bk-2015-1204.ch020

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Chapter 20

Broad-Spectrum PPO-Inhibiting N-Phenoxyphenyluracil Acetal Ester Herbicides Thomas P. Selby,* Marc Ruggiero, Wonpyo Hong, D. Andrew Travis, Andrew D. Satterfield, and Amy X. Ding DuPont Crop Protection, Stine-Haskell Research Center, Newark, Delaware 19711, United States *E-mail: [email protected]

Substituted N-aryluracils were first discovered in the late eighties at Hoffman-La Roche as an extremely active subclass of herbicidal protoporphyrinogen-IX oxidase inhibitors. Interest by Uniroyal followed but it was not until 2001 that uracil-based butafenacil was commercially introduced by Syngenta and saflufenacil by BASF in 2009. In the mid-nineties, unique 3-ring N-phenoxy-phenyl-triazolinones with an oxyproprionate side-chain on the diphenylether part of the molecule were reported by FMC to be very active protox-inhibiting herbicides. Structurally-related N-aryloxy-phenyl-uracils having an oxyacetate group on the diaryl ether were subsequently patented by Sumitomo. Here, we report on the synthesis and herbicidal activity of a series of acetal ester-substituted N-phenoxy-phenyl-uracils where we had interest as potential short-residual herbicides for postemergent-applied weed control (pre-plant) in row crops, especially for control of glyphosate and ALS resistant weeds.

Protoporphyrinogen-IX oxidase (PPO, protox), catalyzes the last common enzymatic step in the biosynthesis of chlorophyll and heme where protoporphyrinogen-IX is oxidized to protoporphyrin IX. Compounds that inhibit this step give quick burn symptoms on plants when applied postemergnece,

© 2015 American Chemical Society In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


generally with limited crop safety and plant systemic properties due to their fast-acting nature that results from singlet oxygen generation and ultimately membrane disruption. Generally higher levels of crop selectivity are obtained preemergence. Traditional PPO-inhibiting herbicides tend to be more effective for control of broadleaf than grass weeds at low rates of application. Although discovered decades ago and commercially used for many years, sales of herbicidal PPO inhibiting products have grown more recently due in part to the on-set of weed resistance to both glyphosate and acetolactate synthase (ALS) inhibitors. Use of both diphenyl ether inhibitors, i.e. fomesafen, and aryl heterocycles (also referred to as “cyclic imides”), i.e. flumioxacin, have increased, especially for control of glyphosate and ALS resistant amaranthus weed species such as palmer amaranth and common waterhemp. Substituted N-aryluracils were first discovered in the late eighties at Hoffman-La Roche as an extremely active subclass of “cyclic imide” PPO-inhibiting herbicides and Uniroyal soon developed commercial interest in flupropacil (1). Uracil-based PPO inhibitors were typically found to be more active than other similarly substituted heterocyclic chemotypes (2–4). However, it was not until 2001 when Syngenta introduced the uracil-containing butafenacil into the marketplace, followed by BASF’s commercialization of saflufenacil in 2009 (Figure 1).

Figure 1. N-Aryluracil Herbicidal Inhibitors of Protoporphyrinogen-IX Oxidase

278 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


In the mid-nineties, George Theodoridis at FMC reported that Nphenoxyphenyltriazolinones, where the diphenylether fragment attached to the ring nitrogen is substituted with a para-oxyproprionate side-chain, i.e. 1, were very active as PPO-inhibiting herbicides (5). As substrate inhibitors, these large molecular weight 3-ring containing compounds were described as potential mimics of the tetrapyrrole, protoporphyringen-IX (5–7). Sumitomo later patented related N-(hetero)aryloxyphenyluracils, preferably with an ortho-oxyacetate side-chain on the diaryl ether group, i.e. 2, as broadspectrum herbicides with broadleaf and grass activity (8, 9). Here, we report on the synthesis and herbicidal activity of structurally-related acetal ester-substituted N-phenoxyphenyluracils, i.e. DP-1 (10). We had special interest in this chemistry for postemergent applications to glyphosate and ALS resistant weeds (i.e. preplant “burndown” in row crops) where short-residual properties might stem from the hydrolytically sensitive acetal ester group.

