Preparation of acylated imidazoles

Acylated imidazoles of the formula ##STR1## where R.sup.1 and R.sup.3 are each H, alkyl of from 1 to 12 carbon atoms, alkenyl of from 1 to 12 carbon atoms, aryl, aralkyl or alkylaryl, R.sup.4 is H, alkyl of from 1 to 12 carbon atoms, alkenyl of from 1 to 12 carbon atoms, aryl, aralkyl or alkylaryl, and R.sup.5 is alkyl of from 1 to 12 carbon atoms, alkenyl of from 1 to 12 carbon atoms, aryl, aralkyl, alkylaryl or carboxyl, are prepared by reacting imidazoles of the formula ##STR2## where R.sup.1, R.sup.2 and R.sup.3 are each alkyl of from 1 to 12 carbon atoms, alkenyl of from 1 to 12 carbon atoms, aryl, aralkyl or alkylaryl, at least one of the radicals R.sup.1, R.sup.2 and R.sup.3 being hydrogen, and R.sup.4 is H, alkyl of from 1 to 12 carbon atoms, alkenyl of from 1 to 12 carbon atoms, aryl, aralkyl or alkylaryl, with widely used acylating agents of the formula ##STR3## where R.sup.5 is as defined above and Y is halide, alkoxy, acyloxy or hydroxyl, in the presence of acidic metal oxides and/or phosphates, preferably in the gas phase.

The present invention relates to a process for preparing acylated 
imidazoles by direct acylation of appropriate unsubstituted or substituted 
imidazoles with widely used acylating agents over acidic metal oxides and 
phosphates. 
Heretofore, direct C-acylations of imidazoles in Friedel-Crafts reactions 
were not known or indeed considered feasible (A. R. Katritzky, C. W. Rees, 
Comprehensive Heterocyclic Chemistry, Vol. 5, page 402 (1984), Pergamon 
Press; K. Hofmann, The Chemistry of Heterocyclic Compounds, Vol. 6; 
Imidazole and its derivatives, Part I, page 49 and page 59 (1953), 
Interscience Publishers). 
For this reason it was necessary to resort to other means, for example the 
photochemical rearrangement of N-acetylimidazoles (J. L. La Mattina et 
al., J. Org. Chem. 48 (1983), 897-8), the reaction of 4-formylimidazoles 
with a Grignard reagent and subsequent oxidation (for example R. Paul et 
al., J. Med. Chem. 28 (1985), 1704-16) or the hydrogenolysis of a 
4-acylamino-5-methylisoxazole (EP 156, 644, Pfizer). 
However, these prior art processes are resource intensive and not suitable 
for industrial application. 
We have found, surprisingly, that C-acylated imidazoles of the formula (I) 
##STR4## 
where R.sup.1 and R.sup.3 are each H, alkyl of from 1 to 12 carbon atoms, 
alkenyl of from 1 to 12 carbon atoms, aryl, aralkyl or alkylaryl, R.sup.4 
is H, alkyl of from 1 to 12 carbon atoms, alkenyl of from 1 to 12 carbon 
atoms, aryl, aralkyl or alkylaryl, and R.sup.5 is alkyl of from 1 to 12 
carbon atoms, alkenyl of from 1 to 12 carbon atoms, aryl, aralkyl, 
alkylaryl or carboxyl, are obtained directly, while avoiding the 
disadvantages of the existing multistage and resource intensive processes 
on reacting imidazoles of the formula (II) 
##STR5## 
where R.sup.1, R.sup.2 and R.sup.3 are each alkyl of from 1 to 12 carbon 
atoms, alkenyl of from 1 to 12 carbon atoms, aryl, aralkyl or alkylaryl, 
at least one of the radicals R.sup.1, R.sup.2 and R.sup.3 being hydrogen, 
and R.sup.4 is H, alkyl of from 1 to 12 carbon atoms, alkenyl of from 1 to 
12 carbon atoms, aryl, aralkyl or alkylaryl, with widely used acylating 
agents of the formula (III) 
##STR6## 
where R.sup.5 is as defined above and Y is halide, alkoxy, acyloxy or 
hydroxyl, in the presence of acidic metal oxides and/or phosphates. 
