Copper-mediated selective oxidation of a C-H bond

Article abstract of DOI:10.1002/anie.200462946

(Chemical Equation Presented) An environmentally friendly procedure has been developed for the oxidation of 2,4,6-trimethylpheriol (TMP) at the para C_sp3-H bond. Upon reaction with H₂O₂ in the presence of catalytic amounts of Cu^II and neocuproine in methanol at 65°C, 4-(methoxymethyl)-2,6-dimethylphenol (MDP) or 4-hydroxy-3,5- dimethylbenzaldehyde (HDB) is formed (see reaction).

Full text of DOI:10.1002/anie.200462946

Angewandte
Chemie
C–H Activation
À
Copper-Mediated Selective Oxidation of a C H
Bond**
Christophe Boldron, Patrick Gamez, Duncan M. Tooke,
Anthony L. Spek, and Jan Reedijk*
Substituted hydroxybenzaldehydes are important feedstock
materials for the pharmaceutical and perfume industries.[1,2]
These compounds are commonly made by the selective
oxidation of aromatic methyl groups. However, this chemical
reaction is difficult and often proceeds to the carboxylic acid
derivative.
Thus,
4-hydroxy-3,5-dimethylbenzaldehyde
(HDB) is a valuable intermediate, especially for the prepa-
ration of drugs.[3–5] A number of synthetic routes to HDB
starting from 2,4,6-trimethylphenol (TMP) involving stoi-
chiometric amounts or an excess of oxidant are known.[6–10] So
far, the only catalytic oxidation of TMP to HDB was achieved
by Takehira and co-workers.[11–14]
Copper-containing enzymes, such as vanillyl alcohol
oxidase[15] or laccase[16] can selectively produce the aromatic
aldehyde functional group from a methyl group. We report
here a bioinspired Cuii/neocuproine system to perform the
selective para-formylation of mesitol [Eq. (1)]. The reaction
of TMP (1) with [CuCl2(neo)x] (neo = neocuproine = 2,9-
dimethylphenanthroline) and sodium methoxide as cocatalyst
in methanol at room temperature leads to the formation of 4-
(methoxymethyl)-2,6-dimethylphenol (2, MDP) and/or HDB
(3), depending on the experimental conditions (Table 1).
Without neocuproine no oxidation products were
observed (entry 1); neo is thus necessary for the reaction to
proceed, most likely to increase the oxidation potential of the
[*] Dr. C. Boldron, Dr. P. Gamez, Prof. Dr. J. Reedijk
Leiden Institute of Chemistry
Gorlaeus Laboratories
Leiden University
PO Box 9502, 2300 RA Leiden (The Netherlands)
Fax: (+31)71-527-4671
E-mail: reedijk@chem.leidenuniv.nl
Dr. D. M. Tooke, Prof. Dr. A. L. Spek
Department of Crystal and Structural Chemistry
Padualaan 8, 3584 CH University Utrecht (The Netherlands)
[**] Financial support from COSTAction (D21/003/2001) and the Dutch
National Research School Combination Catalysis (HRSMC and
NIOK) is thankfully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 3585 –3587
DOI: 10.1002/anie.200462946
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3585

