Imines and Amines from Furfurals
C
R1
(a)
MF
R1
NaBH4
Reactor
coil
O
O
H
in
EtOH
N
N
EtOH, rt
R2
R2
MF flow
rate
R
N
3
4
O
(b)
BPR
(100 psi)
with R1 ꢁ CH2Cl and R2 ꢁ C6H13
Scheme 2. Reduction of furfural imine to the corresponding amine.
Amine
1 ꢂ 10 mL
100ꢃC
Amine
flow rate
Fig. 1. Flow reactor configuration for the synthesis of furfural imines from
As demonstrated herein, the reaction of furfurals with amines
to the resulting imines can be fast and react to completion in
minutes or seconds, if forcing reaction conditions are chosen.
This requires the need for efficient heat management of the
process on large scale, which can be readily achieved using
continuous flow reactor technology. The emergence of compact
continuous flow reactors has begun to transform the way
chemical synthesis is conducted in research laboratories and
small scale manufacturing over the past few years.[26–32] In
several applications, where reaction times are short and heat
management is important, intensified continuous processes
inside tubular or plate-type flow reactors can successfully
replace batch reactions classically carried out in stirred glass
vessels. We have demonstrated the benefits of this superior heat
management in previous work, including exothermic radical
polymerizations in continuous flow,[33,34] the amination of aryl
halides and esters,[35] or the flow synthesis of CMF.[20] The
effective temperature control of a continuous flow reactor was
also important for the intensification of the immination reaction
of MF with aniline (entries 7 and 8). In comparison, the reaction
of HMF with aromatic amines, performed in batch by Cukalovic
and Stevens,[20] took 30 to 50 h at room temperature to achieve
83 to 97 % conversion, whereas we could achieve 93 % conver-
sion at 1408C in only 40 min (entry 8), resulting in a space time
yield of 1.3 kg Lꢁ1 hꢁ1. For the continuous flow imination of MF
with HA (entry 3) we managed to achieve a STY of 11.5 kg Lꢁ1
hꢁ1 and for the reaction with BA (entry 6) it was 11.2 kg Lꢁ1
MF and a variety of different amines.
R1
R1
O
O
ꢀ
H2N R2
ꢀ H2O
O
N
R2
2
3
1
with R1 ꢁ CH3, CH2Cl
and where 2 is:
NH2
O
O
H2N
H2N
H2N
HA
BA
aniline
AME
Scheme 1. Imination of furfurals, 1, with various amines, 2.
MF and CMF, 1, were reacted with an amine, 2, to form the
corresponding imine, 3. Different amines were subjected to this
reaction including the aliphatic amines HA and BA, aniline, and
the amino acid AME.
These experiments were carried out on a batch microwave
reactor system or on a tubular continuous flow reactor (see
experimental section) at temperatures between room tempera-
ture and 1408C, and reaction times between 30 s and 16 h. The
results are presented in Table 1.
h
ꢁ1. All three of these operations are attractive candidates for
scale-up in industrial tubular flow reactors and are believed to
result in efficient, intensified, continuous processes. These
investigations are planned for future work.
When reacting MF with an aliphatic amine (HA or BA,
entries 1–6) at 1008C, the reaction reaches . 90 % conversion
within one minute or less, in both batch and flow. Aniline reacts
significantly slower, which can be explained by the aromaticity
of the molecule. It is less prone to react through nucleophilic
addition of the carbon from the aldehyde moiety; an observation
which is in accordance with results from Cukalovic et al.[21] who
found that there is a decreasing order of reactivity for amines:
aliphatic amines . aromatic amines.
As proof of concept for the reduction of the generated
furfural imines to amines, one example, namely the adduct of
CMF and HA (entry 11), was reacted with 1.5 equiv. of sodium
borohydrate (NaBH4) at room temperature (see Scheme 2). Full
conversion into the corresponding secondary amine was
observed. It is worth noting that the methyl-chlorine group
was not reduced, leaving an extremely reactive site untouched
and available for further reaction.
When applying the same forcing reaction conditions (T $
1008C) to CMF, reaction of the amine with both the aldehyde and
the chloromethyl group was observed, resulting in a mixture of
products (entry 10). In order to selectively react only on the
aldehyde moiety, milder reaction conditions were applied to
CMF, yielding the desired imine product with high conversion
after several hours (entry 11). In order to investigate the imina-
tion/amination reaction of CMF further, we reacted it with
aqueous ammonia at room temperature, which resulted in a
brown insoluble product. The, in parts, inconclusive analysis
results from this reaction suggested that both the aldehyde
functionality and the chloromethyl group reacted with ammonia
to form an insoluble, potentially polymeric product (for further
details see the Supplementary Material).
Conclusion
The condensation reaction between furfurals and amines was
investigated using batch and continuous flow processing. It was
shown that the synthesis of the corresponding imine was com-
plete after only 1 min or less, when forcing conditions could be
used, such as in the case of MF. Milder conditions are suitable
for reactions with CMF, in order to selectively target the alde-
hyde group only, thus avoiding parallel amination on the
chloromethyl moiety. When using continuous flow processing
and elevated temperatures and pressures, the reaction with
less reactive aniline could be performed in 40 min, which is a
significant process intensification compared with classical batch
processing.