Rapid and selective catalytic oxidation of secondary alcohols at room temperature by using (N-Heterocyclic Carbene)-Ni0 systems

Article abstract of DOI:10.1002/chem.201000220

The selective, anaerobic catalytic oxidation of secondary alcohols at room temperature by using an in situ (N-heterocyclic carbene)-Ni⁰ system is presented. The use of non-anhydrous, non-degassed 2,4-dichlorotoluene as both the oxidant and the solvent allows for very short reaction times and very high yields. In addition, a well-defined (N-heterocyclic carbene)-Ni⁰ complex was synthesized and applied to these oxidation reactions.

Full text of DOI:10.1002/chem.201000220

FULL PAPER
DOI: 10.1002/chem.201000220
Rapid and Selective Catalytic Oxidation of Secondary Alcohols at Room
0
Temperature by Using (N-Heterocyclic Carbene)–Ni Systems
[
a]
[a]
[b]
[a]
Christophe Berini, Ole H. Winkelmann, Jennifer Otten, David A. Vicic, and
[
a]
Oscar Navarro*
Abstract: The selective, anaerobic catalytic oxidation of secondary alcohols at
0
room temperature by using an in situ (N-heterocyclic carbene)–Ni system is pre-
Keywords: alcohols
conditions nickel
heterocycles · oxidation
·
anaerobic
· nitrogen
sented. The use of non-anhydrous, non-degassed 2,4-dichlorotoluene as both the
oxidant and the solvent allows for very short reaction times and very high yields.
·
0
In addition, a well-defined (N-heterocyclic carbene)–Ni complex was synthesized
and applied to these oxidation reactions.
Introduction
In theory, the use of molecular oxygen or air as oxidant
for these reactions is ideal because of its availability, price
and ease of handling. In a practical sense and especially on
large scale, this approach is problematic due to the hazard
of oxygen pressures when running oxidations in flammable
In recent years, the transition-metal-catalyzed oxidation of
[1]
alcohols has attracted a great deal of interest. While this
very common transformation can be performed in stoichio-
metric proportions using traditional methods (Dess–Martin,
Jones, Swern, etc.), the use of efficient catalytic systems
allows for a reduction of waste and toxic reagents, as well as
[5b,8b]
organic solvents.
Herein, we describe the use of
[9]
(NHC)–Ni (NHC=N-heterocyclic carbene) catalytic sys-
tems for the selective oxidation of secondary alcohols at
room temperature under anaerobic conditions.
[
2]
less harsh conditions. Although many metals have been
used for this reaction, palladium is arguably the most stud-
[
1,2]
ied, especially in aerobic systems in which molecular
oxygen (or air) is used as oxidant. Seminal work by Swartz
Results and Discussion
[3]
and Blackburn in aerobic systems in the late 1970s provid-
ed the foundation for more recent and extensive develop-
Recently, our group disclosed the use of an (NHC)–Pd cata-
lytic system for the oxidation of secondary alcohols using
[4]
[5]
[6]
[7]
ments by Sigman, Stahl and Stoltz, among others, in
II
what has been called the renaissance of Pd -catalyzed oxida-
aryl chlorides as oxidants, at ambient temperature and
[1,8]
[10]
tion chemistry.
under anaerobic conditions.
The dehalogenation of the
aryl chloride leads to the formation of an unreactive by-
product that becomes part of the solvent. The use of an
NHC ligand allowed for a drastic reduction in reactions
times when compared with analogous phosphine-based sys-
+
[
a] Dr. C. Berini, Dr. O. H. Winkelmann, Prof. D. A. Vicic,
Prof. O. Navarro
[11]
tems. Moreover, we also reported on a novel and more in-
[12]
teresting system using much less expensive
the imidazolium salt IPr·HCl (IPr·HCl=1,3-bis-(2,6-diiso-
propylphenyl)imidazolium chloride) and [Ni(cod) ] to per-
form the same reaction, albeit requiring higher temperature
608C) and longer reaction times than the Pd system. In
mixtures of
Department of Chemistry, University of Hawaii at Manoa
545 McCarthy Mall, Honolulu, HI 96825 (USA)
2
Fax : (+1)808-956-5908
E-mail: oscarnf@hawaii.edu
ACHTUNGTRENNUNG
2
[
b] J. Otten
(
Visiting student: Carrol University, 100 N. East Ave.
