A new catalytic approach for aerobic oxidation of primary alcohols based on a Copper(I)-thiophene carbaldimines

Article abstract of DOI:10.1016/j.mcat.2021.111637

We report here novel Cu(I) thiophene carbaldimine catalysts for the selective aerobic oxidation of primary alcohols to their corresponding aldehydes and various diols to lactones or lactols. In the presence of the in situ generated Cu(I) species, a persistent radical (2,2,6,6-tetramethylpiperdine-N-oxyl (TEMPO)) and N-methylimidazole (NMI) as an auxiliary ligand, the reaction proceeds under aerobic conditions and at ambient temperature. Especially the catalytic system of 1-(thiophen-2-yl)-N-(4-(trifluoromethoxy)phenyl)methanimine (ligand L2) with copper(I)-iodide showed high reactivity for all kind of alcohols (benzylic, allylic and aliphatic). In the case of benzyl alcohol even 2.5 mol% of copper loading gave quantitative yield. Beside high activity under aerobic conditions, the catalysts ability to oxidize 1,5-pentadiol to the corresponding lactol (86% in 4 h) and N-phenyldiethanolamine to the corresponding morpholine derivate lactol (86% in 24 h) is particularly noteworthy.

Full text of DOI:10.1016/j.mcat.2021.111637

Molecular Catalysis 509 (2021) 111637
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.journals.elsevier.com/molecular-catalysis
A new catalytic approach for aerobic oxidation of primary alcohols based
on a Copper(I)-thiophene carbaldimines
Emi Lagerspets, Evelyn Valbonetti, Aleksi Eronen, Timo Repo*
Department of Chemistry, University of Helsinki, A. I. Virtasen aukio 1, 00014 Helsinki, Finland
A R T I C L E I N F O
A B S T R A C T
Keywords:
We report here novel Cu(I) thiophene carbaldimine catalysts for the selective aerobic oxidation of primary al-
cohols to their corresponding aldehydes and various diols to lactones or lactols. In the presence of the in situ
generated Cu(I) species, a persistent radical (2,2,6,6-tetramethylpiperdine-N-oxyl (TEMPO)) and N-methyl-
imidazole (NMI) as an auxiliary ligand, the reaction proceeds under aerobic conditions and at ambient tem-
perature. Especially the catalytic system of 1-(thiophen-2-yl)-N-(4-(trifluoromethoxy)phenyl)methanimine (ligand
L2) with copper(I)-iodide showed high reactivity for all kind of alcohols (benzylic, allylic and aliphatic). In the
case of benzyl alcohol even 2.5 mol% of copper loading gave quantitative yield. Beside high activity under
aerobic conditions, the catalysts ability to oxidize 1,5-pentadiol to the corresponding lactol (86% in 4 h) and N-
phenyldiethanolamine to the corresponding morpholine derivate lactol (86% in 24 h) is particularly noteworthy.
Aerobic oxidation
Primary alcohols
Catalyst
Lactol
Copper(i) complex
1. Introduction
tolerance and high chemo selectivity. [22] For example, the copper(I)
based catalysts are often highly sensitive to water, which is by definition
One of the fundamental transformations in the chemical and phar-
maceutical industry is the oxidation of alcohols to their corresponding
aldehydes. [1–3] The reaction is required to be efficient, selective, fast
and follow the principles of green chemistry. Classically, the method for
this transformation is the use of stoichiometric inorganic oxidants
(hyper valent iodine (Dess-martin reagents), Swern, CrO3 or MnO2).
However, these reactions are costly, produce stoichiometric amounts of
toxic waste, rely on harsh conditions and often show incompatibility
with functional groups. [2,4–6] The main goal of the recent research in
this field is to reduce the environmental burden. This can be achieved
through the use of H2O2 or oxygen, but most preferably utilizing air
under aerobic conditions as the oxidant in combination with a transition
metal-based catalyst. [7–11]
the side-product in aerobic oxidation.
In this work we present new copper(I) catalysts bearing thiophene
carbaldimine-type ligands. The benefit of the here reported copper(I)
system is, that it can be prepared on the bench without any Schlenk or
glovebox methods, while still providing quantitative yields of aldehyde
under true aerobic conditions at room temperature.
2. Experimental
Commercially available compounds were purchased from Sigma-
Aldrich except 4-fluoroaniline (from fluorochem) and benzyl alcohol
(from abcr) and used without further purification unless otherwise
stated. The 1H, 13C, HSQC and HMBC NMR spectra were recorded on a
Bruker Avance NEO 400 MHz spectrometer. GC-FID analyses were
performed on Agilent Technologies 7890B GC equipped with 5977B
MSD, using an Agilent HP-Ms-5-UI (30 m, 0.25 mm, 0.25 µm) column or
GC–MS with an Agilent Technologies 6890 N GC equipped with 5973
MSD, using an Agilent HP-Ms-5-UI (30 m, 0.25 mm, 0.25 µm) column.
The oxidation products were identified via GC–MS by comparison with
commercial samples. The yield determinations were conducted with the
GC-FID using calibration curves with acetophenone or 1,2-dichloroben-
zene as an internal standard. For the in situ IR measurements a Mettler
In the last decade the research has focused on copper based catalysts,
that are commonly bearing N-donor ligands like bipyridine or phenan-
throline together with 2,2,6,6-tetramethylpiperdine-N-oxyl (TEMPO) a
stable radical and N-methylimidazole (NMI) as an auxiliary base. This
combination is known to generate a highly active catalytic species,
which will selectively oxidize a wide range of primary alcohols to their
corresponding aldehydes. [3,12–21] The current goal is to improve the
catalytic activity and stability, to use ambient temperatures, pressure
and air as an oxidant, while still achieving high functional group
* Corresponding author.
E-mail address: timo.repo@helsinki.fi (T. Repo).
https://doi.org/10.1016/j.mcat.2021.111637
Received 12 March 2021; Received in revised form 6 May 2021; Accepted 8 May 2021
Available online 28 May 2021
2468-8231/© 2021 The Authors.
Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

