Synthesis and Chemistry of Agrochemicals V - American Chemical

Chapter 16

Insecticidal 2-Aryl-5-haloalkylthio-, sulfinyland sulfonylpyrroles

Downloaded by CORNELL UNIV on June 18, 2012 | http://pubs.acs.org Publication Date: May 14, 1998 | doi: 10.1021/bk-1998-0686.ch016

K. D. Barnes, Y. Hu, R. E. Diehl, and V. M. Kamhi Cyanamid Agricultural Research Center, American Cyanamid Company, P.O. Box 400, Princeton, NJ 08543-0400

This report describes the synthesis and insecticidal activity of a series of 2-aryl-5-haloalkylthio-,sulfinyl-and sulfonylpyrroles containing a variety of substituents on the 3- and 4-positions of the pyrrole ring.

Insecticidal pyrroles have been under investigation at American Cyanamid for a number of years (1-4). This work which was based on the insecticidal activity associated with the natural product lead dioxapyrrolomycin provided the broad spectrum insecticide/miticide AC 303630.

Dioxapyrrolomycin

AC 303630

The structure activity relationships that developed during the course of this work suggested that lipophilic, strongly-electron withdrawing groups arrayed around the pyrrole nucleus are requiste for good insecticidal activity. Based on these structure activity relationships, studies were carried out in which the lipophilic strongly electron-withdrawing trifluoromethylsulfonyl functionality was introduced onto the pyrrole nucleus to afford a series of 2-aryl-3-trifluoromethylsulfonylpyrroles 1 (5). Many of the 2-aryl-3-trifluoromethylsulfonylpyrroles that were prepared demonstrated good insecticidal activity across several species of insects. As an extension of this work, the synthesis of a series of the isomeric 2-aryl-5-haloalkylthio-,sulfinyl and sulfonylpyrroles 2 was undertaken. ©1998 American Chemical Society

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

157

158

XCF O S 2

n

-rZ


Chemistry The synthetic approaches (Figure 1) toward the targeted molecules involved a variety of methodologies. These methodologies included the introduction of the haloalkythio functionality onto a preconstructed pyrrole nucleus as well as the construction of the pyrrole nucleus from acyclic precursors containing the trifluoromethylthio group. The majority of the 5-haloalkylthiopyrroles were prepared from preconstructed pyrroles. Starting with the appropriate 2-aryl-5-unsubstitued pyrroles 3 a number of targeted compounds were prepared utilizing trifluoromethylsulfenyl chloride or difluoromethylsulfenyl chloride. The use of haloalkylsulfenyl chlorides is a well documented method for the introduction of the haloalkylthio group onto the pyrrole nucleus. 2-Aryl pyrroles could be readily converted to their corresponding 5thiocyanate derivatives 4. The in situ generation of the 5-thiolate pyrrole via either hydrolysis or reduction followed by reaction with difluorochloromethane or a trifluorohaloethylene afforded the difluoromethylthio or l,l,2-trifluoro-2-haloethylthio pyrroles respectively. Oxidation of the 5-haloalkylthio pyrroles afforded the corresponding 5-haloalkylsulfmyl or 5-haloalkylsulfonyl pyrroles. ACYCLIC FRAGMENTS CONTAINING THE SCF FUNCTIONALITY

[O]

3

1. CF SC1 or HCF SC1 3

H

II 3

y Z

Kj>

2.[0]

H-z

XCF O S" 2

2

1. Hydrolysis or Reduction NCS

]T\

2

2 F

n

n

H

II

t Z

X = F,H,CF H,CFClH,CFBrH 2

n = 0,1,2

F

y—s F [F,Cl,Br] orCHF Cl 2

3. [O]

Figure 1. General synthetic approaches utilized. 2-Aryl-5-trifluoromethysulfenylpyrroles. The introduction of a trifluoromethylthio group onto a pyrrole nucleus via trifluoromethylsulfenylation with trifluoromethylsulfenyl chloride is a well known method for the preparation of trifluoromethylpyrroles. As shown in Figure 2 this methodology was applied to a


159 variety of 2-aryl-3-substituted pyrroles, 5-8. The syntheses of 5-8 have been reported previously (1-5).


