Aerobic double dehydrogenative cross coupling between cyclic saturated ketones and simple arenes

Article abstract of DOI:10.1002/chem.201402063

The synthesis of 3-aryl-2-cyclohexenones is a topic of current interest as they are not only privileged structures in bioactive molecules, but they are also relevant feedstocks for the synthesis of substituted phenols or anilines, which are ubiquitous structural elements both in drug design and medicinal chemistry. A simple and sustainable one-pot aerobic double dehydrogenative reaction under mild conditions for the introduction of arenes in the β-position of cyclic ketones has been developed. Starting from the corresponding saturated ketone, this reaction sequence proceeds under relatively low Pd catalyst loading and involves catalytic amounts of electron-transfer mediators (ETMs) under ambient oxygen pressure. A simple and sustainable one-pot aerobic double dehydrogenative reaction under mild conditions for the introduction of arenes in the β-position of cyclic ketones has been developed (see scheme). Starting from the corresponding saturated ketone, this reaction sequence proceeds under relatively low Pd catalyst loading and involves catalytic amounts of electron-transfer mediators (ETMs) under ambient oxygen pressure.

Full text of DOI:10.1002/chem.201402063

DOI: 10.1002/chem.201402063
Communication
&
CꢀH Activation
Aerobic Double Dehydrogenative Cross Coupling between Cyclic
Saturated Ketones and Simple Arenes
Nicolas Gigant and Jan-E. Bꢀckvall*[a]
salt was used as oxidant in both cases. These limitations are
Abstract: The synthesis of 3-aryl-2-cyclohexenones is
due to the unfavorable activation of the CꢀH bond and the
a topic of current interest as they are not only privileged
problematic regeneration of the active PdII species (Sche-
structures in bioactive molecules, but they are also rele-
me 1a).[1b,3,7]
vant feedstocks for the synthesis of substituted phenols
To overcome these limitations in oxidation reactions, our
or anilines, which are ubiquitous structural elements both
group has been involved in a biomimetic aerobic oxidation
in drug design and medicinal chemistry. A simple and sus-
tainable one-pot aerobic double dehydrogenative reaction
under mild conditions for the introduction of arenes in
the b-position of cyclic ketones has been developed. Start-
ing from the corresponding saturated ketone, this reaction
sequence proceeds under relatively low Pd catalyst load-
ing and involves catalytic amounts of electron-transfer
mediators (ETMs) under ambient oxygen pressure.
Transition-metal-catalyzed CꢀH bond activation for CꢀC bond
formation is of importance for constructing valuable building
blocks from simple precursors and has attracted significant at-
tention during the past decade.[1] Among these transforma-
Scheme 1. Comparison of direct re-oxidation by O2 and re-oxidation by low-
energy electron transfer with the use of ETMs.
tions, one of the cleanest processes is undoubtedly the Fuji-
wara–Moritani coupling,[2] forming a CꢀC bond starting from
program for several years.[3i,8] These catalytic aerobic oxidations
two simple CꢀH bonds. Impressive progress was recently ob-
tained regarding this dehydrogenative Heck reaction in terms
of efficiency and selectivity in the reactions of arenes with a,b-
unsaturated carbonyl compounds.[3] These last compounds
constitute a versatile class of synthetic intermediates, which
can easily participate in a large number of reactions. A range
of methods for their preparation from the corresponding satu-
rated ketones are known, including straightforward catalytic
dehydrogenative protocols.[4] However, double dehydrogena-
tion/CꢀH functionalization remains to be an outstanding chal-
lenge.
occur through low-energy electron transfer with the involve-
ment of catalytic electron-transfer mediators (ETMs). These last
species facilitate the catalyst re-oxidation to its active form by
the use of air (O2) (Scheme 1b).[9] Schematically, the electron
transfer for the high-energy barrier reaction is divided into sev-
eral steps, generating a low-energy pathway between the re-
duced catalyst and O2. Based on this concept, we speculated
that we could develop a one-pot aerobic double dehydrogena-
tive/oxidative Heck reaction of 4-substituted cyclohexanones
with arenes under mild conditions. These more challenging ke-
tones have not been targeted before.
