Article pubs.acs.org/accounts
Mesoionic Pyrido[1,2‑a]pyrimidinone Insecticides: From Discovery to Triflumezopyrim and Dicloromezotiaz Wenming Zhang* DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Road, Newark, Delaware 19711, United States CONSPECTUS: One of the greatest global challenges is to feed the ever-increasing world population. The agrochemical tools growers currently utilize are also under continuous pressure, due to a number of factors that contribute to the loss of existing products. Mesoionic pyrido[1,2-a]pyrimidinones are an unusual yet very intriguing class of compounds. Known for several decades, this class of compounds had not been systemically studied until we started our insecticide discovery program. This Account provides an overview of the efforts on mesoionic pyrido[1,2-a]pyridinone insecticide discovery, beginning from the initial high throughput screen (HTS) discovery to ultimate identification of triflumezopyrim (4, DuPont Pyraxalt) and dicloromezotiaz (5) for commercialization as novel insecticides. Mesoionic pyrido[1,2-a]pyrimidinones with a n-propyl group at the 1-position, such as compound 1, were initially isolated as undesired byproducts from reactions for a fungicide discovery program at DuPont Crop Protection. Such compounds showed interesting insecticidal activity in a follow-up screen and against an expanded insect species list. The area became an insecticide hit for exploration and then a lead area for optimization. At the lead optimization stage, variations at three regions of compound 1, i.e., side-chain (n-propyl group), substituents on the 3-phenyl group, and substitutions on the pyrido- moiety, were explored with many analogues prepared and evaluated. Breakthrough discoveries included replacing the n-propyl group with a 2,2,2trifluoroethyl group to generate compound 2, and then with a 2-chlorothiazol-5-ylmethyl group to form compound 3. 3 possesses potent insecticidal activity not only against a group of hopper species, including corn planthopper (Peregrinus maidis (Ashmead), CPH) and potato leafhopper (Empoasca fabae (Harris), PLH), as well as two key rice hopper species, namely, brown planthopper (Nilaparvata lugens (Stål), BPH) and rice green leafhopper (Nephotettix virescens (Distant), GLH), but also against representative lepidoptera species Diamondback moth (Plutella xylostella (Linnaeus), DBM) and fall armyworm (Spodoptera frugiperda (J.E. Smith), FAW). Further optimization based on 3 led to discovery of triflumezopyrim (4), with a 5pyrimidinylmethyl group, as a potent hopper insecticide for rice usage. Optimization of the substituents on the pyrido- moiety of 3 resulted in discovery of dicloromezotiaz (5) as a lepidoptera insecticide. In this Account, we present the discovery and optimization of mesoionic pyrido[1,2-a]pyrimidinone insecticides toward the identification of triflumezopyrim (4) and dicloromezotiaz (5). We hope that knowledge and lessons derived from this discovery program will provide valuable information for future agrochemical and drug discovery. Our successful discovery and commercialization development of two novel insecticides based on meosoionic pyrido[1,2-a]pyridiminones may also stimulate interests of scientists from other disciplines to adopt this uncommon yet intriguing heterocycle ring system in pharmaceutical and other material science discovery research.
1. INTRODUCTION Although modern global agriculture has substantially benefitted from the crop protection industry, there remain significant opportunities for agrochemical discovery and development. Based on The Food and Agriculture Organization of the United Nations (FAO) estimation, current global crop yields are reduced by 20−40% per year due to plant pests and diseases. It is also projected that the world’s food production will need to increase by 60% with the world’s population growing toward 9 billion by 2050.1 On the other hand, urbanization, the demand for better quality food diet richer in protein, and limits of arable land and freshwater supplies provide more challenges for the farmers of tomorrow. In the meantime, many existing crop protection products have been discontinued due to a number of factors, such as the continuing development of resistance, the © 2017 American Chemical Society
regulatory demand for products with more favored toxicological and environmental profiles, and the need for effective control options for integrated pest management (IPM). Modern discovery and development of novel pesticides involves the same set of approaches as those applied in the pharmaceutical industry, spanning from high-throughput screening (HTS) of collections of compounds to investigation of known or novel chemical scaffolds.2a−e Agrochemical discoveries disclosed in the past several years traced their roots to HTS,3 patent scouting,4 natural products,5 privileged structures as novel scaffolds,6 and others.7 A unique class of mesoionic pyrido[1,2-a]pyrimidinones was recently discovered Received: June 20, 2017 Published: August 21, 2017 2381
DOI: 10.1021/acs.accounts.7b00311 Acc. Chem. Res. 2017, 50, 2381−2388
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Accounts of Chemical Research
pyridines B-1 and substituted aryl malonic acids also produces the desired mesoionic pyrido[1,2-a]pyrimidinones.15a Mesoionic compounds often appear as colored materials and their spectroscopic properties have been explored for applications such as pigments,14a liquid-crystalline copolymers,14b or photosensitive components.14c 3-Aryl mesoionic pyrido[1,2-a]pyrimidinones show a characteristic yellow color, with long wavelength absorption maximum between 300 and 450 nm in the UV/vis spectra.15 When exposed outdoors, such compounds absorb sunlight with the potential to decompose. Such compounds are disfavored for commercialization development as agrochemicals, as they will be inevitably exposed to the sun, with a long period of time often desired to garner good residual activity. Despite this concern, our team was determined to pursue the area and explore analogues, due to interesting insecticidal activity of initial compound 1 observed in greenhouse and the uncommon yet very intriguing chemical structure. We surmised that advanced and more potent analogues would possess sufficient translaminar activity (vide infra), which means such compounds would penetrate into plant tissue quickly and be protected by plant chlorophyll,16 for effective insect control.
