New Approaches to the Design and Synthesis of Inhibitors of Acetyl

Chapter 21

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New Approaches to the Design and Synthesis of Inhibitors of Acetyl-CoA Carboxylase James N. Scutt,*,1 Stephane A. M. Jeanmart,2 Christopher J. Mathews,1 Michel Muehlebach,2 Tomas Smejkal,2 Stephen C. Smith,1 Helmars Smits,2 J. Steven Wailes,1 William G. Whittingham,1 and Nigel J. Willetts1 1Syngenta

Ltd., Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, United Kingdom 2Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstrasse 101, 4332 Stein, Switzerland *E-mail: [email protected]

The inhibition of acetyl-CoA carboxylase (ACCase) is one of the most commercially important modes of action for the control of grass weeds. Three chemical classes of ACCase herbicides have been commercialized – FOPs (aryloxyphenoxypropionates), DIMs (cyclohexanedione oximes) and most recently DENs (2-aryl-1,3-diones). This chapter describes new synthetic methodologies which have been developed to prepare novel analogues of pinoxaden, the only current commercial product from the DEN chemical class.

Carbocyclic 2-aryl-1,3-diones have been of high interest to the agrochemical industry since they were first reported as herbicidal (and insecticidal) in the late 1970s (1, 2). Until relatively recently most synthetic approaches were based on the ring-synthesis methodology developed originally by Union Carbide (1), for example Scheme 1. However, with more functionalized examples we have found these approaches to be lengthy and often low yielding. The most problematic steps were typically synthesis of the ketonitrile intermediate 1 (or related ketoester) and the final dione product 2 (Scheme 1).

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


Scheme 1. Example ring-synthesis approach to carbocyclic 2-aryl-1,3-diones

As an alternative, we have investigated various late-stage aryl coupling approaches, including state of the art palladium-catalyzed conditions as reported by Buchwald and co-workers (3, 4). In our hands these have proved only moderately successful and limited to examples with mono-ortho aryl substitution (5). A more reliable procedure, even for highly hindered aryl groups, was the palladium-catalyzed cross-coupling of iodonium ylides with aryl boronic acids (6–9), although even this approach was sometimes only moderate yielding. The most robust method for the direct coupling of hindered aryls was found to be an unusual aryl lead cross-coupling reaction. Using conditions reported by Morgan and Pinhey (10), we observed that a wide variety of aryl lead reagents efficiently C-arylated a diverse range of cyclic 1,3-diones (5) via a proposed intermediate of type 3 (Scheme 2). To the best of our knowledge these are the first examples of mono C-arylation of such compounds. After further optimization of the original reaction conditions this method was used to successfully couple a wide variety of cyclic 1,3-diones and aryl fragments (11–13). Aryl lead reagents were prepared directly from the corresponding aryl boronic acids using lead tetraacetate and catalytic mercury(II) acetate in chloroform (10), followed by scavenging of the residual acetic acid over solid potassium carbonate. This acid scavenging step was critical to achieve high coupling yields. The arylation itself was performed using a large excess of N,N-dimethyl-4-aminopyridine in a 4:1 chloroform / toluene solvent mixture at 80 ºC. Representative iodonium ylide and aryl lead coupling approaches to the 2-aryl-1,3-dione 4 are shown in Scheme 2. 292 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Scheme 2. Example iodonium ylide and aryl lead cross coupling reaction

Although the aryl lead coupling protocol was typically high yielding, scale up issues still remained. We therefore continued to investigate improved synthetic approaches, with a focus on novel intramolecular rearrangement chemistry. These are described in the following examples.