CN

Figure 2. Trifluoromethylsulfenylation of 2-aryl pyrroles. The ease of the sulfenylation is dependent on the electron withdrawing nature of the 3-substituent. The 3-unsubstituted compound 5 is readily trifluoromethylsulfenylated in high yield at -30°C affording 9. The trifluoromethylsulfenylations of the 3-nitro 6, 3-cyano 7 and 3-trifluoromethylsulfonyl 8 pyrroles all require reaction with the trifluoromethylsulfenyl chloride at elevated temperatures in a pressure tube with a catalytic amount of triflic acid, to afford the desired 5trifluoromethylthiopyrroles. Without triflic acid the reactions proceeded sluggishly or failed. As expected, compound 8 being the most electron-deficient in this series because of the strong electron-withdrawing nature of the trifluoromethylsulfonyl group required the most forcing conditions to effect the trifluoromethylsulfenylation. Bromination of pyrroles 10-12 occurred readily to afford the 4-bromo derivatives 13-15 as illustrated in Figure 3. Bromination of the 2-aryl-5trifluoromethylthiopyrrole 9 could be controlled to afford either the 3-bromo or the 3,4-dibromo derivatives 16 and 17 respectively.

Y Y Y Y

= = = =

CN N0 S0 CF Br 2

2

3

10 11 12 9

X = Br Y = CN X = Br Y = N 0 X Y = S0 CF X=H Y = Br X=Br Y = Br 2

=

B

r

2

3

13 14 15 16 17

Figure 3. Bromination of 2-aryl-5-trifluoromethylsulfenylpyrroles.


160


As shown in Figure 4, compound 9 which was readily prepared by trifluoromethylsulfenylation of 5 in excellent yield could be converted to the 3,5-ditrifluoromethylthio derivative 18 by treatment with trifluoromethylsulfenyl chloride in the presence of triflic acid. Alternatively this material could be prepared in 94% yield in one-step from the 2-aryl pyrrole 5 by treatment with excess sulfenyl chloride in the presence of triflic acid. Conversion of 18 to the 4-chloro, bromo and nitro analogs was accomplished in moderate yields with sulfuryl chloride in acetic acid, bromine and nitric acid/acetic anhydride respectively. Whereas mono bromination and trifluoromethylsulfenylation of 9 afforded exclusively the 3-derivatives, nitration afforded the 3-nitro 11 and 4-nitro 22 analogs in 39% and 15% isolated yields respectively.

Figure 4. Derivatization of 2-(4-chlorophenyl)-5trifluoromethylsulfenylpyrrole. Figure 5 illustrates a novel method developed for the construction of the 2-aryl3-cyano-5-trifluoromethylthiopyrrole 10 using an acyclic precursor containing the trifluoromethylthio functionality for construction of the pyrrole ring. Conversion of 4chlorobenzyl amine 23 to the isonitrile 24 followed by reaction with trifluoromethylsulfenyl chloride gave the isothiocarbamoyl chloride 25. Treatment with triethylamine to generate the nitrile ylid and 1,3-dipolar cycloaddition with 2chloroacrylonitrile gave 10 in good yield. This material was identical to that obtained via trifluoromethylsulfenylation of 7 Reaction of the nitrile ylid generated from 25 with l-phenylsulfonyl-2trifluoromethyl ethene 26 (Figure 6) afforded 27 and 28 as a 70:30 mixture. The 1,3-


161


dipolar cycloaddition of the nitrile ylid with 1-bromo-trifluoromethyl ethene 30 which was generated in situfrom1,2-dibromo-l-trifluoromethyl ethane, was regioselective affording exclusively 28. As shown in Figure 7, 27 could also be prepared via trifluoromethylsulfenylation of 29. The synthesis of 29 has been described elewhere (6).

Figure 5. Preparation of 10 via 1,3-dipolar cycloaddition chemistry.

0

:

100

Figure 6. Preparations of 27 and 28 via 1,3-dipolar cycloaddition chemistry.

Figure 7. Preparation of 27 via trifluoromethylsulfenylation. 2-Aryl-5-trifluorohaloethysulfenylpyrroles. The trifluorohaloethylthio groups possess lipophilic and electronic properties similar to those of the trifluoromethylthio group. The rather straightforward introduction of the trifluorohaloethylthio functionalities onto the pyrrole nucleus via reaction of pyrrole thiocyanates with trifluorohaloethylenes as exemplified by examples in the literature prompted us to investigate the synthesis of potentially insecticidally active pyrroles containing these functionalities. As shown in Figure 8, treatment of 2-(p-chlorophenyl)-3-cyano pyrrole 7 with potassium thiocyanate/bromine in methanol at -60°C afforded the 5-thiocyanate 31 in excellent yield. Hydrolysis of the thiocyanate with potassium hydroxide in a wateralcohol mixture to generate the 5-thiolate, followed by reaction with tetrafluoroethylene afforded the desired 5-tetrafluoroethylthio pyrrole 32 in yields of only 30-45% along with significant amounts of the 5-alkylthio pyrroles 33-35


