Synthesis and Herbicidal Activity - American Chemical Society

Chapter 11

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1H-1,4-Benzodiazepine-25-diones and Related Systems: Synthesis and Herbicidal Activity GaryM.Karp, Mark C. Manfredi, Michael A. Guaciaro, Philip M. Harrington, Pierre Marc, Charles L. Ortlip, Laura S. Quakenbush, and Iwona Birk Cyanamid Agricultural Research Center, American Cyanamid Company, PO Box 400, Princeton,NJ08543-0400

The synthesis and structure-activity relationships of a series of 1H-1,4 -benzodiazepine-2,5-diones is described. Many of the analogs exhibit moderate levels of both pre- and postemergence herbicidal activity. These compounds have been found to act by inhibition of photosynthesis by blocking PSII electron transport. In addition, a number of closely related ring systems were prepared by modification of both the benzene and diazepine ring and were also evaluated for herbicidal activity. In nearly all cases there was a significant drop in activity. As part of a broad-based random screening process carried out some years ago at the Agricultural Products Research Division, a small number of benzodiazepinediones were found to have herbicidal properties. The benzodiazepinediones, exemplified by 1, were originally prepared as part of an anxiolytic screening program conducted by American Cyanamid Company's Medical Research Division (previously Lederle Laboratories, now part of Wyeth-Ayerst Research) (7,2). Based on the herbicidal activity of these compounds, a limited synthesis effort was initiated. This program was abandoned shortly thereafter, however, in preference to other areas of research. Recently, the benzodiazepinediones were re-evaluated as potential corn selective herbicides based on the lead compound 1. At an early stage of the more recent synthesis effort, 2 was prepared and was found to have improved activity, both preand postemergence. The observation that the C-ring derivedfromthe proline ester of 1 was not a prerequisite for herbicidal activity was advantageous, as it would simplify the synthesis of potential analogs. In order to establish an effective structure-activity relationship in this class a large number of analogs were prepared (3,4). The initial focus of the synthesis effort consisted of substituent modification in the diazepine ring (N-l, C-3 and N-4) as well as regiochemical variation at all four benzenoid positions (C-6 through C-9). In addition to benzodiazepine-2,5-dione analogs, this effort was ultimately expanded to include several closely related ring systems. Structural modifications included aryl ring replacement (pyridine and thiophene) and modification of the seven-membered diazepine ring, including the addition of heteroatoms and variation in theringsize. ©1998 American Chemical Society

95

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Benzodiazepinedione 2 was found to strongly inhibit photosynthetic electron transport in both in vitro and in vivo systems. Furthermore, the site of action is believed to be the D l protein of PSII as triazine-resistant plants were found to be resistant to compound 2 as well (5).

1

2

Synthesis. Preparation of 1,4-Benzodiazepine-2,5-dione analogs. Many of the benzodiazepinedione analogs were prepared as shown in Figure 1. Commercially available o-nitrobenzoic acids were converted to the respective acid chlorides 3 and treated with N-alkylglycinate esters 4 to afford o-nitrohippuric esters 5. Reduction of the nitro group gave crude o-aminohippuric esters which were readily cyclized under acidic conditions to afford the desired benzodiazepinediones 6 in good yield. For many other analogs, the desired substituents were introduced after benzodiazepinedione ring formation due to the lack of available starting materials. For example, selective C-7 iodination and bromination took place with unsubstituted benzodiazepinedione 7 to afford 8 and 9, respectively (Figure 2) (6). When C-7 is already substituted with a chlorine atom (e.g., 2) bromination is directed exclusively to C-9, although more forcing conditions are required. More complex benzenoid substituents could be introduced by palladium-mediated coupling reactions of the bromo- and iodobenzodiazepinediones. Vinyl, alkynyl, aryl and heteroaryl substituents were introduced in this manner (6). Benzodiazepinediones bearing a hydrogen at N-l could be readily N-alkylated, as reported previously (4).