Waukesha, WI 53186 (USA)
order to study this difference in behavior between our Pd
and Ni systems, we recently carried out experiments at
room temperature with the Ni system using the correspond-
ing free carbene instead of the imidazolium salt (Table 1).
Reaction times were drastically reduced and close to those
+
[
] To whom inquiries regarding the crystal structure of 3b should be ad-
dressed.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000220.
Chem. Eur. J. 2010, 16, 6857 – 6860
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6857

Table 1. Catalytic oxidation of secondary alcohols using [Ni
IPr carbene.
A
H
U
G
R
N
U
G
2
] and
drous, non-degassed 2,4-dichlorotoluene (2,4-DCT) for the
oxidation of 4-methoxy-a-methylbenzyl alcohol, using a
mixture of 5 mol% [Ni
ACHTUNGTNRENUNG( cod) ] and 5 mol% IPr·HCl as cata-
2
lyst precursor and 1.05 equivalents of KOtBu (Table 2).
[
a]
Entry Alcohol
Product
t [h] Yield [%]
Table 2.
ACHTUNGTRENNUNG( NHC)Ni-catalyzed oxidation of secondary alcohols in 2,4-DCT
at room temperature.
1
13
10
5
96
98
96
[
a]
Entry
Alcohol
Product
t [min]
Yield [%]
2
3
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
2a
2b
2c
2d
2e
2 f
2g
2h
90
15
30
15
15
90
15
15
92
97
96
90
98
84
95
99
[
[
[
b]
b]
b]
4
5
6
92
98
9
30
97
[
b]
[c]
14
10
15
88
[
[
b]
b]
6
7
12
11
58
74
[
b]
1
1
1
2
120
30
99
95
8
3
91
[
a] Isolated yields, average of two runs. [b] Catalyst loading was doubled.
1
3
90
96
of our (NHC)–Pd system, albeit still using 5 mol% catalyst
[13]
loading. These results indicate that the “high” tempera-
ture required in our earlier work was needed only to deprot-
onate the imidazolium salt to generate the corresponding
carbene ligand that coordinates to nickel, initiating the cata-
lytic cycle.
[
[
a] Isolated yields, average of two runs. [b] Catalyst loading was doubled.
c] Reaction was performed at 408C.
The ability of performing oxidations without the need of
a strong oxidant, at very mild temperature and without gen-
erating species potentially harmful to the substrate and/or of
difficult removal makes this catalytic system attractive not
only for multistep synthesis, but also for large scale reac-
tions. With this premise in mind, we turned our attention to
the use of an inexpensive chlorinated solvent for the reac-
tion that could play the roles of both oxidant and solvent.
Dichlorotoluenes, for example, are commonly used as high
boiling-point solvents in industry due to their price, stability
and ease of handling. We decided to use bulk non-anhy-
To our delight, the results surpassed our expectations and
the desired ketone was obtained in excellent yield after
15 min (Table 2, entry 1). When compared to our previous
set of conditions (dioxane as solvent and chlorobenzene as
oxidant), this reaction takes places two orders or magnitude
faster. Under these conditions, a variety of secondary alco-
hols were easily oxidized to the corresponding ketones in
high yields and in a matter of minutes. The substrates dis-
play varying degrees of bulk and include functionalities such
as ether (Table 2, entry 2), tertiary amine (Table 2, entries 4,
12) and alkene (Table 2, entry 11). Natural products such as
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Chem. Eur. J. 2010, 16, 6857 – 6860

Rapid and Selective Catalytic Oxidation
FULL PAPER
borneol, menthol and b-estradiol (Table 2, entries 8, 10 and
13, respectively) were also smoothly oxidized to the corre-
sponding ketones in excellent yields. It is worth mentioning
that, in agreement with the dioxane/chlorobenzene system,
primary benzylic and alkylic alcohols were unreactive under
these reaction conditions and cleanly and quantitatively re-
covered after work-up. The development of selective cata-
lytic systems that discriminate one specific class of alcohols
over another has been identified as one of the ultimate
[8b]
goals in alcohols oxidations.