162 corresponding to the alkyl alcohol used as the co-solvent. A mechanism for the formation of alkylthiopyrroles via reaction of alcohols with thiocyanates under basic conditions has been proposed by Olsen and Snyder (7). We found that using the more hindered 2-propanol as a solvent did not significantly decrease this unwanted side reaction. XN H 0-ROH 2

MeOH, -60°C

N

C

S

CF =CF KOH


2

R = C H 33 R = Et 34 R = i-Pr 35 3

R = CH ,Et, i-Pr 3

2

HCF CF S 2

20-30%

2

32 30-45%

Figure 8. Introduction of the 5- tetrafluoroethylthio group via the 5-thiocyanate. Hydrolysis of the 5-thiocyanate and alkylation with tetrafluoroethylene. The 5-thiolate could also be generated in situ as illustrated in Figure 9 by reduction of the thiocyante with sodium borohydride. When the reduction was conducted in methanol followed by treatment with potassium hydroxide/tetrafluoroethylene, the 5-tetrafluoroethylthio pyrrole 32 was isolated in 30% yield along with 8% of the 5-methylthio pyrrole 33. However when the reduction was conducted in a mixture of tetrahydrofuran/2-propanol followed by reaction with the bromo and chloro trifluoroethylenes, the desired trifluorohaloethylthio pyrroles 36 and 37 were obtained in good yields. The addition of the thiolate occurs at the more highly fluorinated carbon of the trifluorohaloethylenes. Using this latter methodology no formation of the 5-isopropylthio pyrrole 35 was observed. LNaBH /MeOH 2. KOH CF =CFX 4

30% X = F 32

8% R = C H

67% X = Br 36

0% R = i-Pr 35

66% X=C1 37

0% R = /-Pr 35

3

33

2

NCS

LNaBR* i-PrOH/THF 2. KOH CF =CFX 2

Figure 9.Introduction of the 5-trifluorohaloethylthio group via the 5-thiocyanate. Sodium borohydride reduction of the 5-thiocyanate and alkylations with trifluorohaloethylenes.


163 A number of 5-trifluorohaloethylthio pyrroles were prepared and derivatized as shown in Figure 10. The ease of the thiocyanation is dependent on the electronwithdrawing nature of the 3-substituent. The 3-nitro pyrrole 6 afforded the 5thiocyanate in only 12% yield whereas the 3-unsubstituted compound 5 was thiocyanated under identical conditions in 99% yield. KSCN, Br

Y=H Y = N0 Y =CN

2


NCS

2

99% 12% 88%

HCXFC2FS

Y = CN,N0 ,Br Z = C1, Br

X = F,Cl,Br

2

Figure 10. Preparation and derivatization of 5trifluorohaloethylsulfenylpyrroles. 2-Aryl-5-difluoromethysulfenylpyrroles. The preparation of difluoromethylthio analogs were also investigated because of the similarities of the electronic and lipophilic properties of this functionality to those of the trifluoromethylthio group. As illustrated in Figure 11, generation of the 5-thiolate from the thiocyanate 31 as described in the preceding section followed by reaction with difluorochloromethane gave the 5-difluoromethylthio pyrrole 38 in 52% yield. CN ^

1. NaBH

4

i-PrQH/THF 2. KOH CHF C1 52%

NCS

Jl

\

HCF S 2

2

Figure 11. Introduction of the 5-difluoromethylthio group via the 5-thiocyanate. The difluoromethylthio group was also introduced via reaction of the 5unsubstituted pyrroles 5-7 with difluoromethanesulfenyl chloride (Figure 12). Difluoromethanesulfenyl chloride was generated in situ by treatment of difluoromethyl benzyl thioether with sulfuryl chloride. The addition of a catalytic amount of triflic acid was necessary for the sulfenylation of the 3-cyano and 3-nitro pyrroles. Bromination gave the 4-bromo analogs. CH C1 2

2

(CF SQ H) 3

3

HCF S 2

Y = N0 Y=CN

2

6

Y=H *Y = N 0 *Y=CN

2

60% 41% 30%

Figure 12. Difluoromethylsulfenylation of 2-aryl pyrroles.