Recently, double dehydrogenative/oxidative Heck couplings
of saturated aromatic ketones and arenes were reported.[5,6]
The ketones used in these studies were either cyclic or linear
aromatic ketones that undergo more facile palladium-promot-
ed dehydrogenation due to a favored keto–enol tautomeriza-
tion. Furthermore the catalyst loading in these studies were
relatively high (20[5] and 10 mol%,[6] respectively) and a silver
In this communication we describe our results regarding the
synthesis of 4-substituted 3-aryl-2-cyclohexenones (Scheme 2)
by using a palladium(II) salt (5 mol%) as the catalyst with small
amounts of p-benzoquinone (BQ) and iron phthalocyanine
(Fe(Pc)) as inexpensive commercial ETMs for the double dehy-
drogenation under ambient oxygen pressure. We demonstrate
for the first time the ability to accomplish this type of se-
quence starting from aliphatic cyclic ketones. Compared to the
previous methods a lower catalyst loading is employed and
molecular oxygen is used in place of a silver salt as oxidant.
Recently, 3-aryl-2-cyclohexenones have been prepared by
means of metal-catalyzed cross-coupling reactions starting
from the corresponding 2-cyclohexenones and pre-functional-
[a] Dr. N. Gigant, Prof. Dr. J.-E. Bꢀckvall
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University, 106 91 Stockholm (Sweden)
Fax: (+46)8-154-908
E-mail: jeb@organ.su.se
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402063.
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Scheme 2. Proposed PdII-catalyzed CꢀH functionalization strategy of 4-sub-
stituted cyclohexanones to generate 3,4-disubstituted 2-cyclohexenones.
ized arenes[10] or by using multistep reactions.[11] Indeed, the
synthesis of 3-aryl-2-cyclohexenones is a topic of current inter-
est because they are not only privileged structures in bioactive
molecules,[12] but they are also relevant feedstocks for the syn-
thesis of substituted phenols or anilines,[10e,13] which are ubiq-
uitous structural elements both in drug design and medicinal
chemistry.[14]
With the optimized reaction conditions in hand,[15] we start-
ed to explore the scope and the limitation of this transforma-
tion (Scheme 3).
The variation of cyclic ketones was carried out with 2a as
the arene and various 4-substituted cyclohexanones. The reac-
tion of 4-arylcyclohexanones proceeded well (3aa–3ba). Grati-
fyingly, the double dehydrogenation occurred smoothly with
ketones having linear or bulky alkyl chains in the 4-position,
and products 3ca–3 fa were isolated in good to high yields. A
trifluoromethyl moiety on the ketone was also tolerated,
giving 3ga in a satisfactory yield, whereas cyclohexanone 1h
with a 4-TBSO group (TBS=tert-butyldimethylsilyl) was less re-
active. An interesting result was obtained with the 4-acetami-
do-substituted ketone 1i, giving cyclohexanone 3ia. The reac-
tion afforded two regioisomers in a 3:2 ratio. The lack of selec-
tivity can be explained by the fact that the amide group can
act as a coordinating auxiliary, partially reversing the regiose-
lectivity of the coupling. Moreover, 2,2-, 3,3-, and 4,4-dimethyl
cyclohexanones were coupled, furnishing the corresponding
products 3ja, 3ka, and 3la, respectively, in moderate to fair
yields. In addition, the reaction was run with other cyclic ke-
tones. Benzosuberone (1m) could be arylated by this protocol,
albeit in moderate yield (3ma). Remarkably, 1H-indanone af-
forded an unprecedented diarylated product 3na.[16]
Encouraged by these promising results, the reaction condi-
tions were also applied to examine a wide range of arenes
(Scheme 4). The effect of the arene substitution pattern was
assessed with a range of electron-rich methoxy-substituted
arenes, which furnished good yields of products with good to
poor selectivity. Whereas 1,4-dimethoxy- and 1,3-dimethoxy-
benzene afforded the desired derivatives 3ca and 3cb as
single isomers, 1,2-dimethoxybenzene provided a 10:90 mix-
ture of isomers 3cc. 1,3-Benzodioxole 2d gave coupling prod-
uct 3 cd with a lower selectivity (44:56), but in an improved
yield. Anisole produced a mixture of ortho:meta:para isomers
3ce (24:16:60) in high yield, whereas 1,2,3-trimethoxybenzene
Scheme 3. Scope of the aerobic oxidative sequence with 1,4-dimethoxyben-
zene (2a). Unless otherwise noted, reactions were performed on
a 0.50 mmol scale of ketone with arene (15 equiv) under ambient pressure
of O2 (balloon) for 12–48 h. Isolated yields. [a] Ratio of regioisomers deter-
mined by NMR spectroscopy of isolated product. [b] DMSO (1 equiv) was
used. PMP=p-methoxyphenyl. TBS=tert-butyldimethylsilyl.