Claisen Rearrangement Approach This methodology represents a novel synthesis of both five and six ring carbocyclic 2-heteroaryl-1,3-diones, inspired by the classical [3,3]-sigmatropic rearrangement of allyl phenyl ethers. In this instance the rearrangement was found to be more challenging due to competing ‘benzyl shift’ by-products, which usually predominated for phenyl substrates. Nevertheless, this approach worked well for the preparation of a diverse range of five-membered heterocycles, such as 2-(2-methyl-3-thienyl)cyclohexane-1,3-dione 5 (Scheme 3) (14). Heteroaryl methyl ether precursors (for example, compound 6) were prepared either by condensation of the required alcohol and cyclic 1,3-dione reaction partners (using catalytic sodium gold chloride as reported by Arcadi et al. (15)), or more generally by a conjugate addition to the specific 3-chloro enone. The 3-chloro enones were prepared from the corresponding 1,3-dione by treatment with phosphorus pentachloride in chloroform. Claisen rearrangements were performed at high temperature under microwave irradiation in dipolar aprotic solvents such as 1-methyl-2-pyrrolidinone, or alternatively in dimethoxyethane in the presence of an ionic liquid, e.g. 1-butyl-3-methyl-imidazolium bis(trifluoromethylsulfonyl)imide, to facilitate higher microwave irradiation temperatures (Scheme 3). Low reaction concentrations were found to increase yields by disfavoring the ‘benzyl shift’ pathway. 293 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Scheme 3. Claisen rearrangement synthesis of 2-(2-methyl-3thienyl)cyclohexane-1,3-dione

This methodology was used to successfully prepare a diverse range of orthomethyl and ortho-ethyl 2-heteroaryl-1,3-diones. The reaction was found to be highest yielding for electron-deficient five-membered heterocycles – thiazole > thiophene > oxazole > furan – which also reflects a lower yield of the ‘benzyl shift’ by-product. We propose this is because of reduced stabilization of the benzyl cation intermediate which leads to the by-product. Representative applications of this methodology using highly functionalized reaction partners are shown in Scheme 4 (16).

Piancatelli Rearrangement Approach Since the Claisen rearrangement approach had proven unsuccessful for the synthesis of 2-phenyl-1,3-diones we continued investigations into alternative routes. The most general method developed for the synthesis of five ring carbocyclic examples of this compound class was based on the Piancatelli rearrangement of furfuryl alcohols (17), such as compound 7 (Scheme 5). The key transformation was promoted using the aqueous polyphosphoric acid conditions as described by Saito and Yamachika for a related reaction (18). The yield of the rearrangement to the corresponding hydroxy-enone product (e.g. compound 8) was usually very high, irrespective of the nature and number of aryl substituents (19).

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


Scheme 4. Example applications of the novel Claisen rearrangement methodology

Scheme 5. Example application of Piancatelli rearrangement methodology



Hydroxy-enone products (for example, compound 8), were subsequently oxidized using Jones reagent, then further derivatized by either cycloaddition or C5-alkylation of the derived enol ether (Scheme 6). Cycloadditions were successfully carried out with furans (leading to compounds such as 9) (11), cyclopentadienes (19), cyclohexadienes (19), nitrones, nitrile oxides and thiophene S-oxides (Figure 1), often in the presence of Lewis acids such as magnesium iodide. Alternative C5-alkylated 1,3-diones were accessed by the zinc / acetic acid reduction of the cyclopentene-1,3-dione precursor, followed by protection as the methyl enol ether. These intermediates were then deprotonated with strong base, such as potassium hexamethyldisilazide, and quenched with various aldehydes such as 2-pyridinecarboxaldehyde to afford the corresponding exocyclic enone. Synthesis of the final products, such as compound 10, was completed by a second zinc reduction followed by acid catalyzed deprotection of the methyl enol ether (20).

Scheme 6. Elaboration of an example hydroxy-enone intermediate by both cycloaddition and C5-alkylation chemistry



Figure 1. Examples of additional 2-phenyl-1,3-diones derived from cycloaddition chemistry

