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better selectivity for direct oxidation over sequential oxidative
dehomologation (Table 3, entries 4–6).
To clarify the mechanism of chemoselectivity for sequential
oxidative dehomologation of alcohols, we synthesized 18O-la-
beled 3-phenylpropanol (IIa’; see the Supporting Informa-
tion).[7] The rational mechanism and explanation for the se-
quential oxidative dehomologation process are described in
Scheme 2. Deprotonation of the hydroxyl group in IIa’ by
1 equiv. of NaOtBu resulted in the formation of 18O-labeled 3-
phenylpropionaldehyde (5) and hydroperoxide anion (4) via
a hydride shift from the a-carbon of the alcohol to molecular
oxygen. 18O-labeled enolate 6 was generated by the reaction
of 5 with a relatively strong base (NaOtBu; pKa of conjugated
acid tert-BuOH=17) instead of NaO2H (pKa of conjugated acid
H2O2 =11.75). Subsequent nucleophilic attack of O2 on the 18O-
labeled enolate 6 produced the 18O-labeled intermediate 1,2-
dioxetan-3-olate (7) via further intermolecular nucleophilic ad-
dition between the peroxy anion and the carbon of the 18O-la-
beled peroxylated aldehyde. 7 readily underwent ring-opening
due to its extremely strained ring structure, producing unla-
beled 2-phenylacetaldehyde (8) as the first fragmented adduct
while releasing formate (9). The resulting formate decomposed
to carbon dioxide and 4 by hydride transfer from formate to
dioxygen. Benzaldehyde (10), the second fragmented adduct,
was formed from 8 through similar iterative steps (as described
in the previous transformations) with the generation of 6’ and
7’. The resulting aldehyde 10 underwent nucleophilic addition
of 4 to yield the tetrahedral intermediate 11, followed by [1,2]-
hydrogen migration to yield unlabeled Ia via a Dakin-type oxi-
dation pathway.[8] Overall, the 18O-labeling experiment clearly
supported the above-mentioned reaction mechanism for oxi-
dative dehomologation.
To our delight, the highest level of selectivity and yield was
achieved in relatively dilute concentrations of benzene
(Table 3, entry 7). Alternatively, the use of polar aprotic solvents
[e.g,. DMF, DMSO, or hexamethylphosphoramide (HMPA)] re-
sulted in the sequential oxidative dehomologation of the
C(sp3)ÀC(sp3) bond in 3-phenylpropanol, leading to the forma-
tion of the short-chain carboxylic acid 1a (Table 3, entries 8–
10). Remarkable chemoselectivity and yield of the desired
product 1a were achieved under the following conditions: 3-
phenylpropanol (1 mmol), NaOtBu (6 equiv.), HMPA [0.33m], O2
(1 bar) and room temperature (Table 3, entry 11).
With the optimized conditions for chemoselective oxidative
dehomologation or direct oxidation in hand, we screened vari-
ous 3-arylpropanols to ascertain the generalization of the reac-
tion (Table 4). Unsubstituted substrates (IIa and IIi) furnished
Table 4. Substrate scope for sequential oxidative dehomologation or
direct oxidation of 3-arylpropanols.
Entry
Ar[a]
Condition[b]
Ratio[c] of
1/2/3
Yield[d]
[%]
1
2
3
4
5
6
7
8
Ph (a)
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
10:0:90
97:3:0
81
90
78
99
70
90
84
80
90
70
48
53
58
51
58
61
4-Cl-C6H4 (b)
4-F-C6H4 (c)
4-Me-C6H4 (f)
4-MeO-C6H4 (h)
2-naphthyl (i)
2-furyl (j)
17:0:83
86:0:14
25:0:75
83:0:16
28:0:72
70:10:20
24:0:73
80:7:13
0:0:100
100:0:0
8:0:92[e]
93:0:7[e]
19:0:81[e]
79:0:21[e]
After completion of the reaction, unlabeled Ia was detected
by mass spectrometric analysis, indicating that oxidative deho-
mologation of the C(sp3)ÀC(sp3) bond smoothly proceeds
under these reaction conditions. Interestingly, in the oxidative
dehomologation process, oxygen molecules play a key role as
carbon element tweezers of the arylalkanols, similar to the
aerobic degradation of carbohydrates in human metabolism.
This discriminative preference between sequential oxidative
dehomologation of the C(sp3)ÀC(sp3) bond and direct oxida-
tion of alcohols is presumably attributed to the following
reason: basicity (or dissociation) of the tert-butoxide ion, which
can be easily controlled by changing solvent polarity, signifi-
cantly influences the chemoselectivity of long-chain (for exam-
ple, chain length n=2) alcohols. For example, the enhanced
basicity of tert-butoxide in HMPA[9] resulted in abstraction of
the acidic a-proton of aldehydes 5’ (see pathway a in
Scheme 3; also in intermediates 5 and 8) and thus strongly
promoted sequential oxidative dehomologations via further
iterative transformations.
In contrast, NaOtBu has relatively low basicity in benzene be-
cause of its poor degree of dissociation. This resulted in direct
oxidation of the alcohol to carboxylic acid upon reaction be-
tween aldehyde 5’ and the hydroperoxide anion (see path-
way b in Scheme 3) via the formation of a tetrahedral inter-
mediate and Dakin-type [1,2]-hydrogen migration, as described
above. In the case of short-chain (for example, chain length
n=1) alcohols, both the low pKa of the a-proton (as in alde-
9
10
11
12
13
14
15
16
2-thiophenyl (k)
[a] Characters in parentheses refer to the aromatic substituent in the
starting material as well as to the respective products. [b] Condition A: II
(1 mmol), NaOtBu (3 equiv.), benzene (0.16m), O2 (1 bar), RT; Condition B:
II (1 mmol), NaOtBu (6 equiv), HMPA (0.33m), O2 (1 bar), RT. [c] Determined
by gas chromatography. [d] Isolated yields. [e] Determined by 1H NMR
spectroscopy.
the corresponding products with high chemoselectivities for
either of the two reactions (>90:10), in moderate to high
yields (48% to 90%; Table 4, entries 1,2 and 11,12). In the case
of substituents with electron-withdrawing (IIb and IIc) or elec-
tron-donating groups (IIf and IIh) on the aromatic ring at the
para-position, the corresponding products were obtained in
high to excellent yields with good chemoselectivities (Table 4,
entries 3–10). The reaction of heteroatom-containing aromatics
(IIj and IIk) also resulted in high to excellent chemoselectivi-
ties (Table 4, entries 13–16).
ChemSusChem 2016, 9, 241 – 245
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