3

5

6 Figure 1. Preparation of l,4-benzodiazepine-2,5-dioneringsystem from substituted o-nitrobenzoyl chlorides.


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2 Figure 2. Selective halogenation reactions of benzodiazepinediones. Diazepineringmodification. We chose to examine the effect of structural changes to the seven-membered diazepineringon the resultant herbicidal activity. Three ring systems were examined in which changes were made to the benzodiazepinedione C-3. One system examined was the l,3,4-benzotriazepine-2,5-dione ring system resulting from the replacement of the C-3 carbon with a nitrogen atom. Other ring systems studied were the 1,5-benzodiazocine-2,6-diones and 1,2,3,4-tetrahydroquinazoline2,4-diones, resultingfromthe insertion of an additional methylene group between C-3 and N-4, and the removal of the C-3 methylene group, respectively. 13?4-Benzotriazepine-2,5-dione ring system. The interesting level of herbicidal activity of benzodiazepinedione 2 prompted the preparation of the 3-aza analogs 14-16 (Figure 3). Treatment of o-nitrobenzoyl chloride 3 with the acetone hydrazone of /-butylhydrazine gave the N-protected o-(nitrobenzoyl)hydrazine 11. Acid-catalyzed N-deprotection gave 12. Nitro reduction afforded the o(aminobenzoyl)hydrazine 13 which cyclized to the parent 14 upon treatment with trichloromethyl chloroformate (diphosgene) (7). N-alkylation of 14 gave the 3-alkyl analogs 15 and 16 exclusively. l,5-Benzodiazocine-2,6-dione ring system. Ring expansion of the benzodiazepinedione at C-3 by incorporation of an additional methylene unit gives rise to the l,5-benzodiazocine-2,6-dione ring system. The o-nitrobenzoyl chloride 3

98


was treated with methyl Ν-ί-butylpropionate to give the nitro ester 17 (Figure 4). Nitro reduction afforded the amino ester 18. Attemps to force closure of 18 to the benzodiazocine ring system under acidic or basic conditions failed. The desired product could be prepared, however, by conducting ester hydrolysis of 18 to give the amino acid 19 followed by treatment of 19 with DCC to give 20.

14

15 R=Me 16 R=Et Figure 3. Preparation and alkylation of l,3,4-benzotriazepine-2,5-diones. l,2,3,4-Tetrahydroquinazolin-2,4-dione ring system. Removal of the C-3 carbon of the benzodiazepinedione leads to the six-membered tetrahydroquinazolin2.4- dione ring system (Figure 5). Treatment of o-nitrobenzoyl chloride 3 with tbutylamine afforded the nitrobenzamide 21. The cyclization precursor, 22, was obtained by nitro reduction. Reaction of 22 with diphosgene followed by treatment of the resultant intermediate with base gave 23. Aryl ring replacement. A brief investigation was carried out whereby the phenyl ring of the benzodiazepinedione system was replaced with heteroaromatic moieties. Two such heterocyclic systems were examined: The 1 H-pyrido[2,3-e][ 1,4]diazepine2.5- dione and the lH-thiopheno[3,2-e][l,4]-diazepine-2,5-dione ring systems. lH-pyrido[23-e][l,4]diazepine-2,5-dione ring system. One regioisomeric pyridodiazepinedione was prepared resulting in replacement of the benzodiazepinedione C-9 with a nitrogen atom (Figure 6). Entry into this series was initiated with the copper promoted amination of 2-chloronicotinic acid 24, affording N-benzylaminonicotinic acid 25 (8). The carboxylic acid functionality of 25 was converted to the acid chloride by treatment with thionyl chloride and then treated with methyl Ν-ί-butylglycinate to afford the nicotinamide 26. Catalytic transer hydrogenolysis caused N-debenzylation and concomitant cyclization to the pyridodiazepinedione 27.

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H , Pd-C EtOAc Synthesis and Chemistry of Agrochemicals V Downloaded from pubs.acs.org by GEORGETOWN UNIV on 09/07/15. For personal use only.

2

Figure 4. Preparation of 1,5-benzodiazocine-2,6-dione ring system. 1 H-Thiopheno[3,2-e] [ 1,4]diazepine-2,5-dioneringsystem. A single regiochemical thiophenodiazepinedione series was examined (Figure 7). Methyl 3-amino-2thiophenecarboxylate 28 was N-protected as the N-o-nitrobenzyl analog 29. Ester hydrolysis afforded 30. Reaction of the amino acid 30 with thionyl chloride followed by treatment with methylter/-butylglycinategave 31. Reductive debenzylation then gave the desired product, 32. Biological Activity The benzodiazepinediones and related analogs were evaluated in the greenhouse in a standard protocol consisting of a variety of broadleaf and grass weeds and crops, both pre- and postemergence. The analogs were applied at rates of 1000 - 32 g/ha to the various plant species as shown in Table I. Structure-Activity Relationships. The benzodiazepinediones as a class are more efficaceous against broadleaf weeds than grass weeds. The structure-activity relationship comparisons shown below, therefore, are based on post- and preemergence broadleaf data. The herbicidal activity is represented as percent broadleaf control averaged over all the broadleaf weeds at 250 g/ha. A "0" designates no activity at 250 g/ha but some activity was observed at higher rates. A compound that was inactive at the highest rate tested (generally 1000 g/ha) is denoted with an "/". The most important structural changes studied include substitution at the


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Figure 6. Preparation of lH-pyrido[2,3-e][l,4]diazepine-2,5-dioneringsystem.

