An outstanding catalyst for the oxygen-mediated oxidation of arylcarbinols, arylmethylene and arylacetylene compounds

Article abstract of DOI:10.1039/c5cc00750j

A convenient and sustainable protocol for the aerobic oxidation of benzyl alcohols to carbonyl compounds, based on the use of 1,2,4-triazole-type ligands and nickel(ii) bromide, is described. This combination leads to the formation of an exceedingly active, enzyme-like system that allows for other oxidative processes, such as benzylic C-H oxidation and oxygen-mediated cleavage of C-C triple bond, a pioneering procedure for transformation of alkynes into carboxylic acids.

Full text of DOI:10.1039/c5cc00750j

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An outstanding catalyst for the oxygen-mediated
oxidation of arylcarbinols, arylmethylene and
arylacetylene compounds†
Cite this:DOI: 10.1039/c5cc00750j
Received 26th January 2015,
Accepted 10th February 2015
G. Urgoitia, R. SanMartin,* M. T. Herrero and E. Domınguez*
´
DOI: 10.1039/c5cc00750j
www.rsc.org/chemcomm
A convenient and sustainable protocol for the aerobic oxidation scavengers is also a common protocol in the food and pharma-
of benzyl alcohols to carbonyl compounds, based on the use of ceutical industries.9 A completely different strategy is to simply
1,2,4-triazole-type ligands and nickel(II) bromide, is described. decrease the catalyst loading to a point below regulatory
This combination leads to the formation of an exceedingly active, requirements, but this is particularly difficult for many transi-
enzyme-like system that allows for other oxidative processes, such tion metal catalysts, with very low levels (o10 ppm) permitted
as benzylic C–H oxidation and oxygen-mediated cleavage of C–C in drug products.9
triple bond, a pioneering procedure for transformation of alkynes
into carboxylic acids.
In an attempt to avoid the use of precious metals, in favour
of lighter, more convenient elements, and to decrease substan-
tially the amount of the catalyst so that the above regulatory
Molecular oxygen is an ideal oxidant (readily available, environ- requirements were fulfilled, we proposed and found that a
mentally benign, water as a byproduct, etc.) for most organic and suitable combination of a nickel(II) salt and a 1,2,4-triazole-
inorganic transformations. Therefore, in recent years, a number of type ligand could significantly improve the activity profile of the
metal catalysts for different oxygen-mediated oxidative processes nickel catalyst for the aerobic oxidation of alcohols.
have been developed. Taking alcohol oxidation to carbonyl com-
Although 1,2,4-triazole and simple N-alkyl-1,2,4-triazole derivatives
pounds as an illustrative example, the yields and selectivities of are relatively common ligands for nickel,10 their joint exploitation as
chain radical non-catalyzed autoxidation of alcohols and saturated catalysts for aerobic oxidative processes is limited to azirination of
hydrocarbons are often low,1 and therefore several metal catalysts alkenes with azides.11 In this communication we wish to demonstrate
(Ir, Cu, Pd, Zn, Ni, Ru, Rh, Fe, Au, Mn, Co, V, and Pt) have been that the exploration of the catalytic activity of a combination of
developed in this context.2–7 Catalyst loadings are generally in the 1,2,4-triazole ligands and Ni(II) salts (NiBr2) led us to find an
range of 0.5–10 mol% of [M], although significantly lower amounts outstanding catalytic system, not only for the aerobic oxidation
(0.1–0.3 mol%) have been reported in some cases.3,5 Regarding of alcohols but also for the oxidative cleavage of alkynes, an
reaction media, toluene and other flammable organic solvents unprecedented transformation mediated by molecular oxygen.
(dichloroethane, acetonitrile, THF, etc.) have been mainly
employed, with just a few examples of oxidations carried out chelating effects in the reaction outcome, two triazole ligands,
in more sustainable (e.g. aqueous) media.3b,7
simple 1,2,4-triazole 1 and pincer-type bis-triazolyl ligand 2 were
In order to analyze the influence of the coordination degree and
Removal of metal traces is a serious concern in the production of assayed. The synthesis of the latter was carried out by treatment of
fine chemicals. Heterogeneous catalysts or biphasic systems have the readily available methyl 3,5-bis(bromomethyl)benzoate12 with 1,
been employed so far to achieve an effective catalyst separation, as displayed in Scheme 1.
since relatively high amounts of the catalysts are required,8 and
On the basis of the encouraging results from the initial assays for
removing residual metals by relatively expensive metal the nickel-catalyzed oxidation of 1-phenylethanol,13 we decided to
use O2, NiBr2, 1 or 2, PEG-400, 120 1C and gradually decrease the
catalytic amount to 10À5 mol% of Ni and 1/2. Blank experiments
Department of Organic Chemistry II, Faculty of Science and Technology, University
of the Basque Country (UPV/EHU), Sarriena auzoa, z/g 48940 Leioa, Spain.
