Environmentally friendly and highly efficient Co(OAc)2-catalyzed aerobic oxidation to access 2,6-di-electron-donating group substituted 4-hydroxybenzaldehydes

Article abstract of DOI:10.1080/00397911.2013.813052

A highly efficient and green aerobic oxidation has been developed for selectively preparing a series of valuable 2,6-dialkyl-, dialkoxyl-, and alkoxylalkyl-substituted 4-hydroxybenzaldehydes from corresponding 4-cresols in good to excellent yields, using a catalytic system of Co(OAc)₂4H₂O (1.0 mol%)-NaOH (1.0 equiv)-O₂(1.0 atm) in aqueous ethylene glycol (EG/H₂O = 20/1, v/v) at 50 °C. Furthermore, a plausible mechanism was proposed for the direct oxyfunctionalization of the aromatic methyl group into the aldehyde group.

Full text of DOI:10.1080/00397911.2013.813052

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Environmentally Friendly and Highly
Efficient Co(OAc)2-Catalyzed Aerobic
Oxidation to Access 2,6-Di-Electron-
Donating Group Substituted 4-
Hydroxybenzaldehydes
Jian-An Jiang a , Jia-Lei Du a , Zhong-Nan Zhang a , Jiao-Jiao Zhai a &
Ya-Fei Ji a
a School of Pharmacy, East China University of Science and
Technology , Shanghai , China
Accepted author version posted online: 18 Mar 2014.Published
online: 29 Apr 2014.
To cite this article: Jian-An Jiang , Jia-Lei Du , Zhong-Nan Zhang , Jiao-Jiao Zhai & Ya-Fei Ji (2014)
Environmentally Friendly and Highly Efficient Co(OAc)2-Catalyzed Aerobic Oxidation to Access 2,6-
Di-Electron-Donating Group Substituted 4-Hydroxybenzaldehydes, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:10, 1430-1440,
DOI: 10.1080/00397911.2013.813052
To link to this article: http://dx.doi.org/10.1080/00397911.2013.813052
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Synthetic Communications1, 44: 1430–1440, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.813052
ENVIRONMENTALLY FRIENDLY AND HIGHLY
EFFICIENT Co(OAc)2-CATALYZED AEROBIC
OXIDATION TO ACCESS 2,6-DI-ELECTRON-DONATING
GROUP SUBSTITUTED 4-HYDROXYBENZALDEHYDES
Jian-An Jiang, Jia-Lei Du, Zhong-Nan Zhang, Jiao-Jiao Zhai,
and Ya-Fei Ji
School of Pharmacy, East China University of Science and Technology,
Shanghai, China
GRAPHICAL ABSTRACT
Abstract A highly efficient and green aerobic oxidation has been developed for selectively
preparing a series of valuable 2,6-dialkyl-, dialkoxyl-, and alkoxylalkyl-substituted
4-hydroxybenzaldehydes from corresponding 4-cresols in good to excellent yields, using a
catalytic system of Co(OAc)2 ꢀ 4H2O (1.0 mol%)–NaOH (1.0 equiv)–O2 (1.0 atm) in
aqueous ethylene glycol (EG/H2O ¼ 20/1, v/v) at 50 ꢁC. Furthermore, a plausible
mechanism was proposed for the direct oxyfunctionalization of the aromatic methyl group
into the aldehyde group.
Keywords Aerobic oxidation; Co(OAc)2; ethylene glycol; 4-hydroxybenzaldehydes;
oxyfunctionalization
INTRODUCTION
Versatile 4-hydroxybenzaldehydes have been incredibly important organic
materials for pharmaceutical, perfume, dye, and agrochemical industries, as well as
for fundamental research.[1] For example, 3,5-dimethyl-4-hydroxybenzaldehyde is a
significant intermediate for the synthesis of potential cancer chemopreventive
agents,[2] nonnucleoside reverse transcriptase inhibitors,[3] and other bioactive com-
pounds.[4] More notably, commercially famous syringaldehyde (3,5-dimethoxy-4-
hydroxybenzaldehyde), widely used for the synthesis of the classical antibacterial
Received April 18, 2013.
