Download - SYNTHETIC APPLICATIONS OF KETENE CYCLOADDITIONS; …/67531/metadc331031/... · SYNTHETIC APPLICATIONS OF KETENE CYCLOADDITIONS; NATURAL AND NOVEL PYRETHROID INSECTICIDES DISSERTATION

311 AJ&ld

yV4 22>8 1

SYNTHETIC APPLICATIONS OF KETENE CYCLOADDITIONS;

NATURAL AND NOVEL PYRETHROID INSECTICIDES

DISSERTATION

Presented to the Graduate Council of the

North Texas State University of Partial

Fulfillment of the Requirements

For the Degree of

DOCTOR OF PHILOSOPHY

By

Jinren Ko, B.S., M.S.

Denton, Texas

August, 1985

Ko, Jinren, Synthetic Applications of Ketene Cyclop

additions, Natural and Novel Pyrethroid Insecticides.

Doctor of Philosophy (Chemistry), August, 1985, 74 pp

4 tables, bibliography, 97 titles.

A new synthetic route to natural and novel pyrethroid

acids was developed utilizing ketene cycloaddition which

is a significant improvement over existing syntheses. The

newly synthesized pyrethroid acids were converted to

pyrethroid esters and used to study structure-activity

relationships•

The cycloaddition of dichloroketene with 2,S-dimethyl-

2,4-hexadiene yields (2+2) cycloaddition products, 2,2-di-

chlorocyclobutanones. The reductive removal of one chlorine

atom from these cycloaddition products gave monochlorocyclo-

butanones which underwent a Favorskii-type ring contraction

to yield cis- and trans-chrysanthemic acids. 4-Methyl

1,3-pentadiene was also used as a precursor in this synthetic

scheme to yield an analogue of the chrysanthemic acid.

These results are consistent with a concerted cyclo-

addition process involving a dipolar transition state. The

zinc reduction is not a regiospecific reaction which accounts

for the two regioisomers of the monochlorocyclobutanones.

The Favorskii-type ring contraction is a regiospecific

reaction.

A variety of different bicyclol3.1.0)alkenecarboxylates

and bicyclot 4.1.0)heptenecarboxylates were synthesized from

alkylcyclopentadiene and fulvene derivatives. These new

bicyclc pyrethroid acids are structurally similar to the

natural chrysanthemic acid but are rigid and locked in a

Single conformation which is likely the least stable confor-

mer of the natural acid. The acids were converted to

pyrethroid esters and tested against the housefly and

cockroach. The test results indicate that the bicyclo

pyrethroids synthesized are. not as active as the natural

pyrethroid. Apparently, these bicyclo pyrethroids with

structures similiar to the less stable conformer of the

natural pyrethroids are of little consequence as it binds

to the target site in the insect.

in an effort to learn more about the conformational

requirements of the pyrethroid acid, a new bicyclo-spiro

pyrethroid system with a structure similar to the most

stable conformation of the natural pyrethroid was designed

and synthesized. These bicyclo-spiro pyrethroids were

derived from a new isopropylidenecyclobutane derivatives

as a starting compound instesd of a conjugated diene.

The test results of these bicyclo-spiro pyrethroid esters

revealed a much greater activity against the housefly

and cockroach. This study establishes that the more stable

conformer of the natural pyrethroid acid provides a much

higher toxicity against the insects tested.

TABLE OF CONTENTS

Page

iv LIST OF TABLES

Chapter

I. INTRODUCTION 1

14 II. EXPERIMENTAL

40 III. RESULTS AND DISCUSSION

67 BIBLIOGRAPHY

ill

LIST OF TABLES

Page Table

I. New Bicyclo( 3.1.0) alkenecarboxylic Aci.ds ^ Synthesized

II. Test Results of Bicyclo(3.1.0)alkene- ^ carboxylates

III. Test Results of Dimethylbicyclo(4.1.0)-heptenecarboxylates

IV. Tset Results of Bicyclo Spiro Pyrethroids.. 62

IV

CHAPTER I

INTRODUCTION

Ketenes are highly reactive organic compounds which

contain a cumulative linkage of an olefinic and carbonyl

group. Most of the halogenated ketenes and monosubstituted

ketenes a r e not stable at room temperature and are usually

trapped in situ *>y certain substrates. However, there

are some dialkylketenes that are relatively stable. The

two most common methods for ketene preparation are the

dehalogenation or dehydrohalogenation of the corresponding

acid halldes as illustrated ( 1, 2. 3, 4, 5, 6, 7, 8, 9 ).

