An efficient synthesis of optically active herbicide ( S )-metolachlor via reductive ring opening of 2-methoxymethylaziridine

An efficient synthesis of a well known chiral herbicide, ( S )-metolachlor has been described using 2-methoxymethylaziridine ring formation and reductive ring opening as key steps using commercially available ( R )-epichlorohydrin. The present protocol delivers the required enantiomer of metolachlor in overall yield of 50.8% and high enantiopurity (>99%)


Introduction
Many pharmaceutical and agrochemical companies have limited the use of racemates which contain both the active and inactive isomers in equimolar ratio.Due to the large variations in biological activities of the two enantiomers, development of new strategies for the production of enantiopure compounds has increased remarkably. 1 Metolachlor is a widely used herbicide which comprises four stereoisomers, of which two are inactive.The stereoisomers arise from the combination of a chiral center in the side chain and a chiral axis between the aromatic ring and nitrogen atom. 2 Previously, metolachlor was applied as a racemate with a brand name Dual ® , but later it was found that about 95% of the herbicidal activity of metolachlor exists in the two 1-S diastereomers which means that (S)-enantiomers possess higher herbicidal activity than the (R)-enantiomers.Therefore the racemate was replaced by the active (S)-isomer which was marketed under the trade name Dual Magnum ® (Figure 1).Several reports are available for the synthesis of (S)-metolachlor, which involves asymmetric processes: mainly hydrogenation of imines or enamides, 4 enzymatic resolution 5 and chiral pool approaches. 6But, most of these methods suffer from at least one of the following drawbacks such as low enantioselectivity, lower overall yield, protection-deprotection sequences, expensive reagents and catalysts, drastic reaction conditions etc. Very recently, Wang and coworkers reported a new route for the synthesis of (S)-metolachlor.Although this method seems to be impressive, but it involves nosylation-denosylation steps that limits the superiority of the method. 7So, still there is a scope for newer methods that can overcome these drawbacks.

Results and Discussion
A retrosynthetic analysis of (S)-1 is depicted in Scheme 1.We envisioned that enantiomerically pure epichlorohydrin (R)-2 can be used as a chiral starting material for the synthesis.Based on the strategies involving regioselective ring opening and Mitsunobu reaction, aziridine (S)-4 could be obtained from the epoxide (R)-2.© AUTHOR(S) This aziridine (S)-4 intermediate can be transformed to the final product (S)-1 via reductive ring opening and subsequent reaction.

Scheme 1. Retrosynthetic analysis of (S)-metolachlor (S)-1.
Accordingly, epoxide (R)-2 on treatment with 2-ethyl-6-methylaniline in refluxing methanol for 6 h afforded chlorohydrin in situ.After the complete conversion of the starting material to the corresponding chlorohydrin derivative (confirmed by TLC), powdered KOH (2.5 equiv.) was added portion wise to the reaction mixture at temperature maintained below 25°C.After stirring the reaction mixture at room temperature for 8 h the required amino alcohol (R)-3 was obtained in high yield (Scheme 2).Subsequently, the amino alcohol (R)-3 in hand was exposed to Mitsunobu conditions (PPh3/DIAD) to afford the key intermediate aziridine (S)-4.Here, it is noteworthy to mention that the formation of aziridine (S)-4 was unsuccessful at room temperature using THF as a solvent as practiced routinely, so the reaction was carried out in toluene under reflux conditions.Further, the aziridine (S)-4 on reductive ring opening using catalytic Pd/C under H2 pressure furnished the required metolachlor intermediate (S)-5 in high enantiopurity (ee>99%).Finally, (S)-5 was acylated using chloroacetyl chloride under basic conditions to furnish the target compound (S)-1 in overall yield of 50.8%.The structure of (S)-1 was confirmed by its IR, 1 H NMR, 7 13 C NMR, 7 and mass spectroscopic analysis.The enantiomeric purity of (S)-5 was determined by chiral HPLC analysis.© AUTHOR(S) Scheme 2. Synthesis for (S)-metolachlor (S)-1.

Conclusions
In conclusion, we have developed an efficient new route for the synthesis of (S)-metolachlor (S)-1 via reductive ring opening of 2-methoxymethylaziridine.The attractive features of the present protocol include readily available chiral starting material, simple chemical transformations, high enantiopurity and good overall yield (50.8%).We envisage that this simple protocol may find application in agrochemical industries for the large scale preparation of active isomer of metolachlor with high enantiopurity.

Experimental Section
General.Solvents were purified and dried by standard procedures prior to use.IR spectra were obtained from Perkin-Elmer Spectrum one spectrophotometer. 1H NMR and 13 C NMR spectra were recorded on a Bruker AC-200 NMR spectrometer.Spectra were obtained in CDCl3.Monitoring of reactions was carried out using TLC plates Merck Silica Gel 60 F254 and visualization with UV light (254 and 365 nm), I2 and anisaldehyde in ethanol as development reagents.Optical rotations were measured with a JASCO P 1020 digital polarimeter.Mass spectra were recorded at ionization energy 70 eV on API Q Star Pulsar spectrometer using electrospray ionization.Enantiomeric excess was determined by chiral HPLC.