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DOI: 10.1039/C8GC00553B
Journal Name
COMMUNICATION
milder conditions for the Baeyer Villiger oxidation. As it was the Baeyer-Villiger oxidation of LGO with added water
shown that 5-member cyclic ketones – such as furanone - provided HBO without affecting the yield. As previously
1
3
12
2 2
could be oxidized in presence of H O only, and taking reported, 2H-HBO can also be readily synthesized from HBO
advantage of the good solubility of LGO/2H-LGO in water, we using a palladium-catalyzed hydrogenation.
dedicated ourselves to the study and optimization of an
organic solvent- and catalyst-free preparation of HBO and its
dehydro-derivative, (
S)-γ-hydroxymethyl-γ-butyrolactone aka
2H-HBO from LGO and 2H-LGO, respectively.
The first stage of this study consisted in verifying the feasibility
of the Baeyer-Villiger oxidation of LGO only in the presence of
2 2
30% aqueous H O , the latter serving as both oxidizing agent
and solvent for the reaction (see Supporting Information –
General organic solvent- and catalyst-free Baeyer Villiger
oxidation procedure for HBO). In this aim, we performed the
Scheme 4. Two-step syntheses of 2H-HBO
2 2
reaction at 50 °C with 1.08 eq. 30% H O . By monitoring the
To confirm the feasibility and the reproducibility of the new
reaction using HPLC, we were delighted to observe that the
oxidation not only occurred but also was quite rapid, reaching
maximal HBO production, ca. 83%, in 8 hours (Figure 1 Top).
Moreover, we also found out that FBO started to be detected
in the reaction medium after 30 minutes, and was almost
entirely hydrolysed after 8 hours (Figure 1 Bottom). This
outcome was particularly fortunate as it demonstrates that
performing the Baeyer Villiger oxidation on LGO using only
Baeyer-Villiger procedure (aqueous 30% H
2 2 2
O , H O), the scale-
up of the two reactions (LGO -> HBO and 2H-LGO -> 2H-HBO
)
was then successfully achieved in a 5-Liter batch reactor,
providing HBO and 2H-HBO at the kilo scale in good yields (ca.
7
2%, after purification).
Regarding the separation and purification of the two targets,
HBO and 2H-HBO although classic silica gel flash
,
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chromatography was already proven effective, we decided to
look for a more industrially relevant technique. As the Baeyer-
Villiger reaction proceeds without any organic solvent, our
choice was to avoid solvent extraction. We therefore decided
to first concentrate the reaction medium under reduced
pressure and then distillate the crude residue. As HBO and 2H-
HBO boiling points are quite high even at reduced pressure
2 2
30% aqueous H O also allows the concomitant hydrolysis of
FBO into HBO without the need of an acid hydrolysis step,
making this procedure simpler and more sustainable than the
previous ones. Willing to push the reaction to completion, the
number of equivalents of 30% H
increased from 1.08 up to 4.9 eq. (Figure 1 Top). Data showed
that increasing H amount resulted in increased LGO
2 2
O was then gradually
2 2
O
(b.p.(HBO) = 135 °C at 0.2 Torr; b.p.(2H-HBO) = 110 °C at 0.08
conversion and reaction kinetics, reaching HBO production up
Torr), and to avoid any degradation, short-path distillation,
commonly used in the fragrance industry, was chosen. This
technique allowed the purification of HBO and 2H-HBO in 71%
and 72% yields, respectively, and with 96% purity. It is
noteworthy to mention that no racemization occurs during this
Baeyer-Villiger oxidation (see optical powers for HBO and 2H-
HBO in Supporting Information). Although this novel
to 100% (in 24 hours) and proceeding with an initial rate of
-1
5
.93
excess H
also rise a serious issue as the excess of H
ꢀ
mol.min . Although completion was achieved using
, such conditions have an economical impact but
has to be
2 2
O
2 2
O
neutralized prior work-up to avoid any explosion. This
quenching can be performed by adding sodium sulphite,
1
4
sodium bisulfite, metabisulfite or even a catalase . It is
noteworthy to mention that many of these techniques
generate waste to be disposed of. Another technique that
avoids the generation of any waste consists in heating the
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procedure proceeds with a lower yield compared to the
previous ones (i.e., 71% vs. 83%), it is economically and
industrially more relevant (e.g., 1 step vs. 2 steps, no organic
solvent, no expensive biocatalyst, no/limited waste to be
disposed of).
reaction medium at high temperature (ca. 90 °C).
A
compromise between high conversions, safety and process
cost thus needs to be made. Finally, to avoid any residual H
the reaction was performed with 0.98 eq. of
2
2
O
O
2
,
.
Conclusion
H
2
1
)
6
Unfortunately, this resulted in both lower HBO production and Levoglucosenone (LGO
slower kinetics (Figure 1 Top).
and its dehydro-derivative (2H-LGO
,
,
Cyrene®) can be readily oxidized into HBO and 2H-HBO
As this novel organic solvent- and catalyst-free Baeyer-Villiger respectively, solely in the presence of aqueous H O . This
2
2
oxidation proceeds successfully on LGO, its implementation to robust and scalable new synthetic procedure gives access to
H-LGO, that can be efficiently obtained through a solvent- these highly valuable chiral building blocks in only one step
2
3
free palladium-catalyzed hydrogenation, was investigated. while avoiding the use of organic solvent, acid and catalyst
Applying the optimized conditions on 2H-LGO provided (i.e., metal, enzyme), and with none to limited waste. Finally,
selectively 2H-HBO, as expected and already observed in the the use of short-path distillation provides an industrially and
1
0,12
literature,
but proved hazardous as the reaction happens economically relevant separation/purification technique. The
to be highly exothermic. Adding water to the reaction allowed combination of organic solvent- and catalyst-free process with
a better heat dissipation, thus providing a better control of the short-path distillation offers a more sustainable alternative to
reaction (Scheme 4). It is important to note that performing those previously reported in the literature, and opens the way
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