Synthesis and Chemistry of Agrochemicals II - ACS Publications

Chapter 5

Synthesis of Heterocyclic Sulfonamides John Cuomo, Stephen K. Gee, and Stephen L. Hartzell

Downloaded by UNIV OF GUELPH LIBRARY on March 10, 2013 | http://pubs.acs.org Publication Date: December 7, 1991 | doi: 10.1021/bk-1991-0443.ch005

Agricultural Products Department, Ε. I. du Pont de Nemours and Company, Stine-Haskell Research Center, Newark, DE 19711

Once it was realized that heteroaromatic sulfonamides could be prepared and converted to sulfonylureas, and that these compounds possessed many of the desirable hebicidal qualities of the benzene sulfonylureas, a large synthetic effort was started to prepare more examples. Using thiophene and pyrazole as representative examples, we have been able to synthesize all of the positional isomers of the mono- and di-substituted sulfonamides. This paper will outline the major synthetic pathways that we have discovered, emphasizing directed metallation processes and nucleophilic substitution reactions, leading to the preparation of these heterocyclic sulfonamides. Many of the methods developed for thiophene and pyrazole sulfonamide synthesis have been extended to the synthesis of pyridine and other heteroaromatic sulfonamides. Since the original discovery of the sulfonylurea herbicides by Dr. George Levitt at Du Pont in the mid 70's, a large synthetic effort has been involved in defining the structural limits for this class of herbicides. While much of the early work centered around the benzenesulfonylureas, replacement of the phenyl portion with heteroaromatic groups is also feasible and results in sulfonylureas which are also biologically active. George Levitt prepared a thiophenesulfonylurea that possessed the necessary herbicidal activity and crop selectivity to warrant commercialization. This sulfonylurea has been sold as "Harmony", a short residual cereal herbicide. The search for other heterocyclic sulfonylurea herbicides has continued since this discovery. Thiophene Sulfonamides While the "Harmony" synthetic scheme outlined below is useful to prepare additional ester analogues or simple derivatives of the ester, new synthetic schemes SQ NH 2

2

=-C0 Me s


"Harmony"

OMe

2

needed to be developed to allow for a wide range of functionality and substitution patterns. Since all of the methods described by George Levitt earlier in this work are available for synthesizing sulfonylureas from sulfonamides, our goal was to find methods to prepare the wide range of sulfonamides represented by the structures shown below. // SS U U

R R

Ci* N

R

ο

2-sub-3-SU R

//l~ SU

icLs*su

4-sub-3-SU

/SU

R

3-sub-2-SU

ySV

R'

R

„i>

$^

2,3-disub-4-SU

2,4-disub-3-SU

s u

3,4-disub-2-SU

2-Substituted-3-bridged Sulfonamides ("Harmony" analogues). Our first task was to prepare a number of sulfonamides with the same substitution pattern as "Harmony". These compounds will have the sulfonamide, the anchor for the sulfonylurea bridge, in the 3 position. Our initial attempts used a group in the 2 position to direct metalation and subsequent sulfonamide formation to the 3 position. Although the literature has reports of metallation directed to the 3 position by a 2-carboxylic acid (1), amide (2), oxazole (3-4) or pyridine (5), these processes are often complicated by metalation in the 5 position. In fact, because of the ease of metalation of thiophene in the α positions, in general any 2 substituted thiophene will give exclusive metalation in the 5 position. For example, when we prepared either the 2- isoxazole 4 or pyrazole 5 derivative, and treated it with n-butyllithium in ether, no 3- lithio species could be detected or trapped. To direct metalation to the 3 position BuLi

in this system, a transmetalation of the 3-bromo intermediate had to be employed. The strong directing effect of 3-bromothiophene (6) with electrophiles is used to prepare 3-bromo-2-acetylthiophene (7). The heterocyclicringsare then elaborated, and finally the bromine is used as a handle to yield the sulfonamide via a transmetalation. Here, the anion is trapped with S0 , followed by oxidation with 2

4

Snci AcCl

4 x

s'

1[ί>^ Λ\

2)NH OHor 2

NH NHM

e

2

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

64

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π Br

S02NH2

l)BuLi

2)S02 8X = 0 9 X = NMe

.

