Synthesis and Chemistry of Agrochemicals IV - American Chemical

Chapter 7

Thiazolo [4,5-b] pyridine-3 (2H)-acetic Acid Derivatives Downloaded by UNIV ILLINOIS URBANA-CHAMPAIGN on November 10, 2016 | http://pubs.acs.org Publication Date: May 5, 1995 | doi: 10.1021/bk-1995-0584.ch007

Synthesis and Herbicidal Activity Shridhar G. Hegde, Martin D. Mahoney, and Claude R. Jones New Products Division, Agricultural Group of Monsanto, Monsanto Company, 800 North Lindbergh Boulevard, St. Louis, MO 63167

Several examples of 5-(haloalkyl) substituted thiazolo[4,5b]pyridine-3(2H)-acetic acid derivatives were prepared as pyridine analogues of the commercial herbicide Benazolin. The heterocyclic ring system was constructed via a novel condensation reaction of certain ß-ethoxyenones with methyl 4-imino-2-thioxo-3-thiazolidine acetate. Most of the compounds in this study exhibited auxin-like herbicidal symptoms and higher activity on broadleaf weeds than narrowleaf weeds.

The auxin-like herbicidal activity of 2-oxo-benzothiazole-3(2//)-acetic acid derivatives were first described by Brookes and Leafe in 1963 (1). The 4-chloro analogue in this series, Benazolin (1) has found commercial utility as a postemergence herbicide. It is principally used in combination with phenoxy herbicides such as 2,4-D, MCPA, and MCPB for the selective control of certain broadleaf weeds such as chickweed and cleavers in cereal crops and oilseed crops (2,3). The herbicidal effects of 1 are similar to those exhibited by phenoxy herbicides with hormonal activity (1,4,5). The auxin-like activity of 1 has been further demonstrated by comparison with indole-3-acetic acid in a pea straight growth bioassay (6).

1 The effect of replacing the benzene ring of 1 with a heterocyclic ring on herbicidal activity has not been previously reported. As part of our effort to utilize 2-(haloalkyl) substituted pyridine substructures in designing newer agrochemicals (7), we have prepared several thiazolo[4,5-5]pyridine-3(2f/)-acetic acid derivatives 0097-6156/95/0584-0070$12.00/0 © 1995 American Chemical Society

Baker et al.; Synthesis and Chemistry of Agrochemicals IV ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

7. HEGDE ET AL.

Thiazolo[4,5-b]pyridine-3(2IL)-acetic Acid Derivatives

Downloaded by UNIV ILLINOIS URBANA-CHAMPAIGN on November 10, 2016 | http://pubs.acs.org Publication Date: May 5, 1995 | doi: 10.1021/bk-1995-0584.ch007

represented by the general formula 2 (Figure 1). In this paper we describe the methods of synthesis and the structure-herbicidal activity correlations of compounds 2.

2 Figure 1.

General formula of compounds in the present study: R = OH, OMe, NHOMe, N(Me)OMe; Ri = Haloalkyl; R =H,C1; X = 0,S 2

Synthesis. Assembly of the Heterocyclic Ring System. We envisioned the construction of thiazolo[4,5-^]pyridine ring system by a cyclocondensation of the appropriately substituted p-ethoxyenones 3 and the previously known methyl 4-imino-2-thioxo-3thiazolidine acetate 4 (S). This condensation, in theory, can produce structure 5 as well as its regioisomer 6 (Figure 2).

>—C0 CH 2

3

6 Figure 2.

Proposed synthetic route for the construction of the thiazolo[4,5-6]pyridine ring system

The p-ethoxyenone intermediates were prepared as shown in Figure 3. Ethyl vinyl ether (7) was acylated with trifluoroacetic anhydride and chlorodifluoroacetic anhydride as reported in the literature (9) to give enones 3a and 3b, respectively. Chlorination of 3a and 3b with N-chlorosuccinimide provided the corresponding chloro derivatives 3c and 3d, respectively. Figure 4 describes the synthesis of methyl 4-imino-2-thioxo-3-thiazolidine acetate (4) and subsequent condensation with p-ethoxyenones 3a-d. Thus, glycine methyl ester was treated with carbon disulfide and sodium hydroxide to produce the dithiocarbamate derivative. Addition


71

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS IV

OCH2CH3

OCH2CH3

OCH CH 2

3


NCS

3a 3b

^C02CH

3c 3d

Ri = CF3 Ri = CF C1 2

Synthesis of |5-ethoxy enone intermediates

Figure 3.

