Tetrahydrophthalimide,Protox herbicide

The diphenyl ether nitrofen (1) [24], introduced in 1963 by Rohm and Haas, now Dow AgroSciences the oxadiazolinone oxadiazon (2) [25, 26] (Explorer , Herbstar , Romax , Ronstar ), introduced in 1968 by Rhone-Poulenc and the tetrahydrophthalimide chlorophthalim 3 [27], introduced in 1972 by Mitsubishi, represent the earliest examples of Protox herbicides (Fig. 3.2). Though all three classes are chemically quite different, they share a common mode of action, inhibition of the protoporphyrinogen oxidase enzyme, though this was not known until the late 1980s. 

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]. 

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). 

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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