E-mail: raul.sanmartin@ehu.es
also showed the need for both nickel and triazole ligands, since
nickel bromide alone provided low yields (20%) at 0.01 mol%, and
no product was detected with lower amounts of the nickel halide.13
The optimized reaction conditions were accordingly applied to a
number of primary and secondary benzyl alcohols, providing good
to excellent results regardless of the nature of the starting carbinol.
† Electronic supplementary information (ESI) available: Full experimental
details, including a summary of the assays performed for the oxidation of
1-phenylethanol, the preparation of the bis-triazolyl ligand 2, the conversion rate
of phenylacetylene vs. time kinetic plot, a summary of poisoning experiments,
spectroscopic data and copies of NMR spectra. See DOI: 10.1039/c5cc00750j
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Table 1 Oxidation of alcohols to carbonyl and carboxy compounds.
General substrate scopea
Scheme 1 Synthesis of bis(triazolylmethyl) derivative 2.
As shown in Table 1, oxidation of primary alcohols provided
the corresponding carboxylic acids, with the exception of 3,4,5-
trimethoxybenzyl alcohol, which rendered the aldehyde. How-
ever, aside from cyclohexanol, other aliphatic, allylic and propargylic
alcohols such as octan-2-ol, (À)-menthol, 2-cyclohex-2-en-1-ol
and hex-2-yn-1-ol did not undergo the desired oxidation and
only dehydration by-products were detected along with the
unreacted material.
Subsequently, we assayed the same conditions in the benzylic
C–H bond oxidation of a series of methylene compounds, and
carbonyl compounds were obtained in good yields (Table 2).
However, the fact that three tetrahydroisoquinoline derivatives
(NH–, N-methyl- and N-Boc-1,2,3,4-tetrahydroisoquinoline) failed
to provide any oxidation product suggests that the presence of
benzylamine or benzylcarbamate moieties is not compatible
with our oxidation procedure. Nevertheless, it should be pointed
out that pyridine derivatives did not interfere with the outcome
of the reaction (e.g. oxidation of phenyl(pyridin-4-yl)methanol to
phenyl(pyridin-4-yl)methanone, as displayed in Table 2). It is
somewhat surprising that a competing ligand for nickel and
therefore potentially catalyst deactivating molecule such as
pyridine has little effect in the reaction outcome. In fact, when
we performed the oxidation of 1-phenylethanol to acetophenone
in the presence of 5 Â 10À3 mol% of pyridine a similar yield
(96%) was obtained.
Interestingly, high-yielding C–C oxidative cleavage was observed
from some benzyl alcohols such as mandelic acid and 1,2-diaryl-
ethane derivatives (benzoin, hydrobenzoin, and diphenylethanol),
as displayed in Table 3. Oxidative cleavage to benzoic acid was
also observed from deoxybenzoin and phenylacetic acid (Table 3).
In both carbinol and methylene oxidation reactions a slightly
better catalytic profile was found for the NiBr2–2 system, as better
yields were observed in all cases and 1,2-diphenylethanol did not
react with ligand 1.
We became interested in such uncommon cleavages undergone
by some alcohols and the latter methylene compounds (Table 3),
and especially by 3-phenylprop-2-yn-1-ol (Table 4), since it, unlike
the other cases, implied the splitting of a C–C triple bond.
a
Isolated yields. Reaction conditions: O2 (1 atm), NiBr2 (10À5 mol%), 1
or 2 (10À5 mol%), NaOAc, PEG-400, 120 1C, 48 h. Reaction time: 72 h.
b
c
Reaction time: 96 h.
need for further harmful chemicals or photochemical activa-
Traditionally, this latter transformation has been carried out by tion is highly desirable.
ozonolysis,14 and due to the risk associated with this procedure, new
To check if other alkynes could be oxidatively cleaved into
alternatives have been developed. In this context, photooxidative carboxylic acids, a set of structurally diverse terminal and internal
cleavage (O2/CBr4/hn),15 and the use of other oxidants (oxone, H2O2, alkynes were subjected to the same conditions. The results shown
tert-butyl hydroperoxide, I(III) reagents)16 alone or in the presence in Table 4 define the scope of this novel protocol, which has
of W, Ru, Os, Fe and In catalysts16,17 provide carboxylic acids been successfully applied to substrates bearing halogen (F, Br, Cl),
from alkynes.
