Synthesis and Fungicidal Activity of 4-Phenethylaminoquinoline and

Chapter 44

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Synthesis and Fungicidal Activity of 4-Phenethylaminoquinoline and its Analogues and Derivatives Barry A. Dreikorn, Glen P. Jourdan, L. Navelle Davis, Robert G. Suhr, Harold R. Hall, and Wendell R. Arnold Lilly Research Laboratories, Eli Lilly and Company, P.O. Box 708, Greenfield, IN 46140

A novel series of analogs and derivatives of 4-phenethylaminoquinoline, 1, was prepared for evaluation as foliar fungicides. These compounds exhibited a high level of fungicidal activity, especially against downy mildew of grape. A summary of the chemistry and the structure-activity-relationships are presented. The synthesis and in vivo screening of heterocyclic compounds for their agricultural fungicidal activity has been and continues to be an important approach to fungicide discovery. Historically, this approach at Lilly has led to the discovery and subsequent development of a number of important agricultural fungicides, including tricyclazole, ariceblast fungicide (1), fenarimol, an apple scab and grape powdery mildew fungicide, and nuarimol(2), a cereal fungicide. While computer-assisted molecular design of fungicides is expected to play an increasingly important role in fungicide discovery in the future, the search for fungicides with novel modes-of-action will continue to rely on in vivo screening in concert with molecular design. We have, for a number of years, been actively screening for compounds that control downy mildew of grape and squash (Plasmopara viticola). Compounds that control downy mildew are particularly important both because of the size of the potential problem (3) and that a number of currently used fungicides are becoming less effective due to resistance problems (4-6). During the course of this search, compound 1,4-phenethylaminoquinoline, was discovered to control both grape and squash downy mildew and was systemic to the extent that it exhibited translaminar movement when applied to the bottom surface of squash leaves. Although the level of field activity of 1 proved to be inadequate for further development, its novel structure and apparently novel mode-of-action encouraged us to initiate a structure-activity study to better determine what characteristics of the structure of 1 led to its activity and to attempt to enhance and broaden the activity of this molecule by synthetic structural modification.

0097-6156/91A)443-0553$06.00A) © 1991 American Chemical Society

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

554

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS II

HN


Ν

1 Development of a structure-activity-relationship In our attempts to optimize the fungicidal activity of this novel series of quinoline compounds, a systematic study of the structure-activity relationships was undertaken. Practically all parts of the phenethylaminoquinoline molecule were subjected to structural variation. The approach we took in developing a structure-activity relationship was to divide the molecule into three areas of interest; A. the quinoline portion, B. the bridge linking the quinoline and phenyl, and C. the phenyl portion. The key structural modifications can be classified as follows: (see Figure 1)

c

Figure 1 1. Determining the optimum position on the quinoline for the phenylethylamino group. 2. Varying the length of the alkyl chain (B). 3. Substitution on die quinoline in either the pyrido-or benzo-portions (A). 4. Substitution on or replacement of the phenyl group (C). 5. Substitution of the chain nitrogen or addition of groups or atoms to the chain (B). 6. Replacement of the nitrogen atom in the chain with other atoms (B).

Position of the phenylethylamino group on the quinoline One of thefirstquestions we needed to answer was the importance of the location of the phenylethylamino group in the 4-position of the quinoline. We needed to


44. DREIKORN ET AL.

4-Phenethylaminoquinoline

555


synthesize and then examine the fungicidal activity of phenethylaminoquinolines substituted at every position on the quinoline. Synthesis The literature route to the synthesis of 4-phenylethylamino quinoline was developed by W. S. Johnson (7), (Scheme I), and involved the reaction of phenylethylamine with l,2,3,4-tetrahydro-4-quinolone. While this approach is useful for the synthesis of compound 1, it proved inadequate for the synthesis of other phenyletiiylaminoquinolines. We were able to synthesize most of the other phenylethylaminoquinolines by the replacement of the chlorine on 4-chloroquinoline by heating it with phenylethylamine 150-220 °C (Scheme Π) In cases where reaction of phenethylamine with chloroquinolines did not occur, a modification of a route through the hydroxyquinoline developed by Hartshorn and Baird proved to be successful (8). This method involves heating the appropriate hydroxyquinoline with phenylethylamine in the presence of sulfur dioxide, under pressure (Scheme ΙΠ). Fungicidal results. The fungicidal activity of all seven phenylethylaminoquinolines was compared and the results against squash downy mildew. Only the "4" substituted quinoline compound possessed significant fungicidal activity. These results confirm the importance of placing the phenylethylamino group at the 4-position on quinoline.

