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attempts at the catalytic hydrogenation of CMF led to the for-
mation of DMF in modest yields. Efforts to maximize selectivity
at high conversion involved the use of different solvents and
catalysts across a range of reaction times, hydrogen pressures,
and temperatures, and the best results were ultimately ob-
tained using commercial Pd/C in a 2:1 N,N-dimethylform-
amide/acetic acid solvent mixture. The conditions were remark-
ably mild (room temperature, 3 atm H , 1.25 h), particularly
2
compared to those used for the hydrogenation of HMF (130–
[
16]
2
008C, 7–40 atm H , 2–24 h), and provided DMF 3 in 76%
2
yield.
The direct hydrogenation of CMF proceeds via 5-methylfur-
Scheme 1. Reagents and conditions: a. H
tBuPhNH , 758C, 98% 6a, or 4-FPhNH , 758C, 98% 6b; c. H
DMF, 73% (of 3, from 7a) or 74% (of 3, from 7b).
2
, Pd/C, toluene-water, 91%; b. 4-
2
2
2
, Pd/C, HOAc-
furyl alcohol 4, which is unstable under acidic reaction condi-
tions and appears to be responsible for the formation of side
products that limit the selectivity to 3. In an effort to bypass
the formation of 4 and hence the issues associated with its in-
termediacy during the hydrogenation of CMF, we shifted our
attention to indirect approaches to the reduction of aromatic
aldehydes.
A little-explored method of reducing benzaldehydes to
methylbenzenes has been reported which involves initial con-
version to an acetal followed by hydrogenation with Pd/C at
[20]
atmospheric pressure.
Since the acetal to methyl group
The catalytic hydrogenolysis of benzylic amines is a well-
known reaction which occurs under mild conditions, and this
method seemed attractive since conversion of the aldehyde in
CMF to a methylamino group could be accomplished via re-
ductive amination. In order, however, to avoid the generation
of an amine hydrochloride byproduct, the application of this
chemistry to the synthesis of DMF involved initial hydrogena-
tion of CMF to 5-methylfurfural (MF) 5, which could be
achieved in a biphasic reaction in high yield. A series of anils
of MF 5 were then prepared and screened for their per-
formance in the conversion to DMF 3. Although these imines
could be produced quickly and efficiently, hydrogenation led
in some cases not only to reductive cleavage of the CÀN bond,
but also saturation of the aniline to the corresponding
cyclohexylamine, which phenomenon has been previously de-
transformation goes via the corresponding ether, we recog-
nized here another opportunity to avoid alcohol intermediate
4. We initially prepared the diacetoxy acetal of CMF, namely 2-
(chloromethyl)-5-(diacetoxymethyl)furan 9, in high yield by the
solvent-free reaction of 2 with acetic anhydride in presence of
an acidic Amberlyst resin catalyst. Palladium-catalyzed hydro-
genation of 9 however resulted in a disappointing 55% yield
of DMF (Scheme 2). Although dialkyl acetals can be prepared
Scheme 2. Reagents and conditions: a. Ac
2
O, Amberlyst-15, 508C, 30 min,
[
19]
scribed. Among the alkyl anilines, the 4-tert-butyl-substituted
92% (of 9); b. BuOH, cat. HCl, 08C, 1 h, 98% (of 10); c. H , Pd/C, HOAc,
2
derivative proved most resistant to ring hydrogenation. Con-
2
30 min, 55% (from 9); d. H , Pd/C, pentane, 40 min, 82% (from 10).
densation of 4-tBuPhNH with MF 5 in a solvent-free reaction
2
proceeded in essentially quantitative yield to give imine 6a. A
solution of 6a in a 2:1 mixture of acetic acid and N,N-dimethyl-
formamide was hydrogenated at room temperature over a Pd/
from aldehydes by the use of orthoformate reagents, and
indeed we found that the diethyl acetal of CMF could be con-
veniently made by this method, we wished to avoid the gener-
ation of a formate ester by-product. The question was whether
CMF would withstand standard acetalization conditions (i.e., al-
cohol plus strong acid catalyst). n-Butanol was selected as the
alcohol of choice due to its renewable production from bio-
mass, low cost, low volatility, low toxicity, and the favorable
formation of a low-boiling azeotrope with water. Pleasingly,
when CMF was treated with n-butanol in presence of a catalytic
amount of acid (HCl), 2-(chloromethyl)-5-(dibutoxymethyl)furan
10 was obtained in 98% isolated yield.
The hydrogenation of 10 using a Pd/C catalyst attempted in
the absence of solvent gave DMF 3 as the major product, but
a colored impurity and some side products were also ob-
served. Careful analysis showed that the acetal functionality in
10 was being compromised to some extent due to the libera-
tion of HCl during reduction of the chloromethyl group, lead-
ing to alternative reaction pathways. However, when the reac-
3
C catalyst at 15 psig (1 psi=6.8948ꢁ10 Pa). The reaction com-
pleted in less than an hour, producing DMF 3 in 73% yield
along with the liberated aniline and minor over-reduction
product 8a (Scheme 1). Carrying out the same reaction se-
quence via 4-fluoroaniline derivative 7b was found to be even
more convenient, in that less catalyst was required to achieve
essentially the same result. Study of the hydrogenation reac-
1
tion by GC-MS and H NMR clearly showed that the imine 6
adds H2 to form the corresponding amine intermediate 7
which undergoes hydrogenolysis in situ to give 3. We explored
several strategies to eliminate byproduct 8, including alterna-
tive solvents and catalyst poisons, but no selectivity trend was
apparent. Although this route provided DMF 3 in three steps
from CMF under mild conditions and in good overall yield, the
occurrence of by-product 8 made it less attractive from an in-
dustrial perspective.
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2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2014, 7, 3028 – 3030 3029
Dutta, Saikat
