Cyano Vinylogous Ureas - American Chemical Society

Chapter 10 α-Cyano Vinylogous Ureas A New Class of Herbicides

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W. J. Michaely, H. M. Chin, J. K. Curtis, and C. G. Knudsen Organic Synthesis Department, ICI Americas Inc., 1200 South 47th Street, P.O. Box 4023, Richmond, CA 94804-0023 A novel class of Ν,Ν'-diphenyl vinylogous urea herbi cides was shown to have several strict structural requirements. All of the following are important for optimum herbicide activity: an alpha-cyano group; a beta-(vinyl)hydrogen; an N-methyl group on the enamine nitrogen and the volume of the substi tuent in the ortho position on the amide phenyl should not exceed 71 cubic Angstroms. Other substi tuents on the enamine phenyl and the amide phenyl groups usually diminish activity.

Several o f t h e o l d e r and more common h e r b i c i d e s have been shown t o i n t e r f e r e w i t h one o r more steps o f p h o t o s y n t h e s i s . A number o f these a r e powerful i n h i b i t o r s a t o r near photosystem I I (PS II) (_1). Beginning i n 1 9 8 1 , J . N. P h i l l i p s and J . L. Huppatz and t h e i r group a t CSIRO ( A u s t r a l i a ) have shown t h a t a s e r i e s of cyanoacrylate (vinylogous carbamate) herbicides are potent i n h i b i t o r s o f PS I I (2-6). A l t h o u g h t h e CSIRO group e l u c i d a t e d t h e p r o b a b l e mechanism of action, the i n i t i a l d i s c o v e r i e s i n t h i s area were r e p o r t e d i n t h r e e p a t e n t s , c l a i m i n g h e r b i c i d e a c t i v i t y , t o BASF (1969-1970) (.7-J9). I n d e t e r m i n i n g t h e i r mode o f a c t i o n , Huppatz and P h i l l i p s demonstrated t h a t s e v e r a l s t r u c t u r a l v a r i a t i o n s c o u l d s i g n i f i c a n t l y enhance t h e PS I I i n h i b i t i o n o f t h e v i n y l o g o u s carbamates {2-6). T h i s enhanced a c t i v i t y , encouraged us t o work i n t h e a r e a . It seemed reasonable t o us t h a t s i n c e both t h e carbamates and v i n y l o gous carbamates a r e h e r b i c i d e s and t h e ureas a r e h e r b i c i d e s , t h e v i n y l o g o u s ureas should be h e r b i c i d e s (see F i g u r e 1 ) . Further more, t h e carbamates ( . e . g . , X=C1 ; F u r l o e ) , t h e v i n y l o g o u s carbamates ( £ . £ . , R'=CH3, R = a l k y l ) and t h e ureas ( e . £ . , X=C1 ; D i u r o n ) a r e all PS I I i n h i b i t o r s a t t h e t h y l a k o i d membrane ( H i l l reaction i n h i b i t i o n ) Q.-J5)« I t i s p o s s i b l e t h a t these v i n y l o g o u s compounds a r e s i m p l y bioisosteres (10) o f t h e i r parents. There a r e some s u b t l e s t r u c t u r a l d i f f e r e n c e s between t h e c l a s s e s which a r e d i s t u r b i n g . The

0097-6156/87/0355-0113$06.00/0 © 1987 American Chemical Society

In Synthesis and Chemistry of Agrochemicals; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.