The reaction of 2-methylimidazole with acetic anhydride to give 
4-acetyl-2-methylimidazole over a catalyst may be represented for example 
by the following equation: 
##STR7## 
The analogous reaction of 4-methylimidazole gives in the main 
5-acetyl-4-methylimidazole, but in addition also 
2-acetyl-4-methylimidazole. 
Examples of suitable starting materials of the abovementioned formula (II) 
for the process according to the invention are imidazole, 
2-methylimidazole, 2-ethylimidazole, 2-propylimidazole, 
2-isopropylimidazole, 2-decylimidazole, 2-dodecylimidazole, 
1-methylimidazole, 4-methylimidazole, 2-ethyl-4-methylimidazole, 
4-n-butylimidazole, 2-isopropylimidazole, 2-isopropyl-4-ethylimidazole, 
2,4-di-n-butylimidazole, 2-phenylimidazole, 4-phenylimidazole and 
4-benzylimidazole. 
Examples of acylating agents are acetyl chloride, acetic acid, acetic 
anhydride, methyl acetate, ethyl acetate, acetamide, propionyl chloride, 
propionic acid, propionic anhydride, butyryl chloride, butyric acid, 
butyric anhydride, isobutyric acid, isobutyryl chloride, isobutyric 
anhydride, crotonic acid, crotonic anhydride, isoprenic acid, valeric 
acid, valeroyl chloride, caproic acid, caproic ester, pivalic acid, 
pivaloyl chloride, acrylic acid, methyl acrylate, methacrylic acid, 
methacrylic esters, methyl 3-pentenoate, methyl 2-pentenoate, methyl 
4-pentenoate, sorbic acid, methyl sorbate, benzoic acid, benzoyl chloride, 
methyl benzoate, o-, m- or p-fluorobenzoic acid, o-, m- or p-fluorobenzoyl 
chloride, o-, m- or p-chlorobenzoic acid, o-, m- or p-methylbenzoic acid, 
o-, m- or p-methylbenzoyl chloride, o-, m- or p-methoxybenzoic acid, o-, 
m- or p-methoxybenzoyl chloride, o-, m- or p-isopropylbenzoic acid, o-, m- 
or p-isopropylbenzoyl chloride, 2,3-dimethyl-, 2,3-difluoro-, 
2,3-dichloro- or 2,3-dimethoxy-benzoic acid or -benzoyl chloride, 
phenylacetic acid, phenylacetyl chloride, phenylacetic anhydride, cinnamic 
acid, cinnamoyl chloride, malonic acid, malonic anhydride, phthalic acid, 
phthalic anhydride, terephthalic acid and terephthaloyl chloride. 
Examples of suitable catalysts are acidic metal oxides such as the acidic 
oxides of elements of main groups II to IV and subgroups III to VI of the 
periodic table, in particular silicon dioxide in the form of silica gel, 
diatomaceous earth, quartz, and also titanium dioxide, zirconium dioxide, 
phosphorus oxides, vanadium pentoxide, niobium oxide, boron trioxide, 
aluminum oxide, chromium oxides, molybdenum oxides, tungsten oxides, or 
mixtures thereof. A modification with metals or acids is possible. 
It is also possible to use catalysts which have been impregnated with 
phosphoric acid or boric acid. Phosphoric acid or boric acid is applied to 
SiO.sub.2, Al.sub.2 O.sub.3 or pumice carriers, for example by 
impregnating or spraying. A catalyst which contains phosphoric acid can be 
obtained for example by impregnating SiO.sub.2 with H.sub.3 PO.sub.4 or 
NaH.sub.2 PO.sub.4 or Na.sub.2 HPO.sub.4 solution and subsequent drying or 
calcination. However, phosphoric acid may also be sprayed together with 
silica gel in a spray tower; this is followed by drying and usually a 
calcination. Phosphoric acid may also be sprayed onto the carrier material 
in an impregnating mill. 
Further catalysts for the acylation of imidazoles are phosphates, in 
particular aluminum phosphates, silicon aluminum phosphates, silicon iron 
aluminum phosphates, cerium phosphates, zirconium phosphates, boron 
phosphates, iron phosphates, strontium phosphates and mixtures thereof. 
Phosphate catalysts used can be precipitated aluminum phosphates. Such an 
aluminum phosphate is obtained on dissolving 92 g of diammonium hydrogen 
phosphate in 700 ml of water and adding 260 g of Al(NO.sub.3).sub.3 
.times.H.sub.2 O in 700 ml of water dropwise over 2 hours, during which 
the pH is maintained at pH 8 by the simultaneous addition of 25% strength 
NH.sub.3 solution. The precipitate formed is subsequently stirred for 12 
hours, then filtered off with suction and washed. It is dried at 
60.degree. C./16 h. 
