Indaziflam: An Innovative Broad Spectrum Herbicide - American

Chapter 17

Indaziflam: An Innovative Broad Spectrum Herbicide Downloaded by TUFTS UNIV on December 8, 2015 | http://pubs.acs.org Publication Date (Web): November 4, 2015 | doi: 10.1021/bk-2015-1204.ch017

Hartmut Ahrens* Research – Weed Control Chemistry, Bayer CropScience AG, Industriepark Hoechst, G836, 65926 Frankfurt am Main, Germany *E-mail: [email protected]

Indaziflam is the innovative active ingredient in the herbicides SpecticleTM and AlionTM (first registrations in 2010/2011), which were followed by other brands. This new compound from Bayer CropScience belongs to the alkylazine chemical class and inhibits cellulose biosynthesis in plants. It is effective against a very wide range of weeds and offers excellent long-term results at very low dose rates. The discovery process and the optimization of the alkylazine class which led to indaziflam, including biological structure activity relationship (SAR) profiles, are presented in this chapter.

Historical Background At the end of the nineties Idemitsu Kosan launched triaziflam (Figure 1), which was the first alkylazine herbicide (1). It is used for weed control in turf and shows a high level of herbicidal activity, with particularly efficient broadleaf weed control.

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

Downloaded by TUFTS UNIV on December 8, 2015 | http://pubs.acs.org Publication Date (Web): November 4, 2015 | doi: 10.1021/bk-2015-1204.ch017

Figure 1. Triaziflam

Interestingly the mode of action involves not only the inhibition of the photosystem II electron transport, but also the inhibition of cellulose biosynthesis. This second novel mode of action, combined with the high level of weed control, raised the question as to whether it might be possible to further improve the herbicidal profile, based solely upon inhibition of cellulose biosynthesis. The introduction of a novel mode of action is a more and more pressing need in order to control and eradicate resistant weeds in agricultural plantations.

First Optimization of Herbicidal Activity In order to try and optimize the herbicidal activity, several sites in the triaziflam molecule were structurally varied (e. g. molecules with different chain lengths between the aryl and the triazine moieties; substitution of a carbon atom in this chain with a heteroatom; introduction of substituents into the aryl ring and/or on the aliphatic side). Unfortunately biological results from greenhouse tests were not encouraging as the level of herbicidal activity was at best equal and often lower than that of triaziflam. However, the introduction of bicyclic systems boosted the herbicidal activity significantly and with the indanyl ring system a new peak of weed control was achieved (Figure 2).

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


Figure 2. Structure variations at positions R1, R2, X and Y

Chemical Synthesis I The general synthetic access to indanylamino triazines comprised a reductive amination of the indanone followed by conversion of the indanylamine to the target product (Figure 3).

Figure 3. General synthetic access to indanylamino triazines


The key question for the design of synthesis programs was how to most efficiently access highly diverse indanones with different aromatic substitution patterns (Figure 4).


Figure 4. Key question for the design of synthesis programs

A one-step approach, based on well known Friedel Crafts chemistry, afforded a broad range of indanones based on readily available starting materials (Figure 5).

Figure 5. One-step approach to indanones

This route provided a very efficient access to screening compounds and enabled detailed structure activity relationships to be established. Whereas the formation of regioisomers contributed towards obtaining a comprehensive SAR picture, their separation was often difficult. Thus, this synthesis strategy was less appropriate for larger amounts. Depending on the targeted substitution pattern, alternative approaches not involving the formation and laborious separation of regioisomers were investigated. For example the 1,2- and 1,4-addition of aryl nucleophiles to α,β-unsaturated systems, followed by acid-catalyzed ring closure, proved to be an efficient approach to indanones with substitution in the 4- or 7-position (Figure 6).

Figure 6. Alternative approaches to indanones 236 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


For the second step, i. e. the reductive amination, several methods were tested. The cyanoborohydride based approach proved to be very sluggish but, after prolonged reaction times, it afforded pure product. The reductive cleavage of oximes with sodium in isopropanol was only appropriate if halogens were absent. An alternative approach was the iron-mediated reduction of oximes followed by formylation of the corresponding enamine. Subsequent hydrogenation, followed by acidic deformylation, yielded the desired indanylamine (Figure 7).

