4606
A. K. Bose et al. / Tetrahedron Letters 47 (2006) 4605–4607
Of special interest to us was the successful formylation
O
of 3-amino-4-hydroxybenzaldehyde (13) in high yield
because compound 14 could serve as an intermediate
for the preparation of the pharmaceutical Foradil and
its analogs. This amino compound (13) was readily
available by the reduction of 3-nitro-4-hydroxybenzal-
dehyde (12) that in turn had been prepared in our labo-
ratory by microwave assisted nitration of commercially
available p-hydroxybenzaldehyde (11).
NH2
HN
NO2
NO2
4
3
O
OH
OH
OH
NH2
OH
HN
H
N
O
NH2
NO2
H
NO2
NO2
H
O
H
O
H
O
H
O
12
13
14
11
5
Scheme 2.
We used the Milestone Ethos low pressure benchtop
microwave reactor for multiple gram scale formylations.
Thus, 20 g of o-nitroaniline (3) was allowed to react with
slightly more than an equivalent of aq formic acid (80%)
with a computer setting for a maximum temperature of
80 °C and a reaction time of 10 min. After letting the
reaction mixture cool, 50 mL of water was added and
this mixture was set aside. Yellow crystals that formed
were separated by filtration and made acid free by wash-
ing with water. After drying, the crystalline product had
the correct melting point (without recrystallization) and
the yield was about 90%. Much larger scale reactions
can be conducted, since this microwave applicator has
been modified to allow reactions on a scale of about 3 kg.
(85% yield) that did not need purification by recrystalli-
zation (Scheme 1).
It is well known that the amino group in o-nitroanilines
(3a) and p-nitroanilines (3b) is of very low basicity and
hence not easily acylated. It was interesting therefore
to observe that both types of compounds could be N-
formylated to 4 and 5 with aq formic acid (80%) under
microwave irradiation in high yield in 3 min on a 2–5 g
scale3 (Scheme 2).
A secondary amine—diphenylamine—was allowed to
react with aq formic acid (80%) using our ‘MORE’
chemistry procedure; after a few minutes of microwave
irradiation the N-formyl product 6 crystallized out on
cooling the reaction mixture. Indole and carbazole also
provided the N-formyl derivatives (7, 8) with equal ease.
It was also possible to formylate an aliphatic amine
(e.g., benzylamine) to 9; hydrazine was converted to
diformamide 10.
We also used the Prolabo 1000 applicator that produces
focused microwaves for large scale experiments. In one
procedure, 100 g of o-nitroaniline and 200 mL of aq for-
mic acid (80%) were allowed to react under microwave
irradiation for 7 min; the computer control was set for
a maximum reaction temperature of about 90 °C (250–
350 W). Product 4 of mp 171 °C (lit. mp 173–175 °C)
was obtained without recrystallization in about 90%
yield.
It is known that an alkyl(phenyl) formamide group can
be converted easily to an isocyanide group (–NC). Many
isocyanides are components of marine natural products.
The isocyanide group is a pseudo-halogen and can be re-
moved by reaction with tributyltin hydride (or deute-
ride). The use of 13C-labeled formic acid would lead to
rapid, inexpensive and convenient labeling with a stable
isotope, providing compounds of value for tracking
metabolites and their quantitative analysis by mass
spectrometry.
N
N
N
H
O
H
O
O
H
O
6
7
8
H
N
O
In conclusion, it may be noted that the ‘MORE’ chem-
istry procedure allows rapid, eco-friendly access to
diverse types of N-formyl compounds with the
expenditure of small amounts of microwave energy. A
large excess of aq formic acid need not be used. N-for-
myl products that crystallize out do not need further
purification by recrystallization.
H2C
C
H
H
N
H
N
H
CH
O
9
10