Enol Lactone Rearrangement Approach In order to synthesize six ring carbocyclic 2-phenyl-1,3-diones additional synthetic methodology was required. The first approach was based on the intramolecular rearrangement of enol lactones (e.g. compounds 11 and 12, Scheme 7). After substantial optimization two complementary sets of reaction conditions were identified. Rearrangement under acidic conditions was performed using Eaton’s reagent (21) (7.7% phosphorus pentoxide in methane sulfonic acid) in toluene at 70 ºC, which very rapidly and reliably led to moderate to high yields of the desired products such as compound 13 (13). The same transformation was also successfully achieved under basic conditions using catalytic potassium cyanide and triethylamine in acetonitrile (22), although this alternative procedure was found to be slightly less general. The enol lactone precursors were prepared by one of two general methods. The first approach involved condensation of a ketone and an aldehyde, followed by regioselective Baeyer-Villiger oxidation. The aldol step was performed under a variety of standard conditions, such as potassium hydroxide in ethanol, and was typically selective for the E-olefin. This methodology was high yielding when the α′-position was blocked, preventing a second condensation. The subsequent regioselective Baeyer-Villiger oxidation was performed using the selenium dioxide catalyzed conditions reported by Guzmán et al. (23), which afforded the E-enol lactone resulting from preservation of olefin geometry, as expected. The second approach was a silver or gold catalyzed lactonisation of an appropriately functionalized aryl-acetylene precursor (e.g. compound 15), via a formal 6-exo-dig cyclisation. Near quantitative conversion was achieved using silver carbonate in acetonitrile (22), which afforded the Z-olefin 12. Representative examples of both the Baeyer-Villiger and silver-catalyzed lactonisation strategies are shown in Scheme 7.



Scheme 7. Example of enol lactone rearrangement approaches to bicyclo[2.2.1]heptan-2-one and dimethylpyrandione 2-aryl-1,3-diones

Semi-Pinacol Rearrangement Approach The final approach developed for the synthesis of carbocyclic 2-aryl-1,3diones was the semi-pinacol rearrangement of epoxy-ketones (24, 25). This method leads to 2-aryl-1,3-diones, rather than isomeric 1,2-diones, through a preferential acyl transfer mechanism (proceeding via proposed intermediates 16 and 17, Scheme 8). This ring expansion has proved very reliable and efficient across a diverse range of phenyl and heteroaryl substituted epoxides, for example compounds 18 and 19 (Scheme 8), using a variety of protic and Lewis acid catalysts. Preferred rearrangement conditions involve treatment with concentrated sulfuric acid in dichloroethane, or boron trifluoride diethyl etherate in dichloromethane (25).



Scheme 8. Example of semi-pinacol rearrangement approaches to tetramethylpyrandione and bicyclo[2.2.1]heptan-2-one 2-aryl-1,3-diones

Epoxide starting materials (compounds 18 and 21, Scheme 9) were synthesized by either addition of hydrogen peroxide to the enone precursor or Darzens epoxidation. Enone epoxidation using basic hydrogen peroxide was initially problematic due to over-oxidation to the carboxylic acid 20 (after hydrolysis), but this Baeyer-Villiger step was minimized by using catalytic rather than stoichiometric metal hydroxide, higher reaction temperatures and lower reaction concentrations. Lithium hydroxide was found to afford higher yields than either potassium hydroxide or sodium hydroxide (25). The alternative Darzens reaction was achieved by deprotonation of the α-bromo ketone (for example, compound 22) using potassium tert-butoxide in the presence of the aryl aldehyde reaction partner (25). Highest yields were obtained in dipolar aprotic solvents such as dimethyl sulfoxide or N,N-dimethylformamide. This reaction was limited to substrates lacking an acidic α′-hydrogen, such as bicyclo[2.2.1]heptan-2-one, Scheme 9.



Scheme 9. Synthesis of example epoxides by hydrogen peroxide and Darzens approaches

Case Study - Meta-Biphenyl Tetramethylpyrandiones During this work meta-biphenyl tetramethylpyrandiones were identified as a novel ACCase chemical class with outstanding herbicidal activity, particularly for the post-emergence control of warm climate grasses (22). The glasshouse biological profile of three example meta-biphenyl tetramethylpyrandiones 23, 24 and 25 is shown in Table 1. The original route to these compounds involved an aryl lead cross-coupling (as described earlier) to access compound 4 (Scheme 2), followed by a palladiumcatalyzed Suzuki cross-coupling as the final step (22). The aryl lead reagent was prepared in four steps starting from 2-ethyl-5-bromonitrobenzene (22), and the 1,3dione coupling partner 2,2,6,6-tetramethylpyran-3,5-dione was prepared in three steps from 2,2,5,5-tetramethyltetrahydrofuran-3-one 26 (26). The overall length of this chemical sequence and undesirable nature of certain reagents led us to investigate an improved large scale process which would also reduce the cost of goods. The optimized route to meta-biphenyl tetramethylpyrandiones is outlined in Scheme 10.



