Synthesis of cyclic enones via direct palladium-catalyzed aerobic dehydrogenation of ketones

Article abstract of DOI:10.1021/ja206575j

α,β-Unsaturated carbonyl compounds are versatile intermediates in the synthesis of pharmaceuticals and biologically active compounds. Here, we report the discovery and application of Pd(DMSO)₂(TFA)₂ as a catalyst for direct dehydrogenation of cyclohexanones and other cyclic ketones to the corresponding enones, using O₂ as the oxidant. The substrate scope includes heterocyclic ketones and several natural-product precursors.

Full text of DOI:10.1021/ja206575j

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pubs.acs.org/JACS
Synthesis of Cyclic Enones via Direct Palladium-Catalyzed Aerobic
Dehydrogenation of Ketones
Tianning Diao and Shannon S. Stahl*
Department of Chemistry, University of WisconsinꢀMadison, 1101 University Avenue, Madison, Wisconsin 53706, United States
S Supporting Information
b
Scheme 1. Hydrogenation/Dehydrogenation of CꢀC
ABSTRACT: α,β-Unsaturated carbonyl compounds are
versatile intermediates in the synthesis of pharmaceuticals
and biologically active compounds. Here, we report the
discovery and application of Pd(DMSO)2(TFA)2 as a
catalyst for direct dehydrogenation of cyclohexanones and
other cyclic ketones to the corresponding enones, using O2
as the oxidant. The substrate scope includes heterocyclic
ketones and several natural-product precursors.
Bonds (A) and Pd-Catalyzed Dehydrogenation of
Cyclohexanones (B)
olecular hydrogen and oxygen are the quintessential redu-
Scheme 2. Proposed Mechanism for PdII-Catalyzed
Dehydrogenation of Cyclic Ketones
M
cing and oxidizing agents, respectively. Whereas hydro-
genation reactions are commonplace in multistep organic
synthesis, aerobic oxidation reactions are seldom used. For
example, numerous highly selective methods and sophisticated
catalysts exist for the hydrogenation of alkenes;1 however, com-
plementary aerobic dehydrogenation methods for alkene synthesis
are unavailable2 (Scheme 1A). We recently reported a method for
PdII-catalyzed aerobic dehydrogenation of cyclohexanones to
phenols.3 These reactions proceed via a cyclohexenone intermedi-
ate that undergoes further dehydrogenation to the phenol under
the reaction conditions (Scheme 1B). Here, we report the
identification of a different Pd catalyst system that enables selective
dehydrogenation of cycloketones to afford enones rather than
phenols. Cyclohexenones and related α,β-unsaturated carbonyl
compounds are key intermediates in the synthesis of pharmaceu-
ticals and other biologically active compounds.4 Their preparation
typically requires two or more steps5ꢀ7 and/or the use of
stoichiometric reagents, such as 2-iodoxybenzoic acid (IBX)8,9 or
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).10 Catalytic
methods for aerobic dehydrogenation of ketones to enones would
provide appealing, atom-economical alternatives to these stoichio-
metric methods.
oxidation and CꢀH functionalization reactions19 provided useful
starting points for our investigation of dehydrogenation catalysts.
Our initial catalyst screening efforts focused on the dehydro-
genation of 4-tert-butylcyclohexanone 1 under relatively mild
conditions: 1 atm O2, 80 °C, 12 h (Table 1).20 Use of the recently
reported PdII catalyst, Pd(TFA)2/2-N,N-dimethylaminopyri-
dine (2-Me2Npy), for conversion of cyclohexanones to phenols3
resulted in incomplete conversion and, as expected, favored
formation of phenol 3 over the enone 2 (entry 1). The best
previous catalyst for the conversion of cyclohexanone to cyclo-
hexenone, reported by Tsuji and co-workers,12e forms enone 2
selectively, but only in 19% yield under these conditions (entry 2).
Improved results were obtained by using catalytic Pd(OAc)2 in
DMSO,21,22 affording a mixture of enone and phenol products in
63% and 14% yield, respectively (entry 3). The best results were
obtained by using DMSO as a ligand (10 mol %) with Pd(TFA)2
(5 mol %; TFA = trifluoroacetate) in acetic acid (entry 7). This
catalyst system led to a 91% yield of the desired enone 2.