8 Z"/Cu \ R R-CBr-C-Br • C-C=0 + ZnBr,, 1 2 ether Rj

R,

R,R,CH-C-C1 3 * /C=C=0 + EtjNH CI 1 2 D'

2

The most useful ketene reaction is the-(2+2) cycloaddition

w ith olefins to form cyclobutanones (10, 11, 12, 13, 14,

15, 16, 17). Theoretically, the major orbital interaction

in ketene cycloaddition reactions is the bond formation

between the HOMO of the ketenophile and the LUMO of the

ketene. The effect of electron withdrawing groups on the

ketene molecule is to lower the energy of the LUMO, and

increase the reactivity of the ketene. The reactivity of

substituted ketenes in cycloaddition reaction is exemplified

by the following order:

Cl2 c=c=0 > Ph 2C=C=0 > Me 2C=C=0 > H 2C=C=0

The (2+2) cycloaddition of halogenated ketenes and

olefins usually provides cycloaddition products that are

most useful for the synthesis of a variety of other impor-

tant compounds. Since the halogen atom provides a good

\

X

/

\

C 1 2 C = C = 0

C 1 2 C = C = 0

leaving group, the (X-halocyclobutanones may undergo a base

catalyzed ring contraction to cyclopropanecarboxylic acids

(18) or easily undergo reductive removal of halogen to give

the dehalogenated product (19).

Br

OH COOH

J-C1

t-BiigSnH

CI AIBN (K

Several examples have recently appeared in the liter-

ature utilizing the (2+2) cycloaddition reaction of halogen-

ated ketenes to olefinic compounds as a key step in the syn-

thesis of natural products and natural product precursors.

Tanaka (20) reported in 1971 a new synthesis of 0-Thujaplicin

by using the cycloadduct of isopropylcyclopentadiene and

dichloroketene as a precursor.

CI

NaOAc ~~7

\ / A 0 H

^3-Thujapl ic in

Fletcher and Hassner (21) reported in 1970 a synthesis

of several derivatives of the natural product, 2-cholestene.

The addition of dichloroketene to 2—cholestene proceeds

in a regioselective manner to give the cyclobutanone in

75% yield. This cycloaddition product was converted to other

derivatives of 2-cholestene by ring contraction and ring

opening reactions.

Cl3CC0Br

Zn

2-cholestene

0

< •

(I) H 3OH

(2) CH2N, CH 3O-C

Kato and Kido (22) reported in 1974 an efficient route

to an important intermediate in the synthesis of colchicine,

a natural product with anti-tumor activity. This synthesis

utilized the cycloaddition of dichloroketene to a cyclo-

pentadiene derivative as an important step.

NaOAc

OCH

Pschorr /Cycl ization

OCH

OCH

There has been much interest in recent years in the

synthesis of pyrethroid insecticides because these compounds

combine a high insect toxicity, low mammalian toxicity and

low environmental persistence (23, 24, 25, 26, 27, 28, 29,

30, 31, 32, 33, 34). The natural pyrethroid insecticide, an

ester, was first isolated from "Pyrethrum Flowers" by

Staudinger and Ruzicka (35) in 1924. The acid part of the

natural pyrethroid is called "Chrysanthemic Acid" and is a

cyclopropanecarboxylic acid with a disubstituted vinyl

substituent on carbon-3 and a geminal dimethyl substituent on

carbon-2. The active pyrethroid alcohol usually contains an

unsaturated ring with an unsaturated side chain.