Scheme I



556


pressure bomb 100 °C Scheme III

Optimum chain length for the "bridge" To determine the effect of alkyl chain length on fungicidal activity, a series of phenylalkylaminoquinolines of Figure 2 was synthesized varying the alkyl portion of the chainfrom0 to 5 carbons in length.

Figure 2 Synthesis. These compounds were all made by a variation of the Scheme II reaction in which 4-chloroquinoline, was reacted at temperatures between 150-200 °C with phenylalkylamines in which the alkylamino chain length was varied from 0-5 carbons.


44. DREIKORN ET AL


Fungicidal results. The compounds were evaluated for control of squash downy mildew and the result indicate that the order of activity for the length of the carbon chain was 2>4>3>1»0. This was an indication that the chain length was critical for fungicidal activity. The fact that long-chain alkyls (C -C ) were also inactive indicated that the role of the phenethylamino group was more than just being a large lipophilic group. Additional studies carried out with either substituted quinolines and/or substituted phenyl groups further confirmed the importance of the chain length to fungicidal activity. One possible explanation for the importance of the chain length to the fungicidal activity is that when n=2 or, to a lesser extent 4, the phenyl group is able to "fold over" the quinolineringin a "folded" conformation and overlap its "π" orbitals (Figure 3, la). This may be a necessary structural requirement for downy mildew activity. From a conformational search within S YBYL (9), using the Tripos force field (10) energy minimizer, some the energetics of various conformations were compared. It appearsfromenergy considerations that this "folded" conformation is not prohibited and, in fact, might actually be favored when compared to the "extended" conformation (Figure 3, lb). 8


557

"Folded"

12

"Extended"

la

lb Figure 3

Quinoline substitution In order to further develop the SAR of this series, it was necessary to determine the effect that quinoline substitution had on fungicidal activity. To answer this question, a number of mono-,di-,and trisubstituted quinolines were synthesized, holding constant the phenylethylamino group in the 4-position of the quinoline.

Synthesis. All of these compounds were synthesized from the reaction of phenylethylamine with the appropriately substituted 4-chloroquinolines. These were synthesizedfromthe corresponding 4-hydroxyquinolines by reaction with phosphorous pentachloride. The 4-hydroxyquinolines were either purchased or, in most cases synthesizedfromthe appropriately substituted anilines by literature procedures (11).



558


Fungicidal Results. Those quinolines substituted only in the pyrido-portion of the quinoline with halogens, methyls, phenyl, and hydroxyl were much less active than the lead compound. The hydrochloride salt and the N-oxide were also synthesized and tested and neither of these had activity superior to 4-phenethylaminoquinoline, 1. Likewise, most of the quinoline analogs mono-substituted in the benzo portion were fungicidally inactive or, at best, less active than 1. The exception was die 8-fluoro analog, 13 which proved to me about twice as active as the lead, compound 1. Of the polysubstituted quinolines tested, only the 2-chloro-8-fluoro analog, 24, was more active than the unsubstituted quinoline and was comparable to the 8-fluoro material. This was somewhat surprising since the mono-substituted 2-chloroquinoline analog, 4, was much less active (Table I). It would appear that, for the most part, substitution on the quinoline does not improve the activity of the corresponding phenylethylquinoline. The activity of the quinoline substituted analogs is more negatively effected by substitution in the pyrido portion than the benzo-portion. However, some substitutions in the 8-position, especially the fluorine, 13, either have at least comparable activity or are more active than the unsubstituted quinoline analog. Phenyl-ring substitution or replacement Our initial plan was to make phenyl-substituted analogs of 4-phenethylamino quinoline. With the discovery that the 8-fluoroquinoline, 13, was more active than the unsubstituted quinoline, we substituted the 8-fluoroquinoline for quinoline in all this work and substituted or replaced the phenyl portion of the phenethylamine. The unsubstituted quinoline analogs of the most active substituted phenyls were routinely synthesized and tested and they were uniformly less active fungicidally.