Address correspondence to Ya-Fei Ji, School of Pharmacy, East China University of Science and
Technology, Campus P. O. Box 363, 130 Meilong Road, Shanghai 200237, China. E-mail: jyf@ecust.edu.cn
1430

Co(OAc)2-CATALYZED AEROBIC OXIDATION
1431
agent Trimethoprim,[5] the antiepileptic drug N-isopropyl-3,4,5-trimethoxycinna-
mide,[6] and many bioactive molecules,[7] was produced on a scale of thousands of
tons annually to meet worldwide demands.[8]
Although some strategies, including Reimer–Tiemann reaction,[9] glyoxylic
acid method,[10] stoichiometric oxidation by oxidants[11] and electric=electrocatalytic
oxidation,[12] have been massively employed for preparing valuable 4-hydroxyben-
zaldehydes, tedious separation and serious pollution did hinder their widespread
application. In this respect, the straightforward catalytic oxidation of the seemingly
inert methyl group of 4-cresols into the fascinating aldehyde group becomes the most
appealing synthetic approach.[13,14] In past decades, notable achievements in
transition-metal-catalyzed oxidation of 2,4,6-trimethylphenol have granted this
direct transformation the limelight.[13] As noted, most of the developed catalyst
systems for this aerobic oxidation were based on coordination complexes of
transition metals, such as cobalt(II)–Schiff base complex,[13a] copper(II)–amine
complex,[13b–d] and copper(II)–neocuproine sodium methoxide complex.[13g,h] While
effective, needs of ligand=additive and greater oxygen pressure have brought
noticeable disadvantages and limitations in view of cost, waste, and safety issues.
However, more desired ligand-free catalytic systems have long remained out of reach
for the oxidation of 2,4,6-trimethylphenol and its analogs. It was only in 2004 that Li
and coworkers reported the first efficient ligand-free, iron-based catalyst, tackling
this interesting task with pressured molecular oxygen.[13e,f] Another ligand-free
stoichiometric copper-mediated oxidation by hydrogen peroxide was reported in
2008.[13i] Not surprisingly, the development of more green catalytic oxidation
has proven to be imperative for sustainable production of the significant
4-hydroxybenzaldehydes.
Herein, we report a highly efficient Co(OAc)2 ꢀ 4H2O (1.0 mol%)–NaOH (1.0
equiv)–O2 (1.0 atm) catalytic system that effects aerobic oxidation of 2,6-di-electron-
donating group substituted 4-cresols in aqueous ethylene glycol (EG, EG=H2O ¼ 20=
1, v=v, Scheme 1). The reactions proceeded in good yields at atmospheric pressure
without any ligand=additive and achieved highly chemoselective and regioselective
C(sp3)-H oxyfunctionalization, giving valuable 4-hydroxybenzaldehydes without
overoxidation to carboxylic acids[14c–e] or quinines.[15] Beyond doubt, it is one of
the most important goals in oxidation chemistry to utilize molecular oxygen in an
atom-economic and environmentally friendly transformation with water as the only
by-product.[16] In addition, general high-boiling-point nonflammable EG can reliably
avoid safety issue associated with low-boiling-point organic solvents.[17]
Scheme 1. Co(OAc)2-catalyzed selectively aerobic oxidation of 2,6-disubstituted 4-cresols into valuable
4-hydroxybenzaldehydes.

1432
J.-A. JIANG ET AL.
