pyrimidine fungicides: a new class of broad-spectrum fungicides

Upload: ferretchromosome

Post on 02-Jun-2018

225 views

Category:

Documents


0 download

TRANSCRIPT

  • 8/10/2019 Pyrimidine Fungicides: A New Class of Broad-Spectrum Fungicides

    1/9

  • 8/10/2019 Pyrimidine Fungicides: A New Class of Broad-Spectrum Fungicides

    2/9

    229

    Synthesis

    Synthesis of different sub-classes of compounds of generic structure 4 will be

    discussed. The -ring and the aromatic moiety come primarily from commercialsources and do not warrant much discussion. Rather, we will concentrate ourdiscussion in the variation of B-ring. Pyrazolines 5 with a 5-membered -ring wereprepared by condensation of the corresponding heterocyclic hydrazines withsubstituted 3 -chloropropiophenones or 3 N N-dimethylpropiophenones (Scheme 1). 3-N N-Dimethy lpropiophenones were prepared via the Mannich reaction (3).

    5Scheme 1

    Tetrahydropyridazines 6 with a 6-membered B-ring were prepared bycondensation of the hydrazines with substituted 4-chlorobutyrophenones. Friedel-Crafts acylation of substituted benzenes with 4-chlorobutyrl chloride provided therequisite butyrophenones (Scheme 2).

    Scheme 2

    1,4-Dihydropyridazines 7 were prepared by condensation of the pyrimidinyl-hydrazines with benzoylpropionic acids to give pyridazinones. Reduction with one

    equivalent of lithium aluminum hydride 4) gave the intermediate aminal. Subsequenttreatment with methanesulfonyl chloride in pyridine afforded the desired 1,4-dihydropyridazines 7 (Scheme 3).

    D o w

    n l o a

    d e d b y C O R N E L L U N I V o n

    J u n e

    1 9 , 2

    0 1 2 | h t t p :

    / / p u b s . a c s . o r g

    P u b

    l i c a t

    i o n

    D a t e :

    M a y

    1 4 , 1

    9 9 8 | d o i : 1

    0 . 1 0 2 1 / b k - 1 9 9 8 - 0

    6 8 6 . c h

    0 2 3

    In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.;ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

  • 8/10/2019 Pyrimidine Fungicides: A New Class of Broad-Spectrum Fungicides

    3/9

    230

    Scheme 3

    The synthesis of 1,6-dihydropyridazines is shown in Scheme 4. Condensationof the pyrimidinylhydrazines with ,-diketones gave the corresponding hydrazonesas mixtures of E/Z isomers. Treatment of the mixtures with sodium hydride followedby addition of vinyltriphenylphosphonium bromide (5) provided the 1,6-dihydropyridazines 8. The latter cyclization reaction did not work when the R group was 2-pyridyl or 2-furanyl.

    B fScheme 4

    D o w

    n l o a

    d e d b y C O R N E L L U N I V o n

    J u n e

    1 9 , 2

    0 1 2 | h t t p :

    / / p u b s . a c s . o r g

    P u b

    l i c a t

    i o n

    D a t e :

    M a y

    1 4 , 1

    9 9 8 | d o i : 1

    0 . 1 0 2 1 / b k - 1 9 9 8 - 0

    6 8 6 . c h

    0 2 3

    In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.;ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

  • 8/10/2019 Pyrimidine Fungicides: A New Class of Broad-Spectrum Fungicides

    4/9

    231

    For the synthesis of 7-membered B-rings tetrahydrodiazepines 9, condensationof the pyrimidinylhydrazines with substituted 5-chlorovalerophenones was followedby treatment with sodium hydride (Scheme 5).

    Scheme 5

    The preparation of pyrazolines 5 in which the phenyl group is replaced by abenzyl group is shown in Scheme 6. The requisite chloroketones were prepared bycoupling reactions between benzyl bromide and 3-chloropropionyl chloride catalyzedby a palladium reagent and zinc powder (

  • 8/10/2019 Pyrimidine Fungicides: A New Class of Broad-Spectrum Fungicides

    5/9

    232

    When condensations carried out using 5-chloro-l -pheny 1-2-pentanone preparedanalogously according to the butanones of Scheme 6 and 2,6-dimemylpyrimidinylhydrazine, the desired benzylpyridazine 11 was not isolated. Instead, cyclic hydrazine

    12 with an exocyclic double bond was isolated (Scheme 7).

    12

    Scheme 7

    Biological Data

    The fungicidal activities of these compounds are shown in the Tables I-IV. TheTables show preventive control though some of these compounds also demonstratedcurative efficacy (data not shown). The greenhouse disease control data were used todevelop structure-activity relationships. Many heterocycles in place of the pyrimidinewere also prepared via Schemes 1-6. These heterocycles include pyridine,quinazoline, benzothiazole, benzoxazole, and pyridazine. The activities of thesecompounds were generally less than those of the corresponding pyrimidines and thedata is not presented.

