Synthesis and Herbicidal Activity of Bicyclic Sulfonylureas - American

Chapter 4

Synthesis and Herbicidal Activity of Bicyclic Sulfonylureas Steven P. Artz, Bruce L. Finkelstein, Mary Ann Hanagan, M. P. Moon, Robert J. Pasteris, and Morris P. Rorer

Downloaded by FUDAN UNIV on December 29, 2016 | http://pubs.acs.org Publication Date: December 7, 1991 | doi: 10.1021/bk-1991-0443.ch004

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

Many ortho substituted-benzenesulfonylureas have recently been commercialized as herbicides. This discovery initiated a program to incorporate the ortho group of the benzenesulfonamide into a second ring, forming a bicyclic sulfonamide. The synthesis of a variety of bicyclic arylsulfonamides, such as, dihydrobenzothiophenes, benzothiopyrans, dihydroisocoumarins, dihydrobenzothiazine -dioxides, indanones and benzisothiazoles, is described. Representative synthetic methods include Claisen rearrangement, Friedel-Crafts acylation and directed metallation. Bicyclic arylsulfonamides are used to prepare herbicidally active sulfonylureas. Biological activity of these sulfonylureas is discussed. One of the many research programs which developedfromGeorge Levitt's discovery of herbicidal benzenesulfonylureas was the preparation and testing of bicyclic sulfonylureas 1. Their general structure contains a benzene ring, fused to a second ring in which the 3-position is attached via a carbon atom. X represents a heteroatom, or is a carbonyl group.

1 All commercial sulfonylureas have a substituent ortho to the sulfonylurea bridge. Herbicidally active ortho groups include: esters, sulfonamides, sulfones, ketones, ethers and thioethers 2. 2,3-Disubstituted-sulfonylureas, possessing

0097-6156/91/0443-0050$06.00/0 © 1991 American Chemical Society

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

4. ARTZ ET AC

51

Bicyclic Sulfonlyureas


a 3-methyl substituent 2, are also herbicidally active. In general, the crop selectivity of sulfonylureas increases with increasing size of Ri; however, the overall activity decreases with increasing size of Ri. Thus, the question was: could we use the larger, more selective Ri groups, but limit their effective size and restrict their rotation by tying the R group back into the benzeneringas in 4?

Ο R = C 0 R i , S 0 N R R , SO2R1, C R i . O R i , or SRi 2

2

1

2

SOoNHCNHHet * 11

We envisioned a variety of bicyclic structures, (1,2,2) such as dihydrobenzofurans, benzothiophenes, benzisothiazoles, isocoumarins and indanones which could answer this question. The diverse synthetic routes to each ring system are described below. Syntheses stop at the sulfonamide, since there are well known techniques to convert it into a sulfonylurea (see G. Levitt, this volume). Tied-Baçk Igopropyl Ethçr§ One cannot prepare dihydrobenzofuran £ by simply eliminating a hydrogen molecule from ether £ to complete the synthesis (Scheme I). The route we chose involved formation of the fusedring,followed by conversion of a nitro group into the latent sulfonamide. Allyl phenyl ethers are know to undergo Claisen rearrangements (41. Thus, starting with a variety of substituted nitro-phenols, we made the allyl ethers ZClaisen rearrangement at elevated temperatures gave over 80% yield of the phenol intermediate 8· The rearrangements were done neat with a magnesium catalyst or in a high boiling solvent. Acid catalyzed ring closure of 2 gave the dihydrobenzofuran system in 60% yield. No benzopyran was isolated. The nitro group was reduced to the amine lfi. The amine could be diazotized and subjected to Meerwein conditions; however, when an electron donating group is ortho, such reactions are often unsuccessful. In our hands, this sequence followed by amination gave the desired sulfonamide 11, in 40% yield. Tied-B?içk n-Propylçthçr$ Benzopyrans 12 were prepared by a Friedel-Crafts alkylation of bisether IS shown in Scheme Π, wherein the electrophilic group is identical to the leaving group. The 6-


52

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π

Scheme L

Synthesis of Dihydrobenzofurans

S0 NHCNHHet II 5 Ο

SOoNHCNHHet II Ο


2

Scheme Π.

