Intermolecular Multiple Dehydrogenative Cross-Couplings of Ketones with Boronic Acids and Amines via Copper Catalysis

Article abstract of DOI:10.1002/adsc.201900419

An efficient and versatile oxidative coupling reaction was developed for the synthesis of valuable β-functionalized unsaturated ketones and meta-substituted phenols. In the case of intramolecular reactions, achieving rapid molecular complexity through multiple dehydrogenative couplings is already a well-established strategy. Herein, we report an intermolecular multiple dehydrogenative coupling between ketones and nucleophilic amines or boronic acids using inexpensive copper(I) oxide as a catalyst. This method provides a facile access to highly desirable chemical products such as α,β-unsaturated ketones, enaminones, and synthetically relevant meta-substituted phenols. (Figure presented.).

Full text of DOI:10.1002/adsc.201900419

Title: Intermolecular Multiple Dehydrogenative Cross-Couplings of
Ketones with Boronic Acids and Amines via Copper Catalysis
Authors: Tianzhang Wang, Guowei Chen, Yu-Jing Lu, Qian Chen,
Yanping Huo, and Xianwei Li
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900419
Link to VoR: http://dx.doi.org/10.1002/adsc.201900419

10.1002/adsc.201900419
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201xxxxxx
Intermolecular Multiple Dehydrogenative Cross-Couplings of
Ketones with Boronic Acids and Amines via Copper Catalysis
Tianzhang Wang,a Guowei Chen,a Yu-Jing Lu,a Qian Chen,a Yanping Huo,a Xianwei
Li,a,*
a
School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006,
People’s Republic of China
E-mail: xwli@gdut.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
nucleophilic substitutions and widely used metal-
catalyzed cross couplings, enable a cost-effective
route to a wide variety of functionalized molecules
using abundant starting materials.[5] Considering the
success of those two oxidative strategies, we
Abstract: An efficient and versatile oxidative coupling
reaction was developed for the synthesis of valuable β-
functionalized unsaturated ketones and meta-substituted
phenols. In the case of intramolecular reactions, achieving
rapid
molecular
complexity
through
multiple
dehydrogenative couplings is already a well-established
strategy. Herein, we report an intermolecular multiple
dehydrogenative coupling between ketones and
nucleophilic amines or boronic acids using inexpensive
copper(I) oxide as a catalyst. This method provides a facile
access to highly desirable chemical products such as α,β-
unsaturated ketones, enaminones, and synthetically
relevant meta-substituted phenols.
envisioned
dehydrogenative transformations with CDC would
generate highly practical intermolecular
dehydrogenative coupling.
that
merging
both
multiple
a
We reasoned that employing readily available
ketones with diverse nucleophilic partners for
intermolecular dehydrogenative coupling would
provide a great template for the quick construction of
synthetically useful structures such as β-
functionalized ketones. In this context, Ueno and
Keywords: Intermolecular multiple dehydrogenative
couplings; α,β-unsaturated ketones; enaminones; meta-
substituted phenols; copper catalysis;
Kuwano
have
reported
a
Ni(0)-catalyzed
dehydrogenative C-H amination of ketones,
delivering various enonamines.[6a] The Su group has
Achieving rapid molecular complexity through a
sustainable pathway is a major challenge for synthetic
chemistry. In light of those new environmental
expectations, the exploration of dehydrogenative
methodologies has proven to be a powerful tool for
retrosynthetic design.[1,2] Recent advances in metal-
also
described
a
practical
metal-catalyzed
methodology for α,β-dehydrogenative couplings
between ketones and heterocycles or other
nucleophiles; Additionally, the same group recently,
achieved an intramolecular multiple dehydrogenation
of both ketones and amines, affording various
unsaturated ketones and heterocycles.[7]
catalyzed
dehydrogenation
processes
have
demonstrated the efficiency of this strategy: In
particular, Stahl, Huang, Dong, Newhouse and others
have greatly contributed to the development of α,β-
multiple dehydrogenation of polar substrates.[3,4]
Aldehydes, ketones, carboxylic acids, esters, nitriles
and amides have all been successfully converted.
However, most of these dehydrogenative pathways
are
transformations. Consequently, expanding this
approach to more general intermolecular
confined
to
specific
intramolecular
a
multidehydrogenative method appears to be a highly
desirable strategy.