afforded an equimolar mixture of isomers 3cf in good yield.
The reaction sequence also tolerated p-methylanisole (2g) and
furnished 3cg in good selectivity. Surprisingly, the selectivity
was total with o- and p-xylene, and isomerically pure arylvinyl-
ketones 3ch and 3ci were obtained in 53 and 64% yield, re-
spectively. Toluene was also successfully employed and 3cj
was isolated as a mixture of isomers. Simple benzene and
naphthalene were also coupled with success, giving 3ck and
3cl, respectively. Interestingly, electron-deficient arenes bearing
halo substituents could be accommodated with this proce-
dure, providing molecules for further functionalization. Nota-
bly, chlorobenzene furnished product 3 cm in 63% yield. Final-
ly p-chloroanisole and p-bromoanisole were also suitable cou-
pling partners (3cn–3co).
The arenes involved in our study are both inexpensive and
readily available, and in addition, the excess arene can be
easily recovered by flash column chromatography or distilla-
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Scheme 5. Kinetic isotopic effect (KIE) studies of the first step of the reaction
sequence.
a-CꢀH bond is the rate-limiting step in the transformation
1c!4c, while the b-H elimination is faster than the a-CꢀH ac-
tivation. We also determined the competitive isotope effect by
starting from a 1:1 mixture of 1c and [Da]-1c and measuring
the product ratio 4c/[Da]-4c (Scheme 5b).[17] 1H NMR analysis
of the reaction mixture showed a product ratio 4c/[Da]-4c=
4.1:1 at 16% conversion, which gives an isotope effect (kH/kD)
of 4.6.[17,18]
The deuterium isotope effect for the overall reaction (1c!
3ca) was determined from two parallel experiments in which
ketones 1c or [Da]-1c were allowed to react with arene 2a
(see Supporting Information). By comparing the initial rates of
the reactions a primary kinetic isotope effect (kH/kD) of 2.5 was
obtained, suggesting that the transformation of the saturated
ketone to the corresponding unsaturated ketone is only partly
rate determining for the overall reaction.[19]
Scheme 4. Scope of the aerobic oxidative sequence with 4-methylcyclohexa-
none (1c). For conditions, see Scheme 3. Isolated yields are given. [a] Ratio
of regoisomers determined by NMR of isolated product. [b] Ratio of regio-
isomers, which could not be assigned and are thus given in no particular
order (determined by NMR spectroscopy of isolated product). [c] Reaction
performed at 808C.
tion from the crude reaction mixtures. To illustrate the practical
use of this method, the biomimetic reaction was carried out
on a multigram scale between 1c (1.0 g, 8.9 mmol) and 2a
(18.5 g). Following our best conditions, the desired product
3ca was isolated in a satisfying 64% yield (1.4 g) and a substan-
tial amount of 2a was recovered after column chromatography
(15.2 g, 12.3 equiv).