Synthesis of Dihydrobenzopyrans

α

S0 NHCNHHet 2

Ο

12

S0 NHCNHHet 2

Ο

lu

AICI3(S), benzene

14

15

Br

Br. 1)CIS0 H 3

U

s

J

2

H , Pd/C^ 2

|

NH

> 3 S0 NH 2

IS

1Z

2

S0 NH 2

IS


2

4. ARTZETAL.

Bicyclic Sulfonylureas

53

bromo-benzopyran formed, allowed theringoxygen of 1£ to direct chlorosulfonation to the 8-position. Amination gave the sulfonamide 12, which was denominated with palladium on charcoal to gave the parent benzopyran 18.


Relative Herbicidal Activity of Tied-Back Ethers Many tied-back ethers shown in Scheme ΙΠ were prepared as in the last two syntheses or methods known in the art Q}. Following our work in Scheme I, the 7amino-benzofuran intermediate to 21, became commercially available. Scheme ΙΠ shows the general activity trends for the tied-back ethers. Other bicyclic systems had similar trends. The 2-methyl-dihydrobenzofuran 12 was the most active. The aromatic benzofurans 2Ω were less active. Comparable in activity were the 2,2-dimethyl, the substituted aryl and parent dihydrobenzofuran. The 6-membered pyranring24 was less active than the 5-membered ring 22 and the multiple substituted, in this case the 2,3-disubstituted compounds (25) were the least active. All of these sulfonylureas were herbicidal. Tied-BaçkThioçtfiers Benzothiophene derivatives 2Q were prepared using a thio-Claisen approach. While investigating this approach, we found the thio-Claisen rearrangement to be very dependent on the R substituent of the aryl ring, Scheme IV. Electron donating substituents slightly favor formation of the 6-member-ring 28 while large and electron withdrawing groups greatly favor 5-membered ring formation 22· The tbutyl sulfonamide group bestfitour need. Lombardino (6) teaches that a t-butylsulfonamide group directs lithiation to the ortho position for which the resultant anion can be quenched with carbon dioxide. TTiis proved to be a efficient way to make substituted sulfonamides, since the sulfonamide handle is already in place. In a similar process we used two equivalents of n-butyllithium (n-BuLi) to give 22, followed by a sulfur quench to give a thiophenoxide, which was capped in siîu to give die allyl thioether 22, as shown in Scheme V. Unlike oxygen based Claisen rearrangements, thio-Claisens do not give the intermediate thiophenol, but the cyclized material direcdy. The t-butylsulfonamide 24 could be deprotected with acid, giving off isobutylene. The primary sulfonamide 35 proved to be versatile intermediate. It can be oxidized to the sulfone 2fi or it can be dehydrogenated to the benzothiophene 22- In turn, 22 can be oxidized with hydrogen peroxide to the vinylsulfone 28- All these sulfonamides can be used to prepare tied-back sulfonylureas. Herbicidal Activity of Tied-Back vs Open-Chain Sulfonylureas Table I compares alkylsulfone isomers 22 and 41 to tied-back ϊ-propylsulfone sulfonylurea 4fi. The numbers are the percent control of a plant species. The tied-back sulfone is the most active on broadleaf weeds, cocklebur and sicklepod. It is weaker on barnyard grass but better on wild oats, than the openchained sulfonylureas. The tied-back sulfone shows tremendous cotton selectivity; whereas the openchained sulfonylureas severely injure cotton. Of the open-chained isomers, the 2,3substituted analog appears to be more active than the 2-substituted analog.



Scheme IV.

Thio-Claisen Rearrangement

Ά NH

1

:

1.5

Η

1

:

1.2

CI

1

:

1

20

:

