Formation of the imidazolinone ring under mild conditions in the presence of sodium hydride

Article abstract of DOI:10.3390/90700535

Substituted imidazolinones containing heterocyclic carboxylic acids as substituents and possessing herbicidal properties were synthesized by cyclization of 2-amino-2,3-dimethylbutyramide with heterocyclic ethyl dicarboxylates under mild conditions. The use of NaH as base leads to a significant increase in the reaction rate and allows the preparation of the target compounds in high yields.

Full text of DOI:10.3390/90700535

Molecules 2004, 9, 535-540
molecules
ISSN 1420-3049
http://www.mdpi.org
Formation of the Imidazolinone Ring Under Mild Conditions in
the Presence of Sodium Hydride
Aleksey N. Vasiliev*, Antonio F. Lopez, Julio D. Fernandez and Anibal J. Mocchi
Center for Chemical Research and Technologies, Cordoba Faculty, National Technological University,
C.C. 17, Suc. 16, Cordoba 5016, Argentina. Tel/Fax: (+54)-351-469-0595.
* Author to whom correspondence should be addressed; e-mail vasiliev@scdt.frc.utn.edu.ar
Received: 11 December 2002; in revised form: 15 September 2003 / Accepted 19 September 2003 /
Published: 30 June 2004
Abstract: Substituted imidazolinones containing heterocyclic carboxylic acids as
substituents and possessing herbicidal properties were synthesized by cyclization of
2-amino-2,3-dimethylbutyramide with heterocyclic ethyl dicarboxylates under mild
conditions. The use of NaH as base leads to a significant increase in the reaction rate and
allows the preparation of the target compounds in high yields.
Keywords: Imidazolinones, herbicides, cyclization, sodium hydride
Introduction
Substituted imidazolinones were found to be exceedingly effective herbicidal agents, useful for the
control of an exceptionally wide variety of plants at the end of the seventies [1]. Their effect is based on
inhibition of the enzyme acetohydroxyacid synthase by reducing levels of valine, leucine and isoleucine
and leading to disruption of protein and DNA synthesis. It was found that bioactivity of these compounds is
appreciably higher when a N-containing heterocyclic carboxylic acid is present as a substituent in the
imidazolinone ring. The first of the heterocyclyl-substituted imidazolinones was synthesized by Los [2,3].
Most methods for the synthesis of these compounds involve multistep processes and result in low
yields of the desired products. One of them is based on oxidative condensation of 2-methylpyridine with

Molecules 2004, 9
536
2-amino-2,3-dimethylbutyramide (ADBA) in the presence of elemental sulfur. The carboxyl group was
then introduced into the pyridine ring by successive treatment with BuLi and CO2 at low temperature [4],
however the yield of the desired product was very low. Chlorination of ethyl
2-methyl-3-quinolinecarboxylate gave a 2-trichloromethyl derivative which was treated with ADBA in the
presence of the phase transfer catalyst [Bu4N]+[HSO4]– to give a 19% yield of imidazolinone [5]. Another
method in which diethyl pyridinedicarboxylate is converted into 2-(2’-imidazolin-2’-yl)-
pyridine-3-carboxylic acid has been described [6]. This last synthesis was carried out in five steps with
isolation of all intermediates and again, the final yield of imidazolinones was low. In the present work we
have developed a novel simple method for obtaining imidazolinones using NaH as base.
Results and Discussion
As we have found, the reaction of diethyl esters of 5-ethylpyridine-2,3-dicarboxylic acid (3a) and
quinoline-2,3-dicarboxylic acid (3b) with 2-amino-2,3-dimethylbutyramide (1) proceeds easily at ambient
temperature. The process is exothermic and a rise in the reaction mixture temperature is observed. In the
presence of sodium hydride, cyclization occurs at a much lower temperature than that observed with other
bases (CH3ONa, t-C4H9OK), and the yields of imidazolinones are higher.
Previously, a cyclization mechanism for the reaction between 1 and 3 was reported for substituted
pyridine-2,3-dicarboxylic anhydride [6]. According to the proposed scheme, in the first step, the amino
group reacts with the anhydride to give 6-(1’,2’-dimethyl-1’-aminocarbonyl)propyl-5H-pyrrolo-
[3,4-b]pyridine-5,7(6H)-dione with the structure shown in Figure 1, below.
Figure 1
R
CONH2
CH3
CH(CH3)2
CO
N
CO
R'
N
The amide group CONH2 is a weaker nucleophile and unable to attack the anhydride. The second step
takes place in the presence of NaOH. The nucleophilic attack of the amide group in alkaline media on one
of the carbonyl groups at pyridine ring of this compound gives a mixture of tricyclic
imidazopyrrolopyridinediones 13 (15%) and 14 (85%). The second of them is unstable and hydrolizes
easily to give
a
final product 15. It is interesting to note that only
2-(2’-imidazolin-2’-yl)-pyridine-3-carboxylic acid is formed and 3-(2’-imidazolin-2’-yl)-pyridine-
2-carboxylic acid was not found in the reaction mixture. In the process described here (Scheme 1), addition
of NaH to the reaction mixture results in formation of sodium salt 2, and the amide anion becomes a
stronger nucleophile than amine. We suggest that in this case the process begins with attack of CONH- on
the carbonyl group of 3, and the amides 4 and 5 are formed as a result of this. 10. The next step is the
formation of imidazopyrrolopyridinediones.

