Synthesis of Heterocyclic Analogs of Herbicidal Aryl Triazolinones

Chapter 5

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Synthesis of Heterocyclic Analogs of Herbicidal Aryl Triazolinones Colin M. Tice and Adam C-T. Hsu Rohm and Haas Company, 727 Norristown Road, Spring House, PA 19477-0904

1-t-Butyl-3-phenyl-4-propargyl-1,2,4-triazolin-5-one 1 possesses lead level herbicidal activity. In an effort to improve the activity of the lead compound, a series of analogs varying in the heterocylic portion of the molecule was synthesized. Three bioisosteric heterocycles, 5-phenyl-4-propargyl-2-propylisoxazolidin-3-one 16, 2,3-dimethyl-6-phenyl-5-propargyl-4(3H)-pyrimidinone25 and 5,6-dimethyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone 27, were discovered. The last of these offered a superior starting point for further analog synthesis.

Phenyl triazolinone R H 88488 (1, Figure 1) was synthesized as part of a program to explore the utility of t-butylhydrazine as a building block for agrochemical synthesis (1). Upon greenhouse screening, the compound's broad spectrum preemergence herbicidal activity immediately attracted attention. New leaf tissue in treated plants was white, a symptom commonly observed with herbicides that interfere with carotenoid biosynthesis. Indeed analysis of affected leaf tissue showed an increase in the carotenoid precursors phytoene, phytofluene and zeta carotene (2). A literature search revealed that workers at Nihon Nohyaku had previously investigated some similar

© 2002 American Chemical Society

In Synthesis and Chemistry of Agrochemicals VI; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2001.

41


42


43 compounds (5). The level of activity of 1 was such that it advanced through the greenhouse screening cascade and was submitted for field testing in several key agronomic crops where it showed good activity preemergence against a number of weeds at 4800 g ha" . Cotton and sunflower were tolerant of the compound. In our experience, it is rather unusual that the initial lead in a new series is sufficiently active to warrant field testing. The S A R of the substituents around the triazolinone ring of 1 was investigated. The conclusions of this study are summarized in Figure 2. None of the analogs synthesized was superior to 1, although several were comparable. The greatest flexibility was found at R , the i-butyl position in 1, where other similarly sized, hydrophobic substituents retained activity. There was a stringent requirement for a propargyl group at R for good activity. Fluorine substitution was tolerated at the 2- and 3-positions of the phenyl ring but larger substituents at these positions and any substitution at the 4-position, including fluorine, diminished activity. 1


2

4

R N-N R

R

2

R

4

2

2

3

C H C = C H > C H C H O M e > Et > C H O M e > Me 2

ο

if

t-Bu, C H C ^ C H , n-Pr, C H C F > η-Bu, i-Bu > Et > Me CH C=CH » 2

2

2

2

C H C H = C H > n-Pr 2

2

5

R = Ph, 2-F-Ph, 3-F-Ph > 2-thienyl > 3-thienyl »

naphthyl, pyridyl, 2-furyl

Figure 2. Summary of Triazolinone Substituent SAR

Five Membered Heterocycle SAR and Model Development In parallel with the effort to optimize the substituents, compounds in which the core triazolinone ring was replaced with other 5-membered heterocycles were targeted for synthesis. Wherever possible the optimal substituents (R = tBu, R = CH C=CH, R = Ph) were maintained around the new 5-membered ring; however, in the interests of synthetic expediency suboptimal substituents (R = methyl, ethyl, methoxymethyl or 2-methoxyethyl in place of propargyl; R = η-propyl or methyl in place of ί-butyl) were used in some cases. O f course, in these cases the activity of the resulting heterocyclic analog was compared to that of the identically substituted triazolinone. The structures of heterocyclic analogs made are shown in Figure 1. In general literature procedures were adapted to the synthesis of these compounds (4) and they were tested in the greenhouse at 4800 g ha" . When the carbonyl group of 1 was replaced with 2

4

5

2

4

2

1


44 other functional groups capable of forming a hydrogen bond, amino in 2, methoxy in 3, sp N in 4 and sulfoxide in 5 (5), only the last compound retained any herbicidal activity and it was much less active than 1. Tying the carbonyl group back into a ring as an ether in 6 or an imino group in 7 and 8 abolished activity. Compounds 9 and 10 in which the N -propargyl unit was deleted and replaced with an oxygen or sulfur atom were inactive. Pyrazolinone 11 in which the propargyl group was retained but N was replaced with a C M e unit was inactive. Replacement of the N -t-Bu moiety with an oxygen atom in 12 or C M e in 13 abolished activity. The inactivity of 11 and 13 suggested that the heterocyclic the substituents. N of the triazolinone was replaced with C H in 14, N M e in 15, Ο in 16, C=0 in 17 and N H in 18; the ether oxygen replacement in isoxazolidinone 16 successfully retained a substantial level of activity. The regioselective synthesis of 16 from β-ketoester 19 and N-propylhydroxylamine, following the method of Sato et al (6), is depicted in Figure 3. 2