Synthesis. The phenylethylamines, including the naphthyl and heterocyclic-ethylamines, were either purchased or synthesized by the reduction of the corresponding nitro styrenes, phenylacetamides or phenylacetonitrile. The reactions with 4-chloroquinoline or the 4-chloro-8-fluoro analog were carried out as indicated earlier.

Fungicidal Results. A number of monosubstituted phenyl derivatives, proved to have greater fungicidal activity than the unsubstituted phenyl (Table Π). It was apparent that both the nature and location of the substituent could greatly enhance the fungicidal activity of the phenylethylaminoquinolines. Electron donating groups in the para-position of the phenyl, especially with branched alkyls, 37 and 38, and alkoxides (other than methoxide), 43-46, were very active while electron withdrawing groups, especially trifluoromethyl groups, were more active in the meta-position. The halogens, with the exception of the iodo, appeared to show good activity in all three positions. In the case of the disubstituted phenyls, a number of analogs had activity comparable to the monosubstituted compounds. The lack of activity of the 2,6-dichlorophenyl analog, 52, was surprising, especially considering that the 2,4- and 3,4-dichlorophenyl compounds, 50 and 51, had activity comparable to 13, the best mono-substituted analog. The 2,6-difluorophenyl analog, 54, proved to be a very active molecule while the 2-fluoro-6-chloro compound, 55, seemed to be intermediate in activity. This further supported the importance of the "folded" conformation to activity, since the two ortho chlorine atoms could inhibit the "π" overlap by steric hindrance.


44. DREIKORN ET AL.

4-Phenethyfominoquinoline

TABLEI


CONTROL OF SQUASH DOWNY MILDEW WITH QUINOLINE RING SUBSTITUTION

COMPOUND NUMBER H 1 H (HCl SALT) 2 2-CH 3 2-C1 4 2-Br 5 2-CF3 6 2-OH 7 6-F 8 9 6-C1 10 6- Br 11 7- F 12 7- C1 13 8- F 14 8-C1 15 8-Br 16 6-CH3 17 6-CH2CH3 18 8-CH3 19 8-CH2CH3 20 8-CF3 21 8-OH 22 2-C1,8-C1 23 6,8-Di F 24 2-Cl,8-F ( ) = ED90 f o r Grape Downy Mildew 3

ED go (ppm) 25 (25) 70 200 70 100 >1000 >1000 70 100 100 100 100 15 (25)* 100 100 70 100 200 >1000 70 >1000 >1000 70 006 (100)*

r


559

560


TABLE Π


CONTROL OF SQUASH DOWNY MILDEW WITH PHENYL RING SUBSTITUTION

F COMPOUND NUMBER

25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 *( ) = EDgo f o r

R

EDQQ ( P P M )

25 (50)* 2'-Cl 3'-F 25 (25)* 6 (25)* 3'-Cl 3'-Br 800 4'-F 15 (50)* 6 (400)* 4'-Cl .12 (15) 4'-Br 4'-I 75 2'-CH 75 3'CH 75 25 (15)* 4'CH 4'-Ethyl 25 (25)* 6 (15)* 4'-i-Propyl 6 (15)* 4'-t-Butyl 4'-OH >1000 2'-OCH 200 25 3'-OCH 4'-OCH 75 4'-OCH CH 6 (400)* 4'-OCH CH CH 6 (200) 6 (100)* 4 -OCH(CH ) 4'-OCH CH CH CH 6 (100)* 2-CF 6 (3)* 3-CF 6 (25)* 4-CF 400 6 (25)* 2,4-Di C l 6 (400)* 3,4-Di C l 2,6-Di C l >1000 2,4-Di F 100 2,6-Di F 6 (75)* 2-Cl,6-F 25 (100)* Grape Downy Mildew 3

3

3

3

3

3

2

2

3

2

3

f

3

2

2

2

2

3

3

3

3


44. DREIKORN ET AL

4-Phenethylaminoquuwline

561

Some of the derivatives in which the phenyl was replaced by other aromatic groups, including 2-naphthyl, 59,3-thiophene, 61, and 2-benzodioxane, 66, proved to have excellent fungicidal activity, indicating that a phenyl group wasn't essential for activity (Table ΠΙ).


