J.-A. Jiang et al. / Tetrahedron Letters 55 (2014) 1406–1411
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Table 1
ONa
CHO
ONa
CHO
Selected optimization for the oxygenation of 1a into 2aa
NaOH
CHO
cobalt salt (n1 mol%)
NaOH (n2 equiv)
B
Br
Br
Br
Br
Br
OH
2a
O
Br
Br
1a
O2 (1.0 atm), EG, T., 8 h
Br
Br
OH 2a
sodium phenolate
sodium enolate
OH
Scheme 2. Possible sodium enolate of 2a under the alkaline conditions.
Entry
Co salt (n1 mol %)
NaOH (n2 equiv)
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
CoCl2 (3.0)
1.0
1.0
1.0
0
2.0
3.0
2.0
2.0
2.0
2.0
2.0
50
50
80
80
80
80
80
80
80
80
100
Trace
53
76
0
90
Co(OAc)2ꢀ4H2O (3.0)
Co(OAc)2ꢀ4H2O (3.0)
Co(OAc)2ꢀ4H2O (3.0)
Co(OAc)2ꢀ4H2O (3.0)
Co(OAc)2ꢀ4H2O (3.0)
Co(OAc)2ꢀ4H2O (2.0)
Co(OAc)2ꢀ4H2O (1.0)
Co(OAc)2ꢀ4H2O (0.5)
Co(OAc)2ꢀ4H2O (1.0)
Co(OAc)2ꢀ4H2O (1.0)
(1d) was regioselectively converted into 3,5-dibromo-4-hydroxy-
2-methylbenzaldehyde (2d) in 86% yield, with the original
meta-methyl group remaining intact (entry 4). For more electron-
deficient 2,3,6-trihalogenated 4-cresols 1e and 1f, the desired
products 2e and 2f were consistently obtained in high yields of
87% and 90%, respectively (entries 5 and 6), under the standard
conditions (80 °C, 2.0 equiv of NaOH, 8 h).
90
90
90
79
10
11
Tracec
90d
As anticipated, in consequence of EDG, the oxidation of 2-EWG-
6-EDG-substituted 4-cresols 1g–r faster proceeded to deliver the
corresponding 4-hydroxybenzaldehydes 2g–r in a short reaction
time of 6 h (otherwise consistent conditions: 80 °C, 2.0 equiv of
NaOH), with good yields of 82–90% (entries 7–18). Of these, as to
more sterically hindered iso-butoxy- and tert-butyl-substituted
4-cresols 1k and 1m, the reactions provided the products 2k and
2m with relatively low yields of 83% and 82%, respectively (entries
11 and 13). With respect to the ortho-methyl group-containing
2-bromo-6-methyl-4-cresol (1l), the oxidation exclusively offered
regioselective 4-hydroxybenzaldehydes 2l, while the original
ortho-methyl group remained unchanged as well (entry 12).
Next, we focused on the oxygenation of more challenging
unhindered 2-EWG-substituted 4-cresols, wherein radical-based
coupling side-reactions usually perplexed chemists (entries
19–22).13 To our delight, with 4.0 equiv of NaOH being employed
(otherwise consistent conditions: 80 °C, 8 h), these 2-bromo-,
2-formyl-, and 2-nitro-substituted 4-cresols 1s–v were success-
fully converted into the desired 4-hydroxybenzaldehydes 2s–v in
high yields of 87–90%, without obvious coupling side-reactions
being observed (entries 19–22). In contrast, the oxidation of the
unhindered electron-rich 2-methoxy-4-cresol (1w) furnished van-
illin (2w) with relatively low yields of 53% or 62% in the presence of
4.0 equiv or 6.0 equiv of NaOH (entry 23), under the otherwise
consistent conditions (80 °C, 4 h). Therein, the concomitant tar
(oligomers), associated with coupling side-reactions, could not be
avoided. These facts illustrated that the EWG in unhindered
2-EWG-substituted 4-cresols and the increased amount of NaOH
would effectively suppress the undesired couplings. Additionally,
2,6-dimethoxy-4-cresol (1x), as a representative of electron-rich
hindered 4-cresols, smoothly underwent the oxidation delivering
syringaldehyde (2x) in a high yield of 91% (entry 24), further dem-
onstrating the practical compatibility of the procedure. As a result
of the EDG, complete conversion of readily oxidizable 1w and 1x
only required a shorter reaction time of 4 h. The results shown in
Table 2 indicated an advantage of the oxidation for EWG-substi-
tuted 4-cresols: broad scope of substrates including hindered and
unhindered 4-cresols. It should be mentioned that 2a and 2s are
two key intermediates for preparing commercially famous syring-
aldehyde (2x) and vanillin (2w), respectively.