4

4

2

2


1

a) NaOH, aq MeOH, -20°C. b) PrHNOH, -20°C. c) cone HC1, reflux. Figure 3. Isoxazolidinone Synthesis A small group of analogs of 16 was prepared to investigate the S A R of this series (7). Structures and greenhouse data for these compounds are shown in Table I. Compound 21, in which the Pr group was replaced with Me, retained activity while replacement of the propargyl group with hydrogen in 22 or ethoxycarbonyl in 23 abolished activity. This results of this limited S A R study paralleled those observed in triazolinone series. Consideration of the activity of the compounds in Figure 2 allowed us to propose the model for herbicidal activity shown as 24 in Figure 4. Key features of the model are the requirements for a planar heterocycle (A) incorporating a carbonyl group, a hydrogen bond acceptor distal from the carbonyl group (B) and open valencies in the appropriate positions to accommodate the phenyl, propargyl and hydrophobic (C) moieties. To test the predictive power of the model the three 6-membered ring heterocycles 25 - 27 (Figure 4) were synthesized and tested.


45


Table I. Preemergence Herbicidal Activity of Isoxazolidinone Analogs

Compd 16 21 22 23

2

R n-Pr Me Me i-Bu

4

R CH C=CH CH C=CH H C0 Et

AAf 62 61 0 0

2

2

2

a

1

Average % control of 5 monocot weeds at 4800 g ha". weeds at 4800 g ha".

b

AI? 70 50 0 0

Average % control of 5 dicot

1

24

25

26

27

Figure 4. Herbicidal Activity Model and Compounds Designedfrom the Model

a) MeC(=NH)NH .HCl, NaOAc, toluene, reflux, Dean Stark trap, K C 0 , acetone, reflux. 2

2

3

Figure 5. 6-Phenylpyrimidinone Preparation


b) M e l ,

46

Six Membered Heterocycle Synthesis and SAR


6-Phenylpyrimidinone 25 was prepared in 2 steps (Figure 5). Reaction of acetamidine hydrochloride with β-ketoester 19 (8) afforded pyrimidinone 28 which was methylated under basic conditions to afford 25 as the major product This compound had bleaching activity in the greenhouse, although it was 2-4x less active than 1. The results of a limited S A R study are shown in Table II and were consistent with our expectations based on the S A R observed in the triazolinone series (9).

Table II. Preemergence Herbicidal Activity of 6-Phenylpyrimidinones R

2

n ^ n '

Cmpd 25 29 30 31 32 33 34 35 a

2

R Me H n-Pr Me -

3

R Me Me Me CH OCH 2

CH2CH2CH2CH2•SCH2CH2-

Me Me

Me Me

r

3

3

R CH C=CH CH OCH CH C=CH CH C=CH CH OCH CH OCH H Br 2

2

2

2

2

2

1

Average % control of 5 monocot weeds at 4800 g ha" .

b

AW 82 39 81 72 79 63 0 2

AI? 79 38 66 78 64 10 0 0

Average % control of 5 dicot

1

weeds at 4800 g ha .

The route used to prepare l,2,4-triazin-5-one 26 is shown in Figure 6. Treatment of methyl benzimidate hydrochloride with hydrazine followed by methyl pyruvate afforded triazinone intermediate 36 which was alkylated with propargyl bromide (10). The major product was the undesired regioisomer 37; however the desired product 26 was isolated in 2% yield. This compound caused only very slight bleaching on new leaf tissue when applied preemergence and was not pursued further.


47

.Ν N'

OMe

Λ Phi

Pli

NH.HC1

P h ^ N ^ O

Ν Η

+

^

Ν

Ph^Ao

36 26 37 a) i . NaOMe, M e O H ; ii. N H ; iii. M e C O C 0 M e . b) B r C H O C H , NaOMe, MeOH Downloaded by PENNSYLVANIA STATE UNIV on June 17, 2012 | http://pubs.acs.org Publication Date: July 29, 2001 | doi: 10.1021/bk-2002-0800.ch005

2

4

2

2

Figure 6. 1,2,4-Triazin-5-one Preparation

NH

N ' ^ f

a

PrT"NH .HCl

b

Prf^N^O H

2

38 27 39 a) M e C O C H M e C 0 M e , NaOAc, xylenes, reflux, Dean Stark trap, b) B r C H C = C H , K C 0 , acetone, reflux. 2

2

2

3

Figure 7. 2-Phenylpyrimidinone Preparation

Pli

Ν "Ο

Figure 8. N-Propargylpyrimidinone Regioisomers The route used to prepare 2-phenylpyrimidinone 27 is shown in Figure 7. Reaction of benzamidine hydrochloride with methyl acetoacetate afforded 38 (8). Propargylation of this intermediate under basic conditions proceeded in 90% yield to afford a 10:1 mixture of the undesired O-propargyl compound 39 and the desired N-propargyl product 27. These isomers were readily separated by flash chromatography. The preemergence herbicidal activity of 27 in the greenhouse was equal to that of the original lead compound 1. However, 27 appeared to offer an improved starting point for analog synthesis. The two sp 2