H2N

3

2

Ri = CF Ri = CF C1

CS

Na^

2

N ^ C0 CH x

Ss

2

3

NaOH

3

H

CI-CH2-CN

3a-d \—C02CH

3

:

HN-

Piperidine (cat)

C02CH

3

5a Ri = CF , R = H 3

5b

0 * 4

2

Ri = CF C1, R = H 2

2

5c Ri = CF , R = CI 3

5d

2

Ri = CF C1, R =C1 2

2

Hg(OCOCF )2 3

R ^ N ^ N >—CO2CH3

8a Ri = CF , R - H 3

8b

Figure 4.

2

Ri = CF R = CI 3f

2

Synthesis of 2-thioxo and 2-oxo-miazolo[4,5-6]pyridine3(2#)-acetates


7. HEGDE ET AL.

Thiaz0lo[4,5-b]pyridine-3(2H)-acetic Acid Derivatives


of chloroacetonitrile to the reaction mixture resulted in the alkylation of the dithiocarbamate derivative and concurrent cyclization to give compound 4. The condensation of p-ethoxyenones 3a-d with compound 4 in the presence of a catalytic amount of piperidine gave the miazolo[4,5-&]pyridine derivatives 5a-d as a single regioisomer in each case. Regiochemistry of cyclization. The exact location of the haloalkyl group in 5a-d was determined by employing Selective INADEQUATE (Incredible Natural Abundance Double Quantum Transfer Experiment) NMR (10), a new technique for establishing carbon-carbon connectivity. In this experiment a selective pulse is applied to one particular carbon resonance. This results in a very characteristic signal, an antiphase doublet, at the NMR frequency of any carbon or carbons directly bonded to the one which was selectively pulsed. In the C spectra of compounds 5a-d, the carbon bearing the haloalkyl group is readily identified due to its coupling with the fluorines. Four separate INADEQUATE spectra were obtained in each case by selectively pulsing at each of the remaining four pyridine ringcarbon frequencies individually. An antiphase doublet at the frequency of the carbon bearing the haloalkyl group was observed in only one of the four spectra indicating only one adjacent ring-carbon. Thus, the haloalkyl group must be at position 5 and not at position 7. 1 3

Desulfurization of 24hioxo4hiazolo[4,5-fr]pyridine-3(217)-acetates. Conversion of thioesters to carboxylic esters has been traditionally carried out via desulfurization with mercuric acetate (11). Desulfurization of thioamides with mercuric acetate is also known, however their reactivity is less than the corresponding thioesters. Although a similar reaction of thiocarbamates has not been reported previously, a substantially lower reactivity is expected based upon the reduced nucleophilicity of the thiocarbonyl group. Indeed, compounds 5 reacted very sluggishly with mercuric acetate even in refluxing chloroform. Generally, less than 10% conversion was observed upon refluxing the reaction mixture for 24 h. This problem was overcome by utilizing a more electrophilic mercury salt, mercuric trifluoroacetate. Refluxing compounds 5 with stoichiometric amount of mercuric trifluoroacetate in methylene chloride for 6 h gave the corresponding oxo compounds 8 in good yield (Figure 4). In general, mercuric trifluoroacetate may be an effective alternative to mercuric acetate in the desulfurization of relatively electron-deficient thiocarbonyl compounds. Derivatization of 24hioxo4hiazolo[4,5-&]pyridine-3(2i7)-acetates. The ester groups of compounds 5a-d were shown to be amenable to further transformations. Thus, compounds 5a and 5b were hydrolyzed to the corresponding acids 9a and 9b, respectively, by treatment with sodium hydroxide (Figure 5). Alkylation of 9a with

10

9a 9b

R = CF R = CF C1

11

-NHOMe

12

-N(Me)OMe

3

2

Figure 5.