in our laboratory as a novel class of insecticides, originated from screening the DuPont internal collection of compounds and possessing exceptional biological activity in controlling a number of insect species.8,9 In this Account, we will summarize the discovery work around this area in the last several years.
2. MESOIONIC PYRIDO[1,2-a]PYRIMIDINONES Mesoionic compounds are an uncommon type of heterocyclic organic compound. Six-membered ring mesoionic heterocycles have been known for several decades, but they have only appeared sporadically in scientific journals.10,11 This Account discusses mesoionic pyrido[1,2-a]pyrimidinones which are pyridine-fused pyrimidinone mesoionic compounds. IUPAC nomenclature of the parent mesoionic pyrido[1,2-a]pyrimidinone is 4-oxo-pyrido[1,2-a]pyrimidin-1-ium-2-olate. In this Account, this compound and its analogs are referred as mesoionic compounds. Such mesoionic compounds cannot be satisfactorily represented by one single covalent or ionic structure. We have been using the drawing pattern A since our research program was initiated. This drawing pattern has been employed in the patent application cases filed by DuPont and has been adopted in the SciFinder database to represent mesoionic compounds. Drawing pattern A will be used throughout this Account. It is worth noting that two development candidates identified from our discovery program, triflumezopyrim (4, ISO-proposed common name approved in August, 2013, DuPont Pyraxalt)12 and dicloromezotiaz (5, ISOproposed common name approved in December 2014),13 are represented in the SciFinder database as structures 4 and 5, as shown in Figure 1, respectively, with negative charge located on the carbon atom at 3-position of the mesoionic ring.
3. DISCOVERY OF MESOIONIC PYRIDO[1,2-a]PYRIMIDINONE INSECTICIDES In the 1990s, DuPont Crop Protection was engaged in a fungicide discovery program for powdery mildew control. An analogue of particular interest to the optimization team was compound 6 (See Scheme 2). This compound was prepared in 70% yield by O-alkylation of the corresponding pyrido[1,2a]pyrimidinone 7. One byproduct was also isolated and identified as mesoionic compound 1, derived from N-alkylation of compound 7.11a When submitted to greenhouse screens, neither compound 1 nor 6 displayed any fungicidal or insecticidal activity at the time. In follow-up screens in 2005 and against an expanded species list, however, 1 showed insecticidal activity against corn planthopper (Peregrinus maidis (ashmead), CPH) and diamondback moth (Plutella xylostella (Linnaeus), DBM). We were intrigued by both the observed biological activity and uncommon mesoionic structure and began to explore analogues of this compound. Two series of analogues of compound 1 were prepared, replacing the n-propyl group with various small alkyl groups or adding a small substituent on the pyridine ring part of the mesoionic core. As shown in Table 1, insecticidal activity of representative analogues indicates better control of CPH and DBM than potato leafhopper (Empoasca fabae (Harris), PLH) or fall armyworm (Spodoptera frugiperda (J.E. Smith), FAW), and compound 1 possesses the most potent insecticidal activity in this series. Substituents at the 1-position larger (n-Bu, Bn) or smaller (Me, Et) than n-propyl group lead to analogues (C-1 to
Figure 1. Mesoionic pyrido[1,2-a]pyrimidinone A and SciFinder representations of triflumezopyrim (4) and dicloromezotiaz (5).
Mesoionic pyrido[1,2-a]pyrimidinones discussed in this Account always have an aryl group substituted at the 3-position of the mesoionic ring, i.e., B-3 in Scheme 1. Such compounds can be prepared effectively through cyclization between 2aminopyridines B-1 and substituted aryl malonates or their acid chloride equivalents B-2 under appropriate conditions.8,9,12,13 Alternatively, amide coupling reaction between 2-amino-
Scheme 1. Preparation of 3-Aryl Mesoionic Pyrido[1,2-a]pyrimidinonesa
a
Lv = alkoxy, 2,4,6-trichlorophenoxy, chlorine, hydroxy. 2382
DOI: 10.1021/acs.accounts.7b00311 Acc. Chem. Res. 2017, 50, 2381−2388
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Accounts of Chemical Research Scheme 2. Alkylation Reaction of Pyrido[1,2-a]pyrimidinone with 1-Iodopropanea
a
Reaction conditions: n-PrI, K2CO3, DMF, 25 °C.
