Benzylnitramines as Herbicides - ACS Symposium Series (ACS

Chapter 9 Benzylnitramines as Herbicides Synthesis, Resolution, and Effect of Configuration on Activity D. W. Ladner, S. J. Rodaway, and Barrington Cross

Downloaded by UNIV LAVAL on May 9, 2016 | http://pubs.acs.org Publication Date: November 3, 1987 | doi: 10.1021/bk-1987-0355.ch009

Agricultural Research Division, American Cyanamid Company, Princeton, NJ 08540 A series of benzylnitramines were prepared by either nitration of the carbamates or N-alkylation of nitrourethane, followed by ammonolysis. These represent one-phenylnitramines, known broadleaf herbicides. Nastic responses and growth inhibition observed for this class suggested similarity to the auxin type herbicides. To determine if the preference for the (R)-configuration extended to nitramines, 1-(2',6'-dichlorophenethyl)nitramine was resolved and the absolute configuration determined by asymmetric synthesis. A comparison of the (+) and (-) isomers in herbicidal and in vitro assays was performed and the results are discussed. The phenylnitramines, 1, a class of plant growth regulators affecting root geotropism and shoot phototropism, was reported in 1954 by ICI (1). Twenty years later American Cyanamid(2) received patent for herbicidal phenylnitramines genetically represented by structure 2 . Efficacy was dependent NHN0

1

2

NHN0

2

2

on substituents and their position and differed from the ICI compounds such as A C 78,167, since 4-substituents were detrimental for herbicidal activity. The 2,3,5,6 tetrachloro-N-nitroaniline, A C 78,299, was the most active in this series. The substituents at the 2,6-positions not only improved activity, but increased the stability of the compounds. Rearrangement can occur with certain nitrosubstituted or electron rich N-nitoanilines, and the decomposition can be explosive. A C 78,299, on the other hand, is stable up to its melting point of 143°. Nastic or leaf curling effects, and stem elongation caused by A C 78,299 and its close analogs contrasted with the growth inhibitory response of A C 78,167 type compounds. This structure-activity behaviour, namely the effect of a 0097-6156/87/0355-0100$06.00/0 © 1987 American Chemical Society

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

9. LADNER ET AL.

Benzylnitramines as Herbicides


A C 78,299

101

A C 78,167

4-substitutent, reminded us of the activity of benzoic acids. This series of herbicides are known to be auxins, but have been shown to be auxin-antagonists when 4-substituted. This particular structural feature has figured prominantly in the development of an auxin receptor model(3). We therefore hypothesized that phenylnitramines interact at the auxin receptor because of three observations: the physiological effects, the structure-activity relationships and the chemical similarity of a nitramino group to a carboxylic acid. The biological resemblence of nitramino groups to carboxylic acids has been examined in other systems (4). Both groups are strong organic acids, a property frequently associated with uptake and translocation (5), however, the pKa's of nitramines reported in the literature are consistently 0.50-0.55 units higher than the corresponding benzoic acids(6). Additionally, in order to ionize, nitramines, require an α-proton. This latter property makes phenylnitamines more closely isosteric with phenylacetic acids (also auxins) rather than benzoic acids, however. If the nitramino group is also acting as a physiological replacement for either COOH or CH2COOH, the logical task would be to prepare and test the benzyl analogs which could be similar to the CH2COOH group, as in the herbicide fenac. Benzyl nitramines are reported to be more thermally stable than the phenyl counterparts(7-8). Improving the known alkylation reaction with halides and nitrourethane seemed plausible(9). Preparation of nitrourethane however, was not a particulary high-yield processQO). Direct nitration with 90% nitric acid succeeded, but a modification using cupric nitrate and acetic anhydride gave a somewhat higher yield. N-nitrourethane was isolated and used as its ammonium salt. The stable salt was reacted in D M F with various benzyl halides at 80° to give initial products which were not isolated, but treated with ammonia and acidified to give the desired products (Table 1). A phase-transfer variation also succeeded, but only for unhindered cases. This D M F reaction was quite satisfactory for most of the nitramines prepared from either the halide or mesylate. A summary of herbicidal activity appears in Charts 1 and 2. Activity was primarily limited to pre-emergence application for most of the series, with the trichloro-analog being the most active. This differs from the phenyl series, in which the tetrachloro was the most active, but compares favorably with the fenac structure. We suspect this is just a reflection of a required ideal lipophilicity for activity. The non-chlorinated analogs were much less active. A more unusual compound was A C 233,866, which showed some beneficial growth-regulating effects as well as being a mildly active herbicide.