164 Oxidation. Most of the haloalkylthio pyrroles prepared were converted to their corresponding sulfoxides and sulfones by oxidation with either MCPBA or hydrogen peroxide/acetic acid as illustrated in Figure 13. Treatment with one equivalent of oxidant at temperatures between 0°C and room temperature afforded the sulfoxides and treatment with two or more equivalents of oxidant at room temperature to 50°C gave the sulfones.


η = 1 1.0 eq of oxidant 0°C - RT η = 2 2.0 eq of oxidant RT - 50°C

Figure 13. Oxidation of haloalkylthiopyrroles. N-Derivatization. Earlier work on insecticidal pyrroles at Cyanamid has shown that N-derivatization, especially with N-ethoxymethyl, can result in an increase in the level and spectrum of insecticidal activity. A number of N-ethoxymethyl derivatives were prepared as illustrated in Figure 14.

\)Et

Figure 14. Synthesis of N-ethoxymethyl derivatives. Insecticidal Activity Approximately one hundred compounds were prepared by the synthetic procedures described in the preceding section. This section will focus on the insecticidal activity of representative examples in order to illustrate the structure activity relationships demonstrated by the compounds prepared. Insecticidal activity was determined using standard leaf dip assays. The compounds in this study were screened against third instar southern armyworms (SAW, Spodoptera eridania) and third instar tobacco budworm (TBW, Helicoverpa virescens). The activity is reported as percent mortality at 100 and 10 ppm. The insecticidal activity of AC 303630 and related pyrroles has been attributed to their ability to function as uncouplers of oxidative phosphorylation. This relationship between uncoupling and insecticidal activity has been described (8). It has been shown that within series of uncouplers there exists an optimum pKa range that is requisite for good activity. Similarly the NH pyrroles have been shown to have an optimum pKa range which falls between 7-8. The insecticidal activity of selected 2-aryl-5-trifluoromethylthio,-sulfinyl-and sulfonylpyrroles and the their calculated pKa values are shown in Table I. The pKa values were generated as described by Gange et. al. (9). This data suggests that the compounds at the lower oxidation states on sulfur are most likely oxidized in vivo. The 3,4-unsubstitued sulfone, having a pKa of 9.7 and with sulfur already at its'


165 highest oxidation state, was devoid of insecticidal activity. The 3,4-dibromo-5trifluoromethylthio and 3-trifiuoromethyl-5-trifluoromethylthio analogs with pKa's of 10.6 and 10.3 respectively however demonstrated activity similar to their higher oxidation state analogs. Similarly the 3,4-dibromo-5-difluoromethylthio compound with the highest pKa of 11.3 demonstrated the best tobacco budworm activity of the compounds shown in Table I. The 3-trifluoromethylsulfonyl-4-bromo-5trifluoromethylsulfinyl and sulfonyl compounds having pKa's of 4.0 and 2.4 respectively show that the low pKa compounds have poor insecticidal activity. Table I


The Effect of Pka on Insecticidal Activity.

% Mortality at 100 ppm(10 ppm)

R

SAW TBW Spodoptera Helicoverpa eridania virecscens Calcd. 3rd instar 3rd instar pKa

Υ

Ζ

H

H

0

0

9.7

SO2CF3

Br Br Br

Br Br Br

100(100) 100(100) 100(0)

100(60) 100(0) 100(0)

10.6 8.3 6.7

SCF S0 CF

CF CF

H H

100(100) 100(100)

100(90) 10(60)

10.3 6.4

100(100) 0 100(0)

100(0) 0 0

6.3 4.0 2.4

100(100) 100(0) 100(0)

100(100) 100(0) 100(0)

11.3 9.2 7.1

S0 CF 2

SCF SOCF

3

3

3

3

2

3

3 3

SOCF3

SO2CF3

SO2CF3

SO2CF3

Br Br Br

SCF H

Br Br Br

Br Br Br

SCF

SO2CF3

3

2

SOCF2H

S0 CF H 2

2

The majority of the compounds prepared were substituted on the aryl ring at the 4-position with chlorine. However a number of 3,4-dichloro, 3,5-dichloro and 4trifluoromethyl phenyl ring substituted compounds were also prepared. In the aryl ring


166 substitution series that were prepared no major changes in the level and spectrum of activities were observed. Similarly N-ethoxymethylation had little effect on southern armyworm and tobacco budworm activity. Table Π compares the activity of AC 303630, Cyanamid's broad spectrum insecticide to a number of the more active compounds prepared in this study. Also given in Table Π are the LC50 values for AC 303630. As shown these compounds showed good activités when tested at 100 and 10 ppm, however little activity was observed when these compounds were tested at lower rates. Table II


