SHORT PAPER
Synthesis of 2-Butyl-5-Chloro-3H-Imidazole-4-Carboxaldehyde
507
HO
O
a
O
b
N
NH
NH
NH
c
Cl
N
H
N
Overall Yield: 54%
H
O
2
Scheme 2 (a) i. MeOH, HCl (g), 12 h, 20 °C, ii. Toluene, KOH (6 M); (b) Glycine, MeOH–H O, 15 h, 40 °C; (c) POCl , DMF, 100 °C, 3 h.
2
3
solvent was not necessary and that a moderate rise in tem- Conclusions
perature would result in faster product formation. Thus,
HCl gas was passed through a solution of valeronitrile and The above report describes a rapid, practical and commer-
MeOH at –10 °C to 5 °C and then the vessel was sealed cially viable process for the preparation of 2-butyl-5-chlo-
tightly and stirred at 20 °C for 12 hours to get a cloudy ro-3H-Imidazole-4-carboxaldhyde. The procedure is
white mass. After evaporating the solvents under vacuum, attractive and speedy as it avoids the isolation and purifi-
toluene was added to the salt obtained and the solution cation of the intermediates at the various stages. The reac-
was neutralized with aqueous KOH solution. The toluene tion conditions are optimized to minimize impurity
solution of the free base was directly added to the glycine formation and to prepare the product in good yields and in
suspension in MeOH–H O without any further treatment. highest purity.
2
After 15 hours, a small amount of the above reaction mix-
ture was evaporated to dryness and analyzed by H NMR
1
General Procedure
In a three-necked 1 L round bottom flask equipped with stirrer, ther-
mometer, and gas bubbler, a solution of valeronitrile (110 g, 1.32
mol) in MeOH (63 g, 1.95 mol) was taken and cooled to –10 °C un-
spectroscopy in D O. The crude reaction mixture showed
singlets at = 3.87 and = 3.55 for methylene protons of
2
NHCH C=O unit of (pentanimidoyalamino)acetic acid
2
der N . HCl gas (65 g, 2 mol) was bubbled below the surface of the
2
and glycine, respectively, in the ratio of 7:3 revealing that
liquid at such a rate that the reaction temperature was maintained
7
0% of the (pentanimidoyalamino) acetic acid was below 5 °C. Stirring was continued at 20 °C for 12 h, to form thick
formed. The butyl signals appeared as a triplet at = 2.53; white slurry, which was flushed with N and dried under vacuum
10 mm) to get a thick white mass. Toluene (500 mL) was added to
2
(
two multiplets at = 1.53 and at = 1.70 and a triplet at
0.91 in the ratio of 7:7:7:10 respectively, were consis-
tent with the product formed (Scheme 2).
the reaction mixture, cooled to –10 °C and neutralized with 6 M
KOH (250 mL) to pH 8 at such a rate that temperature of mixture
was below 5 °C. The toluene layer was decanted and the aqueous
=
The crude reaction mixture was completely evaporated layer was extracted with toluene (3 × 100 mL). The combined tolu-
ene layers of pentanimidate base was added dropwise, to a stirred
under vacuum and the resultant mass was dried by repeat-
mixture of glycine (100 g, 1.32 mol) in MeOH (300 mL) and water
ed evaporation with toluene. This was subjected to the
(
50 mL) at 0 °C to –5 °C. The pH of the reaction mixture was
modified Vilsmeier reaction by treating with POCl at
3
brought to 8 by adding 2–3 drops of 6 M KOH and reaction was
continued for 15 h at 40 °C. The reaction mixture was concentrated
under vacuum and the suspension was dried by co-evaporation with
–
5 °C followed by addition of DMF at a temperature be-
low 75 °C. The reddish brown solution was heated to 100
°
C and maintained at 100 °C for 3 hours. After cooling, toluene (5 × 100 mL). The pale yellow solid material suspended in
the reaction mixture was poured into ice, neutralized to toluene (150 mL), was cooled to –5 °C and POCl (230 mL, 2.5
3
mol) was added drop wise within 20 min, DMF (137 mL, 1.76 mol)
was added at such a rate that the temperature of reaction mixture
was maintained below 75 °C. After complete addition, the contents
of reaction mixture were held at 97–100 °C for 3 h. The reddish
brown solution was cooled to r.t. and poured over crushed ice (1 kg)
at 0 °C. Celite (100 g) was added with stirring and neutralized to pH
pH 6.0, extracted with toluene and concentrated to get an
impure solid material. We devised an efficient method to
isolate the product from the impurities by exploiting the
acid-base nature of the imidazole formed. The toluene ex-
tract having the product in solution was treated with 10%
aqueous KOH and the aqueous portion was carefully acid- 6.0 using 30% NaOH (500 mL). Celite was filtered and washed with
ified with acetic acid to precipitate a solid that was recrys- toluene (100 mL). The combined toluene layer was separated and
the product was extracted with 10% KOH (3 × 100 mL). The basic
tallized in toluene–cyclohexane solvent mixture to give a
pale yellow solid in 99.9% HPLC purity. The purity of the
solution was cooled to 0 °C and acidified to pH 6.0 with acetic acid,
to get a light brown colored solid, which was filtered. The crude
product was taken in 1:5 mixture of toluene and cyclohexane (500
product is much superior to the product prepared by Grif-
1
4
fith’s procedure (96.9%). The product was characterized
mL) and treated with charcoal at 80 °C, filtered and cooled to give
1
3
1
1
4
C and H NMR and mass spectral analysis and is in pale yellow solid (132 g, 54% in overall yield); mp 93 °C (lit. 92–
1
4
1
13
agreement with literature data.
95 °C), 99.9% HPLC purity. The H NMR, C NMR and mass
1
4
spectra are in complete agreement with the literature values.
Synthesis 2004, No. 4, 506–508 © Thieme Stuttgart · New York