna,
S.; Antonchick, A. P. [1 + 1 + 1] Cyclotrimerization for the Synthesis
of Cyclopropanes. Angew. Chem., Int. Ed. 2016, 55, 5290−5293.
(g) Shang, Y.; Jie, X.; Jonnada, K.; Zafar, S. N.; Su, W.
Dehydrogenative desaturation-relay via formation of multicenter-
stabilized radical intermediates. Nat. Commun. 2017, 8, 2273. (h) Li,
H.; Jiang, Q.; Jie, X.; Shang, Y.; Zhang, Y.; Goossen, L. J.; Su, W. Rh/
Cu-Catalyzed Ketone β-Functionalization by Merging Ketone
Dehydrogenation and Carboxyl-Directed C−H Alkylation. ACS
Catal. 2018, 8, 4777−4782. (i) Chen, M.; Dong, G. Copper-
Catalyzed Desaturation of Lactones, Lactams, and Ketones under pH-
Neutral Conditions. J. Am. Chem. Soc. 2019, 141, 14889−14897.
(7) Yoo, J.; Jang, H.; Sutradhar, S. C.; Ha, J.; Choi, K.; Ryu, T.;
Yang, H.; Yoon, S.; Kim, W. Synthesis of sulfonated poly-
(diketonephenylene)s containing dibenzoyl moiety via Ni/Zn
catalyst. Int. J. Hydrogen Energy 2017, 42, 1766−1775.
R. V. Kinetics of Electron-Transfer Oxidation of Alkyl Radicals by
Copper(II) Complexes. J. Am. Chem. Soc. 1965, 87, 4855−4866.
(8) (a) Wombacher, T.; Foro, S.; Schneider, J. J. High-Yielding
Synthesis and Full Spectroscopic Characterization of 5,6:11,12-Di-o-
phenylenetetracene and Its Synthesis Intermediates. Eur. J. Org. Chem.
2016, 2016, 569−578. (b) Thirion, D.; Poriel, C.; Rault-Berthelot, J.;
̀
Barriere, F.; Jeannin, O. (2,1-a)-Indenofluorene Derivatives: Syn-
theses, X-ray Structures, Optical and Electrochemical Properties.
Chem. - Eur. J. 2010, 16, 13646−13658.
(9) Xin, L.; Xue, J.; Lei, G.; Qiao, J. Efficient near-infrared-emitting
cationic iridium complexes based on highly conjugated cyclo-
metalated benzo[g]phthalazine derivatives. RSC Adv. 2015, 5,
42354−42361.
(10) Yi, H.; Liao, Z.; Zhang, G.; Zhang, G.; Fan, C.; Zhang, X.;
Bunel, E. E.; Pao, C. W.; Lee, J. F.; Lei, A. Evidence of Cu(I)/Cu(II)
Redox Process by X-ray Absorption and EPR Spectroscopy: Direct
Synthesis of Dihydrofurans from beta-Ketocarbonyl Derivatives and
Olefins. Chem. - Eur. J. 2015, 21, 18925−18929.
(11) Wu, X.; Zhao, Y.; Zhang, G.; Ge, H. Copper-Catalyzed Site-
Selective Intramolecular Amidation of Unactivated C(sp3)−H Bonds.
Angew. Chem., Int. Ed. 2014, 53, 3706−3710.
(12) (a) Kochi, J. K.; Bemis, A.; Jenkins, C. L. Mechanism of
electron transfer oxidation of alkyl radicals by copper(II) complexes. J.
Am. Chem. Soc. 1968, 90, 4616−4625. (b) Kochi, J. K.; Subramanian,
F
https://dx.doi.org/10.1021/acs.orglett.0c02486
Org. Lett. XXXX, XXX, XXX−XXX