Synthesis and Herbicidal Activity of Conformationally Restricted

Chapter 7

Synthesis and Herbicidal Activity of Conformationally Restricted Butyrolactone Sulfonylureas Mark E. Thompson and Paul H. Liang

Downloaded by GEORGETOWN UNIV on September 6, 2015 | http://pubs.acs.org Publication Date: December 7, 1991 | doi: 10.1021/bk-1991-0443.ch007

Agricultural Products Department, Ε. I. du Pont de Nemours and Company, Stine-Haskell Research Center, Newark, D E 19714

The herbicidal activity of sulfonylureas derived from phenylacetic esters is enhanced when the carboxylate moiety is tied up to form a butyrolactone ring. Extension of this structural modification to weakly herbicidal sulfonylureas derivedfromcinnamate esters gives vinylogous butyrolactones which display significantly improved efficacy. Structure-activity relationships in these two classes of compounds are discussed along with their synthesis involving a novel benzothiazinone dianion and ortho-metallation chemistry. As described in George Levitt's earlier chapter, numerous modifications of the key ortho group in sulfonylurea herbicides have been reported. However, in the vast majority of sulfonylureas commercialized to date, the ortho substituent is a carboxylic ester. Sulfonylureas in which a methylene linkage separates the orf/iocarboxylate from the phenyl ring, such as phenylacetic ester 1, have also proven to be highly active herbicides, especially against broadleaf weeds in postemergence applications (1). Some of these phenylacetic esters exhibit excellent wheat selectivity and compound 1 (R^H, R=CH3> was field tested for this utility several years ago. However, both α-substitution (R^CHs) and higher alkyl esters (R>C3> resulted in diminished overall levels of herbicidal efficacy. Furthermore, both the cinnamate esters of formula 2 and their dihydro analogs 3 were essentially devoid of herbicidal activity at commercially feasible application rates. 2

2

ço*

2

2

3

0097-6156/91Λ)443-0087$06.00Α) © 1991 American Chemical Society

In Synthesis and Chemistry of Agrochemicals II; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

88

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS II

In an effort to further extend this structure-activity information, we wondered if some of the herbicidal efficacy lost by α-substitution and larger alkyl esters in the phenylacetic series could be restored by tying substituents R* and R of formula 1 together, thereby reducing the conformational flexibility and steric bulk of the ortho group. Our initial target molecule, therefore, was the butyrolactone sulfonylurea of general formula 4. If successful, we hoped to apply a similar stractural modification to the cinnamate esters 2 and improve the herbicidal activity of this series of compounds by forming vinylogous butyrolactone analogs of the formula 5.


2

1

4

"TTED-UP" PHENYLACETIC ESTERS Synthesis. Our immediate synthetic goal was sulfonamide 6 as there are numerous methods known for converting such compounds to the corresponding sulfonylureas (2). Earlier work in the phenylacetic ester series had shown that sulfonamide 7 could be monoalkylated by treatment with sodium hydride and methyl iodide although the yield was quite low and the product isolated was the benzothiazinone 8 (2). Ring opening was accomplished by heating 8 with alcohol in the presence of methanesulfonic acid to afford the α-methylphenylacetic ester sulfonamide 9 albeit in poor yield (Equation 1).



7. THOMPSON AND LIANG

o 7

89

Butyrolactone Sulfonylureas

2

8

9

We reasoned that it might be advantageous to generate an α,Ν-acylsulfonamide dianionfromthe preformed benzothiazinone ring system under more carefully controlled conditions. Thus, sulfonamide 7 was cyclized in 81% yield with 10% aqueous sodium hydroxide at room temperature followed by acidification, and the resultant 2//-l,2-benzothiazin-3(4//)-one 1,1-dioxide 10 φ was treated with two equivalents of w-butyllithium at low temperature as shown in Scheme I. Addition of allyl bromide as a test case gave monoalkylated product 12 in good yield after purification. To our knowledge, this was the first example of the controlled generation of dianion 11, although Belletire and Spletzer subsequently reported an acyclic version

