Vanadium-Catalyzed Oxidative Debenzylation of O-Benzyl Ethers at ppm Level

Article abstract of DOI:10.1002/adsc.201600593

An advantageous methodology for the oxidative debenzylation of ethers has been developed. Very low amounts of a catalyst system based on vanadyl acetylacetonate and a triazole type pincer ligand allow the selective oxidative cleavage of a number of O-benzyl ethers in the presence of oxygen as the sole oxidant. The methodology tolerates a number of functional groups such as halo-, alkoxy-, or trifluoromethylarenes, alkyne, alkene, ether, and acetal units. Large-scale deprotections can be also carried out by the optimized procedure, which is amenable to enantioenriched reactants as well. (Figure presented.).

Full text of DOI:10.1002/adsc.201600593

UPDATES
DOI: 10.1002/adsc.201600593
Vanadium-Catalyzed Oxidative Debenzylation of O-Benzyl
Ethers at ppm Level
Garazi Urgoitia,a Raul SanMartin,a,* Marꢀa Teresa Herrero,a
and Esther Domꢀngueza,*
a
Department of Organic Chemistry II, Faculty of Science and Technology, University of the Basque Country (UPV/EHU),
Sarriena auzoa z/g, 48940 Leioa, Spain
Fax : (+34)-94-601-2748; Phone: (+34)-94-601-5435; e-mail: raul.sanmartin@ehu.eus or esther.dominguez@ehu.eus
Received: June 6, 2016; Revised: August 4, 2016; Published online: && &&, 0000
Dedicated to Prof. Timothy C. Gallagher on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600593.
Abstract: An advantageous methodology for the
oxidative debenzylation of ethers has been devel-
oped. Very low amounts of a catalyst system based
on vanadyl acetylacetonate and a triazole type
pincer ligand allow the selective oxidative cleavage
of a number of O-benzyl ethers in the presence of
oxygen as the sole oxidant. The methodology toler-
ates a number of functional groups such as halo-,
alkoxy-, or trifluoromethylarenes, alkyne, alkene,
ether, and acetal units. Large-scale deprotections
can be also carried out by the optimized procedure,
which is amenable to enantioenriched reactants as
well.
tional groups (alkenyl and alkynyl derivatives, carbon-
yls and halo compounds, some alkoxy groups, inter
alia). Among the alternatives to the above proce-
dures,[8] oxidative cleavage is an advantageous strat-
egy to carry out debenzylation in multifunctional sub-
strates, although limitations regarding the type of sub-
strates that can be deprotected have appeared even
by this method.[9]
Oxygen is clearly a sustainable and therefore ad-
vantageous option. However, in spite of the increasing
number of metal-catalyzed aerobic oxidative process-
es reported in the last years,[10] the molecular oxygen-
mediated oxidative cleavage of ethers has been
scarcely explored to date.[9h]
Our research has shown that low amounts of palla-
dium complexes and palladium- or nickel-ligand sys-
tems can promote the oxidation of arylcarbinols and
arylmethylene compounds, arylacetylenes and styrene
derivatives.[11] Following this research line, we wish to
present a general and selective method for the vana-
Keywords: debenzylation; nitrogen ligands; oxida-
tion; oxygen; vanadium
In the last years, process efficiency has become a prior- dium-catalyzed aerobic O-debenzylation of ethers.
ity for organic chemistry. Even so, many structurally To begin our investigation, benzyl pentyl ether 1a
complex organic products have to be prepared by was heated in an oxygen atmosphere for 24–96 h
multistep pathways and, therefore, protection/depro- along with a transition metal source (0.01 mol%). A
tection sequences of functional groups are often un- wide number of bases, ligands and solvents were as-
avoidable.[1] In these cases, the suitability, selectivity sayed in a preliminary set of experiments, and cleav-
as well as the environmental and economical aspects age products were observed in detectable yields only
of the protection process are crucial in order to opti- when NaOAc and the readily available bis-triazolyl
mize the synthetic route.