101


benzodiazepinedione N - l , C-3 and N-4, modification of the substituent and its regiochemistry in the benzene ring (C-6 through C-9), modification of the 1,4diazepine ring and replacement of the benzeneringwith other aromatic moieties.

Figure 7. Preparation of lH-thiopheno[3,2-e][l,4]diazepine-2,5-dione ring system. Table I. Species Utilized In Standard Greenhouse Evaluation Broadleaf Weeds

Grass Weeds

Crops

Bindweed Lambsquarters Morningglory Wild Mustard Black Nightshade Ragweed Velvetleaf

Barnyardgrass Green Foxtail Wild Oats

Cotton Com Rice, Tebonnet Soybeans Sugarbeets Sunflower Spring Wheat

Substitution at N-3 and C-4. Herbicidal activity is highly dependent on the bulk of the acyclic substituent at N-4 as is shown in Table II. The most potent compound was the N-r-butyl analog which controlled both 80% of broadleaves postemergence and 95% of broadleaves preemergence at 250 g/ha. The N-neopentyl analog was slightly less active, controlling 70% and 75% of broadleaf weeds, respectively. With the exception of the i-amyl compound, decreasing the steric bulk of the substituent at N-4

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was accompanied by decreasing potency. When the N-4 neopentyl compound was substituted at C-3 with a methyl group all activity was lost. This was unexpected since herbicidal activity is maintained in the pyrrolobenzodiazepine-diones, e.g., 1, which contain branching at this carbon. Presumably, C-3 branching in the acyclic series must affect the benzodiazepinedione conformation versus the more sterically constrained pyrrolobenzodiazepinedione. Even so, it is difficult to rationalize the drastic effect on activity. In a homologous series of C3 through cycloalkyl substituents at N-4, maximum activity is observed with the cyclobutyl analog. Substitution at N-4 with variously substituted aromatic moieties afforded inactive compounds. Table II. Benzodiazepinedione C-3 and N-4 Substitution vs. Activity

0 )-R

2

H

0 Postemergence

Preemergence

80 70 20 20 30 0 0 /

95 75 45 20 35 20 0 i

H H H H

20 60 20 30

0 55 10 10

H H H

/

0 i

i 0

Ri

R

t-butyl neopentyl t-amyl i-propyl propyl allyl propargyl neopentyl

H H H H H H H CH

cyclopropyl cyclobutyl cyclopentyl cyclohexyl 3,5-F C H 3-(CF )C H 4-(OCH )C H 2

6

3

3

6

3

4

6

4

% Broadleaf control at 250 g/ha

2

3

/

Substitution at N - l . Increasing the bulk of the substituent at N-l leads to decreasing activity as shown in Table III. Aryl Substitution. Extensive substituent modification in the aryl ring (C-6 through C-9) was carried out. Initially, a set of methyl substituted analogs were prepared and evaluated to determine which isomer elicits maximum activity. The order of herbicidal activity was found to be 7-methyl > 9-methyl » 6-methyl (Table IV). We subsequently determined substitution at C-8 to have a deleterious effect on herbicidal activity (4). Based on these observations nearly all subsequent aryl substituent modifications were carried out at C-7 and C-9. Replacement of the 7-methyl substituent with an acetylene moiety resulted in a drop in herbicidal activity. Upon


103 saturation of the acetylene moiety to the vinyl and ethyl analogs activity was completely lost. The herbicidal activity varies greatly with the halogen substituent at C-7. The 7bromo analog was slightly less active than the 7-chloro analog. The 7-fluoro and iodo analogs were less active still. The unsubstituted benzodiazepinedione 7, shown for comparison, falls in between the fluoro and the bromo analogs in activity. Substitution at C-7 with a number of additional electron withdrawing and donating groups (nitro, cyano, amino, hydroxy and methoxy) afforded compounds with poor activity as did substitution with aryl and heteroaryl moieties at both C-7 and C-9 (6). A series of compounds were prepared to examine the effect of C-9 substitution on compounds containing 7-chloro or 7-methyl substitution. As the examples in Table IV demonstrate, introduction of a methyl group at C-9 causes only a slight decrease in activity. Introduction of a halogen atom, on the other hand, causes a significant decrease in herbicidal activity. Table ΙΠ. Benzodiazepinedione N-l Substitution vs. Activity