3)NCS

S

4)NH

10 11

3

χ


NCS and amination to give the 3-sulfonamide 10 or 11 (6). An even more general and useful approach to 2-substituted-3-thiophene sulfonamides is to use the transmetalation and trapping reaction to prepare 3-im-butylthiophene sulfonamide 12 and to then use this group to direct further metalation to the 2 position. A large number of derivatives can be prepared in this B r

SQ NH-t-Bu

}S0 NH-t-Bu

BuLi

y

2

2

2 BuLi NCS t-BuNH

Br 2

2

cl», 13

12

manner (7). For example, 3-bromothiophene was converted to 12 and the directing ability of the im-butyl sulfonamide was used to prepare the 2-bromo derivative 13. The bromide was itself a versatile intermediate. The fm-butyl group can be removed with TFA, givingfreesulfonamide ready for coupling. Or the bromide can be used to introduce other groups. For example, die palladium (0) cross coupling reaction (8-10) with aryl boronic acids can be used to prepare the aryl derivatives

15

14. Reaction with nucleophiles such as copper cyanide or sodium triazole gave 15 and 16 respectively. The sulfonamide 12 was also used to prepare the ketone and aldehyde intermediates 17 and 18 again through a directed metalation to the 2 position. These intermediates were converted to the oximes (19), ketals (20), or difluoromethyl (21) derivatives. 1) BuLi 2) CH CHO/PCC

1) DAST C(Q)R

or DMF l)H NOMe 2

S0 NH 2

2

CHF

2) TFA

17R = Me 18R = H

S0 NH 2

2

OMe

2

2

3

12

SQ NH

S0 NH-t-Bu

2

2) TFA

19


2

5. CUOMO ET AL

65

Synthesis of Heterocyclic Sulfonamides

4-Substituted-3-bridged Sulfonamides. With a versatile synthesis of the "Harmony" isomers in hand we next turned our attention to the synthesis of the alternate isomers. The key compound here was the ester 25, needed for the direct biological comparison with "Harmony". This compound was easily prepared by treating 3,4-dibromothiophene with 1 equivalent of butyllithium followed by a propyl disulfide quench. The thioether 22 can then be treated with another equivalent of butyllithium and trapped with C 0 to give 23. Esterification (23 —» 24) followed by oxidative chlorination/amination gave the 4-ester isomer of "Harmony" 25. 2

Br

Br

(Γ\


SC3H7

Br BuLi

W

"Ss£

C0 H S C H 2

BuLi

3

(ri

C0 R S C H 2

7

DCC

s

3

W

C0 R S0 NH 2

7

Cl /H+

s

23

2

ΖΓΛ

2

"5SH

22

2

24

s ' 25

3,4-Dibromothiophene could also be converted to 4-bromo-3-thiopheneieri-butylsulfonamide (26) by the same transmetalation/trapping sequence used for 3-bromothiophene. This intermediate (26) could also be used for the Pd(0) cata lyzed cross coupling (26 —> 27) or for nucleophilic displacements (26 —» 28 and 29). Br

Br

l)BuLi

W

2

< )>

Br

)

3)NCS

c

4)t-BuNH

Ph

2

2

S0 NH-t-Bu 2

«OTh

^

Pd(0)

*S

KTriazole Ν-Ν

S0 NH-t-Bu

^ W 26

27

/

CuCN C

\

S0 NH-t-Bu

CN

2

28

S0 NH-t-Bu 2

29

It is also possible to replace one of the bromines, by either a nucleophilic displacement, or a transmetalation trapping procedure, prior to the sulfonamide forming transmetalation. For example, 3,4-dibromothiophene may be treated with sodium methoxide to give 4-methoxy-3-bromothiophene (30). The methoxy intermediate is transmetalated, reacted with S0 , oxidized, and aminated to yield 31. 2

Br Ν

Br /

MeOH/NaOMe

MeO \

S o * - *

Q s

Br

BuLi S0

/

2

MeO Ν

S0 NH 2

O

Q

b

reflux 30h

2

/

NH3

30

S

31

3-Substituted-2-bridged Sulfonamides. This isomer is the easiest to synthesize due to the propensity of 3-substituted thiophenes to undergo electrophilic substitutions or directed metalations in the 2 position. Thus, the "Harmony" reverse isomer can be preparedfromacid 32 via a directed metalation to the 2 position. The usual S 0 2

C0 H B u L i 2

fi

C0 Me

2

2

fi NCS

32

C0 H

2

S. /-S0 NH S

2

2

MeOlf

^ ^S0 NH S

2

33


2

66

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π


quench, oxidation, amination sequence gives sulfonamide 33, which is next esterified to complete the synthesis. One can also make use of the directing effect of the 3-bromine to chlorosulfonate directly in the 2 position (3-bromothiophene —• 35). Amination with ammonia give the free sulfonamide, while ferr-butyl amine treatment gives a protected sulfonamide that can be used for the cross coupling reaction and nucleophilic displacements already described for the other isomers. The bromide 36 can also be used to direct transmetalation to the 3 position for the introduction of a variety of electrophiles.

