Efficient, copper-catalyzed, aerobic oxidation of primary alcohols

Article abstract of DOI:10.1002/anie.200353458

An additive is the key to success: Catalytic amounts of N-methylimidazole are crucial for the aerobic oxidation of primary aliphatic alcohols in the presence of CuCl, 1,10-phenanthroline (phen), and di-tert-butyl azodicarboxylate (DBAD). This reaction, under neutral conditions, yields the aldehydes quantitatively and selectively without overoxidation to the carboxylic acids.

Full text of DOI:10.1002/anie.200353458

Communications
Oxidation with Air
Efficient, Copper-Catalyzed, Aerobic Oxidation
of Primary Alcohols**
Istvµn E. Markó,* Arnaud Gautier, Raphal Dumeunier,
Kanae Doda, Freddi Philippart, Stephen M. Brown, and
Christopher J. Urch
Scheme 1. Copper-catalyzed aerobic oxidation of alcohols.
influence of the a-nitrogen substituent, or to a combination of
both. To test the importance of steric hindrance, the aerobic
oxidation of cyclohexanylmethanol (9) and adamantylmetha-
nol (11) was carried out. Much to our surprise, oxidation of 9
afforded 10 in 70% conversion (entry 4) and transformation
of 11 to 12 proceeded with 80% conversion (entry 5). Clearly,
increased substitution at the a-position favors the oxidation
of primary aliphatic alcohols, though the conversions are still
not optimum.
The oxidation of alcohols into aldehydes and ketones is of
paramount importance in organic chemistry and numerous
reagents have been reported to accomplish this transforma-
tion efficiently and selectively.[1] However, most of these
oxidants are either toxic, hazardous, or required in large
excess. From an economical and environmental viewpoint,
catalytic oxidations are particularly interesting,[2] and major
efforts have been devoted over the last few years to the
discovery and development of efficient procedures employing
O2 (or air) or hydrogen peroxide as the ultimate stoichio-
metric oxidant.[3] These attractive catalytic systems utilize
cheap and readily available reactants, display high atom
economy[4] and release only innocuous by-products such as
H2O.[5] Whilst a large variety of ruthenium complexes have
been shown to catalyze this reaction, either on their own[6] or
with the assistance of various co-catalysts,[7] only a limited
number of other metals, such as cobalt[8] and palladium,[9]
have been successfully employed so far. In most cases,
however, the range of substrates tolerated in these aerobic
oxidations is limited to certain classes of alcohols.[10]
Sometime ago, we reported that the inexpensive and
readily available CuCl/phen/DBAD complex (DBAD = di-
tert-butyl azodicarboxylate, phen = 1,10-phenanthroline) was
a competent catalyst for the aerobic oxidation of a wide range
of alcohols 1 to give carbonyl compounds 2 (Scheme 1).[11]
Subsequent optimization of our initial catalytic system led to
an improved and highly efficient protocol for the oxidation of
primary allylic and benzylic as well as secondary aliphatic,
allylic, and benzylic alcohols under neutral conditions.[12]
Unfortunately, and despite extensive efforts, primary ali-
phatic alcohols remained elusive recalcitrant substrates.
In this communication we report that the addition of a
simple and inexpensive additive provides a modified catalyst
that quantitatively oxidizes a large variety of primary alcohols
to the corresponding aldehydes. To the best of our knowledge,
the Yamaguchi–Mizuno heterogeneous ruthenium system[9h]
and our CuCl/phen/DBAD complex are thus far the only
systems for the aerobic oxidation of all classes of alcohols.
Closer examination of the oxidation of several primary
aliphatic alcohols revealed intriguing features (Table 1).
Whilst poor conversion of 1-decanol (3) to decanal (4) was
achieved (Table 1, entry 1), dibenzyl leucinol (5) and N-Boc-
prolinol (7) were quantitatively transformed into the corre-
sponding aldehydes (entries 2 and 3). No racemization is
observed with these enantiomerically pure substrates. The
enhanced reactivity of 5 and 7 could be due either to an
increased steric effect at the a-carbon center, to an electronic
In order to improve this transformation, selected additives
were tested in the aerobic oxidation of 1-decanol (3). The high
affinity of heterocyclic amines for copper salts, coupled with
Table 1: Copper-catalyzed aerobic oxidation of selected primary alcohols.
Entry
1
Substrate
Product
Conv. [%]
60
Yield [%][a]
51
2
100
84
3
4
5
100
70
97
64
77
80
[a] Yield of isolated, pure product.
their ubiquitous presence as ligands in biologically active
copper-containing proteins,[13] prompted us to investigate
them initially. Some selected results are collected in Table 2.
