Synthesis and Chemistry of Agrochemicals V - American Chemical

Chapter 14

Downloaded by STANFORD UNIV GREEN LIBR on June 18, 2012 | http://pubs.acs.org Publication Date: May 14, 1998 | doi: 10.1021/bk-1998-0686.ch014

Synthesis and Insecticidal Activity of N-(4-Pyridinyl and Pyrimidinyl)phenylacetamides PeterL.Johnson, Ronald E. Hackler, JoelJ.Sheets, Tom Worden, and James Gifford Discovery Research Center, DowElanco, 9330 Zionsville Road, Indianapolis,IN46268-1053

Pyridine (I) and pyrimidine (VII) amides have been found to exhibit broad spectrum insecticidal, acaricidal and nematicidal activity through inhibition of mitochondrial electron transport (MET) at site I. The activity of these compounds against Heliothis virescens larvae (tobacco budworm) could be optimized by varying the substituents on both the heterocyclic amine (R , R ) and the phenylring(R ). The discovery, synthesis and structure-activity relationship as it relates to tobacco budworm activity is described. 1

2

3

The control of insects through a novel or unexploited mode of action is a highly desirable goal within insecticide discovery research. Until recently, the control of insects through the inhibition of mitochondrial electron transport had seen very little commercial utilization (i). One of the oldest known MET inhibitors is rotenone, which is known for its insecticidal activity (2). Other MET inhibitors that have been introduced recentiy for the control of mites include Mitsubishi's tebufenpyrad (3) and DowElanco's fenazaquin (4).

Ο

rotenone

tebufenpyrad

fenazaquin

Within DowElanco, we had been pursuing a series of quinolines (III) and quinazolines (IV) that showed broad spectrum activity against insects, mites, nematodes and fungi (5-7). In an effort to broaden the scope of this series, we began to look at heterocyclic replacements for both the quinoline and quinazoline ring systems. One replacement we looked at was the 2,3-disubstituted pyridine (II) as 136

©1998 American Chemical Society

In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

137 shown in Scheme I. In the synthesis of 2,3-disubstituted phenethylaminopyridine derivatives we were going through an amide intermediate (I). It was found that while the phenethylaminopyridines were showing good activity, the amide intermediates were even more active.


Scheme I

I

Π

III,X = OorNH

As a replacement for the quinazolinering( IV), we looked at a 5,6-disubstituted pyrimidinering(Scheme II). While the 5,6-disubstituted phenethylaminopyrimidines (V) were in fact quite active as insecticides, they were also the subject of patents filed by both DuPont and Ube and were not pursued by us. Somewhat suprisingly, the 5,6-disubstituted pyrimidine amides (VI) were found to be inactive as insecticides. Scheme Π

VI

V

IV, X = Ο or NH

We found that pyrimidine amides with substituents in the two position and no substitution in either the five or six position possessed good insecticidal activity (VII). In addition to the pyridine, I (8,9), and pyrimidine, VII (10) amides, the quinoline, IX (11), and isothiazole, VIII (72), amides were also investigated within DowElanco and showed broad spectrum insecticidal activity. This paper will focus only on the pyridine and pyrimidine amides.

vn

Vffl

IX

Synthesis The synthesis of the pyridine and pyrimidine amides can be broken down into two parts: the 4-amino pyridine or pyrimidine head portion of the molecule and the phenylacetic acid tail portion (equation 1).


138


"Head"

"Tail"

Phenylacetic Acids. There were three basic synthetic routes used for the synthesis of the phenylacetic acid "tail" portion of the molecule. The first route, and probably the most general, is outlined in Scheme ΙΠ. This route involves classic chain extension methodology and starts by coupling an appropriate phenol or alcohol with 4fluorobenzonitrile. The resultant benzonitrile is then hydrolyzed to the benzoic acid which in turn is reduced to the benzyl alcohol with lithium aluminum hydride. The alcohol is converted to the benzyl chloride with thionyl chloride. Displacement of the benzyl chloride with cyanide yields the phenylacetonitrile derivative which can then be hydrolyzed to the desired phenylacetic acid. While this route is quite laborious, each step is high yielding and very general. Scheme ΙΠ

(i) NaH, DMF; (ii) NaOH, dioxane/H 0; (iii) LiAlH , Et 0; (iv) SOCl , toluene; (v) NaCN, DMSO; (vi) NaOH, dioxane/H 0 2

4

2

2

2

The second route involves coupling either an alkoxide or phenoxide ion with 4fluoro-acetophenone. Rearrangement of the resultant acetophenone in the presence of boron trifluoride etherate, lead tetraacetate and methanol leads to the corresponding methyl phenylacetate derivative in high yield, as shown in Scheme IV (13). Scheme IV ^ R

.

0H +

A

?

P b

A c

(° >4

^

ΟΓΗ

Χ Τ Υ

™ DMF R O T ^

_

MeOH toluene

RCJ"^

The third, and simplest, route to phenylacetic acids requires generating the dianion of 4-hydroxyphenylacetic acid. The dianion is then reacted with an activated arylfluoride in either DMF or DMSO to give the phenoxyphenylacetic acid in high yield (equation 2). The only drawback to this route is that it is limited to activated arylhalides.


