Iron-Catalyzed ?±,?-Dehydrogenation of Carbonyl Compounds

Article abstract of DOI:10.1021/acs.orglett.1c00043

An iron-catalyzed α,β-dehydrogenation of carbonyl compounds was developed. A broad spectrum of carbonyls or analogues, such as aldehyde, ketone, lactone, lactam, amine, and alcohol, could be converted to their α,β-unsaturated counterparts in a simple one-step reaction with high yields.

Full text of DOI:10.1021/acs.orglett.1c00043

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Letter
Iron-Catalyzed α,β-Dehydrogenation of Carbonyl Compounds
Xiao-Wei Zhang,§ Guo-Qing Jiang,§ Shu-Hui Lei, Xiang-Huan Shan, Jian-Ping Qu,* and Yan-Biao Kang*
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ABSTRACT: An iron-catalyzed α,β-dehydrogenation of carbonyl com-
pounds was developed. A broad spectrum of carbonyls or analogues, such as
aldehyde, ketone, lactone, lactam, amine, and alcohol, could be converted to
their α,β-unsaturated counterparts in a simple one-step reaction with high
yields.
serves as both a Lewis acid and a redox catalyst. Herein, we
report the recent results in detail.
n organic synthesis, α,β-unsaturated carbonyl compounds
Iare useful building blocks. α,β-Dehydrogenation of carbonyl
compounds is among the most straightforward and practical
processes for the construction of α,β-unsaturated carbonyl
compounds. In earlier reports, either two- or multiple-step
procedures or the involvement of stoichiometric halogen-
containing oxidants, such as DDQ and hypervalent iodine
reagents, was necessary.1,2
Recently, catalytic approaches using transition metals,
especially palladium, have been well demonstrated as efficient
and powerful tools for the α,β-desaturation of a wide range of
carbonyl compounds.3−15 Other transition metals including
copper,16,17 ruthenium,18 platinum,19 iridium,20 and nickel21
have also been successfully applied as the catalyst (Scheme 1a).
The economical and ample supply of iron salts make them
ideal catalysts in both academic research and industrial
applications.22 Recently, iron-catalyzed dehydrogenation re-
actions of organic molecules, such as formic acid, alcohols, and
amines, for the alternative energy storage systems or
ecofriendly synthetic methods have been reported (Scheme
1b).23−28 However, the utilization of this earth-abundant metal
for the catalysts of α,β-dehydrogenation is exceedingly rare.
As part of our ongoing research interest in developing a
practical method to access α,β-unsaturated carbonyl com-
pounds via a dehydrogenation process,3,29 we envisioned that it
is possible to use iron as a bifunctional catalyst, in which it
Our investigations started with the reaction of 3-phenyl-
propanal 1a to cinnamaldehyde 2a in the presence of 10 mol %
FeCl3, 10 mol % 1,10-phenanthroline 3a, and 1 equiv of
TEMPO; 81% of 2a was obtained (Scheme 2). After
evaluations of a series of iron salts (see the Supporting
Information), FeCl3 proved to be best catalyst. Additives,
oxidants, and solvents were also investigated (see the
Supporting Information), and the conditions stated in Scheme
2 were finally chosen as the standard conditions for further
investigations.
The scope of aldehydes was first investigated. Both alkyl-
and aryl-substituted aldehydes could be converted to their α,β-
unsaturated counterparts (Scheme 2). When α-disubstituted
aldehyde 1b was subjected to the standard conditions, the
dehydrogenation product 2b was isolated in 61% yield.
Aldehydes bearing heterocyclic substituents, such as 2-, 3-, or
4-pyridyl (1c−1e), thiophenyl (1f), and methylfuryl (1g),
were all suitable. Aldehydes bearing either electron-rich or
electron-deficient aryl substituents (1h−1u) could also be
oxidized to the corresponding products. Dehydrogenation of
N-methyl-6-oxo-N-phenylhexanamide 1v with 2 equiv of
TEMPO afforded α,β-, γ,δ-dehydrogenation product 2v.
When cyclohexanecarbaldehyde 1w was treated with 3 equiv
of TEMPO, benzaldehyde 2w was obtained. Dehydrogenation
of 3-cyclohexylpropanal 1x under standard conditions
produced the corresponding α,β-dehydrogenation product 2x
in 67% yield. When the straight-chain aliphatic aldehyde
dodecanal 1y was subjected to the standard conditions, α,β-
dehydrogenation occurred albeit with low yield. The α,β-, γ,δ-
unsaturated product 2z was observed with prolonged reaction
time. After 17 h of reaction in the presence of 2 equiv of
Scheme 1. α,β-Dehydrogenation of Carbonyl Compounds
Received: January 6, 2021
Published: February 12, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00043
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1611−1615
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a
a
Scheme 2. α,β-Dehydrogenation of Aldehydes
Scheme 3. α,β-Dehydrogenation of Ketones
a
b
Under standard conditions. Yields were calculated based on
c
recovered starting materials. FeCl3 (20 mol %), 3a (20 mol%).
d
e
f
FeCl3 (15 mol %), 3a (15 mol%). 130 °C. DMSO as solvent.
g
FeCl3 (20 mol %), 3a (20 mol%), TEMPO (3 equiv).