Molecules 2004, 9
537
Scheme 1
CH(CH3)2
H2N
CONH2
CH3
1
NaH
CH(CH3)2
R
COOEt
COOEt
-
CONH
H2N
CH3
R'
N
2
3
CH3
R
COOEt
NH2
EtO
NH
-
O
R
O
CH(CH3)2
CH(CH3)2
NH2
-
O
R'
N
O
NH
EtO
R'
N
COOEt
CH3
4
5
-
-
EtO
-
EtO
-
O
O
R
COOEt
NH
CH(CH3)2
NH2
CH3
R
NH2
NH
R'
N
CH3
CH(CH3)2
R'
N
COOEt
O
O
6
7
-
O
O
O
CH3
R
OEt
R
NH2
CH(CH3)2
NH2
N
N
CH(CH3)2
R'
N
OEt
R'
N
-
O
O
O
CH3
8
9
-
EtO
-
O
R
O
CH(CH3)2
NH2
N
R'
N
CH3
O
10

Molecules 2004, 9
538
Scheme 1. (Cont.)
O
R
O
CH(CH3)2
NH2
N
R'
N
CH3
O
10
O
O
OH
N
CH(CH3)2
CH3
R
R
NH
N
CH
3
NH
R'
N
R'
N
CH(CH3)2
OH
O
O
12
11
O
CH(CH3)2
CH3
N
R
R
COOH
NH
R
O
N
N
O
R'
N
R'
N
CH3
CH(CH3)2
R'
N
N
O
N
O
15
14
13
CH(CH3)2
CH3
a: R=C2H5; R’=H
b: R+R’= (CH=CH-CH=CH)
These possess an active hydrogen which reacts with the second molecule of NaH, and the CO_N–_CO
anion obtained participates in an intramolecular nucleophilic attack forming the bicyclic structures 13-14.
Only one isomer converts into final substance, so the resulting product is pure compound 15. The yield of
15 by this method was higher than reported in the literature data [5,6] where the products were obtained in
54.2-76.5% yields upon heating for 1-4 h at 80-110oC. By using NaH, the temperature of the reaction was
decreased to 20oC and the reaction was complete in 15 min. The compounds obtained have a high degree of
purity (98.5-99%).
Conclusions
The method presented allows preparation of substituted imidazolinones in high yields. The low
temperature and short reaction times make the process much more effective compared to literature
methods.