114

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS

N-phenyl vinylogous carbamates require the N-alkyl group for herbicidal activity and the commercial ureas and/or the carbamates do not have this requirement. In the N-aliphatic case, primary amino compounds are equally as active as their secondary amino derivatives. The optimum activity occurs when the number of aliphatic carbons in the ester and the amine group together equal twelve, and the polar vinylogous carbamate moiety is within two carbons of one end of this C12 unit. For example, the ethyl ester with the N-jT-decyl vinylogous carbamate is about equal in activity to the £-decyl ester with the N-ethyl. An oxygen within the ester further enhances activity and allows the ester to be longer. In the N-decyl case the ethoxyethyl ester (C2H5-OC2H5-) is about 200 times more active than its simple ethyl ester (11). Most of the biological data of Huppatz and Phillips were done using a Hill reaction assay (isolated chloroplasts) and included very l i t t l e greenhouse or field data. From inhibition studies with diuron and metribuzin, they concluded that there is binding to the thylakoid membrane at the quinone Β site. The general conclusions were: there is a lipophilic pocket and there is hydrogen bonding to the carbonyl oxygen and to the oxygen of the alkoxyester (£-j>, 11). Preparation of Vinylogous Ureas The BASF procedure (Figure 2) required the use of the highly toxic phosgene (_7, 8). The CSIRO procedure was more advantageous since i t allowed us to easily vary the substituted amine group (Figure 3). The cyanoacetamides were prepared from cyanoacetic acid and diisopropyl carbodiimide (Figure 4). The diisopropyl urea was easily removed via water washes to give the cyanoacetamides in high yield (82-94%). We also obtained the desired cyanoacetamides from the unstable cyanoacetyl chloride in lower yields (35-62%). The cyanoacetamide was then converted into the desired vinylogous urea via either a two step procedure or a convenient one-pot procedure. Both procedures yielded desired product in good yield (69-89%) (Figure 4). As work progressed, we desired an acid intermediate that would allow us a broader spectrum of structural variants on the amide nitrogen. We found that the desired vinylogous carbamic acid could be prepared directly from cyanoacetic acid (Figure 5). When R equals (substituted)benzyl, an approximate 1:1 ratio of desired products and decarboxylated products was obtained. When R equals (substituted)phenyl, only the desired carboxylic acid intermediates were obtained. The impure vinylogous carbamic acids could easily be purified by base extraction. These acids were converted to vinylogous ureas via their stable acid chlorides. These procedures were not useful for the preparation of com pounds containing an electron withdrawing group on the enamine nitrogen. For these compounds we used the procedure illustrated in Figure 6. Although either (or both) hydrogen(s) attached to


10. MICHAELY ET AL.

115

a-Cyano Vinylogous Ureas H


Χ Carbamates

Vinylogous Carbamates

X Ureas

Vinylogous Ureas Figure 1.

Structural Similarities

95%) at doses of 1/10 lb/acre or less. The one major criteria for levels of herbicidal activity was the nature of the ortho substituent (Table I ) . The volume of the ortho substituent should be less than 71 cubic Angstroms,


118

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS 0 NC

C-N
F>C1 »CH3»0CH3 ο 2-Substituents: H>F>CH3>C1>0CH3 n=0 (Phenyl) Ar=(Substituted) aromatic ° 4-Substituents: Η only ο 3-Substi tuents: H>F>CH3~C1»0CH3 ο 2-Substi tuents: H>F»all others Figure 8.

The Aryl Enamine Substituent Requirements

R=H,CH3>C2H5>other aliphatics R'=(Substituted)aryl, aliphatics Figure 9.

The Amide Substituent Requirements


10. MICHAELYETAL. Table I.

a-Cyano Vinylogous Ureas

119

Ortho Substituted Alpha-Cyano Vinylogous Ureas: C6H5N(CH )CH=C(CN)C0NH(ortho-X)Aryl


3

# 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Ti 2. 3. 4. 5.

X H F OH NH CN CL CH 0CH BR I CHO N0 CF C0 H N(CH ) C0CH S0 NH CH CH C0NH CH(CH ) S0 CH S(0)CH SCH C0 CH 0CH CH S0 N(CH ) C0 CH CH 2

3

3

2

3

2

3

2

3

2

2

2

3

2

3

2

2

3

3

3

2

3

2

3

2

2

3

2

3

2

Act(l,2) A Ε Ρ A Ε Ε Ε Α-Ε Ε Ε Α Ε Α-Ε Ρ Ρ-Α Ρ-Α Ρ-Α Α Ρ Ρ Ρ Ρ Α-Ε Ρ Ρ Ρ Ρ

Loq Ρ(3) 0.00 0.14 -0.67 -0.23 -0.57 0.71 0.56 -0.02 0.86 1.12 -0.65 -0.28 0.88 -0.32 0.18 -0.55 -1.82 1.02 -1.49 1.53 -1.63 -1.58 0.61 -0.01 0.38 -0.78 0.51

MR(4) 1.03 0.92 2.85 5.42 6.33 6.03 5.65 7.87 8.88 13.94 6.88 7.36 5.02 6.93 15.55 11.18 12.28 10.30 9.81 14.96 13.49 13.70 13.82 12.87 12.47 21.88 17.47

Vol(5) 6.47 15.17 15.69 31.16 34.01 35.83 39.22 45.14 45.76 61.43 61.77 64.34 70.61 86.91 86.94 109.50 113.10 113.90 120.20 128.92 136.20 142.90 143.50 172.02 174.50 206.80 344.60