In parallel to the development of multiple
dehydrogenative
transformations,
Cross-
dehydrogenative couplings (CDC) have emerged as a
robust oxidative method for the creation of new
carbon-carbon and carbon-heteroatom bonds. By
bypassing the need for prefunctionalized substrates,
CDC reactions occur as an alternative to classic
Scheme 1. α,β-Dehydrogenations and coupling reactions.
1
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10.1002/adsc.201900419
Advanced Synthesis & Catalysis
Inspired by those pioneering works on of TBHP with a catalytic amount of TEMPO.
dehydrogenative reactions, we then hypothesized that Interestingly, using a stoichiometric amount of
two main issues could possibly hinder our design of a TEMPO in the absence of TBHP (entry 9) delivered
new multiple dehydrogenative couplings: Firstly, 3a in yields comparable to the standard conditions.
incompatibility problems could arise if the multiple This indicates that TBHP could be used as the
dehydrogenation of polar substrates would lead to an terminal oxidant, while TEMPO might act both as
over-oxidization of the coupling partners; Secondly, radical initiator and oxidant. When DMSO or 1,4-
an effective regulation of the oxidative system will be dioxane were used as solvents, only traces amount of
necessary to suppress the by-products from Michael product was monitored (entry 10). Lower temperature
addition reactions. Those could originate from in situ also led to decreased yields (entry 11).
generated unsaturated intermediates. Following our
Having identified the optimal conditions, we
group’s continuous research interest in selective subsequently explored the substrate scope of this
oxidations,[8] we hereby report a copper-catalyzed transformation. In general, anilines, heteroaryl and
intermolecular multiple dehydrogenative coupling of aliphatic amines were shown to be efficient amination
ketones for the synthesis of various β-functionalized reagents for this multiple dehydrogenative coupling
unsaturated ketones. In addition, the generation of (Table 2). For aminopyridine derivatives, functional
challenging and synthetically useful meta-substituted groups such as bromo, chloro, iodo, methoxy, nitro
phenols was readily achieved through this method.
and cyano were all well-tolerated (3a-3i). As for
substituted anilines, fluoro, chloro, bromo, methoxy
and ester moieties were equally compatible (3j-3s).
Remarkably, more sterically hindered anilines could
also partake in this dehydrogenative β-C-H amination
(3l-3o).
Table 1. Optimization of reaction conditions.[a,b]
Table 2. Substrate scope of the multiple dehydrogenative
C-H amination of ketones. [a,b]
[a]
Reaction conditions: 1a (0.50 mmol), 2a (1.00 mmol),
catalyst (10 mol %), oxidant (4.0 equiv), ligand (10 mol%),
additive (30 mol%) and solvent (2.0 mL) at 120 °C for 12 h
[b]
under air.
Yields were determined by GC-MS with n-
dodecane as the internal standard. The yield in the
parentheses is the isolated yield.
[a]
Reaction conditions: 1 (0.50 mmol), 2 (1.00 mmol),
Cu2O (10 mol%), TBHP (4.0 equiv.), TEMPO (30 mol%)
in toluene (2.0 mL) at 100 °C for 10 h under air. [b] 1 (10.0
mmol), 2 (20.0 mmol), toluene (20.0 mL) under standard
conditions for 12 h.
Considering the significant synthetic potential of
enaminones[9] as versatile building blocks, we
initiated our study by selecting propiophenone 1a and
pyridin-2-amine 2a as model substrates for the
optimization of the intermolecular dehydrogenative
coupling reaction. A thorough investigation of the
catalyst candidates revealed that Cu(I) showed better
efficiency than Cu(II) salt, and Cu2O gave the optimal
result for the generation of the dehydrogenative C-H
amination product 3a. Other metal complexes such as
Pd(II) and Mn(II) salts failed to deliver any product.
The Addition of base led to a diminished yield of 3a,
while the addition of acid completely shut down the
reaction (entries 5-6). Adding bidentate nitrogen
ligands displayed no significant effect (entry 7),
whereas no desired product 3a was observed in the
absence of TEMPO or if only TBHP was used as the
oxidant (entry 8). The optimized standard conditions
were found when associating a stoichiometric amount
Thiophene substituted ketones (3t-3x) showed
good efficiency for this transformation, thus
exhibiting promising results for the synthesis of
biologically active molecules or material chemistry
frameworks. Significantly, secondary aliphatic amines
such as morpholine and piperidine (3y-3zb), were
also shown to be successful amination coupling
partners. Furthermore, using cyclohexanone as
starting material granted access to synthetically useful
β-Amino cyclohexenones (3zc-3zj), which are
valuable intermediates for the construction of
bioactive molecules.[9e, 9f]
2
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10.1002/adsc.201900419
Advanced Synthesis & Catalysis
Stimulated by the aforementioned results, further
examination of the nucleophilic coupling partners was
undertaken. The use of boronic acids led to
synthetically attractive chalcone-like structures upon
addition of K2CO3 and 1,10-phen as ligand (Table 3).