Scheme 4. Dehydrogenative Desaturation of N-Heterocycles
a
Standard conditions: 1 (1 mmol), FeCl3 (0.1 mmol), 3a (0.1 mmol),
TEMPO (1 mmol), PhCl (2 mL) (DMSO for 2c), 120 °C, under N2,
b
isolated yields. FeCl3 (20 mol %), 3a (20 mol %), pyridine (20 mol
%), p-TsOH (10 mol %), TEMPO (3 mmol), DMSO (2 mL).
c
TEMPO (2 mmol).
TEMPO, 2z was obtained in 19% yield without the
observation of 2y.
The dehydrogenation of less reactive ketones can also
proceed well to give corresponding α,β-unsaturated ketone
products in up to 98% yields (Scheme 3). Both cyclic (5a−5c)
and noncyclic ketones were suitable. With respect to the cyclic
ketones, the reaction is not sensitive to the β-substituents (5a
vs 5b), whereas the α-substituent has negative effects (5c).
Either alkyl (5d−5k) or aryl α,β-unsaturated ketones (5l−5q)
were obtained in moderated to excellent yields. Unsaturated
1,4-dicarbonyl compound 5l was achieved in 52% yield. The
cholesterol analogue could also be oxidized to the correspond-
ing unsaturated counterpart 5r.
a
b
c
Under standard conditions. TEMPO (2 mmol). DMSO as solvent.
Scheme 5. Control Experiments
Besides carbonyl compounds, this iron-catalyzed dehydro-
genative desaturation can be applied to N-heterocycles 6 under
standard conditions, affording corresponding aromatic N-
heterocycles in up to 99% yields (Scheme 4). For examples,
indoline 6a and 1,2,3,4-tetrahydroquinoline 6b could be
converted to indole 7a and quinolone 7b in 85% and 96%
yields, respectively. Substituted indolines (6c−g) and tetrahy-
droquinolines (6h−j) bearing either electron rich or electron
a
Under standard conditions, and the yields were determined by GC
b
analysis of the crude products. Average yield of three parallel
reactions.
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indicates that iron salt has been involved in this α,β-
dehydrogenation reaction. The XPS experiments for the
reaction under standard conditions demonstrated both Fe(III)
and Fe(II). This further confirms that iron salts have been
involved in the reaction as a catalyst (Figure 1).
The kinetic studies show that the dependences of initial rate
on the concentration of [1a], [FeCl3], [3a], and [TEMPO] are
all first-order, suggesting that under the standard reaction
conditions each component participates in the rate determin-
ing step (Figure 2).
In the kinetic isotope experiments, a KIE of 2.05 for the β-H
of PhCH2CH2CHO (1a) was observed (eq 4). This KIE
indicates that in the iron-catalyzed dehydrogenation reaction
the β-C−H bond cleavage should be the rate-limiting step.
Therefore, a process that undergoes an α oxygenation with
TEMPO followed by elimination was possible. However, no α
oxygenation intermediate could be observed under the
standard conditions. Other attempts to find such an
intermediate failed, too.
Figure 1. Detection of Fe(III) and Fe(II) by XPS experiment. XPS
Instrument type, Thermo ESCALAB 250Xi; X- ray excitation source,
monochromatic Al Kα (hv = 1486.6 eV); power, 150 W; X-ray beam,
500 μm; energy analyzer fixed transmission energy, 30 eV.
Figure 2. Kinetic studies.
Scheme 6. Proposed Mechanism
The yield of 2a depended linearly on the amount of
TEMPO indicating that TEMPO works as a stoichiometric
oxidant (see the Supporting Information). The form of
TEMPO after the dehydrogenation reaction was determined.
TEMP (2,2,6,6-tetramethylpiperidine) was obtained in 72%
yield (eq 5), whereas no TEMPOH (2,2,6,6-tetramethylpiper-
idin-1-ol) was detected.