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In Synthesis and Chemistry of Agrochemicals VI; Baker, D., et al.; Washington, DC Society: 20036 Washington, DC, 2001. ACS Symposium Series; American Chemical

48 5

6

carbons C and C allow greater flexibility in the types of substituents that can be stably appended than does N in the triazolinone ring. For example a chlorine substituent at either C or C of the pyrimidinone ring should be reasonably chemically stable whereas an N -chlorotriazolinone would be chemically reactive. Furthermore, the two positions offer greater ability to tailor the substituents to fill the binding pocket occupied by the f-butyl group in 1. Given our interest in 27 as a new lead it was important to establish the regiochemistry of N-propargylation and be certain that the propargyl group was indeed attached at N and not to the N position (40, Figure 8). Literature precedent favored structure 27 since alkylation at N is observed more frequently than at N (//). The stretch of the carbonyl in the IR spectrum was also more consistent with structure 27 (12). No N O E could be detected between the propargyl methylene and the C methyl group, again favoring structure 27. Ultimately all doubt was removed when an X-ray structure was obtained on 41, the 5,6-diethyl analog of 27. At the time this work was in progress we were aware of several other herbicidal chemotypes that function by inhibiting zeta carotene desaturase (75). Dihydropyrone 42 (14) and iminothiadiazole 43 (75) shown in Figure 9 were of particular interest since, like our compounds, they are both phenyl-substituted heterocyclic systems. In the greenhouse 1 and 27 had comparable activity to 42 and were superior to 43 (Table III). Based on the hypothesis that these compounds may occupy the same binding site, we synthesized a number of compounds as hybrids of our compounds and the literature compounds. For example isoxazolidinone 23 (Figure 10) can be considered to be a hybrid of 16 and 42. Similarly 44 and 10 can be considered to be hybrids of 1 and 43. None of the hybrid compounds prepared had significant greenhouse activity. 2

5

6

2

3

1


3

1

6

Figure 9. Zeta Carotene Desaturase'Inhibitors


49 Table III. Comparison with Herbicidal Activity of Known Zeta-Carotene Desaturase Inhibitors

Cmpd

Structure Type

AM'

Alt (600 g ha')


1 27 42 43

Triazolinone Pyrimidinone Dihydropyrone Iminothiadiazole

67 59 62 44

a

A M = average % control of 8 monocot weeds preemergence. of 12 dicot weeds preemergence.

72 75 65 23 b

AD = average % control

,ΐ-Bu N-N

10

Figure 10. Hybrid Compounds

Conclusions Systematic replacement of the triazolinone ring of 1 with other heterocycles led to the discovery of three new herbicidal series of which isoxazolidinone 16, 6-phenylpyrimidinone 25 and 2-phenylpyrimidinone 27 were the lead compounds. The last of these had comparable activity to 1 and offered increased flexibility for analog synthesis.

Acknowledgments The success of this project would not have been possible without the dedicated efforts of many of our coworkers at Rohm and Haas. Scale U p Chemistry: Ronald P. Owen, Judith A . H . Schilling; Greenhouse Biology: Manuel V . Nunez; Molecular Modelling; Ted T. Fujimoto; Biochemistry: Ernest L . Burdge, Christine A . Cayer; Management: Horst O. Bayer.


50

References 1. 2. 3.


4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Hsu, A. C.; Tice, C. M.; U.S. Patent 5,120,347, 1992. Burdge, E . L. personal communication. Akita, T.; Tagaki, K.; Hachitani, Y . ; Yabutani, K . Japanese Patent 60,218,379, 1985. Comprehensive Heterocyclic Chemistry Katritzky, A . R.: Rees, C. W. Ed.; Pergamon: Oxford, U.K., 1984 Heubach, G. Liebigs Ann. Chem. 1980, 1376-1383. Sato K.; Sugai, S.; Tomita, K . Agric Biol. Chem. 1986, 50, 1831-1837 Tice, C. M. U.S. Patent 5,723,414, 1998. Brown, D . J. The Pyrimidines, John Wiley & Sons, Inc.: New York, 1994, pp. 188-193. Tice, C. M. U.S. Patent 5,298,481, 1994. Jacobsen N. W.; Rose, S. E. Aust. J. Chem. 1985, 38, 1809-1813. Brown, D. J. The Pyrimidines, John Wiley & Sons, Inc.: New York, 1994, pp. 461-462. Brown, D . J.; Hoerger, E.; Mason, S. F. J. Chem. Soc. 1955, 211-217. Bramley, P. M. in Target Sites for Herbicide Action, Kirkwood, R. C. Ed.; Plenum Press: New York 1991, pp 114-115. Hirtzbach de Reinach, F.; Borrod, G. U.S. Patent 4,383,849, 1983. Dahle, N. A . U.S. Patent 4,104,053, 1978.


Synthesis of Heterocyclic Analogs of Herbicidal Aryl Triazolinones

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