Communications
Table 1: Results of the CuII/neocuproine-mediated oxidation of TMP (1) to MDP (2) and/or HDB (3)
the quinone methide leads to the forma-
tion of the para-methoxymethyl derivative
MDP. A second step (2eÀ oxidation/
MeOH) yields a ketal compound, which
according to Equation (1).[a]
Entry
Reactant [equiv]
Product distribution [mol%][b]
TMP
CuCl2
NaOMe
neo
TMP
MDP
HDB
1
has been detected by H NMR spectros-
1
2
3
4
5
6
1
4
2
1
0.5
1
1
2
2
2
2
2
2
0.14
0.14
2
2
2
2
0
4
4
4
4
2
100
71
49
–
–
18
–
–
–
–
–
20
copy in the crude mixture after evapora-
tion of the solvent. Hydrolysis during the
work-up affords HDB. The same result
was observed when argon was used in
place of air, suggesting that molecular
29
51
60
–
2
100[c]
–
1.5
0.3
0.3
82[d]
–
7[e]
8[e]
0.105
0.035
100[f]
9
À
oxygen is not involved in the C O bond
formation.
1
11
80[g]
[a] [Ox]=[CuCl2(neo)x] + NaOMe; see the Supporting Information for the experimental procedure.
[b] The yields (Æ5%) were determined by 1H NMR spectroscopy after a reaction time of 30 min. [c] No
products of over-oxidation could be detected; HDB was isolated in 85% yield. [d] Isolated in 69% yield.
[e] Optimized catalytic reactions performed at 658C under argon with H2O2. The yields (Æ5%) were
determined by 1H NMR spectroscopy using 1,2,4,5-tetrabromobenzene as an internal standard. [f] After
a reaction time of 6 h. [g] After a reaction time of 12 h.
To further study the reaction mecha-
nism and detect the proposed active spe-
cies, attempts were made to crystallize a
key intermediate. Reaction of a DMF/
MeOH (9:1) solution of sodium penta-
Cuii/Cui pair. The neo ligand is indeed a highly specific
bidentate ligand for Cui species, while its affinity towards Cuii
species is known to be low.[17,18] The bis-neocuproine copper(i)
complex [Cu(neo)2]+ is extremely stable due to the presence
of ortho-methyl groups, which strongly stabilize the tetrahe-
dral geometry of Cui ions, thereby preventing their reoxida-
tion to Cuii. The driving force of the reaction is thus the more
facile reduction of copper(ii) ions owing to the affinity of neo
for copper(i) species (see the Supporting Information). This is
confirmed when neo is replaced by the sterically far less
crowded 2,2’-bipyridine, as the resulting copper complex is
inactive.
The amount of TMP used in the reaction was then varied.
When 2 or 1 equiv of TMP per CuII/neo were used, total
conversion of the substrate could not be achieved (Table 1,
entries 2 and 3). The oxidation reactions exclusively led to the
Scheme 1. Proposed reaction mechanism for the stoichiometric forma-
tion of MDP (2) and HDB (3) from TMP (1). a) NaOMe (2 equiv),
CuCl2 (2 equiv), neo (4 equiv), MeOH; b) MeOH; c) 2eÀ oxidation:
NaOMe (2 equiv), CuCl2 (2 equiv), neo (4 equiv), MeOH; d) H2O.
formation of MDP in 29% and 51% yield, respectively. These
results are in accordance with the fact that the formation of
MDP is a two-electron process. If 0.5 equiv of TMP is allowed
to react with 1 equiv of CuII/neo, both MDP and HDB are
produced (entry 4). The quantitative formation of the benz-
aldehyde derivative HDB was achieved with a TMP/Cu ratio
of 0.25 (four-electron oxidation; entry 5). A series of experi-
ments was subsequently carried out to improve the selectivity
towards the methoxymethyl derivative. This study showed
that very good selectivities in MDP could only be reached
when moderate amounts of the basic cocatalyst were used
along with one equivalent of neo per copper ion. For instance,
the para-methoxymethyl compound could be produced in
82% yield in the presence of 0.75 equiv of NaOMe instead of
1 equiv (entry 6).
fluorophenoxide (1 equiv)—a phenolate that is inactive
towards oxidation—and neo (2 equiv) with CuCl2 (2 equiv),
NaOMe (1.2 equiv), and acetonitrile yields diamond-shaped
green crystals suitable for X-ray diffraction (see the Support-
ing Information). A PLATON[19] representation of the
molecular structure of this compound is depicted in
[20]
Figure 1. As previously postulated by several authors,
a
dinuclear copper(ii) species bridged by both a methoxide and
a pentafluorophenoxide is obtained. To the best of our
knowledge, this is the first crystallographic evidence of a self-
assembled, mixed m-methoxo-m-phenoxo-bridged dinuclear
copper complex with a mononucleating nonbridging ligand,
namely, neocuproine. This structure is in total agreement with
the proposed active species for the reaction described above.
The investigation was then focused on performing this
oxidation with catalytic amounts of the Cuii/neo complex.
This would provide an environmentally friendly and econom-
ically favorable system for industrial application. This mech-
Based on the active site found in enzymes containing the
type-3 copper site, a dinuclear copper species bridged by a
phenolate and a methoxide is proposed as the key intermedi-
ate of the reaction (Scheme 1). The para-benzylic proton is
activated through the coordination of the phenolate to the
metal ions. Deprotonated TMP reduces each Cuii to Cui. This
2eÀ transfer induces the polarization of the benzylic C H
À
bond, which results in a rearrangement of the aromatic ring to
a quinone methide. The nucleophilic addition of methanol to
3586
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2005, 44, 3585 –3587