Chain substitution We wanted to determine what effect substitution on any part of the bridge, either on the nitrogen or on the alkyl portion, would have on fungicidal activity. Rather than holding the quinoline and phenyl portions constant, bom the quinoline and 8-fluoroquinolines were examined and, for the phenyl portion, that substituted phenyls, naphthyls, and thiophene also be explored. Synthesis. Substitution of the bridge nitrogen with alkyl or acetyl groups was

TABLE ΠΙ CONTROL OF SQUASH DOWNY MILDEW WITH REPLACEMENT OF T H E PHENYL GROUP

COMPOUND NUMBER 56 57 58 59 60 61 62 63 64 65 66 67 68 69

Cyclohexane 2-Cydohexene 1-Naphthalene 2- Naphthalene 2-Thiophene

25 25 (100)* 25 (25)* 6 (12)* 70

3-Indole 100 2-Pyridine 70 2-Imidazo 400 2-Quinoxaline 400 2-Benzodioxane 25 (25)* N-Morpholine >1000 2-N-Methylpyrrole 800 N-Piperidine >1000 * ( ) = EDgo f o r Grape Downy Mildew


562


accomplished by reacting the 4-phenylethylaminoquinolines with acetyl or propionylchloride and reducing the amide with lithium aluminum hydride. Substitution on the alkyl portion of the chain with alkyls, halos, hydroxy or phenyl substitutents was accomplished by starting with phenylethylamines that were appropriately substituted.

Fungicidal results. The compounds with the nitrogen substituted with either alkyl or


acyl groups were very much less active man those with a proton on the nitrogen. Substitution on the alkyl chain with alkyls, halogens, or phenyls were fungicidally less active than the chain-unsubstituted analogs.

Replacement of nitrogen in the bridge One of the last question that needed to be addressed was the importance of the nitrogen in the bridge to fungicidal activity. In order to determine the role played by the nitrogen, it was replaced with sulfur, sulfoxide, oxygen, and carbon. The quinoline portion was kept constant with both quinoline and 8-fluoroquinoline and, for the phenyl portion, the most active phenyls or substituted phenyls were used.

Synthesis. The sulfur and oxygen compounds were synthesized by reacting the appropriately substituted 4-chloroquinoline with phenylethanol or phenylethylmercaptan. These high-yielding reactions were carried out in ethanol at reflux. The carbon analogs required the reaction of the corresponding barbiturate and subsequent hydrolysis to the desired materials (Scheme IV).

Fungicidal results. All of these compounds were widely screened. The sulfur compounds, both the sulfide and sulphone, were entirely inactive against all the screening diseases. The carbon compounds had activity against squash downy mildew but were less active than the comparable amines. Likewise, the oxygen compounds were also less active against squash downy mildew than the comparable amino analogs (Table IV). Both the carbon and oxygen analogs appear to have a broader spectrum of fungicidal activity than the amino compounds, controlling both rice blast and wheat powdery mildew. Cl

F

F Scheme IV


DREIKORN ET AL

563


TABLE IV


CONTROL OF SQUASH DOWNY MILDEW WITH REPLACEMENT OF THE NITROGEN WITH OTHER ATOMS AND GROUPS

COMPOUND NUMBER 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114

X

s s so CH CH CH CH CH CH CH 0 0 0 0 0 0 0 0 0 0 0 0 0

R

l 8-P

2

8-F 8-F

H 8-F 8-F

H 8-F

H 8-F

H 8-F

H 8-F

H 8-F

H 8-F 8-F 8-F 8-F

H 8-F

R

ED

90

Phenyl 4-Chlorophenyl 4-Chlorophenyl Phenyl Phenyl 4-Chlorophenyl 4'-Ethoxyphenyl 4'-Ethoxyphenyl 4'-i-Propyl Phenyl 4'-i-Propyl Phenyl Phenyl Phenyl 4'-Chlorophenyl 4'-Chlorophenyl 4'-Ethoxyphenyl 4'-Ethoxyphenyl 2'-Methoxyphenyl 2'-Methoxyphenyl 1-Naphthyl 2-Naphthyl 4-iPropylphenyl 4-tButylpheny1 4-t-Butvlphenyl