Postemergent broadleaf activity (mustard, sesbania, sicklepod, velvetleaf and annual morningglory) — active means i t exceeds 75% average control at the indicated dose Codes: P=Inactive at 4 lb/acre A=Active at 4 lb - 1/4 lb/acre E=Active at 1/4 lb - 1/40 lb/acre Log Ρ (N-octanol/water) - calculated Molar Refractivity Volume=(Ll)X(B4)(squared)X(3.14)Q2)


120

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS

but larger than hydrogen, for best activity. The compounds in Table I are arranged according to the increasing volume of the ortho substituent, using Verlops parameters (12) to calculate the volume. There are two exceptions to the size criteria. First, small, highly polar groups (e. £ . , OH and NH ; compounds 3 and 4 in Table I ) that can strongly hydrogen bond, are less active than their size would indicate. Second, some large nonpolar groups (£.£., C2H5 and SCH3; compounds 18 and 23 in Table 1 ) are more active than their size would indicate. Other phenyl substituents, including the 2,6-disubstituted phenyl, are less active than the simple ortho-monosubstituted phenyl compounds.


2

Mode of Action Since the ureas, carbamates and vinylogous carbamates are all PS II inhibitors (Figure 1), i t is not surprising that these compounds are also powerful PS II inhibitors. The more active compounds (Table I) were considerably more active than atrazine (Table II) in the Hill reaction assay. The Hill reaction assay frequently does not correlate with whole plant (greenhouse) activity (_1 and 2_ and references cited therein). However, vinylogous ureas do correlate fairly well (Table III). Other assays including the carotinoid biosynthesis and acetolactate synthesis (ALS) assays showed l i t t l e or no activity for these compounds. Due to solubility difficulties and the use of highly polar solvents such as dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO) we had some difficulty in obtaining reproducible results. For all biological tests great care had to be taken to ensure that homogeneous testing solutions were used. As an extra precaution, we usually tested the reference compounds and standards using the same solvents and surfactants. Table II.

Compound Number Atrazine 5 6 8 9 10 12 13 23

Calculated Concentration for 50% Inhibition (IP 50) of Photosynthesis in Thylakoid Membranes From Pea Via the Hill Reaction Substituent X

-

CN CI OCH3 Br I NO2 CF SCH3 3

IP 50 (ppm) 0.48 0.23 0.14 0.63 0.08 0.16 0.23 1.12 0.25


10. MICHAEL Y ET AL. Table III.

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121

Postemergent Broadleaf Control in Greenhouse Tests

Compound Number 5

8 9 10 12 13 23 1.

ct-Cyano Vinylogous Ureas

% Broadleaf Control (1) 67 88 84 88 75 81 97 99 99 90 76 77

Rate (lb/acre) 0.10 0.25 0.10 0.25 0.25 0.25 0.05 0.10 0.25 0.25 0.25 0.25

Broadleaf weeds: mustard, sesbania, sicklepod, velvetleaf and annual morningglory.

Acknowledgments We would like to thank several members of Stauffer's Biochemical Design group: David Diaz and M. M. (Alex) Lay for the Hill reaction assays and Desiree Bartlett for the ALS and carotinoid biosynthesis assays. Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Moreland, D. E. Ann. Rev. Plant Physiol. 1980, 31, 597-638. Huppatz, J. L.; Phillips, J. N. Z. Naturforsch., C 1984, 39 C, 617-22. Huppatz, J. L.; Phillips, J. Ν. Z. Naturforsch., C 1984, 48, 55-58. Huppatz, J. L.; Phillips, J. N. Agric. Biol. Chem. 1984, 48, 55-58. Huppatz, J. L.; Phillips, J. N. Agric. Biol. Chem. 1984, 48, 51-54. Huppatz, J. L.; Phillips, J. N.; Rattigan, Β. M. Agric. Biol. Chem. 1981, 45, 2769-73. Scheurmann, H.; Fisher, A. S. African Patent 6 805 817, 1969; Chem. Abstr. 1970, 72, 20790x. French Patent 1 579 902, 1969; Chem. Abstr. 1970, 72, 121209v. Fischer, A. German Patent 1 950 601, 1971; Chem. Abstr. 1971; 75, 47729h. Thornber, C. W. Chem. Soc. Rev. 1979, 8, 563-579. Phillips, J. N.; Huppatz, J. L. IUPAC Fifth Int. Cong. of Pest. Chem. Aug. 29, 1982, in Kyota, Japan; Paper #IVb-13. Verloop, Α.; Hoogenstraaten, W.; Tipker, J . ; in Drug Design; Ariens, Ε. J . , Ed.; Academic: New York, 1976; Vol. 7, p 165.

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Cyano Vinylogous Ureas - American Chemical Society

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