Activity Comparison of AC 303630 to Selected 2-Aryl-5-haloalkythio- and sulfonylpyrroles. % Mortality at 100 ppm(lOppm) SAW Spodoptera eridania 3rd instar Br,

CN

100(100) L C = 4.58 50

100(100)

Br,

TBW Helicoverpa virecscens 3rd instar

100(100) L C = 7.50 50

100(60)

100(100)

100(100)

100(100)

100(80)

CN

Conclusions Although none of the compounds described achieved the benchmark insecticidal activity of AC 303630, good insecticidal activity was observed for a number of the


167 pyrroles prepared, demonstrating the utility of the haloalkylthio-,sulfinyl,-and sulfonyl groups when a lipophilic electron-withdrawing functionality is essential for activity. The data presented also suggests that the lower oxidation state compounds are oxidized in vivo. Additionally, as part of this work a novel method for construction of 2-aryl-5-trifluoromethythio pyrroles was developed utilizing 1,3-dipolar cycloaddition chemistry.


Acknowledgments The authors wish to thank Drs David Gange and Stephen Donovan for their work in developing an understanding of the structure activity relationships in this area of chemistry and development of the Pka calculations. The authors would also like to thank Dr. Albert Lew, Mr. Barry Engroff and Mr. Mike Rivera for conducting the insecticidal evaluations. Literature Cited 1.

2.

3. 4.

5.

6. 7. 8. 9.

Addor, R. W.; Babcock, T.J. Black, B. C.; Brown, D. G.; Diehl, R.E.; Furch, J. Α.; Kameswaran, V.; Kamhi, V. M.; Kremer, Κ. Α.; Kuhn, D. G.; Lovell, J. B.; Lowen, G. T.; Miller, T. P.; Peevey, R. M.; Siddens, J. K.; Treacy, M. F.; Trotto, S. H.; Wright, D. P.; In Synthesis and Chemistry of Agrochemicals III; Edited by Baker, D. R.; Fenyes, J. G.; Steffens, J.; American Chemical Society: Washigton, D.C., 1992; pp 281-297. Kuhn, D. G.; Kamhi, V. M.; Furch, J. Α.; Diehl, R. E.; Trotto, S. H.; Lowen, G.T.; Babcock, T.J.; In Synthesis and Chemistry of Agrochemicals III; Edited by Baker, D. R.; Fenyes, J. G.; Steffens, J.; American Chemical Society: Washigton, D.C., 1992; pp 298-305. Kameswaran, V.; Addor, R. W.; Ward, R.K.; In Synthesis and Chemistry of Agrochemicals III; Edited by Baker, D. R.; Fenyes, J. G.; Steffens, J.; American Chemical Society: Washigton, D.C., 1992; pp 306-312. Kuhn, D. G.; Addor, R.W.;Diehl, R. E.; Furch,J.Α.;Kamhi,V.M.;Henegar, Κ. E.; Kremer, Κ. Α.; Lowen, G. T.; Black, B. C.; Miller, T.A.; Treacy. M. F. In Pest Control with Enhanced Environmental Safety; Edited by Duke, S. O.; Menn, J. J.; Plimmer, J. R.; American Chemical Society: Washington, D. C., 1993; pp 219-232. Barnes, K. D.; Furch, J. D.; Rivera, M.; Trotto, S.; Ward, R.; Wright, D.; In Synthesis and Chemistry of Agrochemicals IV; Edited by Baker, D. R.; Fenyes, J. G.; Basarab, G. S.; American Chemical Society: Washigton, D.C., 1995; pp 300-311. Kuhn, D. G.; Kamhi, V. M.; Furch, J. Α.; Diehl, R. E.; Lowen, G. T.; Kameswaran, K. Pestic. Sci. 1994, 41, 279. Olsen, R. S.; Synder,H.R.J.O.C.1965, 39, 3712. Black, B. C.; Hollingsworth, R. M.; Ahammadsahib, K. I.; Kukel, C. D.; Donovan, S. Pesticide Biochemistry and Physiology. 1994, 50, 115. Gange, D. M.; Donovan, S.; Lopata, R. J.; Henegar, K.; In Classical and ThreeDimensional QSAR in Agrochemistry; Edited by Hansch, C.; Fujita, T.; American Chemical Society: Washigton, D.C., 1995; pp 199-212.


Synthesis and Chemistry of Agrochemicals V - American Chemical

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