Chemistry The general synthetic route for making N-methyl-4-trifluoromethyluracil N-diphenyl ether acetal esters is outlined in Figure 2. Cyclization of ethyl 3-amino-3-trifluoromethylpropenoate (3) and benzyl isocyanate in the presence of sodium hydride in DMF gave N-benzyl uracil 4. Following methylation and de-benzylation, uracil 5 was reacted with 2,4,5-trifluoronitrobenzene in DMF with potassium carbonate to afford N-aryluracil 6 as the major poduct. Some isomeric product (< 20%), which resulted from displacement of the fluorine ortho versus para to the nitro group by the uracil ring nitrogen, required separation. Reaction of 6 with (un)substituted 2-methoxyphenols, again in DMF with potassium carbonate, give N-diphenyl ether substituted uracils 7 where displacement of fluorine ortho to the nitro group on the phenyl occurred. In the preparation of the chorodiphenyl ether containing uracils 8, introduction of chlorine was achieved via reduction of the nitro group with iron in acetic acid followed by diazotization of the produced aniline with isoamyl nitrite in the presence of copper chloride salts in acetonitrile. De-protection of the methoxy group on the diphenyl ether with boron tribromide gave the free uracil phenols 9, which on alkylation with alkyl 2-bromoalkoxyacetates with sodium hydride in THF or potassium carbonate in DMF afforded final products 10, trifluoromethyl uracils N-substituted by a diphenyl ether with an acetal ester group. In most cases, the alkylating agents were made by bromination of the corresponding alkoxyacetates with NBS.



Figure 2. Synthetic route to N-phenoxyphenyluracil acetal esters

We were interested in the free acids of uracil acetal esters 10 for conversion to other ester and amide derivatives (Figure 3). However, attempted hydrolysis of uracils 10 in aqueous base resulted in mainly decomposition due in part to the hydrolytic instability of the acetal ester functionality. However, we found that transesterification of the ethyl methoxyacetate DP-1 with excess allyl alcohol and a catalytic amount of indium trichloride produced allyl methoxyacetate 10a in good yield. Treatment of 10a with palladium tetrakis-triphenylphosphine in the presence of sodium para-toluenesulfonate in methanolic THF gave reasonable yields of the free acid 11 that could be further purified by reverse phase chromatography. Alternatively, the benzyl acetal ester 10b, which was made by the chemistry outlined in Figure 1, underwent catalytic hydrogenolysis to also provide the free acid 11. Coupling of acid 11 and amines with BOP reagent and diisopropylethylamine in tetrahydrofuran gave amides 12 in reasonable yield. Esterification of 11 with alcohols (generally used in excess) to provide a range of esters (10c) was typically done with 2-chloro-1-methylpyridium iodide and diisopropylethylamine in tetrahydrofuran. 280 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


The preparation of substituted uracil diphenylether thioacetal esters 13 is shown in Figure 4. Made by the chemistry route in Figure 1, uracil diphenylether phenol 9a was alkylated with 2-bromoalkylthioacetates using sodium hydride in tetrahydrofuran or potassium carbonate in DMF.

Figure 3. Converison of a N-phenoxyphenyluracil acetal ester to the free acid, other esters and amides

Figure 4. Synthesis of N-phenoxyphenyluracil thioacetal esters



In Figure 5, the synthesis of a uracil N-phenoxypyridyl acetal methyl ester is outlined. Coupling of N-2,5-difluoro-4-nitrophenyluracil 6 with 3-hydroxy-2methoxypyridine by heating in DMF with potassium carbonate gave the uracil N-phenoxypyridyluracil 14. Reduction of the nitro group on 14 with iron in acetic acid gave the aniline which on diazotization in the presence of copper chloride salts gave the chlorine-containing phenoxypyridyluracil 15. Treatment of 15 with boron tribromide resulted in de-protection of the pyridyl methoxy groug to generate the free pyridinol 16. Although 16 may exist in part as the pyridone tautomer, realkylation with methyl 2-bromo methoxyacetate in acetonitrile with potassium carbonate occurred predominantly on oxygen versus nitrogen to give uracil Nphenoxypyridyl acetal ester 17 in good yield.