* SO NH 2

38

39

2

40

The ease with which thiophene is metalated in the 2 position can be demonstrated by the following scheme where 3-bromothiophene is first converted to 3-methoxythiophene 41 (IT), and then the methoxy group is used to direct metalation giving the sulfonamide 42. Br /

OMe

(

MeOH/NaOMe

/

•

T\ % ^

(

BuLi

f\ S0

reflux 76h

^

/Πν

•

CuOKI

OMe (

,

2)S0 C1 2

^

/r\ N 2

3)H N-t-Bu 2

R = Me,S0 NMe 2

2

J?x

- ^S0 NH-t-Bu N

2

/ri Ν

χ

Ν

έ

R

86

87

^ SO^NH-t-Bu

Further elaborations of 87 (e.g. 88,89, and 90) is facilitated by the electron withdrawing effect of the sulfonamide group.


72

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π

CN

S0 NH-t-Bu 2

S0 NH-t-Bu 2


R

While an in depth discussion of the structure/activity relationships in the pyrazolesulfonylurea area is not appropriate in this chapter, a particularly striking example is illustrative of the variations in biological activity as related to placement of the sulfonamide bridge in the pyrazolesulfonylurea esters. As shown in Table 2, all of the isomeric esters are quite active on broadleaf and grass weeds. The 5-bridged isomer however shows remarkable safety to rice.

Table 2. Postemergence Herbicidal activity at 16 g/Ha of Isomeric Pyrazole Esters. COMPOUND

A

Β

C

D

% Rice Injury

89

89

98

0

Mean Grass Weed % Control

66

87

92

97

Mean Broadleaf Weed % Control

69

86

88

68

Me0 C

SU

2

x

fT

SU

% ^ C 0

I

I

Me

Me

A

2

C0 Me

SU

M e

2

Ν

I Me

Β

C

C0 Me 2

SU Me

SU= S 0 N H C ( 0 ) N H — ( N= 7

2

OMe

Summary The above examples of the thiophene, and pyrazole sulfonamide syntheses are representative of the breath of the synthetic programs in both areas. This is by no means a complete review of all the syntheses we have developed, but rather an indication of some of the synthetic challenges, and solutions that we have encountered in the sulfonylurea program at Du Pont. Much of the chemistry


5. CUOMO ET AL.

Synthesis ofHeterocyclic Sulfonamides

73

described here, as well as considerable additional work, has been applied to the synthesis of other heteroaromatic sulfonylureas. For example, we have prepared imidazole, thiazole, pyrrole, and pyridine sulfonylureas to name a few, as well as, many fused bicyclic heteroaromatic sulfonylureas. The synthesis of those compounds will be presented in future publications.


Acknowledgments We are indebted to many colleagues who have worked on this and related projects over a number of years, without whose contribution this work would not have been completed. In particular, we would like to thank, W. C. Petersen, M. R. Hulce, W. T. Zimmerman, B. A. Lockett, J. C. Carl, and R. Shapiro for their contributions to the synthesis, and a host of extremely talented Herbicide Discovery Biologist who designed, and adapted, many screens for the sulfonylureas. We would especially like to thank George Levitt for the many many contributions he has made to the present work, and the whole field of sulfonylurea chemistry, and wish to take this opportunity to congratulate him for receiving the ACS Award for Creative Invention. We are also indebted to the Du Pont Co. and the management of the Agricultural Products Department for supporting this work, and allowing us a free hand in the design and implementation of many syntheses. Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

Carpenter, A. J.; Chadwick, D. J. Tetrahedron Letters 1985, 1777. Carpenter, A. J.; Chadwick, D. J. J. Chem. Soc., Perkin Trans. 1 1985, 173. Chadwick, D. J.; McKight, M. V.; Ngochindo, R. J. Chem. Soc., Perkin Trans. 1, 1982, 1343. Vlattas,I.;DellaVecchia, L. J. Org. Chem. 1977, 42, 2649. Kauffmann, T.; Mitschker, A. Tetrahedron Letters 1973, 4039. Shapiro, R. U. S. Patents 4 684 393, 1987; 4 723 988, 1988. Christensen, J. R.; Cuomo, J.; Levitt, G. U. S. Patent 4 743 290, 1988; European Patent 88900721.7, 1987; Sharp, M. J.; Sniekus, V. Tetrahedron Letter 1985, 5997. Thompson, W. J.; Gaudino, J. J. Org. Chem. 1984, 49, 5237. Miyaura, N.; Yanagi, T.; Suzuki, A. Syn. Commun. 1981, 11, 513. Gronowitz, S. Arkiv. for Kemi. 1957, 12, 239. Ege, G; Arnold, P. Synthesis 1976, 52. Ege, G; Arnold, P. Angew. Chem. 1974, 86, 237. Gompper, R.; Topfl, W. Chem. Ber. 1962, 95, 2881. Gschwend, H. W.; Rodriguez, H. R. In Organic Reactions; John Wiley and Sons, Inc.: New York, 1979; Vol. 27, p 23. JanLeusen, A. M. Tetrahedron Letters 1972, 2369. Middleton, W. J. J. Org. Chem. 1975, 40, 574.

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Synthesis and Chemistry of Agrochemicals II - ACS Publications

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