Synthesis and Bilogical Activity of Semicarbazone Insecticides - ACS

Chapter 13

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Synthesis and Bilogical Activity of Semicarbazone Insecticides George P. Lahm, Renee M. Lett, Jeffrey K . Long*, Patrick D. Lowder, Thomas M. Stevenson, Martin J. Currie, Milagro P. Folgar, Sandra M. Griswold, Margaret A . Lucas, Robert W . March, and Wendy A . March

Stine-Haskell Research Center, DuPont Agricultural Products, P.O. Box 300, Newark, DE 19714

N - A r y l semicarbazones of substituted indanones, tetralones, coumaranones, chromanones, and thiochromanones were prepared to investigate novel structures related to pyrazoline insecticides. These compounds were found to be potent agents for control of arthropod pests, particularly Lepidoptera and Coleoptera.

In the course of research related to the pyrazoline insecticides and the eventual discovery of indoxacarb (Steward™, Avaunt™), a variety of chemical structural types were investigated for their potential as sodium channel-active insecticides. As described in an earlier chapter of this book on indazole insecticides, substituted tetralones were prepared as precursors to aryl pyrazolines in which the pyrazoline ring and aromatic ring were tethered by a two-atom chain. We recognized that this added ring might favorably position substituent groups such that the overall molecular shape would imitate that of the indazole-type pyrazolines, even if the pyrazoline ring itself were not present.

© 2002 American Chemical Society In Synthesis and Chemistry of Agrochemicals VI; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2001.

133

134


To test this idea, tetralones 1, prepared as intermediates to indazoles, were used to prepare N-aryl semicarbazones 2 as in Figure 1.

Figure 1. Conceptual relationship of indazoles and semicarbazones The first of these compounds 2 was active on southern corn rootworm, confirming the potential for the semicarbazones to be insecticidal.

Chemistry Tetralones were prepared by two major routes. The first utilized a strategy of alkylation of phenylacetates followed by Friedel-Crafts acylation, as in the preparation of 2 from 3 and 4 {Scheme 1).

NaH/DMF

Ο

K A

A I C I a

3

Scheme 1: Preparation of tetralone semicarbazones

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

^ * C I

135

In an alternative approach, tetralones were converted to ketoesters, permitting the use of bismuth arylation chemistry (1) to obtain 5 (Scheme 2).

00 Ο

NaH/DMF

DCu^s coA> Ο

O

DBU/THF

x

^ ^ C 0

2

M e

5 LiCI/H 0


2

o>o % u

D M F 150 °C;

r

H NNH -H 0 nPrOH; ArNCO/Εφ 2

^SZ

2

2

Scheme 2: Bismuth arylation route to tetralones Although formation of hydrazones from ketones is often readily accomplished in hot ethyl alcohol, the 2-aryltetralones required higher-temperature reaction conditions, so 1-propanol or 1-butanol were often used as solvents in this step. Concurrent work on oxyindazole analogs of pyrazolines indicated greater activity for compounds with a heteroatom in the ring tethering the pyrazoline to the aromatic ring, so we made chromanones to test whether their semicarbazones might also have enhanced efficacy. The chromanones 6 were prepared via Fries rearrangement and methylenation.

'Ό

OH

ArCH C(0)CI

AICI

EtgN/THF 0° 9 0 %

100° C 8 5 %

2

3

Na S 03/K C0 2

2

2

CH l2/Bu NI 2

Y

4

3

/

PhH/H 0 2

70° C 3 5 %

HgNNH^nPrOH; Semicarbazones ArNCO/Et 0 2

Scheme 3: Preparation of chromanones


136

Preparation of thiochromanones 8 was similar to that of the chromanones 6, except that methylenation and Michael addition of a thiol were performed before Friedel-Crafts chemistry (Scheme 4). Hydrolysis of the ester group to obtain acids 7 was performed under acidic conditions to avoid a retro-Michael reaction. Friedel-Crafts acylation and standard handling of the resultant ketone afforded the desired semicarbazone products.