RESULTS AND DISCUSSION
To identify an efficient catalyst system that meets the criteria of green chemistry,
we initially investigated various easily available and less toxic cobalt sources with
sodium hydroxide (1.0 equiv) and molecular oxygen (1.0 atm). At first, the influence
of different cobalt catalysts on the model oxidation of 2,4,6-trimethylphenol (1a) was
evaluated in methanol at a mild reaction temperature of 50 ꢁC. We discovered that
halogenated cobalt salts CoCl2, CoBr2, and CoF2 showed some activity toward the
oxidation, giving desired product 3,5-dimethyl-4-hydroxybenzaldehyde (2a) in poor
yields (Table 1, entries 1–3). Then, the slightly improved result was observed by
Table 1. Optimization of the reaction conditions for the aerobic oxidation of 1a into 2aa
Entry
Co source (n1mol%)
CoCl2(5.0)
CoBr2(5.0)
NaOH (n2equiv)
Solvent
Yield (%)b
1
2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.8
0.5
1.5
1.0
1.0
1.0
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
n-PrOH
i-PrOH
EG
26
31
24
45
71
Trace
Trace
13
54
69
65
63
85
0
3
CoF2(5.0)
4
Cobalt(II)acetylacetonate (5.0)
Co(OAc)2 ꢀ 4H2O (5.0)
Co3O4(5.0)
5
6
7
nano-Co3O4(5.0)
CoTMPP (5.0)
8
9c
10
11
12
13
14
15
16
17
18d
19
20
21
22e
23f
24g
Co(OAc)2 ꢀ 4H2O (5.0)
Co(OAc)2 ꢀ 4H2O (5.0)
Co(OAc)2 ꢀ 4H2O (5.0)
Co(OAc)2 ꢀ 4H2O (5.0)
Co(OAc)2 ꢀ 4H2O (5.0)
Co(OAc)2 ꢀ 4H2O (5.0)
Co(OAc)2 ꢀ 4H2O (5.0)
Co(OAc)2 ꢀ 4H2O (5.0)
Co(OAc)2 ꢀ 4H2O (1.0)
Co(OAc)2 ꢀ 4H2O (0.5)
Co(OAc)2 ꢀ 4H2O (1.0)
Co(OAc)2 ꢀ 4H2O (1.0)
Co(OAc)2 ꢀ 4H2O (1.0)
Co(OAc)2 ꢀ 4H2O (1.0)
Co(OAc)2 ꢀ 4H2O (1.0)
Co(OAc)2 ꢀ 4H2O (1.0)
THF
CH3CN
CH2Cl2
EG
0
0
85
74
68
45
85
86
88
55
EG
EG
EG
EG
EG=H2O
EG/H2O
EG=H2O
aReaction conditions: substrate 1a (5.0 mmol), cobalt source (n1 mol%), sodium hydroxide (n2 equiv),
and solvent (5.0 mL), O2 (1.0 atm), 50 ꢁC for 18 h.
bIsolated yield.
cReaction performed at 40 ꢁC.
dReaction time of 24 h.
eReaction time of 16 h, EG=H2O ¼ 5.0 mL=0.1 mL.
fReaction time of 12 h, EG=H2O ¼ 5.0 mL=0.25 mL.
gReaction time of 6 h, EG=H2O ¼ 5.0 mL=0.75 mL.

Co(OAc)2-CATALYZED AEROBIC OXIDATION
1433
applying cobalt(II) acetylacetonate (entry 4). To our delight, the oxidation could
give 2a with a promising yield of 71% in the presence of Co(OAc)2 ꢀ 4H2O (entry
5). However, further screening showed that Co3O4, nano-Co3O4, and CoTMPP
[5,10,15,20-tetra(4-methoxyphenyl)-21H,23H-porphine cobalt(II)] almost were inac-
tive for the transformation (entries 6–8). While lowering the reaction temperature
to 40 ꢁC, the reaction provided 2a in unsatisfactory 54% yield (entry 9). Hence, with
effective Co(OAc)2 ꢀ 4H2O, other reaction parameters would be further optimized
at 50 ꢁC.
While examining solvents, alcohols were found to be generally effective (entries
10–13), and more polar EG is the best choice to provide the dramatically increased
yield of 85% (entry 13). On the other hand, the reactions failed to oxidize 1a into
2a in aprotic solvents, clearly proving the indispensable mediation of alcohols to
the oxidation (entries 14–16). More pleasingly, variation of catalyst loading indicated
that 1.0 mol% Co(OAc)2 ꢀ 4H2O also efficiently catalyzed the oxidation (entry 17),
whereas applying 0.5 mol% Co(OAc)2 ꢀ 4H2O brought about 2a in visibly lowered
yield, albeit prolonging reaction time to 24 h (entry 18). As surveyed, a decreased
amount of sodium hydroxide led to sharply lowered yields (entries 19 and 20), but
more sodium hydroxide did not give better outcome (entry 21). Evidently, 1.0 equiv
sodium hydroxide was a requisite to efficiently achieving the oxidation with 1.0 mol%
Co(OAc)2 ꢀ 4H2O.
