aqueous layer became highly
acidic. A variety of metal cata-
lysts are effective for the trans-
formation. Of the catalysts
tested, those based on rhodium
appear to be the most active
(compare entry 6 to entries 1
and 7). The catalysts were recy-
cled several times without signif-
icant decrease in reactivity.
Table 2. Metal-free synthesis of 5-methylfurfural from fructose.[a]
Entry
Reagents
used
Amount
Solvent
T
[8C]
t
[h]
Gas
P
[psi]
Yield
[%]
1
2
HI
HI
NaI
HI
NaI
HI
3 equiv
1 equiv
2 equiv
1 equiv
2 equiv
3 equiv
20 mg
toluene/H2O
C6H6/H2O
120
105
1
N2
He
300
300
47
38
12
3
C6H6/H2O
105
24
He
300
51
4[b]
5[c]
toluene/H2O
C6H6/H2O
100
90
6
N2
H2
15
300
44
Pd/C
16
No reaction
The reaction I2 +H2 !2 HI, is
favorable from a thermodynamic
standpoint, even in the gas
phase [Keq(1008C)=409]. Howev-
[a] Fructose (1 mmol), HI (57 wt% in water), water (1.6 mL), benzene or toluene (2 mL). [b] Reaction performed
under reflux without an autoclave. [c] HI not added to the reaction mixture.
er, the presence of water provides significant added driving
force because of the solvation of ions derived from HI. The
free energy of hydration of gaseous HI is ꢀ118 kJ molꢀ1 at
1008C [Keq(1008C)=3.3ꢀ1016].
(benzene or toluene) was employed. Fructose and HI were first
dissolved in the aqueous phase before the reaction. Then the
autoclave was flushed with nitrogen or helium and heated in
an oil bath. After the reaction, the organic layer was purple,
with some humin formed at the bottom of the liner. For
entry 1, GC analysis of the organic layer gave a 47% yield of
The fact that a) HI is a strong reducing agent, and b) I2 can
be readily reconverted back to HI in the presence of water has
allowed us to efficiently convert a number of carbohydrate de-
rivatives to useful chemicals without involving a metal catalyst
in the actual biomass reduction step (Scheme 1). This is impor-
tant because it avoids the search for an appropriate metal cat-
alyst that is tolerant of the specific reaction conditions. We il-
lustrate our approach with two important transformations:
a) fructose to 5-methylfurfural, and b) glycerol to 2-iodopro-
pane.
1
MF, and H NMR analysis of the aqueous layer indicated 68%
fructose conversion. Longer reaction times led to decreased
yields of MF, due to its instability. The purple color in the or-
ganic layer was determined to be due to I2 formation, as con-
firmed by a titration experiment with starch solution.
The overall reaction is shown in Scheme 3. The first step in
the reaction is the well-studied acid-catalyzed dehydration of
fructose to 5-hydroxymethyl-2-furaldehyde (HMF),[4,13,14] which
subsequently converts to 5-iodomethylfurfural (IMF) with HI
present. As shown in Table 2, longer reaction times are re-
5-Methylfurfural (MF) is a useful intermediate for the produc-
tion of pharmaceuticals, agricultural chemicals, perfumes, and
other applications.[9] It is also
a common flavoring component
in the food industry,[10] and is
even considered a potential anti-
tumor agent.[11] Recently we
have reported the conversion of
fructose and other hexoses to
Scheme 3. Proposed pathway for MF formation from fructose.
2,5-dimethyltetrahydrofuran
(DMTHF) or MF in the presence
of HI, H2, and an active hydrogenation catalyst.[12] HI was essen-
tial for the reaction; other acids, such as HCl and H2SO4, were
not effective. We now find that the actual conversion of fruc-
tose to MF does not need either H2 or a metal catalyst: compa-
rable yields of MF can be obtained with HI alone (Scheme 2).
This is the first example of MF formation from fructose without
the use of a metal catalyst.
quired if the amount of acid is reduced by substituting part of
the HI by NaI (entries 1 and 4 versus entries 2 and 3). The for-
mation of chloro- and bromomethylfurfural by the reaction of
carbohydrates with HCl and HBr, respectively, is also
known.[15,16] IMF has never been isolated in pure form.[17] The
intermediate 5-iodomethylfurfural (IMF) was found to be easily
reduced to MF with the concomitant formation of iodine as
a byproduct under the given reaction conditions, due to the
weak CꢀI bond (the analogous aromatic compound benzylic
iodide has a bond strength of 180 kJmolꢀ1[18]).
Our results are summarized in Table 2. The reaction was typi-
cally carried out in a glass-lined stainless steel autoclave (al-
though this is not necessary, as shown in entry 4). A biphasic
reaction system with water and an organic extracting solvent
The reaction shown in Table 2, entry 1 was repeated using
HMF as the starting material leading to a 47% yield of MF, the
same yield obtained with fructose. In both instances, dark solid
(humin) was observed to have precipitated out of solution.
HMF, due to its reactive hydroxyl and carbonyl groups, is
highly susceptible to the formation of humin under aqueous
acidic conditions. In the reduction of HMF with HI, the IMF in-
1
Scheme 2. Metal-free conversion of fructose to MF.
termediate was observed by GC and H NMR spectroscopy (see
&2
&
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