Synthesis and Chemistry of Agrochemicals III - American Chemical

Chapter 27

Insecticidal Pyrroles Synthesis of Bis-(trifluoromethyl)pyrroles via Rearrangement of O-Vinyloximes

Downloaded by UNIV OF GUELPH LIBRARY on June 22, 2012 | http://pubs.acs.org Publication Date: September 22, 1992 | doi: 10.1021/bk-1992-0504.ch027

V. Kameswaran, Roger W. Addor, and R. K. Ward Agricultural Research Division, American Cyanamid Company, P.O. Box 400, Princeton, NJ 08543-0400

Among several synthetic strategies considered for the preparation of insecticidal pyrroles with aryl and trifluoromethyl substituents, we examined novel applications of the reported reactions of oximes and acetylenic compounds and the thermal rearrangement of the resulting vinyloximes. Rearrangements of vinyloximes 13a-e were shown to give the targeted 4,5-bis-(trifluoromethyl)pyrroles 17a-e, respectively. In contrast to the proposed mechanism, these rearrangements were shown to proceed via the pyrrolin-4-ols. The 2-aryl-bi(trifluoromethyl)pyrroles were brominated and nitrated and also N-derivatized to give insecticidally active pyrroles. The isolation of dioxapyrrolomycin (LL-F42248oc; Figure 1) (7-3) from the fermentation of a culture of Streptomyces fumanus at the Lederle Laboratories of the American Cyanamid Company and its moderate activity against a variety of insects and mites led to the synthesis of a wide range of aryl-substituted nitro and cyano pyrroles having high broad-spectrum insecticidal and miticidal activity and is discussed in the companion chapters by Addor and coworkers and Kuhn and coworkers. Among several synthetic strategies considered for the preparation of pyrroles with substituted aryl and trifluoromethyl groups, we examined novel applications of the reported reactions of oximes and acetylenic compounds. CI

Dioxapyrrolomycin Figure 1

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In Synthesis and Chemistry of Agrochemicals III; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

27.

KAMESWARAN ET A L

Insecticidal Bis-(trifluoromethyl)pyrroles

307

Rearrangements of Vinyloximes


Thermal rearrangement of O-vinyloxime 1 derived from acetophenone oxime and dimethylacetylene dicarboxylate has been reported by Sheradsky (4) to give the pyrrole derivative 3 (Scheme 1). Sheradsky's proposed mechanism involves the enamine form of the O-vinyloxime 2 which generates the C-3 to C-4 bond of the new pyrrole through a [3,3]sigmatropic rearrangement (5-6). Subsequent work by Trofimov et al., has used acetylene or acetylenic equivalents under strongly basic conditions to generate pyrrole derivatives (7-10). An azirine intermediate (8-10) is proposed for the reactions involving strongly basic conditions (Scheme 2). More recently, Reese (11-12) and co-workers have generated the required O-vinyloximes from 0-(2-hydroxyethyl)ketoximes. Scheme 1