Given that water is the only by-product in the oxidation, the influence of water
content in EG was also investigated. The results revealed that a small amount of water
could facilitate the oxidation, giving greater yields along with reduced reaction time
(entries 22 and 23), and the best yield of 88% was achieved for 2a in aqueous EG
(EG=H2O ¼ 5.0 mL=0.25 mL, entry 23). However, more water badly impaired the
selectivity of this oxidation to result in sharply reduced yield of 55%, though 1a could
be more quickly consumed within 6 h (entry 24). Conclusively, a highly efficient green
catalytic system of Co(OAc)2 ꢀ 4H2O (1.0 mol%)–NaOH (1.0 equiv)–O2(1.0 atm) in
aqueous EG (EG=H2O ¼ 20=1, v=v) at 50 ꢁC has been established as the optimal
reaction conditions to fulfil the selectively aerobic oxidation.
With the optimized conditions in hand, a range of 2,6-dialkyl-, dialkoxyl-, and
alkoxylalkyl-substituted 4-cresols 1a–n were used to explore the generality of the
oxidation. As shown in Table 2, 2,6-dialkyl-4-cresols 1a–c could be oxidized into
the corresponding aldehydes 2a–c in good yields of 81–88% (Table 2, entries 1–3).
Likewise, for 2,6-dialkoxyl-4-cresols 1d–j, these reactions consistently provided the
desired products 2d–j in good to excellent yields of 80%–91% (entries 4–10). As antici-
pated, the oxidation also enabled 2-alkoxyl-6-alkyl-4-cresols 1k–n to smoothly trans-
form into the aldehydes 2k–n in good yields of 80–83% (entries 11–14). All results
undoubtedly demonstrated that this simple Co(OAc)2-catalyzed oxidation could be
successfully applied in the efficient conversion of a range of 2,6-di-electron-donating
group substituted 4-cresols into the corresponding 4-hydroxybenzaldehydes. It was
noteworthy that there was no any formation of salicylaldehydes (with regard to
substrates 1a, 1c, and 1k–n), benzoic acids, or quinones in our reaction system, which
exhibited excellent chemoselectivity and regioselectivity.
Further investigations were undertaken to probe the mechanism of the
Co(OAc)2-catalyzed oxidation (Scheme 2). The model reactions showed that the feed-
stock 1 gradually generated the desired 2 via the corresponding ethereal intermediates

1434
J.-A. JIANG ET AL.
Table 2. Generality of 1 for the oxidationa
Entry
1
Substrate
Product
Yield (%)b
88
2
3
81
83
91
83
82
91
81
84
81
83
4
5
6
7
8
9
10
11
12
81
(Continued )

Co(OAc)2-CATALYZED AEROBIC OXIDATION
1435
Table 2. Continued
Entry
13
Substrate
Product
Yield (%)b
81
14
80
aReaction conditions: substrate 1 (5.0 mmol), Co(OAc)2 ꢀ 4H2O (0.05 mmol, 12 mg),
sodium hydroxide (5.0 mmol), EG=H2O (5.0 mL=0.25 mL), O2 (1.0 atm), 50 ꢁC for 12 h.
bIsolated yield.
3 (Scheme 2a). Indeed, the isolated ethers 3 efficiently underwent the second oxidation
into 2 (Scheme 2b). Unlike in previous reports,[13g–i] the acetal intermediates were not
detected over our whole scenario. Additionally, under argon atmosphere, the oxi-
dation only gave a trace of the desired products even with 10 mol% Co(OAc)2 ꢀ 4H2O
(Scheme 2c), explicitly instructing molecular oxygen as a terminal oxidant (the
experiments see Supplementary Material, available online).
On the basis of these findings, a plausible oxidation mechanism is suggested in
Scheme 3. The reaction is initiated by single-electron transfer from phenolic anion
of 1 to direct oxidant Co(III) species derived from Co(OAc)2 to generate phenoxy
radicals A. The radicals A are rapidly disproportionated to original 1 and transiently
Scheme 2. Mechanistic investigations.

1436
J.-A. JIANG ET AL.
Scheme 3. Plausible mechanism.
highly reactive p-benzoquinone methides B,[13g–i,14a,7a,18] to which the nucleophilic
additions of EG inevitably lead to ethereal intermediates 3. In the same fashion,
the intermediate anions are converted into transitory B0, which give the desired 2
upon fast hydrolysis driven by spontaneous aromatization. In the course of the reac-
tion, molecular oxygen can powerfully activate Co(OAc)2 to regenerate the direct
oxidant Co(III) species.