Figure 5. Synthesis of a N-phenoxypyridyluracil acetal ester

Following chemistry similar to that outlined in Figure 1, regioisomers of DP-1 were also made from a common intermediate, N-2,5-difluoro-4-nitrophenyluracil 6 (Figure 6). The two ether linkages on the terminal phenyl ring of the diphenylether are meta on 18 and para on 19 versus ortho on DP-1.

Figure 6. Synthesis of N-phenoxyphenyluracil acetal ester regioisomers


Herbicidal Activity


Substituted N-phenoxyphenyluracil acetal esters and derivatives made by the described chemistry methods were evaluated postemergence (POST) and preemergence (PRE) against a range of broadleaf and grass weeds with crop selectivity assessed. Table 1 summarizes POST activity for a series of esters and free acids at an application rate of 4 g/Ha against 7 broadleaf weeds, 5 warm season grass weeds and 3 crops. Weed activity is reported as averaged percent control and crop damage as percent injury.

Table 1. Postemergent Weed Control and Crop Injury by N-Phenoxyphenyluracil Acetal Esters and the Free Acids at 4 g/Ha



Broadleaf weeds tested included: Amaranthus retroflexus (redroot pigweed), Chenopodium album (lambsquarter), Stellaria media (chickweed), Ipomoea hederacea (ivy morninglory), Ambrosia artemisiifolia (ragweed), Abutilon theophrasti (velvetleaf) and Kochia scoparia (kochia). Warm Season grass weeds included: Digitaria sanguinalis (large crabgrass), Setaria faberii (giant foxtail), Sorghum halepense (johnsongrass), Cynodon dactylon (bermudagrass) and Eleusine indica (goosegrass). Crop injury was averaged for maize, soybean and wheat. Like traditional PPO inhibitors, all of analogs in Table 1 showed high POST broadleaf weed activity with limited crop safety due to plant necrosis (burn) resulting from quick contact potency. However, our focus was to find analogs with a combination of excellent broadleaf activity and enhanced levels of grass control. Where W is CH and XR1 is methoxy, the highest levels of cross-spectrum weed control were obtained for acetal esters where R2 is ethyl (DP-1), trifluoroethyl (DP-6), methoxyethyl (DP-7), ethoxyethyl (DP-8) and 3-fluoropropyl (DP-11). All of these acetal esters performed similarly in advanced greenhouse testing as non-selective POST contact herbicides. The ethyl acetals DP-14 and DP-15 (where XR1 is ethoxy) and the alkyl thioacetals DP-16 (where XR1 is methylthio) and DP-17 (where XR1 is ethylthio), were less active than their methyl acetal ester counterparts. Free acids DP-12 and DP-15 also had diminished activity versus the esters with the most noticeable activity drop on grasses. Finally, unlike oxyacetate-substituted pyridyloxyphenyluracils previously patented by Sumitomo, significantly lower activity was unexpectedly observed for DP-18, the last entry in Table 1 where the terminal phenyl ring of DP-1 was replaced by pyridine (W is N). The cause for this activity loss was unclear. Table 2 summarizes preemergent activity for a series of acetal esters and a free acid in a sandy loam soil at 16 g/Ha against the same weeds (not including Stellaria media) and crops listed for Table 1. Overall PRE efficacy was less than that of POST applications with the highest activity levels expressed against broadleaf weeds. PRE versus POST crop safety was dramatically improved, but generally with some chlorotic crop effects, still observed. Wheat tended to have better PRE tolerance to this chemistry than maize or soybean. Optimum levels of PRE activity were obtained with acetal esters DP1, DP-8 and DP-10, revealing that the best POST compounds tended to be the best PRE. Interestingly, the free acid DP-14 was not only less efficacious than the esters PRE on weeds but more damaging to crops. In heavier soils, these compounds usually showed some improvement of PRE crop tolerance but accompanied with some reduction of overall weed control. Although not shown in Tables 1 and 2, most cool season grasses were less susceptible than warm season grasses to this class of chemistry PRE or POST. The reason for this was unclear. Tables 3-5 summarizes POST activity for other analogs averaged against 3 broadleaf weeds (Amaranthus retroflexus, Ipomoea hederacea and Abutilon theophrasti Medik) and 3 warm-season grasses (Digitaria sanguinalis, Setaria pumila and Echinochloa crus-galli). In Table 3, herbicidal activity of several acetal amides is reported at 8 g/Ha. The secondary alkyl amide DP-19 (NR2R3 = NHEt) was more active than the anilide DP-21 (NR2R3 = NPh) which in turn was superior to the tertiary amide DP-20 (NR2R3 = NMe2). However, the Weinreb 284 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