ligand L were present in the mixture. These results
The benzyl group is commonly used to mask alco- led us to further explore the reaction conditions. As
hol functionalities in numerous syntheses due to the shown in Table 1, the reaction outcome was highly in-
easy preparation and high stability of benzyl ethers fluenced by the metal species and reaction media (en-
towards a number of reaction conditions.[2] Cleavage tries 1–11). Although no reaction happened when
is most often achieved reductively,[3–5] by transition iron(II) bromide was employed (entries 2 and 7),
metal-catalyzed hydrogenolysis,[3] or by use of Lewis[6] cleavage of the substrate was observed when
or Brønsted acids.[7] However, they are not compati- cobalt(II) chloride, nickel(II) bromide or vanadyl
ble with several labile or reduction susceptible func- acetylACTHNUTRGNEaNUG cetonate were used in dioxane or PEG 400
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Table 1. Screening of reaction conditions for the aerobic oxidative debenzylation of benzyl pentyl ether 1a.[a]
Entry
M (mol%)
L (mol%)
Solvent
Temp. [8C]
Time [h]
2a [%][b]
3a [%][b])
[c]
1
2
3
4
5
6
7
8
FeBr2 (0.01 mol%)
CoCl2 (0.01 mol%)
NiBr2 (0.01 mol%)
VO(acac)2 (0.01 mol%)
CoCl2 (0.01 mol%)
FeBr2 (0.01 mol%)
CoCl2 (0.01 mol%)
NiBr2 (0.01 mol%)
VO(acac)2 (0.01 mol%)
NiBr2 (0.01 mol%)
VO(acac)2 (0.01 mol%)
NiBr2 (0.01 mol%)
0.01 mol%
0.01 mol%
0.01 mol%
0.01 mol%
0.01 mol%
0.01 mol%
0.01 mol%
0.01 mol%
0.01 mol%
0.01 mol%
0.01 mol%
–
dioxane
dioxane
dioxane
dioxane
DMA
PEG 400
PEG 400
PEG 400
PEG 400
THF
1308C
1308C
1208C
1208C
1208C
1208C
1208C
1208C
1208C
1208C
1208C
1208C
1208C
1208C
1208C
1208C
1208C
1008C
1208C
1208C
1208C
1208C
1208C
96 h
96 h
96 h
96 h
96 h
96 h
96 h
96 h
96 h
96 h
96 h
96 h
96 h
48 h
48 h
48 h
48 h
48 h
24 h
48 h
24 h
48 h
48 h
–
–
–
40
48
–
–
–
72
83
<5
–
20
53
50
[c]
–
[c]
–
40
73
87
<5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
[c]
H2O
–
[c]
PEG 400
PEG 400
PEG 400
PEG 400
PEG 1500
glycerol
PEG 400
PEG 400
PEG 400
PEG 400
PEG 400
PEG 400
–
–
VO(acac)2 (0.01 mol%)
VO(acac)2 (0.01 mol%)
VO(acac)2 (0.01 mol%)
VO(acac)2 (0.01 mol%)
VO(acac)2 (0.01 mol%)
VO(acac)2 (0.01 mol%)
VO(acac)2 (0.01 mol%)
VO(acac)2 (10ꢀ5 mol%)
VO(acac)2 (10ꢀ5 mol%)
–
–
65
81
66
80
–
–
–
0.01 mol%
–
[c]
–
[c]
0.01 mol%
0.01 mol%
0.01 mol%
0.01 mol%
10ꢀ5 mol%
10ꢀ5 mol%
10ꢀ5 mol%
–
–
70
[c]
–
–
67
81
53
62
80
49
–
[c]
–
[c]
VO(acac)2 (10ꢀ5 mol%)
–
–
[a]
Reaction conditions: [(pentyloxy)methyl]benzene (1 mmol), Na(OAc) (0.1 mmol), O2 (1 atm), solvent (1 mLmmolꢀ1 of
substrate).
Isolated yield.
Starting material was recovered.
[b]
[c]
(entries 2–4 and 7–9). Whereas cobalt(II) chloride 3a could be also obtained by using 0.01 mol% of
provided 1-pentanol only in moderate yields (entries 5 VO(acac)2 in the absence of bis-triazolyl derivative L,
and 6) better results were achieved from nickel(II) but with a lower yield (Table 1, entry 9 vs. 13). Inter-
bromide and vanadyl acetylacetonate in PEG-400 estingly, the use of ligand L proved to be crucial when
(entries 8 and 9).
shorter reactions times or lower catalytic loadings
Using the best catalyst system so far, that is, were used (entries 14 vs. 15 and 20 vs. 23). Likewise,
VO(acac)2/L, we optimized the reaction time, temper- blank experiments demonstrated that VO(acac)2 was
ature and catalyst loading. Reducing the reaction essential for the oxidative process (entry 22). Other
time by half only caused a slight decrease in reaction vanadium sources (V2O5, VCl3) were evaluated and
yield (entry 9 vs. 14). The drop in the yield was great- found to be ineffective for the target transformation
er when shorter reaction times were used (entry 19).