Molecules 2004, 9
539
Acknowledgements
This research was supported by Tecnomyl SRL. We thank Prof. Eduardo R. Herrero for helpful
discussions.
Experimental
General
1
IR spectra were recorded on a Jasco FT/IR-5300 spectrometer (KBr pellets). H-NMR spectra were
recorded on a Bruker-200X (DMSO, 200.13 MHz). Mass spectra were obtained on a Finnigan 3300 F-100
at 70 eV. The purities of 15a-b were confirmed by HPLC analysis on a Jasco UV-975 chromatograph
equipped with a C-18 column (flow, 1 mL/min; mobile phase: 80:20 methanol-water; λ=254 nm).
Preparation of 2-(4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl)-5-ethyl-3-pyridine-
carboxylic acid (15a) and 2-(4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl)-
3-quinolinecarboxylic acid (15b).
NaH (0.02 mol, 60% suspension in oil) was added with stirring over 15 min. to a solution of 1 (0.01
mol) and 3a or 3b (0.01 mol) in dry toluene (10 mL), When the addition of NaH was complete, the reaction
mixture was extracted with water (2 x 10 mL), and the aqueous phase was acidified to pH=2-3. The white
precipitates formed were filtered, washed with water, and air dried overnight to give 15a (yield: 85.2 %,
o
m.p. 173oC, recrystallized from toluene) and 15b (yield: 83.7 %, m.p. 224 C, from i-propanol),
respectively.
Spectral Data
15a: IR (cm-1): 3246, 1745, 1689, 1649, 613; 1H-NMR (ppm, δ): 0.82 (d, 3H, i-Pr-CH3); 0.86 (d, 3H, i-Pr-
CH3); 1.25 (s, 3H, Me-CH3 ); 1.26 (t, 3H, Et-CH3 ); 1.93 (sp, 1H, CH); 2.78 (q, 2H, CH2); 3.31 (s, 1H, NH);
8,08 (d, 1H, Het 4-CH ); 8.69 (d, 1H, Het 6-CH); MS (m/e, %): 41 (23,3), 77 (16,8), 106 (23,3), 133 (100),
159 (32,9), 177 (81,9), 203 (81,2), 231 (20,2), 247 (83,8), 290 (18,4).
1
15b: IR (cm-1): 3231, 1736, 1703, 1643, 632; H-NMR (ppm, δ): 0.87 (d, 3H, i-Pr-CH3); 1.04 (d, 3H,
i-Pr-CH3); 1.30 (s, 3H, Me-CH3); 1.98 (sp, 1H, CH); 3.34 (s, 1H, NH); 7.79 (d, 1H, Het 5-CH); 7.92 (d,
8-1H, Het CH); 8.19 (m, 2H, Het 6,7-CH); 8.91 (s, 1H, Het 4-CH ); MS (m/e, %): 41 (20,5), 101 (24,2), 128
(64,3), 155 (100), 181 (27,7), 199 (45,1), 225 (90,5), 253 (22,3), 268 (79,7), 312 (10,1).

Molecules 2004, 9
540
References
1. Wepplo, P.J. Imidazolinone herbicides: synthesis and novel chemistry, Pest. Sci. 1990, 29, 293-315.
2. Los, M. Ortho-(5-oxo-2-imidazolin-2-yl)arylcarboxylates – a new class of herbicides. In Pesticide
Synthesis Through Rational Approaches, ACS Symp. Ser. No 225; American Chemical Society:
Washington, D.C, 1984; pp. 29-44.
3. Los, M. Synthesis and biology of the imidazolinone herbicides. In Proceedings of the 6th
International Congress of Pesticide Chemistry (Ottawa, Aug. 10-15, 1986); Greenhaugh, R.;
Roberts, T. R.; Eds.; Blackwell Scientific Publ.: Oxford, UK, 1987; pp. 35-42.
4. Wepplo, P.J. Process for the preparation of pyridyl and quinolyl imidazolinones, US Pat. 4474962,
1984.
5. Maulding, D.R., Doehner, R.F. Process for the preparation of 2-(5-isopropyl-5-methyl-
4-oxo-2-imidazolin-2-yl)-3-quinoline-carboxylic acid and alkyl 2-trichloromethyl-3-quinoline-
carboxylate intermediates therefor, US Pat. 4459408, 1984.
6. Los, M. 2-(2-imidazolin-2-yl)-pyridines and quinolines and use of said compounds as herbicide
agents, US Pat. 4798619, 1989.
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