E. Lagerspets et al.
Molecular Catalysis 509 (2021) 111637
Toledo ReactIR™ 15 was used with a 6.3 mm AgX DiComp as the probe.
carbaldimines to be studied as supporting ligands in copper(I) based
catalysts. The structure of the ligands and the synthetic pathways are
shown in Fig 1.
2.1. Ligand synthesis
The ligands L1-L6 together with copper(I)-iodide as the copper
source were introduced to the oxidation reaction using benzyl alcohol as
a model substrate. In comparison with previous, furan based catalytic
systems, this new Schiff base ligand copper system gave surprisingly
high yields, when prepared in situ (in a 1:1 ratio of copper(I)-iodide to
the ligand) (Table 1, entries 2, 7, 10, 11). In the series of thiophene
carbaldimine ligands, L2 gave the highest activity for benzyl aldehyde
(Table 1, entries 1–6). When considering the catalytic activity in the
ligand series, increasing the electronegativity of the para-substituent
increases the catalytic activity. To rationalize these results, we should
see the thiophene carbaldimines as bidentating ligands with a strongly
coordinating thiophene functionality and with a weakly coordinating
imine functionality. Thiophene coordination will keep the ligand
attached to the copper(I), while the coordination strength of imine can
be controlled by the para substituents; the higher the electronegativity
of the substituent, the weaker the imine coordination and the higher the
activity. This indicates the importance of hemilabile coordination
around the copper(I) center. The dynamic coordination sphere provides
the needed flexibility in the coordination sphere for the substrate
coordination.
The ligands (L1-L6) were prepared according to literature protocol
[23]. L1: 2-thiophenecarboxaldehyde (1 eq., 0.93 ml) and substituted
anilines (1 eq., 0.95 ml) were mixed in a 50 ml round bottom flask with
dry toluene (5 ml) and with two drops of formic acid. The reaction was
stirred in RT for 2 h. The product was filtered and washed with dry
n-hexane and dried under vacuum. 1H and 13C NMR spectra were
recorded from the product in CDCl3. L1: 1H NMR (400 MHz, CDCl3) δ
–
8.57 (s, 1H, N CH), 7.54 (d, J = 5.0 Hz, 1H, ar-H), 7.50 (s, 1H, ar-H),
–
7.20 (m, 2H, ar-H), 7.16 (m, 1H, ar-H), 7.09 (d, J = 17.3 Hz, 2H, ar-H).
13C NMR (100 MHz, CDCl3): δ 161.35, 152.92, 147.57, 142.79, 132.39,
130.50, 127.90, 122.52, 115.98. All the ligands were synthesized
accordingly (see ESI for details).
2.3. Oxidations
Oxidation reactions were performed in 3 ml or 5 ml MeCN solutions
at room temperature under open air conditions. The reaction was set up
by adding 4 mol% of copper(I)iodine, 4 mol% of ligand, solvent, 5 mol%
of TEMPO, 1 mmol of alcohol and 10 mol% of NMI into a 20 ml test tube,
which was equipped with a magnetic stir bar. The reaction was stirred at
1500 rpm for 1 h, 3 h or 24 h depending on the substrate.
Under optimized conditions (5 mol% TEMPO, 4 mol% CuI, 4 mol%
ligand, 10 mol% NMI, 1 mmol alcohol), it was possible to reduce the
catalytic loading of L2CuI to 4 mol%, while still achieving high to
quantitative yields (Table 1, entry 7, Table 2 entry 2). Furthermore, in
the case of benzyl alcohol oxidation the catalytic loading could be
reduced down to 2.5 mol% for the L2CuI catalyst (Table 1, entry 8). [14,
24,25] However, a longer reaction time of 3 h was needed to achieve
quantitative yields.
After the reaction, the reaction solution and an internal standard
(acetophenone 40 µL or 1,2-dichlorobenzene 40 µL, see ESI for more
information) were diluted with EtOAc (50 mL). GC samples (1.5 mL)
were prepared by filtrating the solution through a layer of silica gel (1
cm thick). The yields were determined using GC-FID with calibration
curves and identified using GC–MS and/or 1H/13C/HMBC/HSQC NMR.
To demonstrate the high reactivity of this new copper(I) catalyst, the
oxidation of various primary alcohols were studied under optimized
conditions (4 mol% CuI, 4 mol% ligand, 5 mol% TEMPO, 10 mol% NMI,
3. Results and discussion
1 mmol alcohol). All π-activated substrates (such as cinnamyl alcohol, 3-
Our previous work showed that bidentate Schiff base ligands
combining both an imine and a furan functionality, for example N-(4-
fluorophenyl)ꢀ 1-(furan-2-yl)methanimine, coordinate strongly with
various copper(I) salts and generate in the presence of TEMPO and NMI
highly reactive catalysts for the oxidation of primary alcohols. [14] Here
we were interested to see how changes in this ligand structure would
further improve the catalytic properties. In this regard, we were looking
for ways to improve coordination stability of the heterocyclic part of the
ligand and straightforward the exchange of furan to thiophene substi-
tution was an appealing strategy. We synthesized six thiophene
phenyl-2-propyn-1-ol, 2,4-dichlorobenz alcohol, 2,4-dimetoxybenzyl
alcohol, 4-methoxybenzyl alcohol, 4-nitrobenzyl alcohol, methyl 4-
Table 1
Aerobic oxidation of benzyl alcohol.
Fig 1. Schematic pathway of the synthesis for the different ligands L1-L6 prepared for this work.
2