Scheme I

12


90

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π


Encouraged by this result, we turned to ethylene oxide as the electrophile and were gratified to discover that the desired obutyrolactone sulfonamide 6 could be isolated in about 30% yieldfrombenzothiazinone 10 after purification by flash chromatography on silica gel. Not only had dianion 11 reacted with the ethylene oxide as desired, but the resultant alcohol had opened the benzothiazinone ring via an intramolecular N- to O-acyl migration which had presumably occurred during aqueous workup. Similarly, alkylation of dianion 11 with propylene oxide gave sulfonamide 13 in 25% yield as a 1:3 mixture of diastereomers (Scheme Π). The reasons for the rather modest yields in these reactions were not clear, but we assumed that the moderate reactivity of both ethylene and propylene oxide coupled with possible side products formed in the N- to O-acyl migration were at least partly to blame. Less reactive electrophiles such as 2,3-epoxybutane and 2-(2-bromoethyl)-l,3-dioxolane did not react appreciably with dianion 11. Scheme Π

10

1) 2 eq. BuLi THF Ο 2)

Ζλ

3) H 0

+

3

10

^γ^^^

l)2eq.BuLi THF O CH 2) ΖΛ/ 3) H£f

3

13 (-1:3)

In an effort to improve the yield, we investigated an open-chain version of the alkylation process depicted in Schemes I and Π. It was hoped that the bulky r-butyl substituent in sulfonamide 14 would inhibit cyclization to the benzothiazinone system, thereby obviating the ring opening step. Indeed, the carboxylic ester group in 14 could be saponified (aqueous NaOH) without concomitant ring closure (6). Unfortunately, treatment of 14 with two equivalents of lithium diisopropylamide (LDA) and addition of ethylene oxide gave the i-butylsulfonamide lactone 15 in only 30% yield (Equation 2). Removal of the i-butyl group could be readily achieved with trifluoroacetic acid (7), but the overall yield of sulfonamide 6 was no higher than in the previous synthesis proceeding via the benzothiazinone dianion. In fact, alkylation of the dianion of 14 with allyl bromide gave the α-allyl product in only 47% yield.





91

The ori/w-butyrolactone sulfonamide 6 and γ-valerolactone sulfonamide 13 (mixture of diastereomers) were readily converted to the corresponding sulfonylureas using the base DBU (l,8-diazabicyclo[5.4.0]undec-7-ene) as shown in Equation 3 (&).

2) H 0

+

3

6 (R=H) 13 (R=CH3) Herbicidal Activity. Table I summarizes herbicide data for two representative obutyrolactone sulfonylureas of formula 4 and provides a comparison with their open-chain counterparts. These data were obtained from greenhouse tests in both preand postemergence applications on a variety of weeds and crops. For the sake of clarity, results are presented only for three or four grass weeds, three broadleaf weeds and wheat. The numbers reported in Table I represent percent injury of the particular plant species tested relative to an untreated check (0% injury). In general, the lactones were significantly move active preemergence than the corresponding phenylacetic esters, particularly on grass weeds. Wheat tolerance displayed by the pyrimidine derivative was quite good, but was lost with the triazine lactone. Indeed, the pyrimidine lactone provided excellent preemergent weed control with complete wheat tolerance at 16 g/ha. Differences between the lactones and phenylacetic esters were much less apparent in postemergent applications with the cyclic analogs tending to show greater activity on grasses, but equivalent or lower activity on broadleaves. Within the series of lactones themselves, the unsubstituted γ-butyrolactone sulfonylureas 4a displayed the highest levels of herbicidal activity. The γvalerolactones of formula 4b were less active as were the isomeric butyrolactones of formula 16. Substitution on the phenylringhad little or no effect on the overall level or spectrum of activity.


92

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π Table I.