CONCLUSIONS
In summary, we have developed a highly efficient aerobic oxidation of 2,6-
dialkyl-, dialkoxyl-, and alkoxylalkyl-substituted 4-cresols into commercially and
academically valuable 4-hydroxybenzaldehydes, using simple Co(OAc)2 ꢀ 4H2O
(1.0 mol%)–NaOH (1.0 equiv)–O2(1.0 atm) catalytic system in aqueous EG (EG=
H2O ¼ 20=1, v=v) at 50 ꢁC. This straightforward oxidation protocol has excellent
chemoselectivity and regioselectivity but also features green chemistry: atom econ-
omy, step economy, inexpensive oxidant, only 1.0 mol% catalyst Co(OAc)2 ꢀ 4H2O,
and safe solvent ethylene glycol.
EXPERIMENTAL
All reactions were carried out in oven-dried glassware and monitored by thin
layer chromatography (TLC, precoated silica-gel plates containing HF254). Reaction
products were purified by silica-gel chromatography (200–300 mesh). Melting points
were determined using open capillaries and are uncorrected. NMR spectra were
determined on Bruker AV400 in CDCl3 with Tetramethylsilane (TMS) as internal
1
standard for H NMR (400 MHz) and 13C NMR (100 MHz), respectively. High-
resolution mass spectrometry (HRMS) was carried out on a QSTAR Pulsar I LC=
TOF MS mass spectrometer.

Co(OAc)2-CATALYZED AEROBIC OXIDATION
1437
Typical Procedure for the Co(OAc)2-Catalyzed Aerobic Oxidation of 1
A mixture of substrate 1 (5.0 mmol), Co(OAc)2 ꢀ 4H2O (0.05 mmol, 12 mg), and
NaOH (5.0 mmol, 0.2 g) in EG=H2O (5.0 mL = 0.25 mL) was stirred with O2 (1.0 atm)
and bubbled at 50 ꢁC for 12 h. Hydrochloric acid (10.0 mL, 2%) and chloroform
(10.0 mL) were successively added to the reaction mixture. The chloroform phase
was separated, and the aqueous phase was further extracted with chloroform
(10.0 mL ꢂ 2). The combined organic layer was dried over anhydrous sodium sulfate
and concentrated to give a residue, which was purified by column chromatography
on silica gel (eluents: petroleum ether=ethyl acetate, 5=1) to provide the desired
products 2.
3,5-Dimethyl-4-hydroxybenzaldehyde (2a)[11b,14a]
1
White solid, 0.66 g (88% yield), mp 112–114 ꢁC (lit.[11b] mp 113–114 ꢁC); H
NMR (400 MHz, CDCl3, ppm): d 9.81 (br s, 1H), 7.54 (s, 2H), 5.46 (br s, 1H),
2.31 (s, 6H); 13C NMR (100 MHz, CDCl3, ppm): d 191.5, 158.1 (2C), 131.0, 129.3,
123.7 (2C), 15.8 (2C). HRMS (ESI): m=z [M þ Hþ] calcd. for C9H11O2 151.0759;
found 151.0750.
FUNDING
We gratefully acknowledge the National Natural Science Foundation of China
(Project No. 21176074) for financial support.
SUPPLEMENTAL MATERIAL
1
Complete experimental details and H NMR, 13C NMR, and HRMS spectra
of all products are available online in the Supplemental Material. Supplemental data
for this article can be accessed on the publisher’s website.
REFERENCES
1. (a) Esposito, L.; Formanek, K.; Kientz, G.; Mauger, F.; Maureaux, V.; Robert, G.;
Truchet, F. Kirk-Othmer Encyclopedia of Chemical Technology, 4th ed.; J. I. Kroschwitz
and M. Howe-Grant (Eds.); Wiley: New York, 1997; vol. 24, p. 812 (b) Rao, S. R.;
Ravishankar, G. A. Vanilla flavour: Production by conventional and biotechnological
routes. J. Sci. Food Agric. 2000, 80, 289–304; (c) Lottner, C.; Bart, K.-C.; Bernhardt, G.;
Brunner, H. Soluble tetraarylporphyrin platinum conjugates as cytotoxic and phototoxic
antitumor agents. J. Med. Chem. 2002, 45, 2079–2089; (d) Raic-Malic, S.; Tomaskovic,
L.; Mrvos-Sermek, D.; Biserka, P.; Mario, C.; Mira, G.; Kresimir, P.; Albrecht, M.; Jan, B.;
Erik, D.; Mladen, M. Spirobipyridopyrans, spirobinaphthopyrans, indolinospiropyrido-
pyrans, indolinospironaphthopyrans and indolinospironaphtho-1,4-oxazines: Synthesis,
study of x-ray crystal structure, antitumoral, and antiviral evaluation. Bioorg. Med. Chem.
