10.1002/ejoc.201800380
European Journal of Organic Chemistry
COMMUNICATION
Table 3. Oxidation of 1,4-anhydroerythritol.[a]
achieved with substrates 1f, 4a and 9 demonstrated that more
intricate multistep transformations leading to hemiacetal esters
could be accomplished for properly functionalized substrates.
Thus, the new methodology bears potential for application in total
synthesis and natural products modification.
mCPBA
(equiv)
Time
(h)
Consumption[b]
(%)
Yield[c]
10+11 (%)
Entry
Ratio 10:11
1
2
1.1
2.2
3.3
4.4
6.6
11
6
6
45
33
49
51
59
50
60
67
71
64
66
62
38
2.09
2.06
1.55
0.65
0.57
0.42
0.47
0.31
0.92
0.74
0.72
5.3
80
Experimental Section
3
6
quant.
quant.
quant.
quant.
quant.
quant.
quant.
99
4
6
Typical procedure for TEMPO/mCPBA oxidation: 1a (21 mg, 1.0 equiv, 0.1
mmol) was placed in a small vial charged with a magnetic stir bar, and the
solutions of TEMPO (0.1 M, 20 µL, 0.002 mmol) and TBAB (0.1 M, 20 µL,
0.002 mmol) in DCM were added by syringe at room temperature. mCPBA
(54.2 mg, 2.2 equiv, 0.22 mmol) solution in 0.76 mL DCM was added, and
the reaction was allowed to stir for 75 minutes. Aqueous saturated
NaHCO3 solution (2.5 mL) was added, the mixture was stirred for 5
minutes, the organic phase was separated, and the aqueous phase was
extracted with DCM (4 x 2.5 mL). Subsequently, the combined organic
phase was washed with brine (5 mL), dried over Na2SO4, filtered and
concentrated in vacuo. The crude was analyzed by NMR spectroscopy,
and the product purified by column chromatography.
5
6
6
6
7
6.6
6.6
3.3
3.3
3.3
3.3
3
8
1
9
1
10
11
12[d]
0.5
0.25
6
83
quant.
Acknowledgements
[a] Reaction conditions: 1 equiv of substrate, mCPBA, 2 molar % TEMPO, 2
molar % TBAB, DCM (8 mL/mmol substrate), rt. [b] Consumption of the
starting material as determined by 1H NMR, quant. = quantitative. [c] As
determined by 1H NMR. [d] 5 molar % TEMPO, 5 molar % TBAB.
This research was supported by Grant No. 955/10 from the Israel
Science Foundation and Grant No. 2012193 from the United
States-Israel Binational Science Foundation (BSF). PR is grateful
to the Planning & Budgeting Committee of the Israel Council for
Higher Education for the postdoctoral fellowship.
to the slow hydrolytic/oxidative degradation of 11, under reaction
conditions (entries 7-8 vs. entry 5, and entries 9-11 vs. entry 3).
These results could be explained in the following way. First,
a-hydroxy ketone 12, the first plausible intermediate in any chain
of events proposed in Scheme 7, is preferentially oxidized into the
gem-diol monoester 13. This preference indicates that, again, as
in the case of substrates 1f and 4a, the stoichiometric BV is faster
than the TEMPO-catalyzed oxidation. Furthermore, it indicates
that, in this particular case, the migration of hydroxyalkyl
substituent in the Criegee intermediate is faster than that of
alkoxyalkyl.[4,25] From presumed intermediate 13 two competitive
pathways, one starting with the TEMPO-catalyzed oxidation of the
monoester into diglycolic anhydride (14), and another beginning
with the hydrolytic opening of the monoester into transient
intermediate 15, lead to products 10 and 11 respectively. The
monoester opening is likely to be a reversible step, due to the
favorable ring size of 13. Thus, the higher is the ratio of TEMPO
to mCPBA in the mixture, the more preferred is the pathway
leading to 10. On the other hand, the lower is this ratio the higher
will be the relative amount of 11 in the mixture.
Keywords: Domino reactions • Hemiacetal esters •
Organocatalysis • Oxidations • Synthetic methods
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[2]
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Conclusions
[7]
[8]
In conclusion, we devised an efficient cascade oxidation
procedure, where the stoichiometric reagent of the first catalytic
step serves also as the oxidant of the subsequent stoichiometric,
spontaneously occurring stage. We have shown that the new
methodology can be applied for fast and high-yielding conversion
of primary and secondary b-alkoxy alcohols into the
corresponding hemiacetal esters. Furthermore, the results
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