1

2

SO2NH —|—



Table L

Structure-Activity of Qrtho-Sulfonylbenzenesulfonylureas

11

4Q

% Injury P o s t e m e r g e n c e at 16g/ha Compound 39 40 41

Cocklebur 10 90 80

Sicklepod 40 100 80

Barnyard Grass 80 20 80

Wild O a t s 20 90 50

Wheat 0 40 50


Cotton 60 0 100

56

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π

Tied-Back Butvlsulfones 7-Memberedrings,benzothiepins (2), can be prepared from 2-chlorothiophenol, as shown in Scheme VI. The chlorine will eventually become the sulfonamide handle. Anion formation followed by nucleophilic displacement of the carboxylate of γ-butyrolactone gave the acid in excellent yield. Friedel-Crafts acylation in polyphosphoric acid (PPA) gave a good yield of the cyclic material. The ketone was reduced under Clemmensen conditions. The thioether 4fi was then oxidized with hydrogen peroxide to the sulfone which activates the chlorine for nuclephilic aromatic substitution by potassium propyl mercaptide to give the thioether 48. Oxidative chlorination and amination gave the sulfonamide 42- The cyclic sulfone is not affected by oxidative chlorination.


Tied-Back N-Ethvl Sulfonamides Ortho dialkylsulfonamide sulfonylureas are very active herbicides, but with two large alkyl groups on nitrogen, activity falls off quickly. The target benzothiazines 51, Scheme Vu, need two adjacent sulfonamide groups. Here we used 2-chloro-N-alkyl-benzenesulfonamides to prepare the ring sulfonamide while retaining the chlorine as a latent sulfonylurea bridge. Metallation of a series of N-alkyl sulfonamides gave ethanols 52 when quenched with ethylene oxide. Base induced cyclization to 54 requires N-alkylation to be faster than elimination. Displacement of the mesylate in dimethyl formamide (DMF) with carbonate as the base provided the best yields. The larger R groups gave more eUmination products. Nucleophilic displacement, oxidative chlorination and amination gave the sulfonamide 55Tied-Back N-Methvl Sulfonamides The synthesis substituted 1,2-benzisothiazole-1,1-dioxides (2) was similar to benzothiazines in that metallation of 2-chloro-N-alkyl-benzenesulfonamide provided the required intermediate, Scheme VIII. When the bisanion was quenched with DMF the hermaminal 52, a masked aldehyde, formed. This intermediate can be used in Wittig reactions (see M. Thompson and P. Liang, this volume). 52 could either be reduced with borane, and then acidified to remove the t-butyl group or reacted with toluenesulfonic acid (TsOH) to deprotect and eliminate water to give an imine which was reduced with sodium tetraborahydride. Either route gave equivalent yields. Nucleophilic displacement on the chloro intermediatefifiwith potassium propyl mercaptide and two equivalents of base followed by oxidative chlorination and animation gave the secondary sulfonamide, fil. The bissulfonamide fil is a versatile intermediate for analoging since it gives exclusive alkylation on the secondary sulfonamide fi2 with l,8-diazobicyclo[5.4.0]undec-7-ene (DBU) (Dean, T. R., Ε. I. du Pont de Nemours, unpublished results). Benzisothiazoles substituted with electron donating groups did not cleanly undergo oxidative chlorination of the thioether. In Scheme IX, 5-methoxy- 1,2benzisothiazole does not give the desired sulfonyl chloride, but undergoes electrophilicringchlorination when treated with chlorine in acetic acid. However, when sulfoxide fi5 is preparedfromfi2with 3-chloroperoxybenzoic acid (mCPBA) itsringis deactivated towards electrophiles, thus oxidation to the sulfonyl chloride fifi is carried out effectively. Although a sulfone would accomplish the same deactivation of thering,one cannot oxidize sulfones to the sulfonylchloride, as seen previously in the benzothiepin series.


4. ARTZETAL. Scheme VI.

Bicyclic Sulfonylureas

Synthesis of Benzothiepins

>

SOoNHCNHHet

ô

Ο

42

S0 NH|NHHet 2

Ο

42


OH

KH, DM Ε

CI 4

°

R = HorCH

4

2)H 0 , •2^2' HOAc 2

°

M

PPA CI

CI

45

45

3

2

CI

4Z Scheme Vu.

Synthesis of Benzothiazines

93

Ο

SOoNHCNHHet II Ο

50.

51

S0 NHCNHHet 2

2

OH IJCHsSOgCI/NEta >p

S0 NHR

S0 NHR ^S0

ΖΛ

2

2)K CC^/DMF

22

CI

2

CI

52 R . CH

3f

5a

CHgCHg, CH(CH3) or C(CH ) 3

,NR

3

3

1) K S X * s X 2) CI /HOAc 3) NHa 2

Û

so;

S0 NH 2

54

NR

2

55


58

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS II

Scheme VIII.

