Aerobic oxidation at benzylic positions catalyzed by a simple Pd(OAc)2/bis-triazole system

Article abstract of DOI:10.1039/c5ra22251f

An efficient catalyst system for the Pd-catalyzed aerobic oxidation of benzylic positions has been developed. The combination of palladium(ii) acetate and 3,5-bis((1H-1,2,4-triazol-1-yl)methyl)benzoate ligand allows the selective oxidation at carbon adjacent to arene rings (primary and secondary benzylic alcohols, and other benzyl compounds) to provide the corresponding carbonyl and carboxy derivatives, employing molecular oxygen as oxidizing agent and a very low metal loading (10^-5 mol%).

Full text of DOI:10.1039/c5ra22251f

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Aerobic oxidation at benzylic positions catalyzed
by a simple Pd(OAc)2/bis-triazole system†
Cite this: RSC Adv., 2015, 5, 103210
*
Garazi Urgoitia, Ainhoa Maiztegi, Raul SanMartin, Marıa Teresa Herrero
´
*
and Esther Domınguez
´
An efficient catalyst system for the Pd-catalyzed aerobic oxidation of benzylic positions has been
developed. The combination of palladium(II) acetate and 3,5-bis((1H-1,2,4-triazol-1-yl)methyl)benzoate
ligand allows the selective oxidation at carbon adjacent to arene rings (primary and secondary benzylic
alcohols, and other benzyl compounds) to provide the corresponding carbonyl and carboxy derivatives,
employing molecular oxygen as oxidizing agent and a very low metal loading (10ꢀ5 mol%).
Received 23rd October 2015
Accepted 25th November 2015
DOI: 10.1039/c5ra22251f
www.rsc.org/advances
In this context, several years ago we developed palladium
CNC and NCN pincer complexes 1 and 2 (Fig. 1a) as efficient
palladium sources (10ꢀ2 mol% of [Pd]) for the aerobic oxidation
of secondary benzyl alcohols and benzylic methylene
compounds at atmospheric pressure in a sustainable reaction
medium such as PEG-400.4i
The excellent results provided by these palladium species
encouraged us to investigate whether a preformed palladium
complex was essential for the reaction, or more simple
catalytic systems could show a similar activity. Taking into
account the structure of mentioned palladacycles, we
considered the evaluation of simple azoles or azole-type
ligands.
Introduction
The selective oxidation of benzylic compounds is a trans-
formation of great interest since aryl ketones and arene-
carboxylic acids are not only ubiquitous substructures present
in natural products and pharmaceutically active compounds
but also versatile intermediates in the synthesis of agrochemi-
cals, medicines and other functional materials.1 Classical
approach to such compounds by oxidation of aryl carbinols is
a well established reaction performed by a wide range of
oxidizers.2
In this context, molecular oxygen has displaced most of the
existing oxidants as the reagent of choice, cheap and readily
available, and with water as the only by-product.3 Indeed, the
relevance of carbonyl and carboxy compounds has encouraged
research on this area, which ab initio encountered problems in
the absence of catalysts. An alternative to these potentially risky
procedures was the chain radical non-catalyzed oxidation, but
without metal catalysts lower yields and mixtures of oxidation
products are usually obtained.3f–h Therefore, a number of metal
catalysts (Cu, Pd, Ru, Fe, V, Zn, Ni, Ir, Rh, Au, Mn, Co, and Pt
inter alia) have been reported to promote such benzylic oxida-
tions.3–12 Among them, palladium catalysts stand out due to
their slightly higher efficiency.3,4 However, even in the latter
case, relatively high catalyst amounts are required (>0.01 mol%
of metal, usually 1–5 mol%) and, sometimes, oxygen pressures
above 5 atm.13
This investigation led us to nd a convenient, much more
efficient system for such oxidation reactions based on the use of
Over the last decades, the design and tailoring of ligands and
catalytic species has become a major strategy for improving the
efficiency and even the sustainability of chemical processes.