Boron phosphates which are suitable for use as catalysts for the process 
according to the invention may be prepared for example by mixing and 
kneading concentrated boric acid or phosphoric acid and subsequent drying 
and calcination in an inert gas, air or steam atmosphere at from 
250.degree. to 650.degree. C., preferably at from 300.degree. to 
500.degree. C. 
The aluminum phosphate catalysts used for the process according to the 
invention are aluminum phosphates synthesized in particular under 
hydrothermal conditions. Suitable aluminum phosphates are for example 
APO-5, APO-9, APO-11, APO-12, APO-14, APO-21, APO-25, APO-31 and APO-33. 
AlPO.sub.4 -5 (APO-5) can be synthesized by mixing orthophosphoric acid 
with pseudoboehmite (Catapal SB R) in water to give a homogeneous mixture; 
tetrapropylammonium hydroxide is added, and the mixture is then reacted in 
an autoclave at about 150.degree. C. under autogenous pressure for from 20 
to 60 hours. The AlPO.sub.4 is filtered off, dried at from 100.degree. to 
150.degree. C. and calcined at from 450.degree. to 550.degree. C. 
AlPO.sub.4 -9 (APO-9) is synthesized from orthophosphoric acid and 
pseudoboehmite in an aqueous DABCO solution 
(1,4-diazabicyclo[2.2.2]octane) at about 200.degree. C. under autogenous 
pressure in the course of from 200.degree. to 400 hours. If the DABCO 
solution is replaced by ethylenediamine, APO-12 is obtained. 
AlPO.sub.4 -21 (APO-21) is synthesized from orthophosphoric acid and 
pseudoboehmite in an aqueous pyrrolidone solution at from 150.degree. to 
200.degree. C. under autogenous pressure in the course of from 50 to 200 
hours. 
In the process according to the invention, it is also possible to use known 
silicon aluminum phosphates such as SAPO-5, SAPO-11, SAPO-31 and SAPO-34. 
These compounds are prepared by crystallization from aqueous mixture at 
from 100.degree. to 250.degree. C. under autogenous pressure in the course 
of from 2 hours to 2 weeks, the reaction mixture, which is composed of a 
silicon, aluminum and phosphorus component, being converted in an aqueous 
organoamine solution. 
SAPO-5 is obtained by mixing SiO.sub.2 suspended in aqueous 
tetrapropylammonium hydroxide solution with an aqueous suspension of 
pseudoboehmite and orthophosphoric acid and subsequent reaction at from 
150.degree. to 200.degree. C. under autogenous pressure in a stirred 
autoclave in the course of from 20 to 200 hours. The powder is filtered 
off, dried at from 110.degree. to 150.degree. C. and calcined at from 
450.degree. to 550.degree. C. 
Suitable silicon aluminum phosphates also include ZYT-5, ZYT-6, ZYT-7, 
ZYT-9, ZYT1-11 and ZYT-12. 
To maximize selectivity, conversion and catalyst life, it is advantageous 
to modify the catalysts. 
A possible modifying technique comprises subjecting the material, in molded 
or unmolded form, to a treatment with acids such as hydrochloric acid, 
hydrofluoric acid and phosphoric acid and/or steam. An advantageous 
procedure is to treat the catalysts in powder form with 1 N phosphoric 
acid at 80.degree. C. for 1 hour. After the treatment the catalyst is 
washed with water, dried at 110.degree. C./16 h and calcined at 
500.degree. C./20 h. Alternatively, the catalysts are treated before or 
after molding with binders, for example at from 60.degree. to 80.degree. 
C. with from 3 to 25% strength by weight, in particular from 12 to 20% 
strength by weight, aqueous hydrochloric acid for from 1 to 3 hours. 
Thereafter the catalyst thus treated is washed with water, dried and 
calcined at from 400.degree. to 500.degree. C. 