2004, 12, 1037–1045; (e) Harini, S. T.; Kumar, H. V.; Rangaswamy, J.; Naik, N. Synthesis,
antioxidant, and antimicrobial activity of novel vanillin derived piperidin-4-one oxime
esters: Preponderant role of the phenyl ester substituents on the piperidin-4-one oxime
core. Bioorg. Med. Chem. Lett. 2012, 22, 7588–7592.

1438
J.-A. JIANG ET AL.
2. Youssef, K. M.; El-Sherbeny, M. A.; El-Shafie, F. S.; Farag, H. A.; Awadalla, S. A. A.
Synthesis of curcumin analogues as potential antioxidant, cancer chemopreventive agents.
Arch. Pharm. 2004, 337, 42–54.
3. (a) Mordant, C.; Schmitt, B.; Pasquier, E.; Demestre, C.; Queguiner, L.; Masungi, C.;
Peeters, A.; Smeulders, L.; Bettens, E.; Hertogs, K.; Heeres, J.; Lewi, P.; Guillemont, J.
Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity
against HIV-1 wild-type and mutant strains. Eur. J. Med. Chem. 2007, 42, 567–579; (b)
Sun, L.-Q.; Zhu, L.; Qian, K.; Qin, B.; Huang, L.; Chen, C. H.; Lee, K.-H.; Xie, L.
Design, synthesis, and preclinical evaluations of novel 4-substituted 1,5-diarylanilines as
potent HIV-1 nonnucleoside reverse transcriptase inhibitor (NNRTI) drug candidates.
J. Med. Chem. 2012, 55, 7219–7229.
4. (a) Turnbull, K. D. Chemospecific and regiospecific labeling of nucleic acid molecules
through phosphodiester alkylation by quinone methides. U.S. Patent 6,657,052 B1,
2003 (b) Narayana, B. L.; Rao, A. R. R.; Rao, P. S. Synthesis of new 2-substituted pyrido
[2,3-d]pyrimidin-4(1H)-ones and their antibacterial activity. Eur. J. Med. Chem. 2009, 44,
1369–1376.
5. (a) Manchand, P. S.; Rosen, P.; Belica, P. S.; Oliva, G. V.; Perrotta, A. V.; Wong, H. S.
Syntheses of antibacterial 2,4-diamino-5-benzylpyrimidines: Ormetoprim and trimetho-
prim. J. Org. Chem. 1992, 57, 3531–3535; (b) Ji, Y.-F.; Zong, Z.-M.; Wei, X.-Y. Efficient
and convenient synthesis of 3,4,5-trimethoxybenzaldehyde from p-cresol. Synth. Commun.
2002, 32, 2809–2814; (c) Ji, Y.-F.; Jiang, J.-A.; Liu, H.-W.; Liao, D.-H.; Wei, X.-Y.
Practical preparation of trimethoprim: A classical antibacterial agent. Synth. Commun.
2013, 43, 1517–1522.
6. Hofmann, C. M. 3,4,5-Tri(lower)alkoxycinnamamides. U.S. Patent 3275688, 1966.
7. (a) Ibrahim, M. N. M.; Sriprasanthi, R. B.; Shamsudeen, S.; Adam, F.; Bhawani, S. A. A
concise review of the natural existance, synthesis, properties, and applications of syringal-
dehyde. Bioresources 2012, 7, 1–23; (b) Singh, P.; Kaur, M.; Sachdeva, S. Mechanism
inspired development of rationally designed dihydrofolate reductase inhibitors as antican-
cer agents. J. Med. Chem. 2012, 55, 6381–6390; (c) Blanch, N. M.; Chabot, G. G.; Quentin,
L.; Scherman, D.; Bourg, S.; Dauzonne, D. In vitro and in vivo biological evaluation of
new 4,5-disubstituted 1,2,3-triazoles as cis-constrained analogs of combretastatin A4.
Eur. J. Med. Chem. 2012, 54, 22–32.