Keeping in mind our desire to develop a user-friendly
system that could potentially be used in large-scale reac-
tions, our next goal was to circumvent the use of the very
sensitive and highly flammable [Ni ACTHUNGTERNN(UNG cod) ] in the reactions,
2
and therefore became interested in the use of a well-defined
NHC–Ni complex, ideally air-stable, instead of the previ-
2
Figure 1. Crystal structure of [(IPr)Ni ACTHUNGTRNEGNU( dmfu) ] (3b) with thermal ellip-
0
soids drawn at the 50% probability level. Hydrogen atoms are omitted
for clarity. Selected bond lengths [ꢁ]: Ni1ÀC1 1.9661(16), Ni1ÀC17
2.0240(12), Ni1ÀC18 1.9934(11), C17ÀC18 1.4057(17); selected bond
ously used in situ system. Cavell and co-workers recently re-
0
ported on the synthesis of a number of NHC–Ni complexes,
angles [8]: C1-Ni1-C17 98.55(3), C1-Ni1-C18 137.09(4), N1-C1-N1A
employing dimethyl fumarate (dmfu) and the NHC-ligand
1
02.91(12).
IMes (IMes=1,3-bis(2,4,6-trimethylphenyl)-imidazol-2-yli-
[14]
dene) in varying ratios.
[(IMes)Ni ACHTUNGERTUNNNG( dmfu) ] (3a) caught
2
our attention, representing an air-stable nickel(0) complex
that, however, had not been tested for its catalytic perfor-
mance in any reaction. Since we used the more bulky NHC-
ligand IPr throughout our previous examinations, we synthe-
sized the analogous complex [(IPr)Ni ACHTUNGTERNN(UGN dmfu) ] (3b) to ex-
2
plore its potential in the anaerobic oxidation of secondary
alcohols.
The synthesis of 3b was carried out in an analogous fash-
ion to that reported for 3a by simply mixing [Ni ACHTUNGRETNN(UNG cod) ] with
2
two equivalents of dmfu, followed by addition of the pre-
formed carbene (Scheme 1). Following this procedure
similar catalyst loading. Running the reaction at 408C led to
a more comparable reaction time (2.5 h), while at 608C the
reaction was completed in less than 1 h. A reduction of the
catalyst loading to 2.5 mol% resulted in a reaction time of
12 h at 408C. It is noteworthy that, although 3b may be han-
dled in air without any detectable decomposition and 2,4-
DCT can be used in reagent grade, the oxidation reactions
had to be conducted under an inert atmosphere. No product
formation was observed by gas chromatography when the
reactants were loaded in air.
[15]
Thus, we examined the anaerobic oxidation of a variety of
secondary alcohols employing 5 mol% of 3b in 2,4-dichloro-
toluene at 408C. Some representative results are depicted in
Table 3. High yields of the respective ketones were obtained
Table 3. Catalytic oxidation of secondary alcohols in 2,4-DCT using 3b.
2
Scheme 1. Synthesis of [(NHC)Ni CAHTUNGTRNEUN(G dmfu) ] complexes.
[
a]
Entry
Alcohol
Product
t [min]
Yield [%]
1
[
(IPr)Ni
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(dmfu) ] (3b) was isolated in 90% yield. H and
2
1
3
1
2
3
4
5
6
1a
1b
1c
1e
1g
1h
2a
2b
2c
2e
2g
2h
150
120
60
90
120
30
97
96
97
98
92
95
C NMR spectroscopic data of 3b were in good agreement
with those reported for 3a, with the carbene carbon atom
resonating at 189.5 ppm. The olefinic protons of the fuma-
3
[b]
rates resonate at d 4.72 and 4.07 ppm ( J=10.6 Hz), respec-
tively. Single-crystals suitable for X-ray diffraction were
grown by slow diffusion of hexanes into a solution of 3b in
THF. The crystal structure of 3b is depicted in Figure 1.