Replacing DMSO with other monodentate and bidentate
The synthesis of enones via PdII-mediated dehydrosilylation of
silyl enol etherswas reported by Ito and Saegusa in1978.6a Insome
cases, these reactions have been achieved with catalytic PdII,6b,c but
the use of g0.5 equiv of PdII is commonly required to obtain good
yields of products.4b,c,11 Methods for direct PdII-catalyzed dehy-
drogenation of ketones have been pursued as an alternative to
Saegusa reactions; however, previous examples exhibit quite
limited substrate scope.12ꢀ15 Both Saegusa-type dehydrosilylation
and direct dehydrogenation reactions are expected to be initiated
by formation of a PdII-enolate, followed by β-hydride elimination
to afford the enone product (Scheme 2).16 The resulting
PdIIꢀhydride intermediate can be oxidized by O2 to regenerate
the PdII catalyst.17,18 Recent advances in PdII-catalyzed aerobic
Received: July 14, 2011
Published: August 18, 2011
r
2011 American Chemical Society
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ligands led to inferior results (entries 13ꢀ19; see also Table
S1).23 The benefit of using DMSO as a catalytic ligand, rather
than a solvent, has been observed recently in two other Pd-
catalyzed aerobic oxidation reactions, including chelate-directed
CꢀH arylation of anilides24 and oxidative amination of alkenes.25
The high selectivity for formation of the enone with the
Pd(DMSO)2(TFA)2 catalyst system is noteworthy in light of
the preferential formation of phenols with a Pd(TFA)2/2-
Me2Npy catalyst system.3 A comparison of time courses for
reactions with the two catalyst systems (Figure 1) highlights the
significant differences between the relative rates of the corre-
sponding dehydrogenation steps (cf. Scheme 1B). Fitting of
the time-course data to a simple sequential kinetic model,
A f B f C,26 reveals that the first dehydrogenation step is 33-
fold faster than the second step when Pd(DMSO)2(TFA)2 is
used as the catalyst. In contrast, the first step is nearly 2-fold
slower than the second step with the Pd(TFA)2/2-Me2Npy
catalyst system.27 Further mechanistic studies are ongoing,
but these observations have important implications for use
of the present catalyst system in the synthesis of enones
(Table 2).
Table 1. Catalyst Optimization of Aerobic Oxidative
Dehydrogenation of 4-tert-Butylcyclohexanone 1a
A number of 4-substituted cyclohexanone derivatives under-
went dehydrogenation in good yields with the Pd(DMSO)2-
(TFA)2 catalyst (Table 2, entries 1ꢀ5). Substrates with electron-
deficient substituents (entries 2 and 3) exhibited somewhat faster
rates, and the conditions tolerated various functional groups,
including trifluoromethyl and siloxy groups (entries 2 and 5).
The parent cyclohexanone (entry 1) decomposed under the
acidic conditions, but a good yield of enone was obtained by
performing the reaction in ethyl acetate.28 Dehydrogenation of 2-
and 3-substituted cyclohexanones can afford two enone regio-
isomers, and reactions of 2- and 3-phenylcyclohexanone pro-
ceeded with modest (∼3:1) regioselectivity (entries 6 and 7).
The ability to achieve highly regioselective dehydrogenation was
demonstrated in the reactions of two steroid derivatives (entries
8 and 9), each of which afforded one of two possible cyclohex-
enones in excellent yield. In both cases, the regioselectivity
favored formation of the less substituted alkene. No dehydro-
genation of the cyclopentanone fragment was observed in the
reaction leading to 5α-androst-1-ene-3,17-dione (entry 9). The
lower reactivity of cyclopentantones was also evident in the
dehydrogenation of indanone, which afforded the corresponding
enone in 54% yield, with toluene as the optimal solvent (entry
10). In contrast, 1-benzosuberone underwent dehydrogenation
in good yield (81%, entry 11). Cycloheptanone and cycloocta-
none led to a mixture of dehydrogenation products, with 2,6-
cycloheptadien-1-one and 2,7-cyclooctadien-1-one formed as the
major products in 26 and 25% yields, respectively, based on
GCꢀMS and 1H NMR spectroscopic analysis.