R

Postemergence

Preemergence

80 35 i

95 55 i

H CH p-methoxybenzyl 3

Modification of the 1,4-diazepine ring. A brief effort was undertaken to explore the effect of changes to the 1,4-diazepinedione ring on herbicidal activity. The changes to the basic nucleus included the addition of heteroatoms and variation inringsize. (Table V). In the homologous series of six- to eight-membered benzo-fused systems, the parent benzo-l,4-diazepine-2,4-dione was somewhat more active postemergence than the l,2,3,4-tetrahydroquinazolin-2,5-dione while the former was much more active preemergence. The benzo-l,5-diazocine-2,6-dione was inactive both pre- and postemergence. The 1,3,4-benzotriazepine-2,5-diones were inactive at the highest rates tested. Aryl replacement. The phenylringof the parent benzodiazepinedione 7 was replaced with a pyridine and thiophene moiety (27 and 32, respectively) to assess the effect of introducing a heterocyclic isostere. In both instances all herbicidal activity was lost. In vitro PSII assay. In addition to whole plant activity a majority of the benzodiazepinediones and related compounds were assayed for in vitro photosystem II activity in the Hill Reaction. Potassium ferricyanide reduction of spinach thylakoid membranes were used to determined 7 values. In general, the compounds possessing the highest level of whole plant activity were also the most potent in vitro (Table VI). Compounds substituted at C-7 with 50

104 chloro, bromo and methyl (all containing 4-/-butyl) or at N-4 with neopentyl were highly active PSII inhibitors, with I values rangingfrom0.2-1.7 μΜ. This compares to the in vitro activity of the commercial standard atrazine. Occasionally, the in vitro activity did not correlate with whole plant activity. The 7-fluoro analog exhibited moderate broadleaf activity in the greenhouse but had poor in vitro activity (500 μΜ). Possibly, the herbicidal activity is, at least in part, attributable to some other mode of action. In contrast, the 7-iodo analog represents an example of a compound with poor greenhouse activity but good in vitro activity (4.6 μΜ). It is reasonable that the weak whole plant activity may be due to poor uptake or subsequent metabolic inactivation. Synthesis and Chemistry of Agrochemicals V Downloaded from pubs.acs.org by GEORGETOWN UNIV on 09/07/15. For personal use only.

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Table IV. Aryl Substitution vs. Activity


Postemergence

Preemergence

7-Me 9-Me 6-Me

65 30 i

90 60 i

7-acetylene 7-vinyl 7-ethyl

30 J i

40 i i

7-F 7-C1 7-Br 7-1 Η

15 80 75 5 45

45 95 65 0 55

7-C1 7-C1,9-Me 7,9-Cl 7-C1, 9-Br

80 65 i i

95 70 i i

7-Me 7,9-Me 7-Me, 9-C1

65 60 10

90 50 15

X

2

2

Conclusions The structure-activity profile of the 1,4-benzodiazepine-2,5-diones demonstrates the rather limited substitution pattern that is tolerated for effective weed control. Substitution at N-l and C-3 (in the bicyclic series) and benzenoid substitution at C-6

105 and C-8 has a detremental effect on herbicidal activity. The most active compounds were derivedfromsubstitution at N-4 with bulky moieties (/-butyl and neopentyl) and at C-7, primarily with chloro, bromo and methyl. Substitution at C-9 was limited to methyl. Attempts to alter the diazepine ring led to decreased activity. The few analogs prepared in an effort to introduce an isosteric replacement for the phenyl ring also led to decreased activity.


Table V. Effect of Diazepine Ring Modification on Activity


X

Postemergence

-

CH (CH ) 2

2

2

NH NMe NEt

Preemergence

55 80 i

0 95 i

i i i

i i i

Table VI. In Vitro PSII Activity for Selected Analogs

X

R

/ (μΜ)

CI CI Br CH F I

/-butyl neopentyl /-butyl /-butyl /-butyl /-butyl

1.7 0.2 0.5 1.7 500 4.6

3

50

106


Literature Cited 1. Wright, W. B.; Brabender, H.; Greenblatt, E.; Day, I.; Hardy, R. J. Med. Chem., 1978, 21, 1087. 2. Wright,W.U.S.3,984,562. 3. Guaciaro,Μ.Α.;Harrington,P.M.;Karp,G.M.,U.S.5,438,035 (1995). 4. Karp, G. M.; Manfredi, M. C.; Guaciaro, Μ. Α.; Ortlip, C. L.; Marc, P.; Szamosi, I. T., J. Agric. Food. Chem., 1997, 45, 493. 5. Singh, Β. K.; Szamosi, I. T.; Dahlke, B. J.; Karp, G. M.; Shaner, D.L.Pestic. Biochem. Physiol., 1996, 56, 62. 6. Karp,G.M.J. Org. Chem., 1995, 60, 5814. 7. Karp,G.M.J.Heterocycl. Chem., 1996, 33, 1131. 8. Coppola, G. M.; Fraser, J. D.; Hardtmann, G. E.; Shapiro,M.J.J.Heterocycl. Chem., 1985, 22, 193.

Synthesis and Herbicidal Activity - American Chemical Society

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