Department of Organic Chemistry II, Faculty of Science and Technology, University of
the Basque Country (UPV-EHU), 48940 Leioa, Spain. E-mail: raul.sanmartin@ehu.eus;
Fax: +34-946012748; Tel: +34-946015435
† Electronic supplementary information (ESI) available: Preparation and
characterization of the ligands, general procedures, NMR data and spectra. See
DOI: 10.1039/c5ra22251f
Fig. 1 (a) Palladium complexes employed in our previous works. (b)
Azole-type ligands utilized in this study.
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a commercial palladium source (Pd(OAc)2) and a readily avail- source or the N-heterocyclic ligand (entries 11–12),17 so both
able bis-(1,2,4)-triazolyl ligand.
species were needed to effect alcohol oxidation.
Once it had been proven that L6/Pd(OAc)2 was a valuable
catalyst system to carry out the aerobic oxidation of 1-phenyl-
ethanol, we decided to decrease the catalytic amount of both
ligand and palladium source. To our delight, it could be
decreased down to 10ꢀ4 mol% with no loss in the yield (Table 2,
entry 3). Lower catalyst loadings required longer reaction times
to achieve similar yields (entries 4–6). Therefore, although the
metal and ligand amounts could be decreased to 10ꢀ7 mol%, we
decided to employ a 10ꢀ5 mol% to get a proper balance between
reaction time and substrate/catalyst ratio (TON and TOF values
are displayed in Table 2).
Results and discussion
Considering our previous work,4i and the proven ability of pyr-
azoles, imidazoles and NHCs to form stable transition metal
complexes,14 L1, L2 and L4, L5 azole ligands15 were chosen for
the initial assays. L3 and L6 triazole derivatives were also
included due to their singular coordinative properties.16
Our investigation started with the oxygen-mediated oxida-
tion of 1-phenylethanol to acetophenone. Combinations of
commercially available Pd(OAc)2 and ligands L1–L6 were tested
in the presence of some bases and additives under 1 atm oxygen
pressure and in aqueous or polyol solvents (Table 1), as other
organic solvents (DMSO, Et2O, tBuOMe, THF, DMF, EtOAc, 1,2-
dichloroethane, 1,4-dioxane inter alia) provided negative
results.
Table 2 Minimization of the amounts of Pd(OAc)2 and L6
In no case was the target ketone detected when 1-butylimi-
dazole L1, pyrazole L2 or 1,2,4-1H-triazole L3 were used as
ligands. However, different results were achieved employing
bis-azolyl compounds L4–L6. 1-Phenylethanol oxidation took
place when an alkoxide or carboxylate base (KOtBu, NaOAc),
Pd(OAc)2 and bis-imidazolium salt L4 or bis-(pyrazolylmethyl)
arene L5 were used in polyol media (entries 4–5, 7–10), although
in moderate to low yields. Surprisingly, the bis-triazolyl deriv-
ative L6/Pd(OAc)2 system provided much better results (entries
4–10), and acetophenone was obtained in an excellent yield
(97%) when NaOAc and PEG-400 were employed as base and
reaction solvent respectively (entry 5). The use of additives such
as TBAB or pivalic acid did not have a positive effect. Interest-
ingly, no product was observed in the absence of the palladium
Entrya [Pd]/L6 mol% t (h) Yieldb (%) TON
TOF (hꢀ1
)
1
2
3
4
5
6
10ꢀ2
10ꢀ3
10ꢀ4
10ꢀ5
10ꢀ6
10ꢀ7
24
24
24
48
72
72
97
95
98
99
96
89
9.7 ꢂ 103 404
9.5 ꢂ 104 3958
9.8 ꢂ 105 40 832
9.9 ꢂ 106 206 250
9.6 ꢂ 107 1 333 333
8.9 ꢂ 108 12 361 111
a
1.0 mmol of substrate, NaOAc (0.1 eq.), PEG (1 mL mmolꢀ1), O2
(1 atm). b Isolated yield.
