Palladium-catalyzed dehydrogenation/oxidative cross-coupling sequence of β-heteroatom-substituted ketones

Article abstract of DOI:10.1002/anie.201206610

Concise and selective: The title one-pot sequence allows formation of the enone functionality and subsequent cross-coupling. The process provides access to highly functionalized cyclic enolones and enaminones from readily accessible β-heteroatom-substitut

Full text of DOI:10.1002/anie.201206610

Angewandte
Chemie
DOI: 10.1002/anie.201206610
Synthetic Methods
Palladium-Catalyzed Dehydrogenation/Oxidative Cross-Coupling
Sequence of b-Heteroatom-Substituted Ketones**
Youngtaek Moon, Daeil Kwon, and Sungwoo Hong*
In recent years, impressive achievements have been made
À
toward enhancing the efficiency of a diverse range of C C
À
bond formations through a direct C H bond functionalization
strategy.[1] The palladium(II)-catalyzed dehydrogenation of
ketones has been demonstrated to be a highly efficient
process for generating functionalized enone products.[2,3]
Cyclic enolone and enaminone motifs are prevalent in
a plethora of natural and synthetic compounds which display
a
variety of biological activities.[4] Recently, synthetic
approaches to these heterocyclic scaffolds through the
palladium-catalyzed dehydrogenation of the corresponding
saturated substrates has been investigated.[3b] Furthermore,
Pihko and co-workers have accomplished the oxidative
coupling of b-ketoesters and indoles.[5] Despite these impor-
tant contributions, consecutive reactions of the b-heteroatom-
substituted enone functionality formed through a dehydro-
genation step in one-pot have yet to be reported.
Scheme 1. General strategy for the sequential dehydrogenation/oxida-
tive cross-coupling. The reaction involves successive palladium-cata-
À
lyzed C H functionalization, requires no pre-functionalization, and has
a broad substrate scope.
À
C H functionalization of the resulting enolones or enami-
À
In recent years, a regiocontrolled C H functionalization
nones.
of cyclic enolones and enaminones has been disclosed.[6]
Driven by the need for a more efficient synthetic route to
these derivatives, we were particularly interested in exploring
efficient approaches to functionalized cyclic enolone and
enaminone scaffolds directly from simple saturated ketones,
such as chromanone and dihydroquinolinone. This trans-
formation could be achieved by a two-step sequence involving
dehydrogenation of saturated ketones and subsequent oxida-
tive cross-coupling with a suitable coupling partner. We
speculated that the cyclic enolones and enaminones gener-
ated in situ from palladium(II)-catalyzed dehydrogenation
might be utilized for further oxidative cross-coupling using
same catalytic systems. Herein, we report the first example of
a palladium(II)-catalyzed dehydrogenation/oxidative cross-
coupling reaction sequence of readily available b-hetero-
atom-substituted cyclic ketones in one-pot, thus providing
a straightforward protocol for the preparation of functional-
ized cyclic enolone and enaminone systems (Scheme 1). In
this study, palladium(II) was found to play a dual role in
catalyzing both the oxidation of the saturated ketones and the
To test the hypothesis, we initially focused on the
dehydrogenation/oxidative Heck reaction. Since the discov-
ery of direct olefination of benzene by Fujiwara and co-
workers,[7] substantial progress of the oxidative Heck reaction
has been made to improve the reaction efficiency.[8] Our
efforts began by exploring possible reaction conditions for
a one-pot reaction of 1-methyl-2,3-dihydroquinolin-4(1H)-
one (1a) with tert-butyl acrylate (Table 1). Recent advances in
palladium-catalyzed dehydrogenation provide useful starting
Table 1: Optimization of the dehydrogenation/oxidative Heck reaction.[a]
Entry
Cu
Ag[b]
Solvent
Yield
[%][c]
1
2
3
4
5
6
7
8
9
10
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
–
Cu(TFA)2·nH2O
CuCO3·Cu(OH)2
CuCO3·Cu(OH)2
AgOAc
AgOAc
–
AgOAc
–
DMF
trace
19
23
47
61
32
5
18
57
83
1,4-dioxane
1,4-dioxane
PivOH
PivOH
AcOH
PivOH
PivOH
PivOH
PivOH
–
[*] Y. Moon, D. Kwon, Prof. Dr. S. Hong
Department of Chemistry
AgOAc
AgOAc
AgOAc
–
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon, 305-701 (Korea)
E-mail: hongorg@kaist.ac.kr
[**] This research was supported by the National Research Foundation
of Korea (NRF) through general research grants (NRF-2010-
0022179, 2011-0016436, 2011-0020322).
