Angewandte
Communications
Chemie
[
a]
computational studies (at the wB97XD/6-311 + G(d,p) level,
Table 2: Reaction scope.
see the Supporting Information for details) support the
experimental evidence that HFIP forms rather strong
H bonds with the aldehyde. The lone pairs in the oxygen of
the carbonyl are expected to stabilize the radical in PhC(O)C.
However, with HFIP the lone pair aligned with the radical is
diminished due to charge transfer and polarization to the
solvent, resulting in lower stabilization of the radical product
and a higher BDE value for the CÀH bond. Gas-phase
computations show a relative CÀH homolytic BDE of about
À1
1
5 kJmol higher for the benzaldehyde–HFIP adduct com-
pared with the bare benzaldehyde. If we consider this value as
the difference in activation energy with and without HFIP (a
gross approximation, but qualitatively valid), it corresponds
to a reaction about 400 times slower when HFIP is involved,
enough to make the aldehyde oxidation unobservable within
a reasonable experimental time period.
Like other alcohols, HFIP tends to oligomerize through
[16a,b,17c]
intermolecular H-bonding networks.
As a result, com-
petition exists between the HFIP–HFIP and 2a·HFIP
adducts. Our computations show an almost isoenergetic
relationship between both pairs, and therefore, a dynamic
equilibrium is attained between them (see the discussion in
the Supporting Information). It is expected that the addition
of HFIP drives the equilibrium toward 2a·HFIP, up to the
point of virtual saturation, which has been observed exper-
imentally at a 1:1.5 ratio (Figure 2B). From that point, and as
explained before, the oxidation by a hydrogen atom transfer
(
HAT) mechanism is virtually brought to a halt.
[
a] Reaction conditions: ArCH (0.25 mmol), NHPI (0.025 mmol), Co-
3
The reaction scope was examined by subjecting methyl-
(OAc) ·4H O (0.005 mmol), O (1 atm), HFIP (0.5 mL), RT products
2 2 2
arenes with various substituents at different positions to our
novel conditions (Table 2). To this end, o-, m-, or p-xylenes
were selectively oxidized to the corresponding tolualdehydes
were quantified with chlorobenzene as an internal standard and
1
identified using reference samples, GC-MS and H NMR spectroscopy.
[b] In square brackets: isolated yield. [c] NHPI (5 mol%). [d] 1 mmol
scale. [e] NHPI (20 mol%). [f] Isolated as inseparable constitutional
isomers.
(
4–6) in excellent conversion (92, 99, and 97%, respectively)
and high selectivity (above 91%). Phenols interrupt the
[
1b]
radical chain reaction; therefore, the phenolic group must
be masked in order to recover the reactivity. For example, 3,5-
dimethylphenol failed to produce aldehyde 12, whereas 3,5-
dimethylanisole generated aldehyde (13) in 91% conversion
(
95% selectivity). Methylarenes having electron-withdrawing
groups, such as Cl (14), Br (15 and 16), CO Me (17), and
2
COMe (18) are suitable substrates and could be oxidized with
high yields and excellent selectivity. Primary alcohol, alkene,
and acetamide functionalities, as in compounds 9, 19, and 20,
are compatible with the reaction conditions, emphasizing the
new possibilities that this method offers in multistep synthesis.
Scheme 2. Large-scale synthesis of 4-tert-butylbenzaldehyde.
4
-tert-Butylbenzaldehyde (22) is a key intermediate in
producing 4-tert-butyl-a-methyldihydrocinnamaldehyde
Lilial, 23, Scheme 2), which is an odor compound used in
desired aldehyde 22 in 75% isolated yield. The main draw-
back of this method is associated with the high cost of HFIP;
therefore, upon completion of the large-scale reaction, 3,5-di-
tert-butyl-4-hydroxytoluene (BHT, 0.1 mol%) was added to
prevent over-oxidation of the aldehyde product during the
fractional distillation of the solvent. The recovered HFIP
(34 mL out of 40 mL, 85% yield) was successfully used in
another reaction.
(
[
5c,23]
large quantities in soap and in cosmetic perfumes.
manufacturing from 4-tert-butyltoluene (1c) is a challenging
step that suffers from efficiency and selectivity problems.
Recently, Zhou et al. reported a cobalt-modified APO-5
zeolite system that produced aldehyde 22 in 15.5% conver-
sion and 73.4% selectivity.
conditions, aldehyde 22 was prepared in 99% conversion and
Its
[23b]
[
23a]
In contrast, under our novel
In conclusion, we report that the aerobic oxidation of
methylarenes to benzaldehydes by catalytic amounts of NHPI
8
9% selectivity.
and Co(OAc) in HFIP is highly selective. The green and mild
2
The scalability of the method was validated by oxidizing
compound 1c on a three-gram scale (Scheme 2), affording the
conditions are suitable for oxidizing both electron-deficient
and electron-efficient methylarenes. Based on mechanistic
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3
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