E. Lagerspets et al.
Molecular Catalysis 509 (2021) 111637
Table 2
Aerobic oxidation of different primary alcohols.
(hydroxymethyl)benzoate and 4-chlorobenzyl alcohol) gave quantita-
tive yields of the corresponding aldehyde with the use of 4 mol% loading
of the L2CuI catalyst (see Table 2, entries 3–6, 10–13). Using 1-octanol
as an example of aliphatic primary alcohols gave 75% yield and citro-
nellol gave 91% yield for the corresponding aldehyde (see Table 2, en-
tries 2, 7).
various diols. In general, diols are interesting substrates, due to their
corresponding heterocyclic oxidation products. Oxidation of aliphatic
primary diols with the use of a well-studied bipyridine-copper system
has been reported to proceed through a lactol-intermediate giving lac-
tones at a very high yield. [26] Similarly, a enzymatic pathway is re-
ported to be selective towards lactones. [27,28] Unexpectedly, our
copper(I)-thiophene carbaldimines system has a distinct selectivity.
We were able to obtain corresponding lactols as the main product rather
than the expected lactones (Table 3, entries 1 and 4).
To our surprise the quantitative oxidation of geraniol resulted in only
the E-isomer of citral (Table 2, entry 8). This was confirmed through 1H,
13C, HMBC and HSQC NMR measurements (see ESI). In addition, the
oxidation of (S)-(ꢀ )-perillyl alcohol gave a quantitative yield of the
corresponding aldehyde (Table 2, entry 9), without overoxidized side
products.
The lactol structure was confirmed with 1H, 13C, HMBC and HSQC
NMR of the reaction mixture (see ESI). Experiments with in situ IR
confirmed that the lactol forming cyclisation reaction was immediate,
since there is no aldehyde signal detectable while following the reaction
To broaden our substrate scope, we focused also on the oxidation of
3