amide DP-22 [NR2R3 = N(Me)OMe)] was most active with a level of activity approaching that of the best acetal esters. The significant activity difference between DP-20 and DP-22 might be due to the ability of DP-22 to hydrolyze more readily to the free acid. Activity of uracils with substituents on the terminal phenyl ring containing the acetal ester side-chain is given in Table 4 at rates of 8 and 31 g/Ha. Fluorine substitution at the 3- and 5-positions gave analogs DP-23 and DP-24 with roughly comparable activity to that of the parent DP-1. A small drop in overall activity occurred with going to 4-methyl and 4-chloro substitution (DP-25 and DP-26) followed by another activity drop for 6-methoxy (DP-27) and 4,5-benzo-ring fusion to give naphthalene-containing DP-28.

Table 2. Preemergent Weed Control and Crop Injury by N-Phenoxyphenyluracil Acetal Esters and the Free Acids at 16 g/Ha



Table 3. Postemergent Weed Control by N-Phenoxyphenyluracil Acetal Amides at 8 g/Ha

Table 4. Postemergent Weed Control by N-Phenoxyphenyl Uracil Acetal Esters with Substitution on the Terminal Phenyl Ring


Herbicidal activity of the three positional regioisomers, where the acetal ester side-chain and ether linkage between the two phenyl rings of the diphenyl ether fragment are ortho (DP-1), meta (DP-29) and para (DP-30) to each other, is provided in Table 5. All three were active but optimum weed control was observed with the ortho substitution pattern on DP-1.


Table 5. Postemergent Weed Control and Crop Injury of N-Phenoxyphenyl Uracil Acetal Ester Regioisomers

Instrinsic Activity Inhibition of plant versus mammalian forms of the PPO enzyme by N-phenoxyphenyluracil DP-1 versus the standard azafenidin is shown in Table 6. Both compounds are potent low nanomolar inhibitors of the PPO enzyme from Arabidopsis thaliana (mustard) and rice. Although having a slightly lower level of potency against the mammalian (human) form of the enzyme, there was not a dramatic difference in selectivity for the three enzyme forms.

Soil Degradation Compounds of this chemistry class were found to breakdown readily in soil, both hydrolytically and by microbial pathways. Hydrolysis of the acetal ester to the acetal acid (also herbicidally active) tended to occur first, and rapidly in high pH soils, followed by further degradation involving loss of the acetal acid functionality and/or fragmentation of the uracil ring to a urea degradate. Half-lives of acetal acids resulting from ester hydrolysis were usually less than 20-25 days in soil. Although these soil half-lives were short, substantial levels of preemergence herbicidal activity were still observed with varying lengths of residual weed control, depending on use-rate, soil types and temperature. 287 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.

Table 6. Instrinsic Activity of N-Phenoxyphenyl Uracil Acetal Ester DP-1 against the Plant versus Mammalian Forms of the PPO Enzyme Entry

Rice

Arabidopsis

Human


IC50 Values (nM) DP-1

1.6

0.3

17

Azafenidin

2.8

2.7

16

Field Activity Field testing of DP-1 was carried out at multiple test sites. With insufficient POST crop safety, DP-1 was evaluated in row crops as primarily a pre-plant “burndown” agent retaining some soil residual activity. At higher rates, DP-1 was also looked at in vegetation management (VM) trials (i.e. permanent crops, sugarcane, orchards) for control of larger weeds. DP-1 had very little systemic properties and required good coverage on plant foliage for optimum biological performance. In pre-plant trials in corn and soybeans, use rates of 35-70 g a.i./Ha gave excellent levels of broadleaf weed control (i.e. Amaranthus retroflexus, Ipomoea hederacea and Abutilon theophrasti Medik) with only suppression of most warm season grasses (i.e. Digitaria sanguinalis and Setaria pumila) in most cases. Sufficient levels of crop safety were usually observed on plant-back with corn and soybeans within 3-7 days. In VM field trials of more mature weeds, rates of 70-140 g a.i./Ha gave comparable weed control to that of glyphosate and paraquat at much higher rates (> 1 Kg/Ha). Field tests confirmed high activity against both glyphosate and ALS resistant Amaranthus palmeri (Palmer Amaranth), Amaranthus rudis (common waterhemp) and Conyza canadenesis (marestail).