Herbicidal Activity of ortho-Lactone Sulfonylureas versus Their Open-Chain Counterparts

S0 NHCONHHet

S0 NHCONHHet

2

2


% Injury Het = 4,6-Dimethoxypyrimidine Preemergence

62 g/ha

100 100 90 100 100 90 10

Johnsongrass Giant Foxtail Wild Oats Cocklebur Morningglory Velvedeaf Wheat

0 0 0 50 30 30 0

Postgrnergence

lfi g/ha

Johnsongrass Blackgrass Giant Foxtail Wild Oats Cocklebur Morningglory Velvedeaf Wheat

62 g/ha

Π g/ba 90 80 70 20 85 50 70 0

ο 0 90 70 100 100 100 55

Het = 4-Methoxy-6-methyltriazine Preemergençe

250 g/ha

350 g/ha

0 0 0 20 80 35 0

100 100 100 20 30 40 100

Johnsongrass Giant Foxtail Wild Oats Cocklebur Morningglory Velvedeaf Wheat Postcmcrgcnce Johnsongrass Blackgrass Giant Foxtail Wild Oats Cocklebur Morningglory Velvedeaf Wheat

62

g/ha

0 0 55 100 90 0

62

g/ha 100 100 90 70 20 50 0 70


U g/ha 100 100 80 90 80 100 0


93

Butyrolactone Sulfonylureas Ο


4a

4b

16

These results were sufficiently intriguing to provide the necessary impetus for the next phase, which was to "tie up" the cinnamate ester ortho group of sulfonylureas of formula 2.

"TIED-UP" CINNAMATE ESTERS Synthesis. We envisioned the key step in the synthesis of vinylogous lactones of formula 5 to be formation of the exocyclic double bond via a Wittig-type reaction. The actual synthesis of sulfonamide 21, which was ultimately converted to the target sulfonylureas, is depicted in Scheme ΠΙ. N-r-Butyl rjenzenesulfonarnide (17) has proven to be a valuable synthetic intermediate in Du Pont's sulfonylurea program by virtue of the ease with which it undergoes ori/io-lithiation and subsequent reaction with a wide variety of electrophiles (2). Addition of N,N-(iïmethylformamide (DMF) to dilithio 17 gave the sulfonamide 18, which exists predominantly as the cyclic N-sulfonyl hemiaminal shown (ID). Fortunately, 18 behaves in its reactivity like an aldehyde and underwent smooth condensation with both a-[7-butyrolactonylidene]triphenylphosphorane (11) and the γ-valerolactone analog to give vinylogous lactones 19 and 20. Analysis of 19 and 20 by 200 MHz proton NMR indicated the presence of a single isomer in each compound which was consistent with literature precedent Q2). The i-butyl groups were removed with trifluoroacetic acid (TFA) and the resultant primary sulfonamides 21 and 22 were converted to the respective sulfonylureas according to methods described earlier (12). Herbicidal Activity. Comparative herbicide data for two vinylogous lactone sulfonylureas and their open-chain counterparts are summarized in Table Π. These data were obtainedfromgreenhouse tests in both pre- and postemergence applications on a variety of weeds and crops. Again, for the sake of clarity we have limited the number of test species shown and the numbers reported represent percent injury of the particular plant species tested relative to an untreated check (0%). The lactones displayed significantly higher levels of herbicidal activity than the corresponding cinnamate esters on every test species both pre- and postemergence. The differences were especially striking between the lactones and a-methylcinnamate derivatives in which a compound exhibiting no herbicidal activity at 50 g/ha was transformed to a moderately active herbicide by simply joining the two methyl substituents in the ortho group. Unfortunately, a decided lack of wheat selectivity was also observed with these more active cyclic sulfonylureas.


94



Scheme ITT

19(R=H) 20(R=CH3)

21 (R=H) 22(R=CH3)



Table II.