The double dehydrogenation sequence of 4-phenylcyclo-
hexanone (1a) into 3-arylvinylketone 3aa was monitored by
1H NMR spectroscopy.[19] The reaction showed a low steady-
state concentration of 4-phenylcyclohexeanone (4a), which is
in accordance with a partly rate-determining transformation of
1a to 4a (see Supporting Information).
The process is initiated by the coordination of 1a to
Pd(OAc)2, giving the corresponding PdII enolate 5 (Scheme 6,
path 1). The latter intermediate undergoes b-H elimination to
give unsaturated ketone 4a. Simultaneously, an electrophilic
palladation of 2a occurs to give organopalladium species 6.
Subsequent arylpalladation of the CꢀC double bond of 4a by
intermediate 6 generates organopalladium species 7, which
undergoes b-H elimination to produce the desired arylated
ketone 3aa. Additionally in our biomimetic reaction, catalytic
To gain more insight into the mechanism of the reaction, we
studied the deuterium kinetic isotope effect (KIE) of the first
step (1c!4c) by comparing initial reaction rates of the a- or
b-labeled derivatives with the parent ketone 1c (Scheme 5a). A
large primary isotope effect (kH/kD =4.6) was measured with
the a-deuterated ketone [Da]-4c, whereas a small isotope
effect (kH/kD =1.5) was observed for the b-deuterated ketone
[Db]-4c. These observations support that the activation of the
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Acknowledgements
Financial support from the European Research Council (ERC
AdG 247014) and The Knut and Alice Wallenberg Foundation is
gratefully acknowledged.
Keywords: aerobic oxidation · biomimetic cross-coupling ·
CꢀH activation · double dehydrogenation · synthetic methods
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Scheme 6. Plausible mechanism for the double dehydrogenative sequence
by a biomimetic approach.
amounts of p-BQ and Fe(Pc) as electron-transfer mediators in
combination with O2 at atmospheric pressure are able to re-ox-
idize Pd0 to PdII after each dehydrogenation, concluding the
catalytic cycle (Scheme 6, path 2).
In summary, we have developed a straightforward one-pot
biomimetic aerobic dehydrogenation/oxidative Heck sequence
for the introduction of an aryl group in the b-position of a satu-
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scope as well as good functional group compatibility, involves
simple, inexpensive and easily available reagents, proceeds
under relatively low catalyst loading and uses O2 as the termi-
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Experimental Section
A Schlenk tube, charged with Pd(OAc)2 (5 mol%), p-benzoquinone
(10 mol%), iron phtalocyanine (2.5 mol%), DMSO (10 mol%), arene
2 (15 equiv), ketone 1 (1 equiv), and AcOH (c=1.50 mLmmolꢀ1),
was degassed three times under reduced pressure before introduc-
ing O2 with a balloon. The resulting mixture was stirred in an oil
bath at 908C for 12–48 h. The reaction mixture was cooled to
room temperature, diluted with AcOEt and filtered through Celite.
The organic layer was washed with sat. aqueous NaHCO3 and
brine, dried (MgSO4), filtered, and concentrated. The product was
purified by flash chromatography using pentane/ethyl acetate as
eluent to yield 3.
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[15] See the Supporting Information for optimization.
[16] Unfortunately unsubstituted cyclohexanone and linear aliphatic ketones
decomposed under these acidic conditions.
[17] The value of 4.6 was calculated based on the ratio of the two products
4c:[Da]-4c (4.1:1) and the conversion (16%), by taking into account the
change of the ratio of 1c and [Da]-1c (see Supporting Information).
[18] A competitive experiment between 1c and [Db]-1c gave products 4c
and [Da]-4c in a ratio of 1.8:1 (kH/kD =2.0) (see Supporting Information).
[19] For more details, see the Supporting Information.
Received: February 6, 2014
Published online on March 12, 2014
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