Figure 7. Reductive amination

The final step was the installation of the triazine ring. Basically there were two routes. One method was the reaction of the indanylamine with a chlorotriazine. The other, was a two-step approach involving a reaction of the indanylamine with cyanoguanidine and subsequent ring closure of the biguanidine to the triazine (Figure 8).

Figure 8. Installation of the triazine ring

As an example Figure 9 shows the synthesis of a 5-fluoro-6methylindanylaminotriazine. The sequence started with a Friedel Crafts type alkylation. In this case a second step is necessary to achieve ring closure and this delivers two isomers. After their separation, the 5-fluoro-6-methylindanone is treated with sodium cyano borohydride and ammonium acetate in methanol to achieve a reductive amination. Following condensation with a chloro triazine the desired product is isolated.



Figure 9. Preparation of 5-fluoro-6-methylindanylaminotriazine

Due to their strong herbicidal activity in the greenhouse, the 2-methyl indanyl derivatives were also synthesized (Figure 10). This indanone was prepared in a one-step manner by conversion of ortho-fluoro toluene with methacrylic acid chloride. Again, two isomers were isolated. Following isomer separation, reductive amination and reaction with the chlorotriazine, the 5-fluoro-2,6-dimethylindanylaminotriazine could be isolated. As these compounds were only prepared for screening tests the yields in Figures 9 and 10 are not optimized.



Figure 10. Preparation of 5-fluoro-2,6-dimethylindanylaminotriazine

Structure Activity Relationships Using this “toolbox” of synthetic methods a broad range of indanylaminotriazines were prepared and tested for herbicidal activity, establishing a detailed picture of structure activity relationships (Figure 11). On the triazine ring, a free amino group and a haloalkyl group, notably fluoro alkyl groups, proved to be the most appropriate substituents. The strongest bicyclic substituent was the indanyl system. Within this group the introduction of a methyl group into the 2-position often further increased the herbicidal potency. Numerous aromatic substitution patterns lead to attractive compounds, particularly those with a methyl group or a halogen atom, almost independent of position and number of substituents. Eventually, fine tuning led to the 2,6-dimethylindanylamino backbone. Combination with an aminotriazine bearing a 1-fluoroethyl group afforded the compound with the highest level of weed control (Figure 12).



Figure 11. Structure activity relationships

Figure 12. 2,6-Dimethylindanylamino backbone

However, this compound still showed two modes of action, i. e. inhibition of cellulose biosynthesis and inhibition of the photosystem II electron transport. As the compound contains three chiral centers and thus consists of a mixture of eight stereoisomers, this raised the question as to what influence the configuration of the chiral centers might have upon the mode of action.


Investigation of the Influence of the Chiral Centers


To clarify the influence of chirality on activity, all eight stereoisomers (Figure 13) were separated and tested for both their herbicidal activity and their mode of action.

Figure 13. The eight stereoisomers

The result was that the configuration of the indanyl backbone is decisive for herbicidal activity and for the mode of action. The (1R,2S)-indanyl backbone proved to be biologically the most potent, combined with a clear shift in the mode of action away from the inhibition of the photosystem II electron transport towards the inhibition of cellulose biosynthesis. The corresponding two stereoisomers showed the highest level of weed control and are highly effective inhibitors of cellulose biosynthesis – they are the constituents of indaziflam (Figure 13, box).


Chemical Synthesis II


The 2,6-dimethylindanone is easily accessible via a sequence consisting of benzylation of diethyl methylmalonate, followed by ester saponification with decarboxylation and finally acid catalysed ring closure (Figure 14) (2).

Figure 14. Synthesis of 2,6-dimethylindanone

The enantiopure indanylamine can be prepared via a reductive amination, followed by separation of stereoisomers (Figure 15) (3).

Figure 15. Preparation of the (1R,2S)-indanylamine

This method is suitable for comparative testing of stereoisomers but is not economically viable due to the loss of unwanted stereoisomers. Thus there was a strong need for an enantioselective access to the (1R,2S)-indanylamine. One appropriate method was established in a cooperation with J. M. Lassaletta, and involves a novel dynamic kinetic resolution followed by a nucleophilic substitution (Figure 16) (4).