Table 1 Optimization studies for the oxidation of 1-phenylethanol
Ligandb (L) [%]
Entry
Reaction conditionsa
L1
L2
L3
L4
L5
L6
1
2
3
4
5
6
7
8
DMSO : H2O (1 : 1), 120 ꢁC, 24 h
NaHCO3, DMSO : H2O (1 : 1), 120 ꢁC, 24 h
NaOAc, H2O, 120 ꢁC, 24 h
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
25
40
—
35
20
19
15
—
—
—
—
—
30
60
—
30
10
15
10
—
—
—
—
—
80
97(97)
57
76
65
43
NaOAc, ETG, 120 ꢁC, 15 h
NaOAc, PEG 400, 120 ꢁC, 24 h
K2CO3, PEG 400, 120 ꢁC, 30 h
KOtBu, PEG 400, 120 ꢁC, 30 h
NaOAc, PEG 400, 120 ꢁC, 24 h, TBAB
NaOAc, PEG 400, 120 ꢁC, 15 h, pivalic acid
NaOAc, PEG 400 : H2O (1 : 1), 120 ꢁC, 48 h
NaOAc, PEG 400, 120 ꢁC, 48 h
9
10
11c
12d
50
—
—
NaOAc, PEG 400, 120 ꢁC, 48 h
a
1.0 mmol of substrate, 0.1 eq. of base, 1 mL of solvent per mmol of substrate, O2 (1 atm), 0.01 mol% of Pd(OAc)2 and 0.01 mol% of ligand were
employed. b Conversion rates measured by GS-MS. Isolated yields are shown in parentheses. 0.01 mol% of Pd(OAc)2 was employed without the
c
addition of ligand. d No palladium source. Only 0.01 mol% of ligand was employed.
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Table 3 Oxidation of secondary benzylic alcohols
The scope of the methodology was evaluated by submitting
a number of commercially available benzyl alcohols to the
optimized conditions.
As displayed in Table 3, aryl ketones were obtained in high
yields from secondary benzylic alcohols regardless of the
electronic nature of the substituents, with the only exception
of benzoyl cyanide (entry 4), which was obtained in Entrya
a moderate 54%.18 Longer reaction times (96 hours) were
Substrate
Product
Yieldb (%)
99
required in some cases, probably related to steric hindrance
(entries 3, 5, 6, 13). It should be pointed out that hydro-
benzoin provided the corresponding diketone (benzil) in
excellent yield (entry 15) and 1,2-diphenylethanol was selec-
tively oxidized to deoxybenzoin and no overoxidation prod-
ucts were observed (entry 16).
Our novel catalyst system could also be efficiently used in the 3c
aerobic oxidation of primary benzylic alcohols (Table 4).
Carboxylic acids were obtained in good yields from benzylic
1
2
91
98
54
86
88
alcohols bearing electron withdrawing, neutral or electron
donating groups although longer reaction times were required
in general to ensure complete conversion in this double
4
oxidative process.
5d
Delightedly, benzylic C–H oxidation also proceeded
smoothly under the same reaction conditions. (Table 5).
Moreover, complete conversion to the aryl ketone derivatives
6c
was observed in all cases and, in contrast with previous works
with molecular oxygen or even other oxidants (H2O2, TBHP,
MCPBA, NHPI)19 no partial oxidation by-products (benzyl alco-
hols) were detected.
7
85
It cannot be ignored that deoxybenzoin provided benzil in
almost quantitative yield (Table 5, entry 2) so, by means of the
optimized reaction conditions and just controlling the reaction
time deoxybenzoin (Table 3, entry 16) or benzil can be obtained
from 1,2-diphenylethanol.
Several experiments were performed to extract information
about the reaction mechanism and kinetics. A quasi-linear
kinetic plot (conversion rate vs. time) was found for the
aerobic oxidation of 1-phenylethanol in the presence of L6/
Pd(OAc)2 system. No induction time was observed, thus ques-
tioning the participation of heterogeneous catalysts (Fig. 2). The
results for poisoning assays reinforced the hypothesis of active
homogeneous catalytic species, since the addition of sub-
stoichiometric or overstoichiometric amounts of Hg, CS2, PPh3,
Py and PVPy had no inuence in the outcome of the reaction
(Table 6).20
No proof in support of the in situ formation of a palladium
pincer complex was achieved, and in fact, all our attempts to
synthesize such a complex from L6 and several palladium
sources resulted in unstable species even in solid state under
argon at low temperature. Several authors have explained
palladium-catalyzed aerobic oxidation of alcohols from mono-
and dicoordinated palladium complexes.21 We propose
a similar mechanism for the L6/Pd(OAc)2-catalyzed oxidative
process (Scheme 1).