102

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS

T A B L E 1. S Y N T H E S I S O F

(Et0 C-N-N0 )NH


2

2

Ar-CH-X

BENZYLNITRAMINES

1. N H

3

3

• DMF 80°-90°

I R

• 2. HCI

Ar - C H - N H N 0

I R

Ar

R

X

Ph

H

Br

71

4-CI-Ph

H

Cl

30

2,4-diCI-Ph

H

Cl

55

2,6-diCI-Ph

H

Br

73

2,6-diCH -Ph

H

OMs

53

2,3,6-triCI-Ph

H

Br

64

2,4,6-triBr-Ph

H

OMs

69

2,3,5-tri[H|-Ph

H

OMs

45

2-CI-4,5-methylenedioxy-Ph

H

Cl

20

2,3,5,6-tetra-CI-Ph

H

OMs

45

3

Yield

2,6-diCI-Ph

CH

OMs

18

1-naphthyl

H

Cl

50

1-(2-Me)napthyl

H

Cl

70

3


2

103



9. LADNER ET AL.

2.6-CI -Ph 2

2,6-Me -Ph 2

2-CI-6-MeO-PH

2,4.6-Br -Ph 3

2.3.5-l -Ph 3

1-naphthyl

COMPOUND, Ar

C H A R T 2. A C T I V I T Y O F M I S C E L L A N E O U S ARYLMETHYLNITRAMINES.


1-(2-Me-naphthyl)


104


COOH

NHN02

fenac

N0

2

1

R^H-N-CO^Hs

R^H-X (Et0 C-N-N0 )NH 2

2

4

LNH

R CH-NHN0

3

R DMF

*

2. HCI

80 - 90° X = Cl,Br, O S 0 C H 2

3


2

9. LADNER ET AL.

105



We noted that it possessed the added structural feature of an asymmetric carbon atom, similar in that respect to the 2-phenylpropionic type of herbicides. Our intention was to resolve this material, if sufficient quantity could be prepared. Since steric effects presumably limited yields obtained by standard methods, alternatives were investigated as shown. These involved preparation and

A C 233,498

11

R-CH -CH -N0 2

2

2 2

B

u

L

i

»

R-CH=CH-N0 " 2

2

(Ref. 11)

reduction of a nitrimine, preparation of the carbamate and subsequent nitration, and an attempt to methylate the dianion, 11 , in a procedure analogous to that of Seebach(ll). The first two were moderately successful in some runs, but still not particulary advantageous over the original route. The latter gave benzaldehyde as the only isolable product. The best route was a variation of the original which was an extension of the conditions introduced by Mitsunobu(12), as shown. This very direct approach avoids possible elimination reactions reduces the number of steps. A reaction entirely analogous to this for alkylation of β-nitroesters has subsequently appeared(13) and the mechanisms must be very similar. The reaction was complete in an hour and the yield was 41%. Having sufficient quantity permitted not only more definitive biological testing of the compound, but also a traditional resolution into optical isomers. The preparation of the (+) and (-) - oc-phenethylamine salts was straightfoward and after three recrystallizations and hydrolysis, a 10% recovery of each chiral isomer was obtained.


106


Et0 CNHN0


2

2

25° 30 min

Et0 CN=NC0 Et 2

2

RCH OH

•

2

RCH CH(N0 )C0 Et 2

2

2

Ph P 3

Et0 CCH N0 2

2

2

In the method used for the preparation of A C 233,866, there was the likelihood that the reaction proceeded with stereospecific inversion. Since other Mitsunobu-type reactions are known to do so, an asymmetric synthesis establishing absolute configuration was possible. In order to accomplish this, a resolution of the starting alcohol was carried out as shown via the acid phthalates. The optical purity of (+) - 12a was found to be 94 ±5% by N M R analysis using the optically active shift reagent Eu(tfc)3, or N M R of the diastereomeric O-methylmandelates. Conversion of the (+)-alcohol 12a to the product gave the nitramine with a rotation of -242°. That inversion had taken place was demonstrated by performing the Mitsunobu reaction on the unsubstituted (5)- (-)-l-phenylethanol 13 which gave the (+) product, 14a. In contrast, direct nitration of (S) - (-) 15 under conditions expected to give retention led to the (-) product, 14b. The absolute configuration of 12a was established by reductive removal of the chlorine to obtain the alcohol of (S) configuration, and retention was presumed. The optical isomers were then compared to the racemate in the standard pre-emergence herbicide test described previously. Although the (S) -(-) isomer was generally more active than the (/?)-(-) isomer, the differences were not as striking in all species. (Chart 3) An in vitro bioassay was then performed to measure the auxin-like properties of these compounds, based on a procedure from Cleon Ross(14)(Fig. I). This assay is based in principle on the growth response to auxins of stem segments of Pisum sativum. Measurement of segment weight and transectional area was compared to the untreated control.In this manner, a response curve was obtained for each compound. Indoleacetic acid (IAA) gave a typical response curve, as shown; A C 78,299 gave an auxin-like response while A C 78,167 was inactive(Fig. 2).