[a] Reactions were conducted with ketone (1.0 equiv), tert-butyl acrylate
(1.5 equiv), Pd(TFA)2 (0.2 equiv), and CuII (3 equiv) in PivOH at 1008C
for 6–8 h. [b] 3 equiv of silver species was used. [c] Yields of isolated
products. DMF=N,N’-dimethylformamide, Piv=pivaloyl, TFA=tri-
fluoroacetate.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206610.
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points for our investigation of reactions.[2,3] Among the
palladium sources tested, Pd(TFA)2 displayed the best
catalytic reactivity. Low yields of the coupling products
were obtained, except under reaction conditions employing
pivalic acid[9] as the solvent. The copper source was critical to
the coupling efficiency, and a variety of copper species were
evaluated as the oxidant. Among the copper species screened,
CuCO3·Cu(OH)2 was the most effective and economical
oxidant for promoting the reactions. An interesting feature of
this reaction was that a lower yield of the isolated product was
obtained in the presence of AgOAc, presumably as a result of
competitive oxidative decomposition of starting substrate 1a
or its intermediate under the highly oxidative conditions.
Under the optimized reaction conditions, the dehydrogen-
ation/oxidative Heck reaction of 1a with tert-butyl acrylate
proceeded to provide a high yield (83%) of the isolated
product.
Scheme 2. Proposed mechanistic pathways underlying the present
reactions.
A preliminary mechanistic analysis of the dehydrogen-
ation/oxidative Heck reaction was performed by monitoring
the conversion of 1-methyl-2,3-dihydroquinolin-4(1H)-one
(1a) into 3-vinylquinolinone 2a under standard reaction
conditions (Figure 1). Within 1 hour, the enaminone 3a was
formed (about 50%), and the 3-vinylquinolinone 2a was
subsequently produced with concomitant disappearance of
3a, thus indicating the intermediacy of 3a in the course of the
alkenylation.
cyclic b-amino ketone types. For example, the reaction of 1-
ethyl-7-methyl-2,3-dihydro-1,8-naphthyridin-4(1H)-one pro-
ceeded with complete regioselectivity to provide the C3-
functionalized quinolinone 2c (Table 2, entry 2). The dihy-
dropyrimidine dione and N-acylpiperidone derivatives suc-
cessfully yielded the corresponding vinyl products (2d and
2e). Expanding the scope from the cyclic b-amino ketone to
the cyclic b-oxo ketone system was also possible, thus leading
to the formation of the 3-vinyl chromone 2 f. In addition, the
procedure was successfully applied to a series of C2-substi-
tuted chromanones which are readily accessed by 1,4-addition
to chromones.[10] This strategy thus allows the C2/C3 selective
installation of substituents and provides access to highly
functionalized chromone derivatives by catalytic methods
(2g, 2h, and 2i).
After successfully achieving a one-pot sequential dehy-
drogenation/alkenylation, we preliminarily investigated the
possibility of extending this catalytic system to other trans-
formatons. Based on the above mechanistic proposal, which
suggests the formation of enolone intermediates (Scheme 2),
we envisaged that the sequential dehydrogenation/arylation
of chromanones would be possible because the resulting
chromones would be prone to undergo oxidative cross-
Figure 1. Reaction profile of the palladium(II)-catalyzed dehydrogen-
tation and alkenylation of 1-methyl-2,3-dihydroquinolin-4(1H)-one (1a).
À
coupling with simple arenes through a twofold C H bond
Based on the above observations, a mechanistic proposal
involving a sequential dehydrogenation/oxidative Heck reac-
tion pathway is presented (Scheme 2). First, coordination of
1a or its enol form to PdII and subsequent H abstraction
provides the PdII-enolate A. Next, b-hydride elimination
generates the enaminone intermediate 3a. Electrophilic
palladation of 3a at the C3-position could proceed because
of the more nucleophilic 3-position. In the presence of an
alkene substrate, the C3-palladated species B inserts into the
olefin, and the subsequent reductive elimination of the Pd/
alkyl intermediate C provides the desired coupled product 2a.