Conclusion Substituted N-phenoxyphenyluracil acetal esters represent a unique family of large molecular weight 3-ring containing PPO-inhibiting herbicides that were designed as potentially short-residual “burndown” agents that would perform similarly to that of paraquat or glyphosate but at lower application rates. Although possessing a derivatized acidic functionality, these compounds showed very little plant systemic capability. Nevertheless, DP-1 gave excellent POST control of broadleaf weeds at low rates in field trials accompanied with some suppression of warm season grasses. Higher use rates generally translated to better overall weed control, especially in the case of grasses and more mature weeds. The soil dissipation profile was generally favorable but minor soil residual effects on emerging crops were sometimes observed following pre-plant applications, indicating a longer than expected soil half-life under certain test conditions. While possessing many positive attributes, further interest in this subclass of PPO-inhibiting herbicides was precluded by the constraints around crop 288 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.

safety, concerns of emerging PPO weed resistance in the marketplace and other considerations associated with the mode-of-action.

References


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Bell, A. Method of Defoliating Cotton Plants Employing Uracils. U.S. Patent 4,943,309, July 24, 1990. 2. Theodoridis, G.; Bahr, J. T.; Crawford, S.; Dugan, B.; Hotzman, F. W.; Maravetz, L. L.; Sehgel, S.; Suarez, D. P. In Synthesis and Chemistry of Agrochemicals VI; ACS Symposium Series 800; Baker, D. R., Fenyes, J. G., Lahm, G. P., Selby, T. P., Stevenson, T. M., Eds.; American Chemical Society: Washington, DC, 2002; Chapter 10, pp 96−107. 3. Theodoridis, G. Protoporphyrinogen IX Oxidase-inhibiting Uracil Herbicides. In Bioactive Heterocyclic Compound Classes: Agrochemicals; Lamberth, C., Dinges, J., Eds.; WILEY-VCH Verlag GmbH & Co. KGaA: 2012; Chapter 8, pp 91−101. 4. Theodoridis, G. In Modern Crop Protection Compounds; Krämer, W., Schirmer, U., Eds.; WILEY-VCH Verlag GmbH & Co. KGaA: Weinheim, 2007; Vol. 1, Chapter 3, pp 153−186. 5. Theodoridis, G.; Poss, K. M.; Hotzman, F. W. In Synthesis and Chemistry of Agrochemicals IV; ACS Symposium Series 584; Baker, D. R., Fenyes, J. G., Basarab, G. S., Eds.; American Chemical Society: Washington, DC, 1995; Chapter 8, pp 78−89. 6. Uraguchi, R.; Sato, Y.; Nakayama, A.; Sukekawa, M.; Iwataki, I.; Bőger, P.; Wakabayashi, K. Molecular Shape Similarity of Cyclic Imides and Protoporphyrinogen IX. J. Pestic. Sci. 1997, 22, 313–320. 7. Theodoridis, G.; Bahr, J. T.; Hotzman, F. W.; Sehgel, S.; Suarez, D. P. New Generation of Protox-inhibiting Herbicides. Crop Prot. 2000, 19, 533–535. 8. Tohyama, Y.; Sanemitsu, Y.; Gotou, T. Uracil Compounds and Use Thereof. U.S. Patent 6,451,740, September 17, 2002. 9. Tohyama, Y.; Sanemitsu, Y. Uracil Compounds and Use Thereof. U.S. Patent 6,537,948, March 25, 2003. 10. Hong, W.; Selby, T. P. Herbicidal Uracils. World Patent Application WO 2011/137088, November 3, 2011.


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