We evaluated the performance of 3b in the anaerobic oxi-
dation of 1-phenyl-1-propanol at different temperatures. Al-
though 3b allowed to perform this reaction at 258C, a con-
siderably longer time was needed for the reaction to reach
completion (12 h) when compared to the previously used
[
b]
7
8
90
69
[
b,c]
180
<5
[
a] Isolated yields, average of two runs. [b] Reaction performed at 608C.
1
IPr·HCl/[Ni
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(cod) ] catalytic system that requires 1.5 h using
[c] Estimated by H NMR of the recovered starting material.
2
Chem. Eur. J. 2010, 16, 6857 – 6860
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6859

O. Navarro et al.
from secondary aryl–alkyl and aryl–aryl alcohols (Table 3,
entries 1–4). Except for borneol, which was oxidized particu-
larly well (Table 3, entry 6), alkyl–alkyl substrates required
higher reaction temperature (608C) to reach completion in
comparable reaction times (Table 3, entries 5–7). As for the
in situ system, primary alcohols are not oxidized to the re-
spective aldehydes and also the use of 3b produced only
trace amounts of benzaldehyde from benzyl alcohol, being
the starting material recovered almost quantitatively after
work-up (Table 3, entry 8).
Acknowledgements
Financial support from the University of Hawaii at Manoa is gratefully
acknowledged.
[
[
1] a) M. J. Schultz, M. S. Sigman, Tetrahedron 2006, 62, 8227–8241;
b) J. Muzart, Tetrahedron 2003, 59, 5789–5816.
2] a) J.-E. Bꢂckvall, Modern Oxidation Methods, Wiley-VCH, Wein-
heim, 2004; b) G. Tojo, M. Fernꢃndez, Oxidation of Alcohols to Al-
dehydes and Ketones, Springer, Berlin, 2006; c) M. Hudlicky, Oxida-
tions in Organic Chemistry, ACS, Washington, 1990; d) R. A. Shel-
don, J. K. Kochi, Metal-catalyzed Oxidations of Organic Compounds,
Academic Press, New York, 1981.
Conclusion
In summary, we have presented highly active, anaerobic
(
NHC)–Ni catalytic systems for the selective oxidation of
[3] T. F. Blackburn, J. Schwartz, Chem. Commun. 1977, 157–158.
[
4] Some representative articles by this author: a) D. R. Jensen, M. J.
secondary alcohols at room temperature. These constitute,
to our knowledge, the first nickel-catalyzed reactions to ac-
complish this task under these mild conditions. The use of
non-anhydrous, non-degassed 2,4-DCT as both solvent and
oxidant allows for a drastic reduction of the reaction tem-
perature and time. Yields of products are comparable to
those of the most common state-of-the-art Pd-catalyzed
aerobic oxidations, although reaction times are significant-
ly shorter and using inexpensive nickel. In addition to this
activity, these NHC–Ni catalysts are very selective toward
secondary alcohols, and primary aliphatic and benzylic alco-
hols subjected to the same reaction conditions remain un-
changed even after prolonged exposure to reaction condi-
tions. The use of a new air-stable, well-defined (NHC)–Ni
complex as pre-catalyst avoids the use of flammable [Ni-
Schultz, J. A. Mueller, M. S. Sigman, Angew. Chem. 2003, 115, 3940–
3
943; Angew. Chem. Int. Ed. 2003, 42, 3810–3813; b) M. S. Sigman,
D. R. Jensen, Acc. Chem. Res. 2006, 39, 221–229.
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Fix, S. S. Stahl, J. Am. Chem. Soc. 2002, 124, 766–767; b) B. A.