(ppm) XL000 >1000 >1000 400 400 800 25 25 400 200 100 25 25 25 25 25 25 25 >1000 800 400 100 25


564


Field results


Some representative compoundsfromthe family of 4-phenethylaminoquinolines were examined under field conditions to determine their level of control against grape downy mildew of Niagara grapes and compared to the initial lead, compound 1. As can be seen in Table V , a number of these compounds gave good-to-excellent control at levels of 100-500 ppm, much lower than the comparable activity shown by the parent compound, compound 1.

TABLE V FIELD EFFICACY OF SELECTED COMPOUNDS AGAINST GRAPE DOWNY MILDEW (NIAGARA GRAPES) COMPOUND NUMBER

R A T E TESTED

(ppm)

PERCENT CONTROL

1

250 500

0 27

47

50 100 250 500

95 57 97 95

59

50 100 250 500

40 82 97 99

60

50 100 250 500

25 55 80 79

Conclusions Some of the specific conclusions reached concerning structural requirements of this series for the control of squash and grape downy mildew were as follows; 1. The phenylethylamino group needs to be in the 4-position of the quinoline for maximal activity. 2. The optimum length of the alkyl chain between the 4-amino group on the quinoline and the phenyl moieties is 2 carbons. 3. Of all the substituted quinolines synthesized and screened, only the 8-fluoro quinolines analogs were consistently superior in downy mildew activity to the unsubstituted quinoline. 4. A variety of substituents on the phenyl group improved fungicidal activity over that of the unsubstituted phenyl group. Also, the phenyl group could be replaced by certain heterocycles or naphthalene with retension of high activity.


44.

DREIKORN ET A L

4-Phenethyfaminoquinoline

565


5. Substituting the bridge nitrogen with alkyl or acetyl groups reduced activity. 6. Substitution on the alkyl portion of the chain did not substantially improve activity. 7. Replacing the nitrogen in the bridge with carbon, sulfur, or oxygen reduced the level of downy mildew activity while broadening the fungicidal scope. This work confirmed the value of randomly screening heterocyclic compounds for their fungicidal activity. Although the initial lead, phenethylaminoquinoline, 1, did not have product potential, we were able, by a systematic study of the SAR to better understand the structural requirements for activity as well as to significantly improve the level of activity, both in the greenhouse and the field.

Acknowledgments The authors would like to thank Mr. George Babbitt for aiding in the interpretation of the physical chemical data covered in this paper and Mrs. Anita Alexander for carrying out the fungicidal evaluations in the greenhouse.

Literature cited 1. Froyd, J.D.; Paget, C.J.; Guse, L.R.; Dreikorn, B.A.; Pafford, J.L. Phytopathology, 1976, 66, 1135-1139, 2. Brown, I.F.; Taylor, H.M.; Hackler, R. E. Pesticide Synthesis Through Rational Approaches, 1984, Chapter 5, ACS Symposium Series 255 3. Boyce-Thompson Institute Report, 1985 4. Holmes, S. J. I.; Channon, A. G. Plant Pathology, 1984, 33, 347-354 5. Davidse, L. C. ; Looijen, D. ; Turkensteen, L. J. ; Van der Wal, D. ; Neth. J. Pl. Pathol,1986,87,65-68 6. Cohen, Y.; Samoucha, Y. Plant Disease, 1984, 68: 137-139 7. Johnson, W.S. U. S. Patent 2,653,940 (1951) 8. Hartshorn, M. J.; Baird, W. R. J. Am. Chem Soc., 1946, 68, 1562 9. Tripos Asscoiates, St. Louis. Mo. 10. Vinter, J. G.; Davis, Α.; Saunders, M. R. J. Comput.-Aided Mol. Des.; 1987, 1,31-51 11. For specific references see G. Jones, Quinolines, 1978, 32, The Chemistry of Heterocyclic Compound, John Wiley and Sons RECEIVED February 9, 1990


Synthesis and Fungicidal Activity of 4-Phenethylaminoquinoline and

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