8. Syringaldehyde importantly acts as commercial feedstock to synthesize the pharmaceutical
intermediate 3,4,5-trimethoxybenzaldehyde. For the main manufacturers of syringalde-
hyde and 3,4,5-trimethoxybenzaldehyde, see (a) http://www.shouguangpharm.com/cgi/
search-en.cgi?f=product_en_1_+company_en_1_&id=1456&t=product_en_1_; (b) http://
www.xinhuashouguang.com/cgi/search-en.cgi?f=product_en_1_+company_en_1_&id=
59463&t=product_en_1_; (c) http://www.rongyuanpharm.com/cgi/search-en.cgi?f=
product_en1+product_en_1_+company_en_1_&id=28651&t=product_en_1_.
9. Komiyama, M.; Hirai, H. Selective syntheses using cyclodextrin as catalyst, 1: Control of
orientation in the attack of dichlorocarbene at phenolates. J. Am. Chem. Soc. 1983, 105,
2018–2021.
10. (a) Kamlet, J.; Conn, E. Manufacture of vanillin and its homologues. U.S. Patent 2640083,
1953; (b) Zou, B.; Du, D.; Zhou, Y.; He, G.; Mao, H. Treatment method for wastewater
generated from process of vanillin synthesis from glyoxylic acid. CN Patent 101580319A, 2009.
11. (a) Coppinger, G. M.; Campbell, T. W. Reaction between 2,6-di-t-butyl-p-cresol and
bromine. J. Am. Chem. Soc. 1953, 75, 734–736; (b) Goldstein, S. L.; Mcnelis, E. Migrations
in oxidations of mesidine. J. Org. Chem. 1984, 49, 1613–1620; (c) Omura, K. Oxidation of
phenols with iodine in alkaline methanol. J. Org. Chem. 1984, 49, 3046–3050.
12. Ohmori, H.; Ueda, C.; Tokuno, Y.; Maeda, H.; Masui, M. Electrochemical oxidation of
2,6-di-tert-4-methylphenol in basic methanol. Chem. Pharm. Bull. 1985, 33, 4007–4011.

Co(OAc)2-CATALYZED AEROBIC OXIDATION
1439
13. For oxidation of 2,4,6-trimethylphenol, see (a) Ganeshpure, P. A.; Satish, S. Oxygenation
of (E)-4-stilbenols catalysed by cobalt(II) Schiff base chelates. Tetrahedron Lett. 1988, 29,
6629–6632; (b) Takehira, K.; Shimizu, M.; Watanabe, Y.; Orita, H.; Hayakawa, T. A
novel oxygenation of 2,4,6-trimethylphenol to 3,5-dimethyl-4-hydroxybenzaldehyde by
dixoygen with copper(II)-amine complex catalyst. Tetrahedron Lett. 1990, 31, 2607–
2608; (c) Shimizu, M.; Watanabe, Y.; Orita, H.; Hayakawa, T.; Takehira, K. A facile
synthesis of 4-alkoxymethylphenols by a copper(II)-acetoxime catalyst=O2 system. Tetra-
hedron Lett. 1991, 32, 2053–2056; (d) Shimizu, M.; Watanabe, Y.; Orita, H.; Hayakawa,
T.; Takehira, K. The oxidation of 2,4,6-trimethylphenol with molecular oxygen catalysed
by a copper(II)-oxime or copper(II)-amine system. Bull. Chem. Soc. Jpn. 1993, 66, 251–
257; (e) Li, K.-T.; Liu, P.-Y. Oxidation of 2,4,6-trimethylphenol using iron-based
catalysts. Appl. Catal. A: Gen. 2004, 272, 167–174; (f) Li, K.-T.; Liu, P.-Y. 2,4,6-
Trimethylphenol oxidation with ferrous chloride catalyst: Effect of acetoxime addition.
J. Mol. Catal. A: Chem. 2005, 241, 72–78; (g) Boldron, C.; Gamez, P.; Tooke, D. M.;
Spek, A. L.; Reedijk, J. Copper-mediated selective oxidation of a C–H bond. Angew.
¨
Chem. Int. Ed. 2005, 44, 3585–3587; (h) Boldron, C.; Ozalp-Yaman, S.; Gamez, P.; Tooke,
D. M.; Spek, A. L.; Reedijk, J. Selective copper(II)-mediated oxidative coupling of a
nucleophilic reagent to the para-methyl group of 2,4,6-trimethylphenol. Dalton Trans.