Figure 16. Dynamic kinetic resolution, followed by installation of the amino group



In the first step the indanone is hydrogenated to the corresponding indanol, mediated by the ruthenium based Noyori/Ikariya type catalyst. The approach of the reductant occurs from the sterically less hindered side, i. e. opposite to the methyl group, leading to the cis-configured indanol. With the chiral induction of the ruthenium catalyst only the (2S)-indanone is reduced, leaving the (2R)-indanone. However, the (2R)-isomer undergoes equilibration under the reaction conditions to give (2R/S)-indanone. Therefore, the racemic indanone is transformed completely into the (1S,2S)-indanol with a high diastereo- and enantioselectivity. In a second step the hydroxy group is replaced by an azide group (via conversion with diphenylphosphorylazide) with strict inversion of configuration. This is followed by a Staudinger-type reduction with triphenyl phosphine to yield the desired (1R,2S)-indanylamine. For completion of the indaziflam synthesis, the (1R,2S)-indanylamine was converted with cyano guanidine to the corresponding biguanidine. However, the biguanidine synthesis based on literature precedent had several problems and was technically unacceptable. High temperatures of at least 140 °C were needed, which caused several side reactions. The addition of aluminium alkoxide simplified the biguanidine synthesis significantly (Figure 17) (5).

Figure 17. Biguanidine synthesis and conversion to indaziflam

The coordination of this Lewis acid with the cyanoguanidine activates the nitrile group towards nucleophilic attack by the indanylamine. The resulting biguanidine is stabilised via an aluminium chelate. Consequently, a much lower reaction temperature is needed and the product is formed with a good yield and in high purity. The aluminium atom is released smoothly via ring closure of the biguanidine with 2-fluoro propionic acid ester. The fluorinated ester is generated from lactic acid in an enantiomeric ratio of approx. 95 : 5, in favor of the (2R)-fluoro propionic acid ester (6). As this stereoconfiguration is stable under the reaction conditions, this ratio is reflected in the ratio of the two stereoisomers of indaziflam.

Herbicidal Profile and Application In numerous field trials indaziflam has shown broad weed control of both grasses and broadleaf weeds, in most cases achieved with low application rates of about 50 – 75 g/ha (Figure 18).



Figure 18. Pome fruit, untreated versus application of 75 g/ha indaziflam

With the novel mode of action, i. e. the inhibition of cellulose biosynthesis, indaziflam is an effective tool to manage weed populations that are resistant to other herbicidal modes of action. So far there is no evidence for any cross-resistance. The residual pre-emergence weed control lasts for several months and consequently the number of applications can be reduced, thereby saving time, fuel and labor costs. Indaziflam is used for weed control in established permanent crops such as citrus, grapes, fruit trees, tree nuts, industrial plantations, and for use in perennial sugarcane, lawns, golf course, turf farms, recreational turf, ornamentals, non-crop areas, Christmas tree farms and forested areas.

Summary Indaziflam proved to be the strongest alkylazine herbicide and was discovered following an extensive program of optimisation. The optimisation of the herbicidal profile also resulted in a highly effective inhibitor of cellulose biosynthesis. An efficient technical synthesis was realised via a novel biguanidine intermediate. Indaziflam from Bayer CropScience represents a breakthrough for broad spectrum residual weed control. It is an innovative tool for effective resistance management. Indaziflam is the active ingredient in brands like Specticle®, Alion®, Esplanade® and DuraZone®.

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Fernandez, R.; Ros, A.; Magriz, A.; Dietrich, H.; Lassaletta, J. M. Enantioselective synthesis of cis-α-substituted cycloalkanols and trans-cycloalkyl amines thereof. Tetrahedron 2007, 63, 6755–6763. Ford, M. WO Patent 2009/077059, 2009. Lui, N.; Pazenok, S. WO Patent 2008/049531, 2008.


Indaziflam: An Innovative Broad Spectrum Herbicide - American

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