Functional groups such as fluoro (5g), chloro (5b),
bromo (5c, 5e, 5f) and ester (5i) were tolerated. Fused
arenes and heterocycles including naphthalene (5j),
anthracene (5k), pyrene (5l) and thiophene (5m) were
all successfully coupled. Dienyl ketone (5n) was also
readily synthesized from alkenyl boronic acid as the
arylating
reagent.
Moreover,
twofold
α,β-
Figure 1. Meta-amino phenol skeletons found in
bioactive molecules.
dehydrogenations (5o) and multiple α,β,γ,δ-C-H
dehydrogenative couplings (5p) of ketones were also
achieved, yielding highly conjugated unsaturated
ketones as products. Finally, dehydrogenative
coupling of cyclohexanone afforded β-arylated
cyclohexenones (5q, 5r).
After exploring the effect of various additives, we
found that adding a catalytic amount of iodine
afforded meta-functionalized phenols in moderate
yields (Table 4). Primary, secondary amines and
arylboronic acids also showed good reactivity for this
coupling, thus delivering various meta-substituted
phenols.
Table 3. Substrate scope of the multiple dehydrogenative
C-H arylation of Ketones. [a]
Table 4. Meta-substituted phenols synthesis from multiple
dehydrogenative couplings of cyclohexanone. a
[a]
Reaction conditions: 1 (0.50 mmol), 2 or 4 (1.00 mmol),
Cu2O (10 mol %), TBHP (4.0 equiv.), TEMPO (1.0 equiv.),
I2 (20 mol%) and toluene (2.0 mL) at 100 °C for 12 h under
air.
[a]
Conditions: 1 (0.50 mmol), 4 (1.00 mmol), Cu2O (10
mol %), 1,10-phen (10 mol%), TEMPO (30 mol%), TBHP
(4.0 equiv.), K2CO3 (20 mol%) in toluene (2.0 mL) at
100 °C for 12 h under air. with additional TEMPO (0.5
[b]
To further demonstrate the synthetic potential of
the β-functionalized unsaturated ketones, we utilized
the previously isolated enaminones and α,β-saturated
ketones products for the rapid construction of diverse
heterocycles. As depicted in Scheme 2, imidazo[1,2-
a]pyridine (8), triazole (9), isoxazole (10) and
pyrazole (11), all of which are important
pharmacophores in many biologically active
molecules, could be produced.[9]
equiv), TBHP (2.0 equiv.).
Meta-functionalized phenols appear as a ubiquitous
backbone in many natural products and
pharmaceuticals (Figure 1).[10d] However, this
structure is not directly accessible from phenol
through common approaches.[10] Encouraged by
recently
published
achievements
using
cyclohexanones as phenol precursors under oxidative
conditions,[11,12] we speculated that with a careful
catalytic system design, meta-functionalized phenols
might be accessible via this intermolecular multiple
dehydrogenative coupling.
3
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10.1002/adsc.201900419
Advanced Synthesis & Catalysis
With these results in hand, although elusive, we
elaborated a tentative mechanism depicted in Scheme
4. We speculated that this transformation would start
with an α-TEMPO substitution of ketone 1a yielding
intermediate A, followed by the subsequent
elimination of TEMPO-H, thus releasing enone III in
situ.[13] Then, a copper-catalyzed oxidative cross-
couplings between enone III and the amine took place,
affording the α-TEMPO-β-amine substituted ketone
intermediate B. The latter underwent elimination of
TEMPO-H generating the desired β-functionalized
unsaturated ketone product 3a, while TEMPO was
regenerated via the stoichiometric oxidation of
TBHP.[14]
[a]
Conditions: (i) 3a (0.2 mmol), CuI (50 mol%), DMSO
(2.0 mL), 100 °C, 12 h, air. (ii) tBuONa (1.5 equiv), 3a (0.2
mmol), TsN3 (1.5 equiv), MeCN (2.0 mL), 25 °C, 12 h, air.