2005, 3535–3541; (i) Sun, X.; Judeh, Z. M. A.; Ali, B. F.; Alshahateet, S. F. A facile syn-
thesis of 3,5-dimethyl-4-hydroxybenzaldehyde via copper-mediated selective oxidation of
2,4,6-trimethylphenol. Catal. Today 2008, 131, 423–426.
14. For oxidation of 2,6-dimethoxy-4-cresol and other 4-cresols, see (a) Baik, W.; Lee, H. J.;
Jang, J. M.; Koo, S.; Kim, B. H. NBS-promoted reactions of symmetrically hindered
methylphenols via p-benzoquinone methide. J. Org. Chem. 2000, 65, 108–115 (b)
Yoshikuni, T. Cerium complexes with acetato acylbis(pyrazolinone) ligands as an efficient
catalyst for the oxidation of cresols by molecular oxygen. J. Mol. Catal. A: Chem. 2002,
187, 143–147; (c) Wang, F.; Yang, G.; Zhang, W.; Wu, W.; Xu, J. Oxidation of p-cresol
to p-hydroxybenzaldehyde with molecular oxygen in the presence of CuMn-oxide hetero-
geneous catalyst. Adv. Synth. Catal. 2004, 346, 633–638; (d) Rode, C. V.; Sonar, M. V.;
Nadgeri, J. M.; Chaudhari, R. V. Selective synthesis of p-hydroxybenzaldehyde by
liquid-phase catalytic oxidation of p-cresol. Org. Process Res. Dev. 2004, 8, 873–878;
(e) Barton, B.; Logie, C. G.; Schoonees, B. M.; Zeelie, B. Practical process for the air
oxidation of cresols, part A: mechanistic investigations. Org. Process Res. Dev. 2005, 9, 62–
69; (f) Tripathi, A. K.; Sama, J. K.; Taneja, S. C. An expeditious synthesis of syringaldehyde
from para-cresol. Indian J. Chem. B 2010, 49, 379–381; (g) Hu, J.; Hu, Y.; Mao, J.; Yao, J.;
Chen, Z.; Li, H. A cobalt Schiff base with ionic substituents on the ligand as an efficient cata-
lyst for the oxidation of 4-methyl guaiacol to vanillin. Green Chem. 2012, 14, 2894–2898.
15. Bozell, J. J.; Hames, B. R. Cobalt–Schiff base complex catalyzed oxidation of para-
substituted phenolics: Preparation of benzoquinones. J. Org. Chem. 1995, 60, 2398–2404.
16. For selected reviews on molecular oxygen as sole oxidant, see (a) Wu, W.; Jiang, H.
Palladium-catalyzed oxidation of unsaturated hydrocarbons using molecular oxygen.
Acc. Chem. Res. 2012, 45, 1736–1748; (b) Punniyamurthy, T.; Velusamy, S.; Iqbal, J.
Recent advances in transition metal–catalyzed oxidation of organic substrates with molecu-
lar oxygen. Chem. Rev. 2005, 105, 2329–2363; (c) Enache, D. I.; Edwards, J. K.; Landon, P.;
Solsona Espriu, B.; Carley, A. F.; Herzing, A. A.; Watanabe, M.; Kiely, C. J.; Knight, D.
W.; Hutchings, G. J. Solvent-free oxidation of primary alcohols to aldehydes using Au-Pd=
TiO2 catalysts. Science 2006, 311, 362–365; (d) Piera, J.; Backvall, J. E. Catalytic oxidation
of organic substrates by molecular oxygen and hydrogen peroxide by multistep electron
transfer—A biomimetic approach. Angew. Chem., Int. Ed. 2008, 47, 3506–3523.
17. (a) Caron, S.; Dugger, R. W.; Ruggeri, S. G.; Ragan, J. A.; Ripin, D. H. B. Large-scale
oxidations in the pharmaceutical industry. Chem. Rev. 2006, 106, 2943–2989;

1440
J.-A. JIANG ET AL.
(b) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer, J. L.;
Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang,
T. Y. Key green chemistry research areas—A perspective from pharmaceutical
manufacturers. Green Chem. 2007, 9, 411–420.
18. (a) Neureiter, N. P. New reaction of a quinone methide. J. Org. Chem. 1963, 28,
3486–3490; (b) Omura, K. The reaction of the 2,6-di-tert-butyl-4-methylphenoxy radical
with phenols. J. Org. Chem. 1991, 56, 921–927.