Organic Process Research & Development
Article
but also provides an atom-economic, easy-to-handle, and
scalable process for maximizing the liquid-fuel product from
carbohydrates and bioresources.
Further, we know that hydrazine hydrate is a costly reducing
agent in comparison to hydrogen, but compared to the overall
complexity of the earlier processes, such as over-reduction,
costly catalyst, difficult to handle under high pressure in
general laboratory practices, the proposed process is highly
selective to the carbonyl group and much easier to handle
under general laboratory conditions. Moreover, hydrazine
hydrate after decomposition gives N2 gas, which is also easy to
handle, separable, and also has commercial value. The
proposed approach is a very common Wolff Kishner (WK)
reaction but rarely investigated by researchers due to its
unspecific reactivity with furfurals. In this study, these
challenges have been overcome through modification of its
processing technique.
Figure 2. Time-based progress of the reaction of 5-HMF to 5-MFA
under standard reaction conditions.
t
(2.92 mL, 1.5 equiv), and BuOK (4.45 g, 1.0 equiv) in a 2-
RESULTS AND DISCUSSION
butanol (25 mL) solvent system at reflux temperature (∼120
°C) for 4 h. The reaction was monitored using a thin-layer
chromatograph (TLC), and after completion of the reaction,
distilled water was added to the reaction mixture, and the final
product was extracted with diethyl ether two to three times.
The solvent was further removed by fractional distillation in a
controlled manner, which finally gave 5-MFA 2a in a 70% yield
(Table 1, entry 1) with >99% purity by gas chromatography−
mass spectrometry (GC−MS) (SI, spectrum S4).
■
In the reported literature, the WK approach for the reduction
reaction of 5-HMF has not been investigated yet. Herein, we
critically explored the WK reduction approach specifically for
5-HMF reduction to MFA. Moreover, this approach of 5-HMF
reduction is quite tough to perform, as when we used 5-HMF
directly in the reaction system, we obtained a very poor yield of
the desired product. This might be why the WK reduction
approach in the case of 5-HMF is underexplored. After
continuous efforts and a critical study, we observed that the
main reason for this was the acidic nature of 5-HMF (pH ∼ 3),
as most of the furan products are synthesized in acidic media
and stable in acidic environments. Keeping this observation in
mind, we neutralized 5-HMF (pH ∼ 7) prior to the reaction.
Then, when we carried out the reaction with neutral 5-HMF,
the yield of the desired product enhanced dramatically.
Similarly, furfural (1b) was also subjected under established
reaction conditions to yield 2-MF (2b). In this study, as soon
as 2-MF (2b) was formed in the reaction mixture, it
simultaneously distilled out through the condenser and was
collected in a collection flask. After completion of the reaction,
the liquid in the collection flask was redistilled carefully to
remove 2-butanol, giving the final compound 2-MF (2b) in a
72% yield and >95% NMR purity (Table 1, entry 2).
Interestingly, when we extended the same process for 2,5-
diformylfuran (DFF), which is a tricky and highly reactive
substrate as it constitutes two aldehyde groups, we obtained
2,5-dimethylfuran 2c (DMF) with high selectivity and a
considerably good yield of 56% after distillation with GC
purity >95% (Table 1, entry 3). Any alteration in the reagent
equivalency led to a decrease in the product yield of 2c.
Complex unidentified mass formation was noticed during the
reaction, which may be responsible for lowering the yield of
the desired product 2c. To avoid the difficulties in handling
DFF, a less stringent substrate, 5-methyl-2-furfuraldehyde
(1d), was selected for the synthesis of the same product, 2c,
using a similar approach, and the reaction displayed an
improvement of the yield by 5−10% compared to the earlier
reaction (Table 1, entry 4).
Scale-Up Synthesis of 5-MFA and 2-MF. There are a
number of successful processes available in small-scale
reactions, but it is not possible to apply all of these processes
in a scale-up reaction, which limits their technological
applications. Therefore, we tested our developed process
further only on two industrially challenging targets of 5-MFA
and 2-MF production from 5-HMF and 2-furfuraldehyde,
respectively. We begin our scale-up trial with 5-HMF up to 250
g scale for the synthesis of 5-MFA (2a) under optimized
reaction conditions described in Table 2 and the Experimental
Section. The stepwise addition of the reagents is crucial for the
fruitful conversion of the product. Initially, 5-HMF was
dissolved in the 2-butanol solvent, and then N2H4·H2O was
In this process, we have used a hydrazine hydrate (N2H4·
t
H2O) and BuOK combination in a 2-butanol solvent system
as the reducing agent instead of H2 gas and a metal catalyst.
Initially, the aldehyde group of furfural in the presence of
N2H4·H2O was immediately converted to hydrazone, which
further under basic conditions reduced to an alkane, followed
by oxidation of hydrazine to gaseous N2 (Scheme 2).37 As the
reaction proceeded through the hydrazone intermediate, only
the carbonyl group selectively participated in the reduction
reaction to its corresponding alkane similar to that in the WK
reduction approach.
Initially, we have investigated the effect of different
conditions, such as temperature, base, the equivalence of
base, alcoholic and nonalcoholic solvents, and simultaneous
optimization of hydrazine hydrate, to obtain the best-
optimized process for the synthesis of 5-MFA from 5-HMF
(Figure 1).
Further, to estimate the time-based progress of the reaction,
we performed a reaction under our established protocol using
5-HMF as the model substrate. Under this investigation, we
observed an increase in the yield of the desired product 5-MFA
with an increase in the reaction time up to 4 h, which then
decreased gradually, as shown in Figure 2 (Supporting
Five-Gram Scale Synthesis of Alkyl-Substituted
Furans. After optimization of the process, the conditions
were further tested with a five-gram scale reaction. Under this
study, the standard protocol was first applied on a tested
substrate, i.e., 5-HMF 1a (5.0 g, 1.0 equiv), hydrazine hydrate
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Org. Process Res. Dev. 2021, 25, 892−899