alkyl, carboxy, keto and ester moieties. The reaction outcome was
Therefore, the development of a protocol based on the use of conditioned more by the ligand than in previous oxidative pro-
simple dioxygen as the most convenient oxidant without the cesses (alcohols and methylene compounds), as in several cases
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Table 2 Oxidation of aryl methylene compounds to ketonesa
Table 4 Oxidative cleavage of alkynesa
a
Isolated yields. Reaction conditions: O2 (1 atm), NiBr2 (10À5 mol%), 1
or 2 (10À5 mol%), NaOAc, PEG-400, 120 1C, 48 h. Benzoic acid was
also obtained (35% from 1 and 47% from 2). Benzophenone was also
b
c
isolated (30% from 1 and 20% from 2).
and medicinal purposes.18 The role of this solvent in the reported
oxidative process might be related to its unusual coordinating
properties, similar to those of crown ethers.19
The combination of the above properties, and those of 1,2,4-
triazoles 1–2, enhance nickel catalytic properties to an exceptional
catalytic profile (turnover number and frequency – TON and TOF –
values were found to be in the range of 9 700 000–4 700 000 and
202 083–97 916 respectively)20 that avoid the need for further
purification steps in order to remove metal traces. In fact, ICP-MS
analysis of p-bromobenzoic acid (obtained from p-bromo-
phenylacetylene) revealed a Ni content of 1.2 ppm, which is
below the concentration limit for oral and parenteral drugs
with a maximum daily dose of 10 g per day.9c
a
Isolated yields. Reaction conditions: O2 (1 atm), NiBr2 (10À5 mol%), 1
or 2 (10À5 mol%), NaOAc, PEG-400, 120 1C, 48 h. Reaction time: 72 h.
b
Table 3 Oxidative cleavage of alcohols and methylene compoundsa
Although the exact mechanism of nickel catalyzed oxidative
cleavage of alkynes is still being studied, the participation of nickel
nanoparticles or other heterogeneous catalysts can be dismissed.21 No
poisoning effect was observed when adding sub- and overstoichio-
metric (up to 300 equiv.) quantities of several poisons used in this
a
Isolated yields. Reaction conditions: O2 (1 atm), NiBr2 (10À5 mol%), 1
or 2 (10À5 mol%), NaOAc, PEG-400, 120 1C, 48 h. Reaction time: 72 h.
b
( p-bromophenylacetylene, diphenylacetylene, and 1-phenyl-1- context (Hg drop test, CS2, PPh3, pyridine, polyvinylpyridine).13 More-
propyne) simple triazole 1 resulted in being ineffective to aid over, a pseudolinear kinetic curve (conversion rate vs. time) was
the target metal-catalyzed cleavage.
plotted for the oxidative cleavage of phenylacetylene.13 Besides, the
The newly developed method proved to be suitable for large- addition of radical initiators as AIBN neither affected the reaction
scale processes, since benzoic acid was obtained in an excellent outcome nor enabled the process with lower NiBr2/1 amounts, and no
yield by reacting 1.5 grams of phenylacetylene, although at the difference was detected in the presence of radical inhibitors or radical
cost of longer reaction times (67% yield after 48 h, 96% after trapping agents (e.g. 3,5-dihydroxybenzoic acid), so that a chain radical
120 h). A similar assay was performed with phenylethanol autoxidation-like process could also be discarded.
(1.5 g) providing acetophenone with a 96% yield after 120 h.13
In summary, in addition to the advantages in terms of safety
In addition to the fact that oxygen mediates this transforma- and sustainability associated with the use of molecular oxygen
tion at atmospheric pressure, it should be also pointed that the at atmospheric pressure and PEG-400, the infinitesimal amounts
reaction is conducted in an environmentally friendly solvent, of the metal–ligand system allow isolation of ‘‘metal-free’’ com-
PEG-400, widely used as a very convenient media for chemical pounds for pharmaceutical uses. These features, close to those
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This research was supported by the Basque Government
(IT-774-13), the Spanish Ministry of Economy and Competitive-
ness (CTQ2013-46970-P) and the University of the Basque Country
(UFI QOSYC 11/12). G.U. thanks the University of the Basque
Country (UPV/EHU) for a predoctoral scholarship. The authors
also thank Petronor, S.A. for generous donation of hexane. Finally,
technical and human support provided by SGIker (UPV/EHU,
MICINN, GV/EJ, ESF) is gratefully acknowledged.
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