Sets of analogues with small substituents on the pyridine ring moiety were also prepared and evaluated. Table 1 shows analogues with the methyl group “walking around” the pyridine ring moiety, i.e., compounds C-5 to C-8. None of them display any insecticidal activity at any rates tested. We then decided to explore the chemistry beyond the Nalkyl analogues, focusing on analogues with a functionized alkyl group at the 1-position to replace the n-propyl group. As shown in Table 2, examples of such analogues include compounds containing an ester, amide, or ether group (compounds D-1, D2, and D-3, respectively) or a 2,2,2-trifluoroethyl group, such as compound 2. As indicated in Table 2 for compounds D-1 to D3, all three functional groups are tolerated but those analogues do not display the same level of insecticidal activity as compound 1. The corresponding 2,2,2-trifluoroethyl analogue, i.e., compound 2, however, provides significantly more potent activity against both CPH and PLH. This modification give the first breakthrough of the optimization program and produces analogues with potent and consistent broad-spectrum hoppercidal activity (vide infra). Compound 2 possesses a greater than 120-fold increase in insecticidal activity against CPH when compared to the original hit compound, an analogue of compound 1 with a 3,5-difluorophenyl group at 3-position of the mesoionic core ring. Encouraged by this finding, we prepared and evaluated additional 2,2,2-trifluoroethyl analogues with different substituents on the 3-phenyl group, analogues
Table 1. Insecticidal Potency of 1-Alkyl Mesoionic Compoundsa
entry b
C-1 C-2b 1b C-3b C-4b C-5c C-6c C-7c C-8c
R1
R2
CPH
PLH
DBM
FAW
H H H H H 6-Me 7-Me 8-Me 9-Me
Me Et n-Pr n-Bu Bn n-Pr n-Pr n-Pr MeO(CH2)3
106.6 250 >250 >250
>50 >50 33.4 >250 >250 >250 >250 >250 >250
>250 84.2 28.1 92.1 >250 >250 >250 >250 >250
no data no data >50 >250 no data no data no data no data no data
a
Insecticidal potency shown as LC 50 in ppm; CPH (corn planthopper); PLH (potato leafhopper); DBM (diamondback moth); FAW (fall armyworm). bData from ref 8. cData from ref 13.
C-4) with decreased biological activity. In hindsight, it is surprising that inferior biological activity was observed for benzyl analogues C-4. We will discuss more about this later.
Table 2. Insecticidal Potency of 1-Substituted Mesoionic Compoundsa
entry b
D-1 D-2b D-3b 2b D-4c D-5c D-6c D-7c D-8c D-9c D-10c D-11c D-12b
R2
CPH
PLH
DBM
FAW
CH3OCOCH2 (CH3)2NCOCH2 CH3O(CH2)2 CF3CH2 3-pyridyl-CH2 6-Cl-3-pyridyl-CH2 6-F-3-pyridyl-CH2 4-Cl-benzyl 6-CF3-3-pyridyl-CH2 5-Br-3-pyridyl-CH2 5-CN-3-pyridyl-CH2 5,6-Cl2-3-pyridyl-CH2 (R,S)-tetrahydro-3-furanyl-CH2
13.3 >50 6 1 50 2.1 250 250 >250 250 >50 50 250 >250 >250 >250 19.7 7
>250 >10 243.4 250 >250 >250 >250 >250
>250 >10 >250 >250 >250 243.4 46.0 >250 >250 >250 >250 >250 >250
a
Insecticidal potency shown as LC50 in ppm; CPH (corn planthopper); PLH (potato leafhopper); DBM (diamondback moth); FAW (fall armyworm). bData from ref 8. cData from ref 12. 2383
DOI: 10.1021/acs.accounts.7b00311 Acc. Chem. Res. 2017, 50, 2381−2388
Article
Accounts of Chemical Research Scheme 3. Seven “Traditional” Neonicotinoid Insecticides and Sulfoxaflor and Flupyradifurone
Table 3. Insecticidal Potency of Mesoionic Compounds with Hoppercidal Activitya
entry b
2 D-5c E-1b E-2b 3b E-3b 4c
R2
R3
CPH
PLH
BPH
GLH
DBM
FAW
CF3CH2 6-Cl-3-pyridyl-CH2 thiazol-5-yl-CH2 2-methylthiazol-5-yl-CH2 2-chlorothiazol-5-yl-CH2 2-chlorothiazol-5-yl-CH2 5-pyrimidinyl-CH2
H H H H H 2-F 3-CF3
1 2.1 0.6 9.2