Angewandte
Chemie
to the bis-alkoxo-bridged complex. The substrate scope for
this catalytic oxidation reaction is currently being investi-
gated.
Received: December 15, 2004
Revised: March 9, 2005
Published online: May 4, 2005
À
Keywords: biomimetic synthesis · C H activation · copper ·
homogeneous catalysis · oxidation
.
[1] F. Wang, G. Y. Yang, W. Zhang, W. H. Wu, J. Xu, Adv. Synth.
Catal. 2004, 346, 633.
[2] L. Weisse, R. Neunteufel, H. Strutz (Hoechst AG), US Patent
5,395,978, 1995.
[3] K. M. Youssef, M. A. El-Sherbeny, F. S. El-Shafie, H. A. Farag,
S. A. A. Awadalla, Arch. Pharm. 2004, 337, 42.
[4] K. D. Turnbull (University of Arkansas), US Patent 6,657,052
B1, 2003.
Figure 1. Molecular structure of [Cu2Cl2(neo)2(m-CH3O)(m-C6F5O)].
Selected bond lengths [ꢀ] and angles [8]: Cu1–O1 2.066(7), Cu1–O10
1.950(6), Cu1–Cl1 2.276(3), Cu1–N20 2.025(8), Cu1–N29 2.270(9),
Cu1–Cu2 3.137(8), Cu2–O1 1.947(6), Cu2–O10 1.966(7), Cu2–Cl2
2.265(3), Cu2–N40 2.043(8), Cu2–N49 2.256(8); Cu1-O1-Cu2 102.8(3),
Cu1-O10-Cu2 106.4(3). See also the Supporting Information.
[5] H. Luebbers, R. A. Neunteufel (Hoechst AG), German Patent
27 32 227, 1979.
[6] H. D. Becker, J. Org. Chem. 1965, 30, 982.
[7] W. E. Smith, J. Org. Chem. 1972, 37, 3972.
[8] S. L. Goldstein, E. McNelis, J. Org. Chem. 1984, 49, 1613.
[9] K. Omura, J. Org. Chem. 1984, 49, 3046.
[10] W. Baik, H. J. Lee, J. M. Jang, S. Koo, B. H. Kim, J. Org. Chem.
2000, 65, 108.
[11] K. Takehira, M. Shimizu, Y. Watanabe, H. Orita, T. Hayakawa,
Tetrahedron Lett. 1990, 31, 2607.
[12] M. Shimizu, Y. Watanabe, H. Orita, T. Hayakawa, K. Takehira,
Tetrahedron Lett. 1991, 32, 2053.
[13] M. Shimizu, Y. Watanabe, H. Orita, T. Hayakawa, K. Takehira,
Bull. Chem. Soc. Jpn. 1993, 66, 251.
[14] K. Takaki, Y. Shimasaki, T. Shishido, K. Takehira, Bull. Chem.
Soc. Jpn. 2002, 75, 311.
[15] R. H. H. van den Heuvel, M. W. Fraaije, M. Ferrer, A. Mattevi,
W. J. H. van Berkel, Proc. Natl. Acad. Sci. USA 2000, 97, 9455.
[16] C. Crestini, D. S. Argyropoulos, Bioorg. Med. Chem. 1998, 6,
2161.
[17] B. R. James, R. J. Williams, J. Chem. Soc. 1961, 2007.
[18] G. F. Smith, W. H. Mccurdy, Anal. Chem. 1952, 24, 371.
[19] A. L. Spek, J. Appl. Crystallogr. 2003, 36, 7.
[20] J. Gao, S. H. Zhong, R. A. Zingaro, J. Mol. Catal. A: Chem. 2004,
207, 15.
anism would imply the reoxidation of the Cui species, which a
priori seems to be unlikely due to the very high stability of the
[Cu(neo)2]+ cation. For this purpose, only 1 equiv of neo was
used per Cuii ion, as we anticipated a more facile reoxidation
of the resulting Cui complex [Cu(neo)]+. The first logical
procedure was to perform the catalytic reaction in air, or in
pure dioxygen, and heat the reaction mixture to promote the
Cui oxidation. Only one catalytic cycle can be completed
under these experimental conditions, suggesting that molec-
ular oxygen is not strong enough to achieve the Cui
reoxidation. To overcome this difficulty, hydrogen peroxide,
an activated form of dioxygen, was successfully used as
oxidant, and the experimental conditions were optimized.
Thus, 0.14 equiv of [CuCl2(neo)], in the presence of 2 equiv of
H2O2 and 0.3 equiv of NaOMe as basic cocatalyst, could
catalyze the quantitative formylation of 1 equiv of TMP after
6 h (Table 1, entry 7). The selective oxidation was performed
under argon and refluxing methanol. The controlled produc-
tion of MDP could be carried out using a smaller amount of
neo (0.035 equiv instead of 0.105 equiv; entries 7 and 8). Most
likely, the presence of less ligand leads to the formation of
different active species, allowing the isolation of the inter-
mediate product 2. No effective catalytic method for prepar-
ing MDP has yet been reported. Therefore, the synthetic
procedure described here is the first effective catalytic
preparation of MDP.
In conclusion, a new environmentally friendly, high-
yielding procedure has been developed for the para Csp3-H
oxidation of TMP. This compound can be selectively oxidized
to form either MDP or HDB, two valuable industrial
compounds. A key reaction intermediate, a self-assembled
m-methoxo-m-phenoxo-bridged dinuclear copper complex
involving a mononucleating ligand, was isolated and structur-
ally characterized. This dicopper complex suggests the
participation of bimetallic active species in the catalytic
cycle as well as the nucleophilic attack of a methanolate anion
Angew. Chem. Int. Ed. 2005, 44, 3585 –3587
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3587