9.

LADNER ET AL.

107



NUMBER OF SPECIES SHOWING ACTIVITY

R-(-)

(±)

S-( + )

COMPOUND C H A R T 3. P R E - E M E R G E N C E A C T I V I T Y R A N G E O F R A C E M I C A N D C H I R A L A C 233,866

F I G U R E 1. P E A E P I C O T Y L G R O W T H B I O A S S A Y F O R A U X I N S



FIGURE 2. PEA EPICOTYL BIO ASSAY OF BENZYLNITRAMINES



9. LADNER ET AL.


109

(+),(-) (+) 50 mole % Eu(tfc)

δ 3.43 (3.41)

3

Δδ = 6.45 94.5% o.p.

a

C0 H 2

[cc] =5.89° D

era-

A C 239,171 was also auxin-like(Fig. 3), and although less responsive than IAA, its activity continued to increase at the higher rate. A C 233,866, the racemic compound, showed only a slight inhibitory effect; the (/?)-(-) isomer was inactive. The (S)-(+) isomer, on the other hand showed a stronger growth inhibitory response. The slight enhancement at lower concentrations is not necessarily significant. A simple test for auxin antagonism on this compound was negative: lower doses of the compound had no effect on I A A activity, and at the higher rate, no amount of IAA could reverse the inhibitory response. We concluded from these tests that some of these nitramines are indeed behaving like auxins, but that neither the racemic nor individual antipodes of the α-methylbenzyl compound can be so classified. Underscoring the difference in behavior was the greater activity shown by the (S) isomer rather than the expected (/?), as in the case of phenylpropionic and phenoxypropionic acids(15). While the most herbicidally active nitramines seem to be auxins, others which are interesting growth régulants (e.g. A C 78,167 and A C 233,866) are apparently neither auxins nor auxin antagonists. We conclude that our initial hypothesis concerning the interchangeability of carboxyl and nitramino may be correct, but the mode of action of nitramines is not confined to the auxin/anti-auxin class.




110

F I G U R E 3. P E A E P I C O P Y L B I O A S S A Y O F P H E N Y L N I T R A M I N E S



9. LADNER ET AL.


15

111

14b a. PhP, Et0 CN=NC0 Et, E t 0 C N H N 0 2

b. N H

2

2

2

3

c. HC1 d. H , NaOMe, 10% Pd-C, MeOH, 1 atm 2

e. H N 0 , A c 0 3

2

Patents covering these compounds and their use as growth régulants have issued(16). Acknowledgment The authors acknowledge the following individuals who contributed to the preparation of compounds and the biological evaluations: B . Walworth, R. Herrick, P. Bhalla, T. D. O'Neal, M . Blair, R. Depew, J. Cadet, D. Whitehead and L. Larue.


112

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Literature Cited

1. 2. 3. 4. 5.


6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Jones, R.L.; Metcalfe, T.P.; Sexton, W.Α.; J. Sçi. Food Agric., 1954, 5, 38. Cross, B; Gastrock, W.; 1974, US 3 844 762. Katekar, G.F.; Geissler, A.E.; Phytochemistry, 1983, 21, 27 and references therein. Alston, Τ. Α.; Porter, D. J. T.; Bright, H. J.; Acc. Chem. Res., 1983, 16, 418. Crisp, C.E.; Larson, J.E.; 5th Inter. Symp. of Pest. Chem.(IUPAC), Kyoto, 1982. Salymon, G.S.; Grachev, I.V.; Porai-Koshits, B.A.; Sbornik Staiei Obshei Khem., 1935, 2, 1315. Lamberton, A.H.; Quarterly Rev., 1951, 5, 75. Soil, H.; in Houben-Weyl. 1958, 11, pt.2, 99. Gillibrand, M.I.; Lamberton, A.H.;J. Chem. Soc., 1949, 1883. Brian, R. C.; Lamberton, A.H.; J. Chem. Soc., 1949, 1663. Henning, R.; Lehr, F.; Seebach, D.; Helv. Chem. Acta,, 1976, 59, 2213. Mitsunobu, O.; Wasa, M.; Sano, T.; J. Amer. Chem. Soc., 1972, 94, 679. Mitsunobu, O.; Yoshida, N.; Tetrahedron Lett., 1981, 22, 2295. Ross, C.; Plant Physiology Lab Manual; Wadsworth Publishing Co.: Belmont, CA , 1974; p. 124. Aubert, B. et al.; Swed. J. Agric. Research, 1979, 9, 57. Neal, T.D.; Bhalla, P.R.; Cross, B.; 1983, US 4 367 339.

RECEIVED May 29,

1987


Benzylnitramines as Herbicides - ACS Symposium Series (ACS

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