Synthesis of 1,2-Benzisothiazoles

α

ÇH

N—R

Û

3

so r

s6

2

2

S0 NHCNHHet II Ο

S0 NHCNHHet

2

2

Ο

5fi

5Z


OH 2) CF3CC2H or 1) TsOH

1) 2 eg />BULL 2) DMF *

a

soyH

CI

2

2) NaBH

S0 NH 2

SO NH Z

2

Oo 2

Ê2

§1

Scheme IX.

4

sa

5S

Oxidative Chlorinations of 5-Methoxy-Benzisothiazoles CH O 3

N

N-CH

3

CH 0, 3

m-CPBA


4. ARTZ ET AL.


59

Tied-Back Esters Many commercial sulfonylureas contain an ortho ester, therefore, preparation of tiedback ester £8 was of great interest. We could use the target intermediate monomethylamide £2 (Scheme X), as both a directing group for metallation and as the latent lactone group. The sulfonamide handle could be added via metallation and quenched with propyl disulfide. Sulfide 2fi can also be prepared via a nucleophilic displacement of the chlorobenzamide 21. A second metallation of 2Û gave the ethanol derivative 22. Base hydrolysis to the amide to the carboxylate, then lactonization under acidic conditions, gave the isocoumarin 22- Oxidative chlorination and amination proceeded without a problem. Synthesis of Isocoumarins


Scheme X.


60

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS II

Herbicidal Activity of Tied-Back Esters vs Open-Chain Esters The isocoumarin 26, shown in Table II, is clearly more active on broadleaves and grasses than either analogous open-chain ester 2£ and 77, but has no wheat tolerance. Here, the isopropyl ester is more active than the 2,3-isomer. This anomaly, when compared to the earlier alkylsulfonyl isomers, can be explained by different metabolic and degradative pathways (See H. Brown and P. Kearney, this volume).


Tied-Back Ketones Indanone 22 was prepared by chlorosulfonation of indane to give both the 4- and 5positional isomers (2), which are difficult to separate. However, we could aminate the sulfonylchlorides and metallate the activated methylene of the 4-isomer in the mixture to give, upon quenching with oxygen, the indanol 82- This could be easily separated from any other products, in 25% yieldfromthe sulfonamide mixture (Scheme XI). We could not deprotect the sulfonamide in the presence of the alcohol group. It was necessary to oxidize with pyridinium chlorochromate (PCC) first, then deprotect the ketone to give sulfonamide S i Table Π.

Structure-Activity of Ortho-Carboxybenzenesulfonylureas

Z5

% Injury Postemergence at 4g/ha Compound

Z5

m 21

Sicklepod 70 100 0

Velvetleaf 90 100 20

Crabgrass 0 100 0

Giant Foxtail 0 80 0


Wheat 0 100 30

4. ARTZETAL.


Scheme XL

61


Synthesis of Indanones

££

S2

Summary We have demonstrated a wide variety of known and adaptive measures to prepare previously unknown bicyclic sulfonylureas. These compounds are herbicidally active at low rates and have some crop selectivity. This information has expanded our QSAR knowledge in the area, which will aid us in directing future research. Acknowledgments This work could not have been achieved without the competent help of numerous technical support staff, biologists and George Levitt, for whom this chapter is honoring. Literature Cited 1. Rorer, M. P. U. S. Patent 4 514 211, 1985. 2. Pasteris, R. J. U. S. Patent 4 492 596, 1985. 3. Pasteris, R. J. U. S. Patent 4 586 950, 1986. 4. Netherlands Patent 6 602 601, 1966; Chem. Abstr. 1967, 66: 463196. 5. Deady, L.; Topsom, R.; Vaughan, J.; J. Chem. Soc. 1963, 2094; & 1965, 5718. 6. Lombardino, J. G., J. Org. Chem. 1971, 36, 1843. 7. Arnold, R., and Zaugy, H., J. Am. Chem. Soc. 1941, 63, 1317. RECEIVED

December 15, 1989


Synthesis and Herbicidal Activity of Bicyclic Sulfonylureas - American

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