E. Lagerspets et al.
Molecular Catalysis 509 (2021) 111637
Table 3
Aerobic oxidation of different primary diols.
over time (Fig 2B). The evolving signal of benzyl aldehyde in Fig 2A at
1704 cmꢀ 1 is a typical example of a oxidation reaction, where the re-
action proceeds quickly, aldehyde product accumulates and becomes
the dominant signal in the in situ IR spectra.
Conclusion
In conclusion we have developed a new highly efficient copper(I)
catalyst for the selective aerobic oxidation of aliphatic, allylic and
benzylic primary alcohols to their corresponding aldehydes in high
yields. Also, the system affords the selective oxidation of diols to pri-
marily lactols. The novelty of this system lies in the bench stability of the
new thiophene carbaldimine-copper(I)-iodide catalyst and in the lower
catalytic loading of the system combined with the high reactivity in
aerobic conditions. Due to its Schiff base character the ligand system is
easy to synthesize and modify. However, electron withdrawing substi-
tution at the para position of the aniline is deemed necessary for the high
reactivity with CuI. In general, this work together with our previous
work underlines the key role of the ligand for the further development of
novel copper(I) base catalysts for the aerobic oxidation of alcohols.
Further studies on CuI catalysts are ongoing.
When following the aerobic oxidation, the lack of aldehyde signal in
the in situ IR (Fig 2B) spectra is striking and explains why a lactol is
obtained as the main product instead of the lactone. Our copper(I)
system is selective towards the oxidation of primary alcohols to alde-
hydes and when the lactol forms in the cyclisation reaction, one of its
hydroxyl groups changes into secondary alcohol, which is not further
oxidized under these conditions even by longer reaction times (see ESI
Table S3). The catalytic approach for the aerobic oxidation of N-phe-
nyldiethanolamine to its lactol is a novel and straightforward synthesis
of a valuable morpholine derivate (4-phenylmorpholin-2-ol) (Table 3,
entry 4). [29,30] However, with 1,4-butandiol, the lactone is in the most
thermodynamically stable form and is observed in very high yields
(Table 3, entry 3). The oxidation of 2,6-pyridinedimethanol astonished
us, since we were able to selectively oxidize only one of the two primary
alcohols to aldehyde (Table 3, entry 2). The lactol structures were all
confirmed with 1H, 13C, HMBC and HSQC NMR (see ESI).
CRediT authorship contribution statement
Emi Lagerspets: Conceptualization, Data curtion, Investigation,
Writing – original draft, Writing – review & editing. Evelyn Valbonetti:
Fig 2. A) In situ IR spectra of the aerobic oxidation of benzyl alcohol with the L2CuI catalyst for 1 h. B) In situ IR spectra of the aerobic oxidation of 1,5-pentadiol with
the L2CuI catalyst for 4 h.
4

E. Lagerspets et al.
Molecular Catalysis 509 (2021) 111637
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Timo Repo: Conceptualization, Supervision, Writing – review & editing,
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T. Repo, Schiff base Cu(I) catalyst for aerobic oxidation of primary alcohols, Mol.
Catal. 468 (2019) 75–79, https://doi.org/10.1016/j.mcat.2019.02.003.
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