Finally, reoxidation by CuII regenerates PdII to complete the
catalytic cycle.
functionalization. Indeed, we were delighted to observe that
the sequential processes were very facile under slightly
altered reaction conditions in which Cu(TFA)2·nH2O
(0.2 equiv) and AgOAc (3 equiv) were employed as oxi-
dants.[11] The reaction site switched to the C2-position,[6h] and
the C2 phenylchromones were obtained in moderate to good
yields with excellent regioselectivity (Table 3).[12] Although at
this stage we cannot be certain of the mechanism underlying
the process, we believe that the arylpalladium species, which
is formed by the concerted metallation/deprotonation pro-
cess, adds to the 2-position of the chromones, and subsequent
b-hydride elimination generates Heck-type products. The
catalyst tolerated useful substrate functional groups. Notably,
a chromanone bearing a triflate substituent resulted in the
isolation of the synthetically versatile 4p with an intact triflate
moiety under the reaction conditions, thus providing an
With the optimized reaction conditions in hand, we next
investigated the substrate scope of the ketones (Table 2). To
our delight, our methodology was amenable to a variety of
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Chemie
Table 2: The one-pot dehydrogenation/oxidative Heck reactions of b-
Table 3: Sequential dehydrogenation/arylation of chromanones.[a]
heteroatom-substituted ketones.[a]
Entry
1
Arene
Product
Yield
[%][d]
2b
2c
2d
79
93
67
4a: 89%
4c: 81%
4e: 64%
4b: 75%
4d: 69%
4 f: 61%
2
3
4[b]
2e
2 f
64
78
5[c]
6[c]
2g
50
4g: 79% (m/p=2:1)
4h: 42%
4j: 71%
4l: 83%
4n: 69%
4p: 79%
7[c]
2h
2i
61
54
8[c]
4i: 53%
[a] Reactions were conducted with ketone (1.0 equiv), tert-butyl acrylate
(1.5 equiv), Pd(TFA)2 (0.2 equiv), and CuCO3·Cu(OH)2 (3 equiv) in
PivOH at 1008C for 6–8 h. [b] Reaction was conducted with PivOH/1,2-
dichloroethane (1:10) as the solvent. [c] Reactions were conducted with
chromanone (1.0 equiv), n-butyl acrylate (1.5 equiv), Pd(OAc)2
(0.2 equiv), Cu(OAc)2 (3 equiv), and Ag2CO3 (3 equiv) in PivOH at 1108C
for 10–16 h. [d] Yields are those of the isolated products.
4k: 76%
À
À
opportunity for the formation of additional C C or C
heteroatom bonds.
We also observed that 1a reacted with benzene under the
same reaction conditions, and a 41% yield of the C3-product
5 was provided [Eq. (1)]. The switch in the regioselectivity
seems to indicate that electrophilic palladation of enaminone
at the C3-position proceeds through a pathway similar to that
of the alkenylation.[6a]
4m: 68%
4o: 71%
[a] Reactions were conducted with chromone, arene (30 equiv), Pd(TFA)2
(0.2 equiv), Cu(TFA)2·nH2O (0.2 equiv), and AgOAc (3 equiv) in PivOH
at 1008C for 48 h. [b] Yields are those for the isolated products.
Tf =trifluoromethanesulfonyl.
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Communications
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In summary, we developed the palladium(II)-catalyzed
sequential dehydrogenation/oxidative cross-coupling reac-
tion, which offers an unprecedented one-pot route to highly
functionalized cyclic enaminones and enolones from readily
accessible b-heteroatom-substituted cyclic ketones. The pro-
cess is desirable because of considerable advantages in both
simplicity and efficiency. The substrate scope was broad and
permitted the construction of a variety of C3-vinyl-substituted
cyclic enaminones and chromones. In addition, a slightly
altered catalytic system was successfully applied to the C2-
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Received: August 16, 2012
Revised: August 29, 2012
Published online: October 4, 2012
À
Keywords: C H functionalization · cross-coupling ·
dehydrogenation · heterocylces · palladium
.
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[11] See the Supporting Information for more details.
[12] In all cases, an appreciable amount of the C3 products (2–4%)
1
was formed (determined by H NMR spectroscopy).
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