A special embodiment of acid treatment comprises treating the material 
before it is molded at elevated temperatures with from 0.001 N to 2 N 
hydrofluoric acid, preferably from 0.05 to 0.5 N hydrofluoric acid, by 
refluxing for from 0.5 to 5 hours, preferably for from 1 to 3 hours. After 
the material has been isolated by filtering and washing, it is 
conveniently dried at from 100.degree. to 160.degree. C. and calcined at 
from 450.degree. to 600.degree. C. In a preferred embodiment of the acid 
treatment, the material, after it has been molded with a binder, is 
treated at an elevated temperature, conveniently at from 50.degree. to 
90.degree. C., with from 3 to 25% strength by weight hydrochloric acid, 
preferably with from 12 to 20% strength by weight hydrochloric acid, for 
from 1 to 3 hours. Thereafter the material is washed, dried at from 
100.degree. to 160.degree. C. and calcined at from 450.degree. to 
600.degree. C. A successive treatment with HF and HCl may also be 
advantageous. 
Another procedure comprises modifying the catalysts by applying phosphorus 
compounds, such as trimethyl phosphate, trimethoxyphosphine, or primary, 
secondary or tertiary sodium phosphates. The treatment with primary sodium 
phosphate has proved to be advantageous. In this case, the zeolites are 
impregnated in extruded, tablet or fluidizable form with aqueous NaH.sub.2 
PO.sub.4 solution, dried at 110.degree. C. and calcined at 500.degree. C. 
The catalysts described may as a matter of choice be used in the form of 
extrudates from 2 to 4 mm, as tablets from 3 to 5 mm in diameter, as chips 
from 0.1 to 0.5 mm in particle size or as fluidizable material. 
The reaction according to the invention is preferably carried out in the 
gas phase at from 300.degree. to 600.degree. C., in particular at from 
400.degree. to 550.degree. C., in a fixed or fluidized bed using a weight 
hourly space velocity (WHSV) of from 0.1 to 20 h.sup.-1, in particular of 
from 0.5 to 5 h.sup.-1 (g of starting mixture per g of catalyst per hour). 
It is also possible to carry out the reaction in the liquid phase (by the 
suspension, trickle bed or liquid phase procedure) at from 50.degree. to 
300.degree. C., in particular at from 100.degree. to 250.degree. C., with 
a starting material:catalyst weight ratio of from 100:1 to 5:1, preferably 
from 60:1 to 10:1. 
The process may be carried out under atmospheric pressure or, depending on 
the volatility of the starting compound, under reduced pressure or 
superatmospheric pressure, preferably continuously. 
Sparingly volatile or solid starting materials are used in dissolved form, 
for example in THF, toluene or petroleum ether solution. In general, the 
starting material may be diluted with solvents or with inert gases, such 
as N.sub.2, Ar, He or H.sub.2 O vapor. 
After the reaction, the acylated imidazoles are isolated from the reaction 
mixture in a conventional manner, for example by distillation; unconverted 
starting mixture is recycled, if appropriate.

EXAMPLES 1 TO 10 
The reaction is carried out in the gas phase under isothermal conditions in 
a tubular reactor (coil, 0.6 cm in internal diameter, 90 cm in length) for 
at least 6 hours. The reaction products are separated off in a 
conventional manner and characterized by GC/MS, NMR and melting point 
determination. The quantitative determination of the reaction products and 
the starting materials is done by gas chromatography. 
The catalysts used in the application examples below are: 
Catalyst A 
Commercial Al.sub.2 O.sub.3 (D 10-10.RTM., BASF) in the form of extrudates 
Catalyst B Commercial SiO.sub.2 (D 11-10.RTM., BASF) in the form of 
extrudates 
Catalyst C 
Commercial zirconium phosphate Zr.sub.3 (PO.sub.4).sub.4 is molded with a 
molding aid into 2-mm extrudates and dried at 110.degree. C. and calcined 
at 500.degree. C./16 h. 
Catalyst D 
Catalyst D is a precipitated boron phosphate prepared by adding together 49 
g of H.sub.3 BO.sub.3 and 117 g of H.sub.3 PO.sub.4 (75% strength) in a 
kneader, evaporating off excess water and molding the product into 3-mm 
extrudates. These extrudates are dried at 110.degree. C. and calcined at 
350.degree. C. Catalyst D contains 9.24% by weight of B and 29.5% by 
weight of P. 
Catalyst E 
Catalyst E is a precipitated aluminum phosphate prepared by precipitation 
from Al(NO.sub.3).sub.3 and H.sub.3 PO.sub.4 solution with NH.sub.3 at pH 
6-7. After filtration the precipitate is dried at 110.degree. C. and 
calcined at 500.degree. C. Catalyst C contains 22.7% by weight of Al and 
25.3% by weight of P. 