Table 1. Herbicidal activity of example meta-biphenyl tetramethylpyrandiones

Scheme 10. Optimized large scale route to meta-biphenyl tetramethylpyrandiones



Synthesis of biphenyl 27 was achieved by a nickel-catalyzed Kumada cross-coupling of 4-ethylphenylmagnesium bromide with the required 4-chloro bromobenzene. This process was considered more attractive than the more conventional palladium-catalysed Suzuki cross-coupling due to the lower cost of the metal catalyst and shorter reaction sequence. Various catalytic systems were thoroughly explored before we identified the nickel(II) fluoride / 1,3-bis-(2,6-diisopropylphenyl)imidazolium chloride conditions, originally reported by Nakamura and co-workers (27), as highly efficient. This reaction was not only halogen selective (oxidative insertion into the carbon-bromine not carbon-chlorine bond), but also very selective for the desired cross-reaction product. Almost all other conditions evaluated afforded relatively high yields of both the Grignard and aryl halide homocoupling products, which were difficult to separate and, in the case of polyhalobiphenyls, also associated with toxicity alerts. The mechanism of this catalytic system is proposed to proceed via a nickel (II) – nickel (IV) cycle which promotes a fast reductive elimination, therefore minimizing ligand scrambling leading to homocoupling (27). Conversion of biphenyl 27 to benzaldehyde 28 was achieved by regioselective formylation using dichloromethyl methyl ether and titanium tetrachloride in dichloromethane in 70% yield. During this program we also successfully developed a novel protic acid rearrangement of 2,5-dimethyl-3-hexyne-2,5-diol 29 to 2,2,5,5-tetramethyltetrahydrofuran-3-one 26. All literature reports of this transformation use mercury catalysis (for example (28)), however we identified that specific formic acid / concentrated sulfuric acid conditions were very effective. The highest yields were achieved by an overall one pot, two-step process, in which compound 29 was stirred at room temperature to afford the intermediate enone 30 (via a presumed Meyer–Schuster type rearrangement), then briefly heated at 80 ºC to effect the formal 5-endo-trig cyclisation (Scheme 10). The final stages of this new synthesis relied upon the recently developed Darzens epoxidation – semi-pinacol rearrangement sequence outlined earlier in the chapter. In this instance the fully assembled biphenyl aldehyde 28 reacted very smoothly with the bromo ketone 31 using potassium tert-butoxide in N,N-dimethylformamide to provide epoxide 32 in excellent 90% yield. The subsequent acid-catalysed rearrangement using concentrated sulfuric acid / dichloroethane was also highly efficient, affording the final target compound(s) in approximately 90% yield (Scheme 10).

Conclusion A range of novel synthetic methodologies have been developed and introduced into the discovery program of ACCase-inhibiting carbocyclic 2-aryl-1,3-diones. These new approaches have allowed the rapid SAR exploration of a diverse range of chemical classes, leading to the identification of meta-biphenyl tetramethylpyrandiones as highly active post-emergence graminicides. An extremely efficient and concise large scale synthesis of this exciting chemical class was also developed. 302 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.

Acknowledgments The authors would like to thank additional co-workers Alaric Avery, Emma Briggs, John Finney, Matthew Hotson, Régis Mondière, Melloney Morris, Rod Mound, Sean Ng, Tony O’Sullivan, Robert Parsons, Mangala Phadte, Mark Slater, John Taylor, Louisa Whalley and Franz Zumpe who have also made invaluable contributions to this work.


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New Approaches to the Design and Synthesis of Inhibitors of Acetyl

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