Herbicidal Activity of ortho-Vinylogous Lactone Sulfonylureas versus Their Open-Chain Counterparts

C0 CH 2


95


3

S0 NHCONHHet 2

^S0 NHCONHHet 2

% Injury Het = 4,6-Dimethoxypyrimidine; R = H Pr^mergençe Cheatgrass Barnyardgrass Wild Oats Cocklebur Morningglory Velvedeaf Wheat Postemergence Cheatgrass Barnyardgrass Wild Oats Cocklebur Morningglory Velvedeaf Wheat

50 g/ha

50 g/ha

20 30 0 50 70 50 0

90 55 50 80 80 90 60

50 g/ha

50 g/ha

0 50 0 55 10 50 0

75 90 50 100 100 100 80

Het = 4-ChIoro-6-methoxypyrimidine; R = C H 3 Postemergence Cheatgrass Barnyardgrass Wild Oats Cocklebur Morningglory Velvedeaf Wheat

50 g/ha

50 g/ha

0 0 0 0 0 0 0

65 100 40 80 50 55 60


96



Within the series of vinylogous lactone sulfonylureas themselves, herbicidal effectiveness was found to decrease in the following order:

SUMMARY We have shown that 2//-l,2-benzothiazin-3(4//)-one 1,1-dioxide can be efficiently dilithiated and the resultant c^N-acylsulfonamide dianion trapped with electrophiles on carbon. Use of ethylene oxide results in alkylation followed by an intramolecular Ν ιο O-acyl migration to give arifo-butyrolactone benzenesulfonamide. The sulfonylureas derived from this sulfonamide are highly active herbicides and show improved activity over their open-chain phenylacetic ester counterparts, particularly with respect to preemergent control of grass weeds in wheat This same principle of tying up the ori/io-cinnamate ester group in weakly herbicidal sulfonylureas affords ortho-vinylogous lactones with greatly improved overall activity, but little or no crop selectivity. ACKNOWLEDGMENTS The authors gratefully acknowledge the technical assistance of Thomas P. Boyle, John P. McCurdy and Pauline N. Winner. Biological testing was carried out by David J. Fitzgerald, Frank P. DeGennaro, Stephen D. Strachan and Patrick L. Rardon.




97


LITERATURE CITED

1. Levitt, G . U.S. Patent 4,348,219, 1982. 2. Beyer, Ε. M . ; Duffy, M . J.; Hay, J. V.; Schlueter, D . D . "Sulfonylureas" in Herbicides. Chemistry, Degradation and Mode of Action, Vol. 3, Kearney, P. C.; Kaufman, D . D., eds., Marcel Dekker, Inc.: New York, 1988, pp. 126-127. 3. Buchanan, J. Β., Ε . I. du Pont de Nemours & Co., unpublished results. 4. Sianesi, E . ; Redaelli, R.; Bertani, M . ; Re, P. D . Chem. Ber., 1970, 103, 1992. 5. Belletire, J. L . ; Spletzer, E. G . Tetrahedron Lett., 1986, 131. 6. Catsoulacos, P. J. Heterocyclic Chem., 1971, 8, 947. 7. Catt, J. D.; Matier, W. L . J. Org. Chem., 1974, 39, 566. 8. Thompson, M . E . U.S. Patent 4,662,931, 1987; U.S. Patent 4,755,221, 1988. 9. Lombardino, J. G . J. Org. Chem., 1971, 36, 1843. 10. Pasteris, R. J. U.S. Patent 4,586,950, 1986. 11. Flizar, S.; Hudson, R. F.; Salvadori, G. Helv. Chim. Acta, 1963, 46, 1580; Zimmer, H.; Pampalone, T. J. Heterocyclic Chem., 1965, 2, 95. 12. Sanemitsu, Y.; Uematsu,, T.; Inoue, S.; Tanaka, K. Agric. Biol. Chem., 1984, 48, 1927. 13. Christensen, J. R.; Liang, P.H.; Thompson, M . E . U.S. Patent 4,685,955, 1987; U.S. Patent 4,764,207, 1988. RECEIVED December 15, 1989


Synthesis and Herbicidal Activity of Conformationally Restricted

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