Carboxylic acid, ester and amide derivatives from compound 5a


73

74

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS TV


ethyl 2-bromopropionate in the presence of potassium carbonate gave the lactate ester 10. Alternatively, the carboxylic acid group of 9a was first converted to the acid chloride by reaction with thionyl chloride and the acid chloride was treated with methoxyamine or N,0-dimethylhydroxylamine to obtain amides 11 and 12, respectively. Figure 6 describes the hydrogenolysis of the chlorodifluoromethyl group of compound 5b to produce the 5-(difluoromethyl)-thiazolo[4,5-6]pyridine derivative 5e. Finally, an a-methyl substituted thiazolo[4,5-6]pyridine-3(2//)acetate derivative 13 was synthesized startingfromDL-alanine ethyl ester (Figure 7) and utilizing a similar sequence of reactions as described in Figure 4.

Figure 6.

Synthesis of the 5-(difluoromethyl) derivative 5e

L

CH, f*

CSo,NaOH 2. ClCH CN 2

JL

HN 2

C02CH CH 2

3

3

.

f\T -

F

3

\=S JU/

C ^ N ^ N

3a, Piperidine

)—C02CH CH 2

3

HC 3

13 Figure 7.

a-Methyl substituted thiazolo[4,5-^]pyridine-3(2f/)-acetate derivative

Determination of Herbicidal Activity.

All of the synthetic compounds described above were evaluated in pre-plant incorporated and postemergence herbicide assays. The evaluations included two crops: corn and wheat, two narrowleaf weed species: barnyard grass (Echinochloa crus-galli) and downy brome (Bromus tectorum) and four broadleaf weed species: velvetleaf (Abutilon theophrasti), morning glory (Ipomoea spp.), cleavers (Galiu aparine) and common chickweed (Stellaria media). The application rates of test compounds rangedfrom0.07 to 11.2 kg/Ha. The activity data are expressed as GR 20's for crops and GR 80's for weeds which is the rate of herbicide (kg/Ha) that causes 20% crop injury and 80% weed injury, respectively. Structure-Activity Correlations. Tables I and II provide the herbicidal activity datafromthe pre-plant incorporated and post-emergence assays, respectively. In general, the compounds were more active on broadleaf than narrowleaf species with the difference being most apparent in post-emergence evaluations. All of the active compounds exhibited auxin-like


7. HEGDE ET AL.

Thiazolo[4,5-b]pyridine-3(2M)-acetic Acid Derivatives

herbicidal symptoms characterized by epinastic response and formative action. Shoot apex inhibition was also noted in several post-emergence evaluations. Most compounds showed a high degree of selectivity in corn in both pre-plant incorporated and postemergence assays. Selectivity in wheat was high in postemergence tests and moderate in pre-plant incorporated tests.


Table I.

Pre-Plant-Incorporated Herbicidal Activity of Compounds 5,813, and Benazolin (1) against Crop Plants and Representative Weed Species 3

GR20 (Kg/ha)

GR80 (Kg/ha)

compd

corn wheat

BG

DB

VL

MG

GA

cw

5a 5b 5c 5d 5e

>11 5.6 >11 >11 >11 4.7 >11 >11 >11 >11 >11 >11 >11 >11

6.4 >11 >11 >11 11.0 5.6 6.9

7.5 >11 7.5 >11 6.9 5.2 >11 10.0 0.2 >11 >11 >11 >11 8.6

4.9 4.6 >11 >11 4.7 1.1 9.0

0.4 2.0 0.7 9.0 2.0 0.7 0.2 0.2 0.2 2.6 3.4 >11 >11 0.9

0.7 0.7 0.9 7.5 0.9 0.8 0.2

0.9 0.7 0.2 6.4 3.0 2.2

8a 8b 9a 9b 10 11 12 13 1

11.0 11.0 5.6 >11 5.6 2.2 5.6 1.1 0.8 >11 5.6 >11 >11 2.0

7.5 11.0 >11 >11 >11 >11 5.0

3.0 0.6 5.9 4.4 >11 >11 0.8

0.7 7.5 0.9 4.6 >11 >11 0.5

1.1 0.8 5.9 1.9 3.4 >11 >11 0.1

a

Key to the weed species in this study: BG, barnyard grass; DB, downy brome; VL, velvetleaf; MG, morning glory; GA, cleavers; CW, common chickweed.