As can be seen, the conversion of 1-decanol (3) to the desired
aldehyde 4 proceeded poorly in the absence of additive
(Table 2, entry 1). In the presence of 5 mol% DMAP (4-N,N-
dimethylaminopyridine), a significant increase in the trans-
formation of 3 to 4 was observed (entry 2) and complete
conversion was eventually reached using 10 mol% DMAP
(entry 3). Interestingly, only 7 mol% NMI (N-methylimida-
zole) was required to transform 3 completely into 4 (entry 4).
These conditions were next applied to the aerobic
oxidation of a variety of primary alcohols. A selection of
pertinent examples is displayed in Table 3. All the primary
alcohols employed were quantitatively converted into the
corresponding aldehydes with 100% selectivity. It is note-
worthy that no trace of carboxylic acid was observed under
these aerobic conditions.[14] The reaction tolerates both simple
aliphatic primary alcohols (Table 3, entry 1) and more
hindered derivatives (entries 2 and 3) as well as various
protecting groups (entries 4 and 8). Simple alkenes are
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DOI: 10.1002/anie.200353458
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Angewandte
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Table 3: The copper-catalyzed aerobic oxidation of primary alcohols with
NMI as an additive.[a]
unaffected (entry 5), and base-sensitive substrates are
smoothly oxidized (entry 6). It is interesting to note that
under these neutral conditions, highly acid-sensitive sub-
strates are also quantitatively converted into the correspond-
Entry
1
Substrate
Product
Yield [%][a]
95
Table 2: Influence of additives on the aerobic oxidation of 1-decanol (3).
2
93
3
4
5
95
94
94
Entry
Additive
–
Amount [mol%]
Conv. [%][a]
60
1
2
–
DMAP
DMAP
NMI
5
10
7
80
100
1
3
4
00
[a] The conversions were measured by capillary gas chromatography with
an internal standard.
6
7
83
82
ing aldehydes (entry 7). Finally, a serious impediment in all
the other reported aerobic oxidation protocols is their
inability to oxidize alcohols possessing a chelating function,
a nitrogen atom or a sulfur substituent. Such is not the case for
the copper catalyst which transforms the strongly coordinat-
ing substrate 21 quantitatively into the aldehyde 22 (entry 8)
and tolerates both heteroatoms (entries 9 and 10).
8
9
97
93
The remarkable effect of DMAP and NMI on the ability
of the copper catalyst to oxidize efficiently a wide range of
primary alcohols is surprising, and the origin of this effect was
investigated, initially with the mechanistically simpler anae-
robic system. In the absence of oxygen and NMI, 1-decanol
was smoothly and quantitatively oxidized to decanal. Addi-
tion of 7 mol% NMI did not improve the conversion, nor the
rate of the reaction; rather, NMI had a slightly retarding
effect.[15]
In order to reconcile these observations with the pre-
viously established catalytic cycle for the aerobic oxidation of
alcohols using the CuCl/phen/DBAD system, a new catalytic
manifold has to be operative in the presence of NMI. The
productive catalytic cycle begins with the ternary loaded
complex A (Scheme 2). Intramolecular hydrogen transfer
from the alkoxo ligand to the azo ligand generates copper(i)
hydrazide B. Subsequent release of the aldehyde produces
complex C, which is rapidly captured by oxygen, affording
CuII hydrazide derivative D. Reorganization of D under the
thermal conditions of the reaction leads to the hydroxocop-
per(i) species E. Finally, ligand exchange and elimination of
water regenerates the active, loaded complex A, and a new
catalytic cycle ensues.
10
95
[a] Reaction conditions: entry 4, Table 2. [b] All yields are for pure,
isolated products.
In the case of secondary alcohols, competitive coordina-
tion to C of the OH function or of dioxygen, largely favors the
latter and the bis(copper) peroxide D is formed. However,
when primary aliphatic alcohols are employed, coordination
of the less hindered OH group now becomes competitive. The
formation of inactive complex G gradually depletes the
catalytic cycle in the active oxidizing species, and the reaction
grinds to a halt. This mechanistic proposal also explains the
observed increased conversions when more hindered ali-
phatic primary alcohols are employed.
The role of NMI and DMAP would thus be to bind rapidly
and reversibly to copper complex C, generating intermediate
H. Such coordination would preclude the competitive addi-
tion of the alcohol and suppress the undesired formation of
the inert derivative G.[19,20]
In summary, we have shown that the use of the simple and
inexpensive additive NMI strongly modified the course of the
copper-catalyzed aerobic oxidation of primary aliphatic
alcohols. Under these novel conditions, a wide range of
primary substrates could be transformed efficiently into the
corresponding aldehydes with no trace of overoxidized
carboxylic acids. Moreover, the neutral conditions employed
are compatible with base- and acid-sensitive substrates.