ligand
2
3
entry
1
PdX2
(mol %)
solvent (%)b (%)b
Pd(TFA)2 2-Me2N-pyridine (10)/
TsOH(20)
Pd(TFA)2 5,50-Me2bpy (5)/
DMSO 23
PhCl 19
33
0
2
4 Å MS
3
4
5
6
7
8
9
Pd(OAc)2
DMSO 63
DMSO 34
14
56
1
Pd(TFA)2
Pd(TFA)2
HOAc
HOAc
HOAc
24
86
91
Pd(OAc)2 DMSO (10)
Pd(TFA)2 DMSO (10)
Pd(TFA)2 DMSO (10)
Pd(TFA)2 DMSO (10)
8
8
Toluene 67
THF 66
Dioxane 84
3
8
10 Pd(TFA)2 DMSO (10)
10
6
11 Pd(TFA)2 DMSO (10)
EtOAc
PhCl
30
11
55
3
12 Pd(TFA)2 DMSO (10)
0
13 Pd(TFA)2 pyridine (10)
14 Pd(TFA)2 2-Me2N-pyridine (10)
15 Pd(TFA)2 2-F-pyridine (10)
16 Pd(TFA)2 bipyridine (5)
17 Pd(TFA)2 5,50-Me2bpy (5)
18 Pd(TFA)2 phenanthroline (5)
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
2
1
Chromones29 and flavones have important biological activity,30
and the saturated dihydrobenzopyranones are readily prepared via
condensation of simple precursors.31 Aerobic dehydrogenation
reactions to form chromone, 6-fluorochromone,32 and flavone33
proceeded in good yield (entries 12ꢀ14). Related N-methyl- and
N-Boc-piperidone derivatives underwent successful dehydrogena-
tion to the corresponding dihydro-4-pyridone derivatives (entries
15 and 16).
37
0
2
0
0
0
0
0
19 Pd(TFA)2 1,2-bis(phenylsulfinyl)ethane (5) HOAc
9
4
a Conditions: [1] = 0.2 M (15.4 mg, 0.1 mmol), 5% PdX2 (0.005 mmol),
10% ligand (0.01 mmol), Solvent (0.5 mL), 1 atm O2, 80 °C, 12 h.
b Determined by GC, external standard = tetradecane.
Figure 1. Comparison of kinetic profiles of Pd(DMSO)2(TFA)2- and Pd(TFA)2/2-Me2Npy-catalyzed dehydrogenation of 1. Reaction conditions:
(A) [1] = 0.2 M (0.1 mmol), Pd(TFA)2 (5 µmol), DMSO (10 µmol), AcOH (0.5 mL), 1 atm O2, 80 °C; (B) [1] = 0.2 M (0.1 mmol), Pd(TFA)2
(5 µmol), 2-Me2Npy (10 µmol), TsOH (20 µmol), DMSO (0.5 mL), 1 atm O2, 80 °C. Int. std. = 1,4-dimethoxybenzene. Error bars represent std. dev.
from 3 indep. measurements.
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Table 2. Pd-Catalyzed Aerobic Dehydrogenation of Diverse
Cycloketonesa
Saegusa-type6c and stoichiometric IBX8 oxidation methods failed
in the synthesis of a cyclopentene-α-dione precursor to the
natural product (ꢀ)-terpestacin, and stoichiometric Pd(OAc)2
was used instead.35 Application of an aerobic Pd(TFA)2/DMSO
catalyst system to this reaction afforded the enedione in 90%
yield (eq 2).
In summary, we have identified a PdII catalyst system that
enables direct dehydrogenation of cyclic ketones to the corre-
sponding enones with a number of important substrates. The
high selectivity for enone rather than phenol formation sharply
contrasts other PdII-catalyzed dehydrogenation methods3,13 and
warrants further mechanistic investigation. The ability to replace
stoichiometric reagents (e.g., Br2, organoselenium reagents, and
IBX) with O2 as an oxidant has important implications for large-
scale applications of these methods in pharmaceutical and fine-
chemical synthesis.36
’ ASSOCIATED CONTENT
S
Supporting Information. Reaction procedure and spec-
b
tra. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
stahl@chem.wisc.edu
’ ACKNOWLEDGMENT
We thank Clark Landis (UW-Madison) for assistance with
COPASI to carry out kinetic simulations, and David Mannel
(UW-Madison) for assistance with the flow-reactor. Financial
support was provided by the NIH (RC1-GM091161) and East-
man Chemical (summer fellowship to T.D.). High-pressure
instrumentation was partially supported by the NSF (CHE-
0946901).
a Reactions conditions: [substrate] = 0.2 M (0.8 mmol), [Pd(TFA)2] =
0.01 M (0.04 mmol =5 mol %), [DMSO] = 0.02 M (0.08 mmol), solvent =
HOAc (4 mL), 1 atm O2. b Isolated yield. c Ethyl acetate was used
as solvent to prevent product decomposition in acetic acid, [substrate] =
0.8M (0.8 mmol), ethyl acetate (1 mL). d [substrate] = 0.4M (0.8 mmol),
[Pd(TFA)2] = 0.02 M, [DMSO] = 0.2 M, solvent = toluene (2 mL). e In
DMSO; no additional ligand.
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