(iii) 5a (0.2 mmol), TsNHOH (4 equiv.), K2CO3 (1.0
equiv.), EtOH/H2O (2.0 mL, 9:1), 60 °C, 4 h. (iv) 5a (0.2
mmol), 4-CNC6H4NHNH2 (0.2 mmol), MeOH (2 mL),
reflux, 1 h; Cu(OAc)2 (10 mol%), DABCO (30 mol %), O2
(1 atm), DMSO (2 mL), 100 °C, 12 h.
Scheme 2. Transformations of the obtained products into
valuable heterocyclic structures. [a]
In order to get mechanistic insights, various control
experiments were conducted (Scheme 3). Firstly,
when propiophenone 1a was added to
a
stoichiometric amount of TEMPO under the standard
reaction conditions but in the absence of any coupling
partner, α-TEMPO substituted propiophenone A was
isolated in good yield. Secondly, when isolated A was
added to boronic acids or amines in the presence of
the copper catalyst, the desired dehydrogenative
coupling adducts B were obtained efficiently. These
observations indicated that α-TEMPO substituted
ketones might act as key intermediates in this
Scheme 4. Proposed Mechanism.
transformation.
Thirdly,
when
β-amino
In summary, we have designed an intermolecular
multiple dehydrogenative coupling between ketones
and amines or boronic acids, thus providing a new
and straightforward access to diverse enaminones and
highly unsaturated ketones. This methodology
notably features a new route to produce synthetically
challenging meta-substituted phenols structures by
using simple cyclohexanone as a substrate. Further
efforts toward the exploration of novel intermolecular
multiple dehydrogenative couplings are underway.
cyclohexenone 3zh was subjected to Cu(I)-catalyzed
oxidative conditions, the desired meta-amino phenol
product 6e was obtained in high yield. This
observation implies that further dehydrogenation and
subsequent ketone-enol tautomerization of 3zj might
be involved in the generation of functionalized
phenols.
Experimental Section
Typical procedure for the preparation of (E)-1-phenyl-
3-(pyridin-2-ylamino)prop-2-en-1-one (3a)
To a Schlenk tube was added sequentially Cu2O (7.1 mg,
0.05 mmol), TBHP (180.0 mg, 2 mmol), TEMPO (23.4 mg,
0.15 mmol), propiophenone 1a (67.1 mg, 0.5 mmol), 2-
pyridine amine 2a (121.9 mg, 1.0 mmol) in toluene (2.0
mL) under air, and the reaction mixture was vigorously
stirred at 100 °C for 12 h. After cooling down to room
temperature and concentrating in vacuum, the residue was
purified by flash chromatography on a short silica gel
(eluent: petroleum ether/ethyl acetate = 50:1) to afford 80.6
Scheme 3. Preliminary mechanistic studies.
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900419
Advanced Synthesis & Catalysis
1
mg (72%) of 3a; yellow solid, mp 170-171 °C; H NMR
(400 MHz, CDCl3) δ 12.15 (d, J = 10.0 Hz, 1H), 8.30 (dd, J
= 1.6 Hz, 5.2 Hz, 1H), 8.25 (dd, J = 8.4 Hz, 11.6 Hz, 1H),
7.98-7.95 (m, 2H), 7.64-7.59 (m, 1H), 7.54-7.49 (m, 1H),
7.48-7.44 (m, 2H), 6.96-6.93 (m, 1H), 6.83 (d, J = 8.4 Hz,
1H), 6.14 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 191.9, 151.7, 148.5, 142.9, 139.0, 138.3, 131.8, 128.5,
127.5, 118.5, 111.7, 95.3.
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Acknowledgements
We are grateful for the financial support by the National Natural
Science Foundation of China (21602032, 81473082), Natural
Science Foundation of Guangdong Province, China
(2017A030313078) and the One Hundred Young Talent program
of Guangdong University of Technology. We also appreciate for
doctoral candidates Sosthene Ung and Lida Tan in Professor
Chao-Jun Li’s group at McGill University for valuable comments
and revision.
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Advanced Synthesis & Catalysis
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10.1002/adsc.201900419
Advanced Synthesis & Catalysis
UPDATE
Intermolecular Multiple α,β-Dehydrogenative
Cross-Couplings of Ketones with Boronic Acids
and Amines via Copper Catalysis
Adv. Synth. Catal. Year, Volume, Page – Page
Tianzhang Wang, Guowei Chen Yu-Jing Lu, Qian
Chen, Yanping Huo, Xianwei Li,*
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