Furthermore, these results have shed some light on an
unsuspected decomposition pathway, the inhibition of which
held the key to a highly successful aerobic oxidation
Amongst the various active species in this system,
complex C, bearing an empty coordination site, appears to
be the most likely candidate to suffer a competitive deacti-
vation by the primary alcohols.[16] Indeed, whilst C usually
reacts rapidly with oxygen, it can occasionally undergo
competitive coordination to an alcohol, producing the
copper derivative F that might undergo hydrogen transfer
and loss of the hydrazine substituent, resulting in the inactive
complex G.[17,18]
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Communications
Scheme 2. Proposed mechanism for the copper-catalyzed aerobic oxidation of alcohols.
[3] a) R. A. Sheldon in Dioxygen Activation and Homogeneous
procedure for primary alcohols. To the best of our knowledge,
the Yamaguchi–Mizuno heterogeneous ruthenium system
and our copper-catalyzed aerobic protocol are thus far the
only catalytic procedures that are able to oxidize, with equal
efficiency, substrates from all classes of alcohols.
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Experimental Procedure
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[5] For an excellent review, see: P. T. Anastas, M. M. Kirchhoff, Acc.
Chem. Res. 2002, 35, 686, and references therein.
Aerobic oxidation of 3: First 1,10-phenanthroline (180 mg, 1 mmol,
5 mol%) and then solid CuCl (100 mg, 1 mmol, 5 mol%) were added
to 200 mL anhydrous FC6H5. After the suspension had been stirred
for 5 min at room temperature, 3 (3.16 g, 20 mmol) was added
followed by solid KOtBu (112 mg, 1 mmol, 5 mol%). The resulting
yellowish solution was stirred at room temperature for 10 min before
NMI (120 mg, 1.4 mmol, 7 mol%) and DBAD (230 mg, 1 mmol,
5 mol%) were added. The reaction mixture was heated at reflux
under a gentle stream of O2 for 100 min. After the reaction mixture
was cooled to 208C, celigel (4 g, 80/20 w/w mixture of celite and silica
gel) was added and stirring was continued for 2 min. The solid residue
was removed by filtration and washed with 200 mL ether. Evapo-
ration of the solvents in vacuo afforded pure 4 as a colorless liquid
(2.95 g, 95%).
[6] a) K. Masutani, T. Uchida, R. Irie, T. Katsuki, Tetrahedron Lett.
2000, 41, 5119; b) M. Lee, S. Chang, Tetrahedron Lett. 2000, 41,
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Received: December 4, 2003 [Z53458]
Keywords: aerobic oxidation · alcohols · aldehydes ·
.
molecular oxygen · oxidation
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[10] See for example, refs. [7a, 7d, 9a,9e, and 9f].
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[14] The overoxidation of the aldehyde into the corresponding
carboxylic acid has never been observed with this aerobic
oxidation protocol. Whilst no proper explanation can be
provided at this stage, it is possible that the copper catalyst
protects the aldehyde towards further reaction with dioxygen. A
similar observation has been reported by Sheldon et al.[7a]
[15] Whilst quantitative conversion of 3 into 4 occurred in the
absence and presence of 7 mol% NMI, the oxidation of 3
proceeded more slowly in the presence of this additive (87%
conversion after 30 min in the absence of NMI and 75%
conversion after 30 min in the presence of NMI). The coordi-
nation of NMI to copper results in a slower exchange with the
excess DBAD and hence, in a longer reaction time.
[16] Studies performed on the anaerobic version of this catalytic
system revealed that aliphatic primary alcohols were oxidized
with the same efficiency as all the other classes of alcohols, thus
ruling out complexes A, B, and E as the culprit for the
decomposition pathway. Whilst we could not experimentally
rule out complex D, coordination of an alcohol to D should
involve the participation of a pentacoordinated copper species.
Whilst these are not uncommon, their formation requires a
higher activation energy than the coordination to C.
[17] This hydrogen transfer is essentially an intramolecular acid–base
reaction. The hydrogen on the coordinated alcohol function is
acidified by coordination to the copper centre whilst the
hydrazine ligand has basic properties. The elimination of the
hydrazine substituent is irreversible under these neutral con-
ditions. Indeed, in the absence of excess base, DBADH2 is
unable to displace the alkoxo ligand from the copper complex G.
[18] We have previously demonstrated[11a] that G was not a com-
petent catalyst in the aerobic oxidation protocol when R = alkyl.
Under anaerobic conditions, that is, in the presence of 1 equiv
DBAD, G can efficiently regenerate the loaded ternary complex
A and smooth oxidation ensues.
[19] I. E. Markꢀ, M. Tsukazaki, P. R. Giles, S. M. Brown, C. J. Urch,
Angew. Chem. 1997, 109, 2297; Angew. Chem. Int. Ed. Engl.
1997, 36, 2208.
[20] In full accord with this mechanistic rationale, the use of NMI and
other heterocyclic nitrogen derivatives allows the preferential
kinetic oxidation of primary aliphatic alcohols over secondary
ones. Whilst the selectivities are not yet perfect, initial experi-
ments have shown that the nature of the additive strongly affects
the selectivity of this oxidation.
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