Diethyl

0

^A

-100%

ΚΓ-100/ο ArSH/NaOEt EtOH R T 8 0 % ; MeS0 H AcOH 8 5 % Δ 3

Y

^(Oû*

Semicarbazones

8

N

^ R

-S H

AlClg/DCE 0° C 8 0 %

°X|f\ 7

0

^ " R

Scheme 4: Thiochromanone preparation Smaller ring sizes were also of interest in this area, leading to the investigation of benzofuranones (coumaranones) 9 (Scheme 5).

o

r

1

y V

DMF NaH/THF |

9

Heat

Not isolated

Scheme 5: Preparation of 2-substituted coumaranones


137 Under the conditions of this Dieckmann reaction, the ester group is lost, likely forming dimethyl carbonate (2). This suggests considerable stability and low reactivity of the resultant coumaranone anion, which could be viewed as the anion of a 3-hydroxybenzofuran, 10. The anion can, however, be alkylated with iodomethane to prepare 2-methylfuranones 11 (Scheme 6).

Ο

NaH/THF

.


^N^O R

1

°^

"OMe

R1

Not isolated

R1 = various alkyl, aryl

R1

v-ttfc

~

v-Of

9 R=H 11 R = Me

10

Scheme 6: Formation of decarhoxylated coumaranones In most cases in which R l was an aromatic group, only 2-methylfuranones 11 (containing a quaternary center) were successfully converted to semicarbazones by standard procedures. We expect that the corresponding intermediates 9 likely existed as the enol (hydroxyberizofuran) tautomers and were resistant to conversion to semicarbazones. Indanones 12 were also targeted as ketone substrates early in this project. The first examples were prepared by alkylation of phenylacetates and cyclization using Friedel-Crafts conditions (Scheme 7).

XT*

-on?

NaH/THF;

H

NaOH

,

s

o

0

c

|

AICL

'XXK>

X 12

Scheme 7: Preparation of 2-Arylindanones


138

Semicarbazones of 2-substituted indanones proved to be quite active, which spurred us to make this our largest area of research on insecticidal semicarbazones. Thus, a variety of synthetic approaches to indanones were employed to accommodate different substitution patterns. Oxyindazoles with a trifluoromethyl substituent on the aromatic ring were potent insecticides (see earlier indazole chapter of this book), so we particularly desired indanones with this substitution. However, C F groups generally undergo undesired side reactions under Friedel-Crafts conditions, and our other methods of indanone preparation, mostly electrophilic cyclizations, were not successful with this strongly electron-withdrawing group. However, the method of Parham (3) was successfully employed to make the indanones 13.


3

Commercially available indanones were functionalized by several routes. Acylation with dimethylcarbonate and optional further alkylation provided estersubstituted indanones 14. (MeO) C(0) 2

Mel NaH/THF

14 Saponification of the esters 14 provided 2-alkylindanones. We attempted to prepare 2-indanones by direct alkylation of the ketones, and found that we obtained 3-alkylindanones as well (see 4). Use of excess sodium hydride as base


139 in alkylation of 5-haloindanones led to the formation of the 3-alkylindanones 15 as well as the 2-alkylindanones 16.

NaH/DMF

Ο

Ο

Ο


15

16

The route below cleanly accomplished this reaction, providing only the 3alkyl regioisomer 15. Formation of the silyl enol ether and deprotonation formed a benzo-cyclopentadienyl anion that reacted selectively at the 3-position (5). In situ hydrolysis of the enol ether afforded the product in a one-pot procedure. LDA/THF -78° C; Me SiCI;

Me

Mel;

3

o-su

nBuLi 0°C

1 NHCI

15a

Good activity of the 3-alkylindanone semicarbazones inspired us to pursue 3-arylindanones 17. These were prepared by the known Nazarov-style cyclization (6) of the readily available chalcones. ,**V Y

s

n

i

3

PPA

X

° "

i

3

5

o

c

^ Y

Ο

Ο

17 This successful use of the Nazarov cyclization also led us to explore it as a route to other indanones, for which it proved to be particularly effective. Preparation of the Nazarov precursor 18 was readily accomplished by Friedel-Crafts reaction of halobenzenes followed by methylenation under a choice of standard conditions. Reaction of compounds 18 in sulfuric acid (7) afforded the desired indanones in high yield.