9

10

11


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SYNTHESIS AND CHEMISTRY O F A G R O C H E M I C A L S ΙΠ

Results and Discussion During our investigations on the synthesis of pyrroles containing trifluoromethyl group(s), we examined this vinyloxime approach using hexafluorobut-2-yne to prepare 2-aryl-4,5-&w(trifluoromethyl)pyrroles. Base-catalyzed reaction of acetophenone oximes 12 a-d with hexafluorobut-2-yne using potassium f-butoxide in methanol gave the required O-vinyloximes 13 a-d respectively (Scheme 3; all new compounds were analyzed by appropriate spectral data and elemental analysis). On refluxing in xylene for 4 hours, 13a gave instead of a pyrrole a product 15a in 43% yield which contained the elements of the expected pyrrole and a molecule of water and which on treatment with alcoholic HC1 gave the 4,5-fcw(trifluoromethyl)pyrrole 17a. The U NMR (CDC1 ) of 15a showed an AB pattern at δ 3.51 for the C-3 methylene protons (J =18.2 Hz) and a quartet at δ 4.88 for the C-5 methine proton (J =7.7 Hz), indicating that the hydroxyl group was on C-4 and not on C-5, which would be expected in a possible intermediate if the [3,3] sigmatropic rearrangement as proposed by Sheradsky is operative. This unexpected observation prompted us to examine this reaction more thoroughly. From the reaction mixture containing the O-vinyloxime 13b (65% yield), a minor product, 14b (7% yield) was also isolated by flash chromatography. The H NMR (DMSO-d ) of 14b showed a complex multiplet at δ 3.3-3.7 for the methylene and methine protons, and the C NMR (DMSO-d ) showed the methine carbon at the 4-position as a quartet at δ 43.3 ( J =27.2 Hz) in the proton decoupled spectrum, thereby fixing the hydroxyl group at C-5 (for the assignment of stereochemistry, see below). This product would be the expected intermediate resulting from a [3,3] sigmatropic rearrangement of the enamine form of 13b as proposed by Sheradsky and subsequent ring closure without the dehydration (Scheme 1). Refluxing the vinyloxime 13b in xylene gave 15b which crystallized out in 37% yield, and flash chromatography of the filtrate gave additional 15b, a second dihydropyrrole 16b (9.5% yield), and trace amounts of 14b (Scheme 3). The H NMR (DMSO-d ) of 15b and 16b once again showed the methylene protons as an AB pattern similar to those in 15a while the C NMR (DMSO-d ) showed that the methine carbon bearing the trifluoromethyl group was deshielded relative to that in 14b, appearing at δ 75.0 ( J =27.5 Hz) and δ 79.8 ( J =28.4 Hz) respectively, thus placing the hydroxyl group on both of these structures on C-4. Their spectral similarity also indicated that they were the two possible geometric isomers. The F - F coupling constants in their F NMR spectra provided the necessary information to assign the stereochemistry (75). Theris-stereochemistrywas assigned to 16b due to greater F - F coupling observed in 16b than in 15b. Similarly, the rra/w-stereochemistry was also assigned to the O-vinyloximes 13 a-e, as no F - F couplings were observable in the F NMR spectra. All the three pyrrolinols were then converted to the same 4,5-&/s(trifluoromethyl)pyrrole 17b in almost quantitative yields with alcoholic HC1 (Scheme 3). In the case of the 3,4-dichloro analog, 13c, the two pyrrolinols, 15c and 16c, obtained by thermolysis were not separated, but instead the mixture was converted to the pyrrole, 17c, with alcoholic HC1.


l

3

AB

HF

l

6

13

6

2

CF

l

6

1 3

6

2

CF

2

CF

19

19

19

19

19

19

19


19

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KAMESWARAN E T

309


Scheme 3

15 a-d Abs B O H HCI

16b-d Abs EtOH HCI

Finally, the monotrifluoromethyl vinyloxime, 13e, was prepared using 3,3,3-trifluoropropyne. On heating at 150-160°C, it gave directly only the 2aryl-5-trifluoromethylpyrrole, 17e, which was independently synthesized by another route ( Lowen, G. T., unpublished results), thereby indicating that the β-carbon of vinyloxime bearing the trifluoromethyl group ends up at C-5 and not the C-4 of the pyrrole during this rearrangement. Proposed Mechanism The formation of pyrroles in the reaction can be accounted for by the mechanism shown on Scheme 4. In contrast to the [3,3] sigmatropic rearrangement presumably operative in Scheme 1, we propose that in the case of vinyloxime 18 an alternate [1,3] shift would provide the iminoketone 19. A subsequent [1,3] proton shift initiates the formation of an intermediate enaminoketone 21 which readily undergoes ring closure to the pyrrolinols 22 (Scheme 4). Alternatively,