Catalyst F 
Catalyst F consists of pyrogenic TiO.sub.2 molded in the presence of a 
molding aid into 2-mm extrudates, dried at 110.degree. C. and calcined at 
500.degree. C./16 h. The extrudates are treated with 15% strength HCl 
(weight ratio=1:10) at 80.degree. C. for 1 hour, then washed until 
chloride-free, and dried at 110.degree. C. and calcined at 600.degree. 
C./1 h. 
Catalyst G 
Catalyst G consists of catalyst B impregnated with dilute phosphoric acid, 
dried at 130.degree. C. and calcined at 540.degree. C./2 h. The P content 
is 4.73% by weight. 
Catalyst H 
Catalyst H consists of commercial niobium oxide hydrate (61.2% by weight of 
Nb; 9.5% by weight of H.sub.2 O) molded with a molding aid into 2-mm 
extrudates, dried at 110.degree. C. and calcined at 500.degree. C./16 h. 
Catalyst I 
Catalyst I consists of catalyst B impregnated with dilute NaH.sub.2 
PO.sub.4 solution, dried at 110.degree. C. and calcined at 500.degree. 
C./14 h. It contains 6.2% by weight of Na and 7.7% by weight of P. 
EXAMPLES 1 TO 3 
A mixture of 2-methylimidazole, acetic acid and acetic anhydride (molar 
ratio=1:4:1) is vaporized and passed with a 6 l/h nitrogen steam at 
450.degree. C. over the 
catalyst under a WHSV of 4 h.sup.-1. 
The reaction product is condensed in a glass apparatus and analyzed by gas 
chromatography. 
TABLE 1 
______________________________________ 
Acetylation of 2-methylimidazole 
GC analysis of output* 
4-acet- 
2- yl-2- 
Tem- meth- N-acetyl- 
methyl- 
Ex- pera- yl imi- 
2-methyl- 
imid- 
am- Cata- Run ture WHSV dazole 
imidazole 
azole 
ple lyst [h] [.degree.C.] 
[h.sup.-1 ] 
[%] [%] [%] 
______________________________________ 
1 I 6 450 4 19.5 0000 14.1 
2 C 6 450 4 16.9 8.4 15.5 
3 D 6 450 4 14.3 8.4 19.3 
______________________________________ 
*output collected over 2 h following a run of 6 h. 
EXAMPLES 4 TO 10 
A mixture of imidazole, acetic acid and acetic anhydride (molar 
ratio=1:4:1) is vaporized and passed with a 6 l/h nitrogen stream at 
450.degree. C. over the catalyst under a WHSV of 3 h.sup.-1. 
The reaction product is condensed in a glass apparatus and analyzed by gas 
chromatography. 
TABLE 2 
______________________________________ 
Acetylation of imidazole 
Tem- GC analysis of output* 
Ex- pera- Imid- N-acetyl- 
c-acetyl- 
am- Cata- Run ture WHSV azole imidazole 
imidazole 
ple lyst [h] [.degree.C.] 
[h.sup.-1 ] 
[%] [%] [%] 
______________________________________ 
4 B 6 450 3 3.6 31.7 1.3 
5 E 6 450 3 15.8 12.8 3.1 
6 C 6 450 3 22.4 6.2 2.0 
7 F 6 450 3 25.7 0.2 1.4 
8 A 6 450 3 19.0 3.8 3.0 
9 G 6 450 2 6.2 15.0 2.0 
10 H 6 450 3 12.2 9.7 1.2 
______________________________________ 
*averaged over 6 h runs. 
EXAMPLE 11 
The reaction is carried out in a 1-liter fluidized bed reactor in the gas 
phase. The temperature is 400.degree. C. 60 g/h of a mixture of 
2-methylimidazole and acetic anhydride (1:1.3 moles) are added, and 150 
l/h of nitrogen are passed in as fluidizing gas. The reactor has been 
packed with 300 ml of catalyst in fluidizable form. 
The catalyst used is commercial SiO.sub.2 in fluidizable form. 
Analysis of the reactor output indicates a 2-methylmidazole coversion of 
87% and selectivity of 75% for 4-acetyl-2-methylimidazole.