8
9
84
97
10
94
11
12
13c
90
91
74
14
15
97
95
Thus, metal-alkoxide complex A is generated by a ligand
displacement with starting alcohols. b-Elimination generates
target carbonyl product and metal hydride B. The next step
involves the transfer of a hydrogen atom to a dioxygen species,
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Table 3 (Contd.)
Table 5 Catalytic oxidation of benzylic C–H bonds
Entrya
1
Substrate
Product
Yieldb (%)
95
Entrya
Substrate
Product
Yieldb (%)
94
16
2
97
97
a
1.0 mmol of substrate, 0.1 eq. of NaOAc, PEG (1 mL mmolꢀ1), O2 (1
atm), Pd(OAc)2 (10ꢀ5 mol%), L6 (10ꢀ5 mol%), 48 h. Isolated yields.
b
c
d
96 h. 72 h.
3c
4
97
Table 4 Oxidation of primary benzylic alcohols
5c
89
96
Entrya
1c
Substrate
Product
Yieldb (%)
83
6
a
1.0 mmol of substrate, 0.1 eq. of NaOAc, PEG (1 mL mmolꢀ1), O2
(1 atm), Pd(OAc)2 (10ꢀ5 mol%), L6 (10ꢀ5 mol%), 48 h. Isolated
b
yields. c 72 h.
2
94
3c
4
86
83
5
6
76
82
Fig. 2 Conversion rate (%) of 1-phenylethanol vs. time.
7d
91
h-peroxide complex D. Hydroperoxide E would be generated by
attack of acidic AcOH.22
a
1.0 mmol of substrate, NaOAc (0.1 eq.), PEG (1 mL mmolꢀ1), O2 (1
atm), Pd(OAc)2 (10ꢀ5 mol%), L6 (10ꢀ5 mol%), 72 h. Isolated yields.
b
c
d
48 h. 96 h.
Recently it has been suggested that the hydride complex B
may not decompose, but instead it might react directly with O2
to afford the hydroperoxide E without involving Pd(0) interme-
diates.23 Finally, ligand displacement by a molecule of starting
alcohol would regenerate key alkoxide complex A and release
hydrogen peroxide oxidizer, which could be also responsible for
the further oxidation of aldehydes to carboxylic acids.
a process that can occur by two different pathways. Reductive
elimination of acetic acid from B would provide metal(0) species
C, which upon reaction with molecular oxygen would provide
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absorptions are reported in cmꢀ1. Drying of organic extracts
during work-up of reactions was performed over anhydrous
Table 6 Poisoning experiments
¨
Na2SO4. Evaporation of solvents was accomplished with a Buchi
rotatory evaporator. MS and HR-MS were measured using
a Waters GCT mass spectrometer.
General procedure for the aerobic oxidation of alcohols in
the presence of Pd(OAc)2 and L6. A round bottom ask equip-
ped with a magnetic stirrer bar was charged with the alcohol (1
mmol), NaOAc (8.0 mg, 0.1 mmol), Pd(OAc)2 (20 mL of a 5 ꢂ
10ꢀ6 M solution in PEG-400, 10ꢀ7 mmol), L6 (20 mL of a 5 ꢂ
10ꢀ6 M solution in PEG-400, 10ꢀ7 mmol) and PEG 400 (1 mL) at
room temperature. The system was purged with molecular
oxygen, and an oxygen-lled balloon (1–1.2 atm) was connected.
Entrya
Poisoning additive
Yieldb (%)
1
2
3
4
5
6
7
8
Hg (1 drop)
CS2 (0.5 equiv.)
CS2 (2 equiv.)
PPh3 (0.03 equiv.)
PPh3 (0.3 equiv.)
PPh3 (4 equiv.)
Py (150 equiv.)
PVPy (150 equiv.)