139 OH (2) DMF or DMSO heat


R = electron withdrawing group

4-Aminopyridines. The synthesis of 2,3-disubstituted-4-aminopyridines started with an appropriately substituted 2-alkylpyridine (Scheme V). The 2-alkylpyridine was oxidized with either hydrogen peroxide in acetic acid (14,15) or 3chloroperoxybenzoic acid in dichloromethane to give the pyridine-iV-oxide. The pyridine-N-oxide was then nitrated with nitric acid in sulfuric acid to give the 4-nitropyridine-N-oxide (16). Reduction of the nitropyridine-N-oxide with iron in acetic acid gave high yields of 2-alkyl-4-aminopyridines (17). The 4-aminopyridines could then be either chlorinated with chlorine gas in sulfuric acid (18) or brominated with hydrobromic acid in hydrogen peroxide (19) to give the 2-alkyl-3-halo-4aminopyridines. Scheme V 2

a N

NO

H 0 / HOAc or "

R

HN0

2

m-CPBA/CH Cl 2

a. ©

2

g

3

R H

0

2 °4 S

Fe(0) HOAc 100°C NH-,

Ν

χ

Cl , H S0 ,0°C, X = CI or

R

HBr, H 0 ,70°C, X = Br

2

2

4

2

Ν

R

2

4-Aminopyrimidines. The synthesis of 2-alkyl-4-aminopyrimidines, Scheme VI, started with alkylnitriles which were transformed to imidates with hydrogen chloride in ethanol and then to the amidates by treatment with ammonia gas via the Pinner reaction (20). The amidates were then cyclized to 4-aminopyrimidines by first generating the free base with sodium methoxide followed by reaction with 3-ethoxyacrylonitrile (21). Scheme VI HC1 ^ γ Ν Η HC1 R-CN EtOH OEt

N H

3 »

y NH

R

1. NaOCH

NH A

3

2

N

" ί JL

NH HC12. EtOCH=CHCN heat 2

Ν

R

Amides. The reaction of 4-aminopyridines with acid chlorides or with carboxylic acids and DCC gave very poor yields of the desired amides. However, treatment of the 4-aminopyridines with trimethylaluminum followed by reaction with methyl phenylacetates gave good yields of the desired amides, equation 3 (22).


140


reflux The reaction of 4-aminopyrimidines with acid chlorides in refluxing toluene gave moderate yields of the desired amides (equation 4). Attempts to improve the yield by treating the 4-aminopyrimidine with trimethylaluminum and a phenylacetate gave very poor yields of the amides.

Structure-Activity Relationships The structure-activity relationship (SAR) was driven by lepidoptera activity, in particular tobacco budworm. However, some of the early leads showed very weak or no activity against tobacco budworm and in these cases the activity against cotton aphids was used to guide the SAR. Table I. Effect of Variations of the Pyridine Ring

Entry 1

2 3

4 5 6

7 8 9

Rl H CH3 CH3 CH3

CH CH H H CH

2 H H

R

3

3

3

3-CH3 5-CH3 6-CH3 3-C1 3-CH3 3-C1 3,5-di-CH3

Tobacco Budworm

Cotton Aphid

LC50 (ppm)

LC50 (ppm)

>400 >400 >400 >400 >400

>400 >400 27 >400 >400 0.9 3.7 0.2 >400

6.3

>400 >400 >400



141 The effects of variations on the pyridine ring on both tobacco budworm and cotton aphid activity are shown in Table I. Both the unsubstituted and the 2-methylpyridine derivatives were inactive (entries 1 and 2). The 2,3-dimethyl derivative had weak activity against cotton aphids whereas the 2,5- and 2,6-dimethyl derivatives were inactive (entries 3-5). With the 2-methyl-3-chloro- derivative we started to see good activity against both tobacco budworm and cotton aphids (entry 6). Substitution in only the three position with either a chlorine or methyl gave compounds that were active against aphids but lost activity against tobacco budworm (entries 7 and 8). A 2,3,5-trisubstituted analog, entry 9, proved to be inactive. From these initial results, it appeared that optimum activity could be achieved with 2-alkyl-3-halo substitution on the pyridine ring. The SAR about the pyridine was probed further, thistimelooking at variations in only the 2 and 3 positions and with the 4-(4-chlorophenoxy)phenyl tail as shown in Table II. In going from a 2-methyl to a 2-ethyl, with a chlorine in the 3-position, there was about a six fold increase in the activity against tobacco budworm (entries 1 and 2). Extending the length to propyl resulted in a slight decrease in activity (entry 3). A 2methoxy derivative, entry 4, was much less active. Variations in the 3-position were now looked at while holding the 2- position constant as an ethyl group. In comparing 3-chloro versus 3- bromo (entries 2 and 5) we saw very similar activity. As mentioned earlier, with a hydrogen in the 3-position the activity began to drop off (entry 6). A 2ethyl-3-methyl derivative was prepared, entry 7, and found to be less active than the 2ethyl-3-halo analogs. From the results in Tables I and II we felt that optimum activity was realized when the 2-position of the pyridine ring was substituted with an ethyl group and the 3-position was substituted with either a chlorine or bromine. Table Π. Variations in the 2- and 3-Position of the Pyridine Ring

Entry 1 2 3

4 5 6 7

Rl CH

3

CH2CH3 CH2CH2CH3 CH3O CH2CH3 CH2CH3 CH2CH3

R2 CI CI CI CI Br H CH

3

Tobacco Budworm

Cotton Aphid

LC50 (ppm)

LC50 (ppm)

3.0 0.5 3.1 33

Synthesis and Chemistry of Agrochemicals V - American Chemical

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