310

SYNTHESIS A N D CHEMISTRY O F A G R O C H E M I C A L S ΠΙ


Scheme 4

H

22 the iminoketone 19 can arise by a simple heterolysis of the N-0 bond in 18 to give the tight ion pair 20, followed by recombination (Scheme 4). The formation of an azirine intermediate was, however, ruled out since such a scheme would require highly basic conditions and the regiochemistry of the resulting pyrrole would be different. Also, Nickel(II)-catalyzed synthesis of pyrroles from azirines and activated ketones has been reported (14) and was shown to involve the opening of the three- membered ring only at the C=N double bond, and the regiochemistry at C-2 and C-3 should be different from the present case. Experimentally, it was shown that addition of catalytic amount of fcw(2,4-pentanedionato)nickel enabled the thermal reaction to be carried out in refluxing toluene instead of xylene, but the regiochemistry was unchanged. Conversions to Bromo- and Nitropyrroles Conversion of the above &/j(trifluoromethyI)pyrroles to the 3-cyano derivatives with the chlorosulfonyl isocyanate/dimethyl formamide procedure failed (75). However, they were nitrated with 90% HN0 in acetic anhydride to the 3-nitro derivatives and brominated with bromine and sodium acetate in acetic acid to the 3-bromo compounds (Scheme 5). A few N-derivatives were also prepared as shown in Scheme 5. These new pyrroles were found to be active in our insecticide screen. For example, compound 24c had an L C of 1.8 ppm on third-instar tobacco budworm ( Tracey, M., unpublished results). 3

5 0


27.


KAMESWARAN E T A L .

311

Scheme 5 CLN

-CF H

^

A

HN

°3, 23 a-d

17 a-d


Bromine

Br

CF.

25 b-d

R 26b-d:

R =CH OC H 2

2

1

a: H

2

5

b: 4-CI

27b-c: R =CN 2

c: 3,4-di-CI

28 c:

R =CH

29 c:

R =CH(CH )OCH(CH )

2

3

2

3

3

d: 4-CF

3

Acknowledgments The authors wish to acknowledge the APBR Section, Agricultural Research Division, American Cyanamid Company for obtaining the mass spectral data, and the Insecticide Discovery Section for the screening data. Literature Cited 1.

2.

3. 4. 5.

Dioxapyrrolomycin was originally designated LL-F42248α: Carter, G . T.; Nietsche, J. Α.; Goodman, J. J.; Torrey, M . J.; Dunne, T. S.; Borders, D . B.; Testa, R. T. J. Antibiotics 1987, 40, 233. Nakamura, H . ; Shiomi, K.; Iinuma, H . ; Naganawa, H . ; Obata, T.; Takeuchi, T.; Umezawa, H . ; Takeuchi, Y . ; Iitaka, Y . J. Antibiotics 1987, 40, 899. Yano, K.; Oono, J.; Mogi. K.; Asaoka, T.; Nakashima, T. J. Antibiotics 1987, 40, 961. Sheradsky, T. Tetrahedron Letters 1970, 25-26. A similar mechanism is proposed for the synthesis of pyrroles from arylhydrazones and acetylenic esters; Barluenga, J.; Palacios, V . ; Gotor, V . Synthesis 1975, 642-643.


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SYNTHESIS A N D CHEMISTRY O F A G R O C H E M I C A L S III

6. 7. 8.

9. 10.


11. 12. 13. 14. 15.

Baumes, R.; Jacquier, R.; Tarrago, G. Bull. Soc. Chim. France 1974, 1147. Trofimov, Β. Α.; Kovostova, S. E . ; Mikhaleva, A . I.; Sobenina, L . N.; Vasel'wv, A . N.; Nesterneko, R. N. Khim. Geterotsikl. Soedin. 1983, 273. For a review on azirines in reactions involving the formation of pyrroles, see Trofimov, Β. Α.; Mikhaleva, A . I. Chem. Hetero Compounds 1987, 23, 1037-1049 and references cited therein. For a review on reactions on ketoximes with acetylenes, see Trofimow, B. Α.; Mikhaleva, A . I. Chem. Hetero Compounds 1980, 979-991. Korsotova, S. E . ; Mikhaleva, A. I.;Sobenina, L . N . ; Shevchenko, S. G . ; Polovnikova, R. I. Org. Chem. (USSR), 1986, 436-438. Reese, C. B.; Dhanak, D.; Romana, S.; Zappia, G. J. Chem. Soc., Chem. Commun. 1986, 903-904. Ellames, G . J.; Hewkin, C. T.; Jackson, R. F. W.; Smith, D. I.; Standen, S. P. Tetrahedron Letters 1989, 30, 3471. Gunther, W. "NMR Spectroscopy", John Wiley and Sons, New York, 1980, 350-354. Faria dos Santos, F.P; Schuchardt, V. Angew. Chem. Int. Ed. 1977, 16, 647-648. Loader, C. E.; Anderson, H. J. Can. J. Chem., 1981, 59, 2673-2676.

RECEIVED March 19,

1992


Synthesis and Chemistry of Agrochemicals III - American Chemical

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