Three general correlations of structure and activity are surnmarized as follows: (1) A dramatic difference in activity against weeds was observed between compound 5a and the corresponding a-methyl analogue 13. The former had some activity against most broadleaf weeds whereas the latter was virtually inactive indicating a large variability of activity with respect to the a-substituent. (2) Interestingly, among the carboxylic esters in the 2-thioxo series, compound 5d (5-CF2CI, 6-C1) was significandy less active than compounds 5a ( 5 - 0 % 6-H), 5b (5-CF Cl, 6-H), 5c (5-CF , 6-C1) and 5e (5-CF H, 6-H). Thus, the herbicidal 2

3

2


75


76

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS IV

activity was critically dependent on the combined effect of the 5- and 6-position substituents. (3) Amides 11 and 12 were less active than most of the corresponding acid and ester derivatives. Further correlations can be made between structure and activity on specific weeds. Thus, in pre-plant incorporated tests, cleavers and morning glory were the most succeptible species (Table I). Although several compounds had high activity on cleavers, compound 8b had higher combined activity on cleavers and morning glory than all other compounds including Benazolin (1). On the remaining broadleaf weed species, Benazolin was generally more active than the compounds in this study. In post-emergence tests, morning glory was the most sensitive species (Table II). Again, compound 8b was the most active, closely followed by the lactate ester 10. Compound 8b was also substantially more active than Benazolin. On all other species, Benazolin had higher activity than the analogues in this study. Table II.

Postemergence Herbicidal Activity of Compounds 5,8-13 and Benazolin (1) against Crop Plants and Representative Weed Species 3

GR20 (Kg/ha)

GR80 (Kg/ha)

compd

corn wheat

BG

DB

VL

MG

GA

CW

5a 5b 5c 5d 5e 8a 8b 9a 9b 10 11 12 13 1

>U >11 >11 >11 >11 >11 >11 >11 >11 >11 >11 >11 >11 >11

>11 >11 >11 >11 >11 >11 >11 >11 >11 >11 >11 >11 >11 >11

>11 >11 >11 >11 >11 >11 >11 >11 >11 >11 >11 >11 >11 >11

5.6 9.0 7.5 >11 6.9 4.1 >11 5.9 6.4 1.1 >11 >11 >11 0.9

1.1 11.0 5.6 >11 1.1 0.5 0.2 1.1 4.5 0.3 >11 >11 >11 5.6

1.1 7.5 3.7 >11 7.5 4.5 8.2 1.1 2.4

0.3 11.0 1.1 >11 >11 3.7 4.1 6.4 4.7 4.7 >11 >11 >11 0.3

11.0 11.0 >11 >11 7.5 11.0 7.5 >11 9.5 >11 >11 >11 >11 >11

7.5 >11 >11 >11 0.1

a

Key to the weed species in this study: BG, barnyard grass; DB, downy brome; VL, velvetleaf; MG, morning glory; GA, cleavers; CW, common chickweed.


7. HEGDE ETAL.

Thiazolo[4,5-b]pyridine-3(2Yl)-acetk Acid Derivatives

Conclusions


The results from this study demonstrated that replacing the benzene ring of Benazolin (1) with a pyridine ring did not alter the general nature and the spectrum of activity. However, the levels of activity varied significantly depending on the species. Structure-activity correlations of several compounds of the general formula 2 revealed that a combination of 2-oxo and 6-chloro substituents resulted in higher activity than 1 in certain broadleaf weeds. Literature Cited

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Brookes, R.F.;Leafe, E. L. Nature (London) 1963, 195, 589. Pass, H. A.; Watt, B. J. Canadian Patent 956,132, 1974. Molberg, E. S.; Ashraff, M. A. Can. J. Plant Sci. 1971, 51, 371. Muhlethelar, P. Proc. Brit. Weed Contr. Conf. 1968, 9, 1205. Lush, G. B.; Leafe, E. L.; Mayes, A. J. Proc. Symp. New Herbicides, Paris 1965, 2, 201. Whately, L. L.; Slife, F. W. Weed Sci. 1983, 31, 801. Hegde, S. G.; Mahoney, M. D. J. Agric. Food Chem. 1993, 41, 2131. Dovlatyan, V. V.; Avetisyan, F. V. Arm. Khim. Zh.. 1973, 26, 494. Hojo, M.; Masuda, R.; Kokuryo, R.; Shioda, H.; Matsuo, S. Chem. Lett. 1976, 499. Berger, S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1196. Ellis, J.; Frier, R. D.; Schibeci, R. A. Aust. J. Chem. 1971, 24, 1527.

RECEIVED August

12, 1994


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Synthesis and Chemistry of Agrochemicals IV - American Chemical

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