When 1 equiv of TEMPOH was used instead of TEMPO, 2a
was obtained in 34% yield with 74% of TEMP (eq 6). Reaction
of ferrous chloride with TEMPOH at room temperature gave
TEMP (eq 7), and the iodometric titration confirms the
generation of Fe(III). These suggested that TEMPOH might
be involved in the catalytic cycle. The radical clock experiment
with 13 yields ring opening product 14 in 72% yield which
confirms the radical nature of this reaction (eq 8).
deficient groups could be transformed to the corresponding
heterocycles.
The iron-catalyzed α,β-dehydrogenation of other carbonyl
analogues were investigated. Dehydrogenation of lactone 8
afforded α,β-unsaturated lactone 9 in 31% yield (eq 1), while
lactam 10 could also be oxidized to α,β-unsaturated lactam 11
in 68% yield (eq 2). Alcohol 12 was subjected to the
dehydrogenation conditions and α,β-unsaturated aldehyde 2a
was obtained in 69% yield (eq 3).
Although the details of this reaction are unclear, a
preliminary mechanism has been proposed based on above-
mentioned experimental evidence. In the reaction model in
Scheme 6, enolization of 1 promoted by FeCl3 as a Lewis acid
generates intermediate A. The following abstraction of the
hydrogen atom by TEMPO forms radical intermediate B. B is
quickly oxidized to 2 via the SET reduction of Fe(III)
The reaction mechanism has been investigated with
experimental evidence. As demonstrated in Scheme 5, either
FeCl3 or TEMPO is necessary for the completion of reaction.
Effects on the purity of FeCl3 were then investigated. The fact
that yield of 2a increased along with the growth of purity
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(2) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. A New Method for
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affording Fe(II) species C, wherein Fe(III) acts as a redox
catalyst. The oxidation of C regenerates Fe(III).
In conclusion, we have developed a general FeCl3-catalyzed
α,β-dehydrogenation for the construction of α,β-unsaturated
compounds. A broad spectrum of carbonyls or analogues can
be converted to their α,β-unsaturated counterparts in a simple
one-step reaction.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00043.
■
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Soc. 2015, 137, 5875−5878.
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1
copies of H NMR and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
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Dehydrogenation of Aldehydes and Ketones with a Pd(TFA)2/4,5-
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Chem. Soc. 2011, 133, 14566−14569.
Jian-Ping Qu − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech
University, Nanjing 211816, China; orcid.org/0000-
0002-5002-5594; Email: ias_jpqu@njtech.edu.cn
Yan-Biao Kang − Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026,
China; orcid.org/0000-0002-7537-4627;
Email: ybkang@ustc.edu.cn
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ation of Aldehydes and Ketones. J. Org. Chem. 1998, 63, 5640−5642.
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Synthesis of α,β-Unsaturated Carbonyl Compounds by Pd(II)
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Synthesis of Enones and Enals via Dehydrogenation of Saturated
Ketones and Aldehydes. Adv. Synth. Catal. 2018, 360, 4774−4783.
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Dehydrogenative Desaturation-Relay via Formation of Multicenter-
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Authors
Xiao-Wei Zhang − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech
University, Nanjing 211816, China; Department of
Chemistry, University of Science and Technology of China,
Hefei, Anhui 230026, China
Guo-Qing Jiang − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech
University, Nanjing 211816, China
Shu-Hui Lei − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech
University, Nanjing 211816, China
Xiang-Huan Shan − Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026,
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00043
Author Contributions
§X.-W.Z. and G.-Q.J. contributed equally.
Notes
(18) Yi, C. S.; Lee, D. W. Efficient Dehydrogenation of Amines and
Carbonyl Compounds Catalyzed by a Tetranuclear Ruthenium-μ-oxo-
μ-hydroxo-hydride Complex. Organometallics 2009, 28, 947−949.
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Desaturation of Lactams, Ketones, and Lactones. Angew. Chem., Int.
Ed. 2018, 57, 16205−16209.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21922109, 21672196, 21831007) and the Fundamental
Research Funds for the Central Universities of China
(WK2060190086) for financial support.
(20) Wang, Z.; He, Z.-Q.; Zhang, L.-R.; Huang, Y. Iridium-
Catalyzed Aerobic α,β-Dehydrogenation of γ,δ-Unsaturated Amides
and Acids: Activation of Both α- and β-C-H bonds through an Allyl-
Iridium Intermediate. J. Am. Chem. Soc. 2018, 140, 735−740.
(21) Huang, D.; Szewczyk, S. M.; Zhang, P.-P.; Newhouse, T. R.
Allyl-Nickel Catalysis Enables Carbonyl Dehydrogenation and
Oxidative Cycloalkenylation of Ketones. J. Am. Chem. Soc. 2019,
141, 5669−5674.
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