    Structure-Activity Relationships

    For the -ring pyrimidine gave the best activity. For substitution on the pyrimidinering, 4,6-dimethyl- was better than 4-methyl and unsubstituted pyrimidine in overallfungicidal activity when the rest of the molecules are otherwise the same.

    D o w

    n l o a

    d e d b y C O R N E L L U N I V o n

    J u n e

    1 9 , 2

    0 1 2 | h t t p :

    / / p u b s . a c s . o r g

    P u b

    l i c a t

    i o n

    D a t e :

    M a y

    1 4 , 1

    9 9 8 | d o i : 1

    0 . 1 0 2 1 / b k - 1 9 9 8 - 0

    6 8 6 . c h

    0 2 3

    In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.;ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

  • 8/10/2019 Pyrimidine Fungicides: A New Class of Broad-Spectrum Fungicides

    6/9

    233

    For the B-ring, tetrahydropyridazines (Table II) gave better activity thanpyrazolines (Table I) and tetrahydrodiazepines (Table III). Among the 6-memberrings, the 1,4,5,6-tetrahydropyridazine ring was better than the two types of dihydro-

    pyridazines (Table IV

    In the pyrazoline series, the methylene group between the aromatic ring and firing afforded compounds at comparable fungicidal activities to those without themethylene. However, since the synthesis was more difficult, only a few compoundswere prepared (Table I).

    Table I. Biological data

    Percent Disease Control at 200 P PM

    R i R 2 R 3 n A r W P M W L R W F R W G B R C B1 M e H H 0 1-naph tha leny l NT NT 1 0 0 1 0 0 8 62 M e M e H 0 1-naph tha leny l 8 5 2 5 NT 1 0 0 9 63 M e M e H 0 2 - M e -P h 9 2 6 2 1 0 0 NT 8 74 M e M e H 0 2 CI Ph 9 0 8 4 1 0 0 NT 6 25 M e M e H 0 3-CI-Ph 6 3 9 5 7 5 NT 9 96 M e M e H 0 3 - M e - P h 2 0 5 3 1 0 0 1 0 0 9 37 Me M e H 0 4 -M e -P h 3 9 4 5 1 0 0 9 6 NT8 M e M e H 0 2 - OM e -P h 2 8 3 6 8 4 NT 1 0 09 M e H M e 0 P h 9 1 9 9 NT NT NT

    10 H H H 3 - M e -P h 9 6 8 9 0 9 3 011 M e H H 3 - M e -P h 9 8 8 9 4 9 9 7 7 412 M e M e H 3 - M e -P h 9 8 9 8 6 1 1 0 0 9 1

    N T - Not Tested.

    W PM - Wheat Powdery Mildew Erysiphe graminis)W L R - Wheat Leaf Rust Puccinia recondita)W FR - Wheat Foot Rot Pseudocercosporella herpotrichoides)W GB - Wheat Glum Blotch Septoria nodorum)R C B - Rice Blast Pyricularia oryzae)

    D o w

    n l o a

    d e d b y C O R N E L L U N I V o n

    J u n e

    1 9 , 2

    0 1 2 | h t t p :

    / / p u b s . a c s . o r g

    P u b

    l i c a t

    i o n

    D a t e :

    M a y

    1 4 , 1

    9 9 8 | d o i : 1

    0 . 1 0 2 1 / b k - 1 9 9 8 - 0

    6 8 6 . c h

    0 2 3

    In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.;ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

  • 8/10/2019 Pyrimidine Fungicides: A New Class of Broad-Spectrum Fungicides

    7/9

    234

    For the aromatic group, phenyl appeared to be superior to heterocyclicaromatic groups. In the tetrahydropyridazine series (Table II), alkyl and halosubstitutions on the phenyl ring were better than alkoxy and trifluoromethyl groups in

    overall activities. A methyl or ethyl group as R3

    group in the structure shown in TableII also improved the activity. Compound 14 from Table II was the most activecompound and was therefore tested in the field. Unfortunately, the promisinggreenhouse activity of this class of chemistry was not maintained in the field.

    Table II. Biological dataR i

    R 2 A r

    Percent Disease Control at 200 PPMR , R 2 R 3 A r W P M W L R W F R W G B R C BM e H H P h 8 8 1 0 0 9 7 NT NT

    2 M e M e H P h 9 6 9 9 6 2 NT 6 03 M e M e H 4 - F - P h NT 8 9 3 8 NT 6 14 M e M e H 3-CI-Ph 9 7 21 9 2 1 0 0 9 85 M e M e H 4 -CI -Ph 9 1 1 0 0 1 0 0 1 0 0 1 0 06 M e M e H 4 OH P h 5 7 7 9 NT NT 9 17 M e M e H 4 -O M e -P h 6 6 9 8 8 5 1 0 0 9 9

