Phenyl Tetrahydrophthalimide

In the course of developing herbicides possessing N-phenyl tetrahydrophthalimide structure (20), Ohta et al. investigated structural requirements for the activity against sawa millet, Echinochloa utilis, of m- and p-substituted derivatives42 . As shown by Eq. 43, the steric dimensions expressed by the STERIMOL length parameter Lp and maximum width B of p-substituents play a decisive role in determining activity. 

Irrmost correlations in this review, the steric parameters are supposed to be best among others. In deriving Eq. 43 for N-phenyl tetrahydrophthalimide herbicides, STERIMOL parameters are the best ones 42). In Eq. 53 for lindane analogs, Vw works much better than MR 70). However, this does not necessarily mean that the correlations mentioned here are always finalized. Further improvement may be possible using other steric parameters. 

The 2,4-dihalo-5-substituted pattern at the aromatic ring would become the basis for much of the 2,4,5-trisubstituted phenyl tetrahydrophthalimide 10 [43] research that followed in the Protox area of chemistry. 

Fig. 3.4. Incorporation of the 2,4-dihalo-5-alkoxy aromatic pattern of oxadiazon into new phenyl tetrahydrophthalimide ring systems.

Phenyl tetrahydrophthalimides represent the third class of early Protox herbicides. They were introduced in the early 1970s, after the diphenyl ether and l,3,4-oxadiazol-2(3H)-one chemistries. Following the introduction by Mitsubishi of chlorophthalim (3) [27] in 1972, incorporation of the 2,4,5-trisubstituted-phenyl pattern in the 1980s resulted in the synthesis of highly active molecules such as S-23142 (12) [45], and S-23121 (20) [45, 56] (Fig. 3.8). 

The phenyl tetrahydrophthalimides are primarily post-emergence herbicides for the control of broadleaf weeds, though they will show pre-emergence activity at higher rates of application. Flumiclorac-pentyl is a post-emergence herbicide for the control of broadleaf weeds such as cocldebur, common lambsquarters, jimsonweed, amaranthus, prickly sida, and velvetleaf in soybean and corn at 25-... 

R = CF3SO2-, acetate, alkyl, acetyl Fig. 3.9. Derivatization of aromatic position 5 of phenyl tetrahydrophthalimide. 

Another breakthrough discovery was the boost in biological activity caused by the replacement of chlorine by fluorine at the 2-phenyl position. In 1976, DuPont introduced the first example of a 2-fluoro-4-chlorophenyl tetrahydrophthalimide Protox inhibitor (11) [44] (Fig. 3.4). The dramatic increase in biological activity caused by the fluorine in the 2 position of the phenyl ring would, in the next decade, the 1980s, influence work in the Protox area, such as the discovery of the 4-chloro-2-fluorophenyltetrahydrophthalimide herbicide S-23142 (12) [45]. 

A class of Protox inhibitors that redefined the accepted SARs and QSARs of the aromatic 4 position was the substituted benzyloxyphenyl heteroaryl area. As discussed earlier, SAR and QSAR studies of the phenyl ring of Protox herbicides demonstrated the need for halogens in the 2- and 4 positions of the phenyl ring, with the exception of the 4-chlorobenzyloxy group such as that of 4-chlorobenzyloxyphenyl tetrahydrophthalimide outlier 55 (Fig. 3.15) and reported by Ohta and coworkers in 1980 [79]. Chlorine at the para position of the benzy-loxy was reported to provide optimum biological activity. 

In terms of recent patent activity related to Protox inhibitors, a series of N-substituted phenyl isothiazolone Protox herbicides were prepared to investigate the potential of the isothiazolone heterocycle ring to act as a bioisostere for comparable tetrahydrophthalimides such as compound 80 [93] (Fig. 3.21). The 2-(4-chloro-3-isopropoxycarbonyl)phenyl isothiazole-1,1-dioxide 83 was the most active... 

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