Steinhoff, S. S. Stahl, J. Am. Chem. Soc. 2006, 128, 4348–4355.
[
6] Some representative articles by this author: a) D. C. Ebner, R. M.
Trend, C. Genet, M. J. McGrath, P. OꢄBrian, B. M. Stoltz, Angew.
Chem. 2008, 120, 6467–6470; Angew. Chem. Int. Ed. 2008, 47, 6367–
6370; b) J. T. Bagdanoff, B. M. Stoltz, Angew. Chem. 2004, 116, 357–
361; Angew. Chem. Int. Ed. 2004, 43, 353–357.
[16]
0
[
7] a) E. Gꢅmez-Bengoa, P. Noheda, A. M. Echavarren, Tetrahedron
Lett. 1994, 35, 7097–7098; b) T. Nishimura, T. Onoue, K. Ohe, S.
Uemura, Tetrahedron Lett. 1998, 39, 6011–6014; c) K. P. Peterson,
R. C. Larock, J. Org. Chem. 1998, 63, 3185–3189; d) R. A. Sheldon,
I. W. C. E. Arends, G.-J. ten Brink, A. Dijksman, Acc. Chem. Res.
0
2
002, 35, 774–781.
8] Some more key reviews: a) S. S. Stahl, Angew. Chem. 2004, 116,
480–3501; Angew. Chem. Int. Ed. 2004, 43, 3400–3420; b) K. M.
[
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(cod) ] in the oxidation reactions. Studies to expand the
2
3
scope of the reaction and applying it to enantioselective sys-
tems are currently ongoing in our laboratories.
Gligorich, M. S. Sigman, Angew. Chem. 2006, 118, 6764–6767;
Angew. Chem. Int. Ed. 2006, 45, 6612–6615; c) M. S. Sigman, M. J.
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[
9] N-Heterocyclic Carbenes in Synthesis (Ed.: S. P Nolan), Wiley-VCH,
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Experimental Section
[
10] C. Berini, D. F. Brayton, C. Mocka, O. Navarro, Org. Lett. 2009, 11,
244–4247.
4
General procedure for the catalytic oxidation of secondary alcohols: In
the glovebox, KOtBu (59 mg, 0.53 mmol) and either 3b (18 mg,
[11] X. Bei, A. Hagemeyer, A. Volpe, R. Saxton, H. Turner, A. S.
Guram, J. Org. Chem. 2004, 69, 8626–8633.
0
5
0
.025 mmol, 5 mol%) or bis(cyclooctadiene)nickel(0) (7 mg, 0.025 mmol,
mol%) and 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (11 mg,
.025 mmol, 5 mol%) were added to a vial equipped with a magnetic stir-
2 2
[12] PdCl : $5 mmol; NiCl : $0.05 mmol (Strem catalog 2008).
[13] See the Supporting Information for more examples.
[14] N. D. Clement, K. J. Cavell, L. Ooi, Organometallics 2006, 25, 4155–
4165.
bar. The vial was sealed with a screw cap fitted with a septum. Outside
the glovebox, 2,4-dichlorotoluene (1 mL) and the alcohol (0.50 mmol)
were added sequentially via syringe. The resulting mixture was allowed
to stir the corresponding temperature until completion or no further con-
version was observed by gas chromatography. The mixture was then puri-
fied by flash column chromatography on silica gel (hexane/ethyl acetate
mixtures) affording the corresponding product, whose identity and purity
1
[15] Samples of 3b showed no decomposition by H NMR after several
hours in open air.
[16] For a substrate-dependent comparison of Pd-catalyzed aerobic sys-
tems, see: M. J. Schultz, S. S. Hamilton, D. R. Jensen, M. S. Sigman,
J. Org. Chem. 2005, 70, 3343–3352.
Received: January 26, 2010
Published online: May 7, 2010
1
was confirmed by H NMR spectroscopy.
6860
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Chem. Eur. J. 2010, 16, 6857 – 6860