    8 M e M e H 4 - O P h - P h 7 2 8 6 7 9 1 0 0 9 09 M e M e H 2 - M e -P h 8 0 4 1 8 7 1 0 0 9 010 M e M e H 3 - M e -P h 9 4 9 9 9 8 1 0 0 8 511 M e M e H 4 -M e -P h 8 9 1 0 0 7 4 9 7 1 0 012 M e M e H 4 - n - P r- Ph 9 9 1 0 0 9 2 9 8 9 913 M e M e 4 - t e f f - B u - Ph 8 3 9 7 1 0 0 NT 9 914 M e M e M e P h 9 8 6 7 5 9 1 00 9 91 5 M e M e M e P h 9 8 6 7 5 9 1 0 0 9 91 6 M e M e Et P h 9 5 9 3 6 2 1 0 0 9 31 7 M e M e M e 3 - M e -P h 9 9 9 9 7 7 1 0 0 9 6

    18 M e M e H 3 - C F3 - Ph 7 1 5 3 0 1 0 0 3 519 M e M e H 2-thienyl 4 6 6 7 1 0 0 1 0 0 5 7

    * indicate disease control at 40 PPM.

    D o w

    n l o a

    d e d b y C O R N E L L U N I V o n

    J u n e

    1 9 , 2

    0 1 2 | h t t p :

    / / p u b s . a c s . o r g

    P u b

    l i c a t

    i o n

    D a t e :

    M a y

    1 4 , 1

    9 9 8 | d o i : 1

    0 . 1 0 2 1 / b k - 1 9 9 8 - 0

    6 8 6 . c h

    0 2 3

    In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.;ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

  • 8/10/2019 Pyrimidine Fungicides: A New Class of Broad-Spectrum Fungicides

    8/9

    235

    Table III. Biological data

    Percent Disease Control at 200 PPMX WPM W L R W F R W G B RCB

    4 CI 8 9 8 3 1 0 0 9 5 712 4 - OM e 6 0 6 6 3 9 9 9 7 33 4 -M e 7 9 7 0 4 1 1 0 0 8 24 H 9 6 8 3 3 3 1 0 0 8 3

    * indicate disease control at 40 PPM .

    Table IV. Biological data

    For compounds -4 For compounds 5-7 For compounds 8-10

    Percent Disease Control at 200 PPMR X W P M W L R W FR W GB R C B

    H H 9 6 9 9 6 2 NT 6 02 H 4 - M e 8 9 1 0 0 7 4 9 7 1 0 03 H 4 -OM e 6 6 9 8 8 5 1 0 0 9 94 H 3 , 4 -d i M e 91 9 8 NT 1 0 0 9 05 H H 0 9 7 0 3 136 H 3 , 4 - d i M e 6 0 8 3 0 9 5 6 77 4 -M e -P h 4 - M e 5 7 0 0 0 08 P h H 2 4 7 7 0 7 8 2 49 4 -M e -P h 4 - M e NT 8 0 4 8 5 8 3 210 4 -O M e -P h 4 -OM e 8 4 8 8 6 1 3 5 0

    D o w

    n l o a

    d e d b y C O R N E L L U N I V o n

    J u n e

    1 9 , 2

    0 1 2 | h t t p :

    / / p u b s . a c s . o r g

    P u b

    l i c a t

    i o n

    D a t e :

    M a y

    1 4 , 1

    9 9 8 | d o i : 1

    0 . 1 0 2 1 / b k - 1 9 9 8 - 0

    6 8 6 . c h

    0 2 3

    In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.;ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

  • 8/10/2019 Pyrimidine Fungicides: A New Class of Broad-Spectrum Fungicides

    9/9

    236

    Conclusions

    The pyrimidinyltetrahydropyridazines discussed demonstrated broad spectrum of

    fungicidal activity, especially against wheat foot rot, wheat glum blotch and rice blast,in the greenhouse. Dimethyl substitution on the pyrimidinyl group boosted thefungicidal activity. The greenhouse activity was not maintained in the field.

    Acknowledgments

    The authors wish to thank those biologists who contributed to this work. We wouldalso like to thank John Daub, Ed Adams, Debbie Frasier and Simon Xu for sharingideas in this area of chemistry.

    Literature Cited

    1. JP03044304, (Takeda, 1989)2. EP259139 (Sumitomo, 1987)3. Maxwell, C. E. Org. Synth. 1955, 305.4. Aubagnac, J. L.; Elguero, J.; Jacquier, R.; Robert, R. Bull. Soc. Chim. France,

    1972, 2859.5. Schweizer, E. E.; Kopay, C. M. J. Org. Chem. 1972, 37 1561.6. Sato, T.; Naruse, K.; Enokiya, M; Fujisawa, T. Chem. Lett. 1981, 1135.

    D o w

    n l o a

    d e d b y C O R N E L L U N I V o n

    J u n e

    1 9 , 2

    0 1 2 | h t t p :

    / / p u b s . a c s . o r g

    P u b

    l i c a t

    i o n

    D a t e :

    M a y

    1 4 , 1

    9 9 8 | d o i : 1

    0 . 1 0 2 1 / b k - 1 9 9 8 - 0

    6 8 6 . c h

    0 2 3

    I S h i d Ch i f A h i l V B k D l