The optimized reaction conditions (Table 1,
It was necessary to carry out the reaction at 1208C entry 20) were then successfully applied to a number
since only starting material was recovered when the of benzyl ethers. As shown in Table 2, the oxidative
reaction mixture was heated at 1008C (entry 18).
rupture of alkyl benzyl ethers provided selectively
Cleavage to benzoic acid was also observed in glyc- benzoic acid and the corresponding alcohol regardless
erol, but we were unable to isolate n-pentanol proba- of the electronic nature of the alkyl radical and the
bly due the high affinity between both aliphatic alco- steric hindrance present in the substrate. Moreover,
hols. With regard to the activity of the catalyst the cleavage occurred with total retention of configu-
system, we were delighted to observe that comparable ration at stereogenic centers, even when bearing the
yields were obtained when only 10ꢀ5 mol% of benzyloxy moiety. This fact was confirmed by compar-
VO(acac)2/L were used (entry 14 vs. 20). 1-Pentanol ison of the optical rotation of (1R,2S,5R)-(ꢀ)-menthol
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Table 2. Substrate scope for the oxidative cleavage of benzyl
Table 3. Oxidation of other benzyl-based protecting
alkyl ethers.[a]
groups.[a]
[a]
Reaction
conditions:
1
(1 mmol),
VO(acac)2
(10ꢀ5 mol%), L (10ꢀ5 mol%), Na(OAc) (0.1 mmol), O2
(1 atm), PEG (1 mLmmolꢀ1), 1208C, 48 h.
Isolated yield.
[b]
benzyl (PMB), m-methoxybenzyl (MMB), and 2-
naphthylmethyl (NAP) ethers of 1-pentanol were ef-
fectively cleaved to provide the latter carbinol and
the corresponding arenecarboxylic acids. Slightly
better yields were obtained for the cleavage from sub-
strates bearing non-substituted (Bn) or electron-do-
nating groups (PFB, PMB, NAP) (Table 1, entry 1 and
Table 3, entries 1, 3, 5, 6 vs. Table 3, entries 2 and 4).
A clear effect of electronic or steric factors on the
reaction rates was not found, although the presence
of alkoxy groups provoked a decrease in the rate of
[a]
[b]
Reaction conditions: 1 (1 mmol), VO(acac)2 (10ꢀ5 mol%),
L (10ꢀ5 mol%), Na(OAc) (0.1 mmol), O2 (1 atm), PEG
(1 mLmmolꢀ1), 1208C, 48 h.
Isolated yield.
3g and (1S,2R,4S)-(ꢀ)-borneol 3h performed before the reaction (e.g., full conversion was achieved for
the etherification and after the clean debenzylation ethers 1a or 1l after 36 h under the optimized reaction
step.[12] On account of the excellent results so far, we conditions, but 48 h were required for substrates 1m
attempted to broaden the scope of the procedure to or 1n).
other benzyl-based protecting groups.
Interestingly, only the cleavage product resulting
As displayed in Table 3, the p-methylbenzyl, p-fluo- from the selective oxidation of the O-benzylic posi-
ꢀ
robenzyl (PFB), p-trifluoromethylbenzyl, p-methoxy- tion was observed when other unsaturated C C
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bonds were present in the starting material (Table 4, benzodioxole 1r provided both carboxylic acid 2a and
entries 7–9). No other type of oxidation products piperonyl alcohol 3j (entry 3).
were detected, and the high selectivity for the O-ben-
zylic position was evidenced by the cleavage of benzyl the methylenedioxy group, following the aforemen-
phenethyl ether 1s (Table 4, entry 4). tioned trend of alkoxylated substrates, slows down the
It can therefore be proposed that the presence of
Benzoic acid derivatives were exclusively obtained oxidation of the benzylic position next to the benzo-
from symmetrical dibenzyl ethers 1p and 1q (Table 4, dioxolane. This fact opens new possibilities for the de-
entries 1 and 2). However, the aerobic debenzylation benzylation of benzyl alcohol derivatives.
of non-symmetric 5-[(phenylmethoxy)methyl]-1,3-
Phenol 3l was also obtained from (benzyloxy)ben-
zene (entry 5), and other alkoxylated or phenoxylated
substrates underwent reaction most effectively under
the optimized conditions (1i and 1u, Table 2, entry 9
and Table 4, entry 6 respectively).