95
93
94
96
95
93
94
93
ꢁ
The mixture was heated at 120 C under stirring until comple-
1
tion. The reaction outcome was monitored by H-NMR. Aer-
a
0 mmol of substrate, 0.1 eq. of NaOAc, PEG (1 mL mmolꢀ1), O2 (1 atm),
wards, the mixture was cooled to room temperature and water
was added (50 mL aprox.). The resulting solution was acidied
with HCl 1 M (pH z 1–2) and extracted with Et2O (4 ꢂ 6 mL),
and the combined organic layers were washed with brine, dried
over anhydrous Na2SO4 and evaporated in vacuo to give
a residue which was puried by ash column chromatography
using hexane:ethyl acetate as eluent.
Pd(OAc)2 (10ꢀ5 mol%), L6 (10ꢀ5 mol%), 48 h. Isolated yields.
b
General procedure for the aerobic oxidation of benzylic CH
bonds in the presence of Pd(OAc)2 and L6. A round bottom ask
equipped with a magnetic stirrer bar was charged with the
methylene compound (1 mmol), NaOAc (8.0 mg, 0.1 mmoꢀl)7,
Pd(OAc)2 (20 mL of a 5 ꢂ 10ꢀ6 M solution in PEG-400, 10
mmol), L6 (20 mL of a 5 ꢂ 10ꢀ6 M solution in PEG-400, 10ꢀ7
mmol) and PEG 400 (1 mL) at room temperature. The system
was purged with molecular oxygen, and an oxygen-lled balloon
ꢁ
(1–1.2 atm) was connected. The mixture was heated at 120 C
under stirring until completion. The reaction outcome was
1
monitored by H-NMR. Aerwards, the mixture was cooled to
room temperature and water was added (50 mL aprox.). The
resulting solution was acidied with HCl 1 M (pH z 1–2) and
extracted with Et2O (4 ꢂ 6 mL), and the combined organic layers
were washed with brine, dried over anhydrous Na2SO4 and
evaporated in vacuo to give a residue which was puried by ash
column chromatography using hexane:ethyl acetate as eluent.
Scheme
aerobic oxidation of alcohols.
1 Proposed mechanism for the Pd(OAc)2/L6-catalyzed
Experimental
Conclusions
Material and methods
In conclusion, we have presented an extremely active, more
convenient system for the oxidation of primary and secondary
benzylic alcohols based on the use of air stable and relatively
inexpensive palladium acetate and a readily available bis-(1,2,4)-
triazolyl ligand, a combination also suitable for the benzylic
C–H oxidation. A variety of alcohols and benzylic methylene
compounds are selectively oxidized under 1 atm oxygen pres-
sure at catalyst loadings as low as 10ꢀ5 mol%.
Commercially available reagents were used throughout without
purication unless otherwise stated. H and 13C NMR spectra
1
were recorded on a Bruker AC-300 instrument (300 MHz for 1H
and 75.4 MHz for 13C) at 20 ꢁC. Chemical shis (d) are given in
ppm downeld from Me4Si and are referenced as internal
standard to the residual solvent (unless indicated) CDCl3 (d ¼
1
7.26 for H and d ¼ 77.00 for 13C). Coupling constants, J, are
reported in hertz (Hz). Melting points were determined in
a capillary tube and are uncorrected. TLC was carried out on
SiO2 (silica gel 60 F254, Merck), and the spots were located with
UV light. Flash chromatography was carried out on SiO2 (silica
gel 60, Merck, 230–400 mesh ASTM). IR spectra were recorded
on a Perkin-Elmer 1600 FT and JASCO FTIR-4100 infrared
spectrophotometer as thin lms, and only noteworthy
Acknowledgements
This research was supported by the Basque Government (IT-
774-13 and S-PC13UN018), the Spanish Ministry of Economy
and Competitiveness (CTQ2010-20703) and the University of the
Basque Country (UFI QOSYC 11/12). G. U. thanks the University
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of the Basque Country (UPV/EHU) for a postdoctoral scholar-
ship. The authors also thank Petronor, S. A. for generous
donation of hexane. Finally, technical and human support
provided by SGIker is gratefully acknowledged.
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