a
Performed with 1a (1.0 mmol), cobalt salt (n1 mol %), NaOH (n2 equiv), and EG
(5 mL), O2 (1.0 atm) for 8 h.
b
Isolated yield via column chromatography.
Performed under argon atmosphere.
Reaction time of 24 h.
c
d
Initially, the model oxidation of 2,6-dibromo-4-cresol (1a) into
3,5-dibromo-4-hydroxybenzaldehyde (2a) was manipulated in EG
with commercially available cobalt salts (3.0 mol %) and NaOH (1.0
equiv) under pure O2 atmosphere (atmospheric pressure, 1.0 atm)
for 8 h. Very low yields of the desired 2a were obtained by employ-
ing CoCl2 and other halogenated cobalt salts (Table 1, entry 1, and
see Table S1). Then, we turned to commercial organic cobalt salts,
the ordinary Co(OAc)2ꢀ4H2O proved to be fruitful giving 2a in a
promising yield of 53% at 50 °C (entry 2). Furthermore, the effi-
ciency of oxidation was remarkably enhanced at an elevated reac-
tion temperature of 80 °C to provide 76% yield (entry 3). On the
other hand, no desired product was observed in the absence of
NaOH, indicating an essential role of NaOH in initiation of the oxi-
dation (entry 4). Further improved yields were achieved by
increasing the amount of NaOH, and 2.0 equiv of NaOH turned
out to be adequate to offer the best yield of 90% (entries 5 and
6). More pleasingly, these reactions still worked well to afford 2a
in the excellent yield of 90% when using 2.0 or 1.0 mol % Co(OAc)2-
ꢀ4H2O (entries 7 and 8, entry 8 as the standard reaction conditions).
But, the yield sharply reduced to 79% when the catalyst loading
was lowered to 0.5 mol % (entry 9). Besides, only trace of 2a was
observed under anaerobic conditions (entry 10). It was noteworthy
that, further screening of solvents showed that the oxidation was
generally effective in alcohols, but ineffective in aprotic solvents.
These experiments indicated an indispensable mediation of alco-
hols, and only more polar EG gave the best yield (Table S1).
Impressively, no observable overoxidation product 3,5-di-bro-
mo-4-hydroxybenzoic acid was detected in the oxidation, even ele-
vating reaction temperature and prolonging reaction time (entry
11). We considered that its sodium enolate, derived from the isom-
erization of sodium phenolate of 2a via dearomatization-enoliza-
tion under the alkaline conditions, should account for the highly
selective conversion, and synchronously effective protection of
the susceptive aldehyde group (Scheme 2).11
Expansive investigations were undertaken to probe the reaction
mechanism (Scheme 3). The control experiments showed that the
feedstock 1a gradually produced the desired 2a via the correspond-
ing ethereal intermediates 3a (Scheme 3a). Indeed, the isolated
ethers 3a efficiently took part in the further oxidation incurring
2a (Scheme 3b). Moreover, stoichiometric radical scavenger
2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) completely inhib-
ited the reaction, clearly indicating a free radical oxidation process
(Scheme 3c). Next, the oxidations of 2-cresol and 4-chloro-2-cresol
With the standard reaction conditions in hand, a variety of
EWG-substituted hindered 4-cresols 1b–r were examined to
explore the potential scope of the Co(OAc)2-catalyzed oxygenation
(Table 2, entries 2–18).12 Firstly, we were pleased to observe that,
similar to the case of entry 1, this simple protocol smoothly
oxidized 2,6-dihalogenated 4-cresols 1b and 1c into 2b and 2c in
high yields of 91% and 88%, respectively (entries 2 and 3). Also,
meta-methyl group-containing 2,6-dibromo-3-methyl-4-cresol