It should be pointed out the simple catalyst–prod-
uct separation was achieved by extraction from the
polyethylene glycol solution. As expected, both cleav-
age products could be easily separated by acid-base
extraction strategies. This aqueous protocol for the
separation of oxidation products prevented recovery
of the PEG reaction medium. Alternatively, the latter
solvent could be recovered by extraction of the crude
with ethyl acetate and then reused.
Table 4. Oxidative rupture of symmetric and labile groups-
containing benzyl ethers.[a]
Moreover, O-debenzylation could be performed at
a larger scale. Treatment of 1.5 g of ether 1a provided
benzoic acid 2a and alcohol 3a in 80% and 77% yield,
respectively.[12]
Finally, there are no conclusive results regarding
the reaction pathway. The conversion rate vs. time ki-
netic plot for the debenzylation of ether 1a clearly
shows an induction time which could suggest the par-
ticipation of heterogeneous catalysts.[12] However, the
results for poisoning assays support the hypothesis of
active homogeneous catalytic species, since the addi-
tion of substoichiometric or overstoichiometric
amounts of Hg, CS2, PPh3, Py and PVPy had no influ-
ence in the outcome of the reaction.[12] A partial deg-
radation of polyethylene glycol under thermal aerobic
conditions is expected to occur,[13] thus forming small
amounts of formate groups at the end of the polymer
chains that would account for hydride transfer pro-
cesses and hydroperoxide formation by oxygen inser-
tion.[11d,14]
In conclusion, a general, efficient procedure for the
oxidative debenzylation of ethers has been developed.
The methodology is clearly advantageous since infini-
tesimal amounts of the vanadium-based catalyst
system and molecular oxygen as the only oxidant at
atmospheric pressure are needed. A number of func-
tionalities usually affected by other debenzylation
procedures are tolerated by our method, thus featur-
ing an excellent selectivity for the oxidation at the O-
benzylic carbon over other labile positions. Chirality
is preserved under the reaction conditions, which are
also suitable for the aerobic deprotection of other
benzyl-based protecting groups (PMB, MMB, PFB,
and NAP inter alia). Gram-scale reactions can be
easily performed, and the use of the polyethylene
[a]
Reaction conditions: 1 (1 mmol), VO(acac)2 (10ꢀ5 mol%),
L (10ꢀ5 mol%), Na(OAc) (0.1 mmol), O2 (1 atm), PEG
(1 mLmmolꢀ1), 1208C, 48 h.
Isolated yield.
Reaction time: 96 h.
[b]
[c]
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ness (CTQ2013-46970-P) and the University of the Basque
Country (UFI QOSYC 11/12). G.U thanks the University of
the Basque Country for a postdoctoral scholarship. Finally,
technical and human support provided by SGIker of UPV/
EHU is gratefully acknowledged.
glycol 400 as solvent facilitates catalyst–product sepa-
ration.
Experimental Section
General Information
References
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and are referenced as internal standard to the residual sol-
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General Procedure for the Aerobic Cleavage of
Benzyl Ethers in the Presence of VO(acac)2 and
Methyl 3,5-Bis[(1H-1,2,4-triazol-1-yl)methyl]benzoate
L
A round-bottom flask equipped with a magnetic stirrer bar
was charged with ether
1 (1 mmol), NaOAc (8.0 mg,
0.1 mmol), VO(acac)2 (20 mL of a 5ꢃ10ꢀ6 M solution in
PEG-400, 10ꢀ7 mmol), L (20 mL of a 5ꢃ10ꢀ6 M solution in
PEG-400, 10ꢀ7 mmol) and PEG 400 (1 mL) at room temper-
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an oxygen-filled balloon (1–1.2 atm) was connected. The
mixture was heated at 1208C under stirring for 48 h. The re-
1
action outcome was monitored by H NMR. Upon comple-
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These are not the final page numbers!

UPDATES
Vanadium-Catalyzed Oxidative Debenzylation of O-Benzyl
7
Ethers at ppm Level
Adv. Synth. Catal. 2016, 358, 1 – 7
Garazi Urgoitia, Raul SanMartin,* Marꢀa Teresa Herrero,
Esther Domꢀnguez*
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!