140 aq. H C H O piperidine/ HOAc (cat.) MeOH

Cl'

OR

AICI3

(CH 0)

97-99%

2

n

Me NH CI DMF 95% 2

H S0 /CH CI


2

4

2

2

OR neat cone. H S0 2

2

Ο 4

18

66-68% on small scale; up to 97% on kilo scale

Figure 9: Nazarov preparation of indanones

In general, indanones were readily converted to the final semicarbazones under milder conditions than needed for the tetralone semicarbazones. The indanones reacted readily with hydrazine (hydrate) in refluxing ethanol, and the resultant hydrazones 19 reacted with a variety of aryl isocyanates 20 in aprotic solvents such as ether, tetrahydrofuran, or toluene. ArNCO

However, for indanone substrates such as the esters 14, an alternate approach was necessary to avoid side-reactions of the ester group. Condensation of the ketone in alcohol or acetic acid with a pre-formed semicarbazide 21 (prepared by reaction of hydrazine with aryl isocyanates in toluene or ether) was successful in these cases.

14

Ο

Η


141

Reaction of ketones with pre-formed semicarbazides was also advantageous on larger scale, due to the stability of the ketones and semicarbazides. Isolated hydrazone intermediates that were convenient to use on a research scale tended to form azines on larger scale, affecting the purity of the final products.


Insecticidal Activity General trends in the activity of the semicarbazones were consistent with those of the pyrazolines and indazoles, with some differences specific to the semicarbazones. We observed these generalizations for semicarbazones prepared from different types of ketone substrates: 4

•

• • •

•

•

3

Indanones (A = CH2) provided the most active compounds against Lepidoptera and Coleoptera, with coumaranone types (A = O) also being quite effective, especially on Coleoptera. A single substituent was favored at the 2-position (R2 = H). The best R l groups for Lepidopteran activity were haloaryl, aryl, and various branched and unbranched alkyls (isopropyl, propyl, and isobutyl). Small alkyl groups (especially methyl) provided excellent activity on Coleoptera. Ester groups afforded only modest activity on Coleoptera and low activity on Lepidoptera, in contrast to the indazoles and indoxacarb. Substitution at the 5-position of indanones and the equivalent position in other substrates was optimal, with the 4-position also giving good activity. The best substituents Y were halogens, nitrile, and to a lesser extent haloalkoxy and trifluoromethyl. Substitution of the N-aryl group of the semicarbazones followed the trends of the pyrazolines and indazoles, providing the best activity for Ζ = CF3 and

OCF3, and good activity for Ζ = bromo and OCHF2, all at the para-position of the phenyl ring.


142


The most-active semicarbazones were evaluated in field trials, and they showed levels of insect control competitive with commercial standards on selected species of insects. Compound 22 controlled Colorado potato beetle at field rates of 5-10 g/Ha and boll weevil at 75-100 g/Ha, but did not control Lepidoptera well. Compound 23 provided excellent plant protection and controlled Lepidopteran pests such as tobacco budworm (Heliothis virescens) and fall armyworm (Spodopterafrugiperda)at field rates of 28-56 g/Ha and 84-112 g/Ha, respectively.

Ο

Η

22 R = C H , Z = C F 3

3

23 R = p F P h , Z = O C F

3

Conclusions

In conclusion, we found that semicarbazones of cyclic ketones were potent insecticides, similar to pyrazolines in their favored substitution patterns and symptomology of action, although more selective in spectrum of activity. These compounds also shared some of the problems of pyrazolines in soil persistence and/or bioaccumulation, although selected compounds demonstrated favorable properties in these regards, albeit generally with attenuated efficacy.

References 1. D . H. R. Barton, et al, J. Chem. Soc. PerkinTrans. 1 1985, 12, 2667-75. 2. With the reaction performed in alcohol solvents, the decarboxylation is reported as a separate step. See, e.g., D. C. Schroeder, et al, J. Org. Chem. 1962, 27, 586-591.


143

3. W . E. Parham, et al, J. Org. Chem. 1975, 40, 2394-2397. 4. Barry M. Trost, Lee H . Latimer, J. Org. Chem. 1977, 19, 3212-14.


5. For an analogous reaction of indanone enamines (multistep), see H . W . Thompson, et al, J. Chem. Soc. Perkin Trans 1, 1976, 1603-1607. A strategy using silyl enol ethers was recently published: Hendrik J. G . Luttikhedde, et al, J . Organomet. Chem. 1998, 1, 127-134. 6. R. G . Shotter, et al, Tetrahedron 1977, 33, 2083-2087. 7. S. J. deSolms, et al, J. Med. Chem. 1978, 5, 437-443.


Synthesis and Bilogical Activity of Semicarbazone Insecticides - ACS

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