R= CH3 C00CH3

Staudinger and Campbell (35, 36) were the first to

synthesize ethyl chrysanthemates by reacting 2,5-dimethyl-

2,4-hexadiene with diazoacetic ester with or without adding

the copper bronze or rhodium acetate as catalysts.

/

N2CHC00C2H5

Catalyst

R,

/ *~C00C2H5

R r R2 = CH3 CH3; CH3, C00C2H5; CI, CI; CI, CF3

In 1960 Julia et.al. (30, 37, 38, 39) prepared Pyro-

cines, starting with isobutyraldehyde and acetone and after

the ring opening reaction and cyclization obtained ethyl-

trans-chrysanthemate.

BrCH?C00C?Hs j

CI <i> S 0 C 12 \ *

(2) C2H50H

"OH

C00C2H5

00C2H5

CH-Mgl

Pyrocine

COOC 2H 5

Bellus (40) recently reported a newly developed

pathway to permethrinic acid. The addition product (I) of

carbon tetrachloride and acrylyl chloride was treated with

triethylamine to generate the chloro-(2,2,2-trichloro-

ethyl)ketene. Cycloaddition of this ketene with isobutylene,

followed by a cine rearrangement and Favorskii rearrange-

ment resulted in permethrinic acid.

Et,N CI3CCH2CHCI-COCI

3 \ ' — 0

CC1.

"OH

Cine

f Rearrangement

Et3N

WOCOOH

v

Based on structure-activity relationship studies,

Elliot (41) has proposed that the geminal dimethyl group

on the cyclopropanecarboxylic acid is the most important

functional group to insecticidal activity. Thus, after

1975, a series of dimethyl and tetramethyl substituted

cyclopropanecarboxylic acids (II) were synthesized by Greuter

and Holan (32, 42, 43) and proved to have similiar insecti-

cidal activity as the natural pyrethroids. In 1978, Serale

(44, 45) synthesized spirocyclopropanecarboxylic acids(III)

that revealed good activity. Addor et.al. (46, 47, 48)

synthesized the spiro(2,4)heptanecarboxylic acid system

(IV) with fairly good activity.

R R

COOH COOH

II R= Me, Et III R= alkyl, dichlorovinyl

n= 0, 1, 2, 3

^-COOH

IV X= halogen, alkyl

Recently, Fujimoto (34, 49) reported a new pyrethroid

system (V) without a cyclopropane ring that proved to have

a very high activity. Since this discovery, there has been

a renewed interest in conformational structure-activity

studies. The high activity of isopropylphenylacetic acid

esters may be due to a conformational mimic of the structure

of the natural pyrethroid (VI). More recently, Wheeler (50)

has synthesized some linear halo-4-alkenoic acids (VII) as

novel pyrethroids that showed good broad spectrum insecti-

cidal and some miticidal activity.

10

^ - 7 - ^ - C O O H / N ^ c O O H

V X= a l ky l , halogen V I

X v _ ^ z

CH-COOH

VII X, Y, Z= a lky l , halogen

The objective of this research is the development of

a new synthesis of pyrethroid acids by utilizing the (2+2)

ketene cycloaddition reaction as a key step in this syn-

thesis. It is anticipated that such a synthesis will offer

an attractive and alternative route to existing pyrethroid

acid syntheses and provide for the synthesis of new acids.

A further objective will be the conversion of the pyrethroid

acids to esters with insecticidal testing on the esters.

Hopefully, structure-activity relationships can be developed

which will result in potent new insecticides.

CHAPTER BIBLIOGRAPHY

1. Brady, W.T., Synthesis, 8, 415 (1971).

2. Brady, W.T., Tetrahedron, 37, 1939 (1981).

3. Ruden, R.A. , _J. Org. Chem. , 39, 2607 ( 1974).

4. Ward, R.S., The Chemistry of Ketenes, Allenes, and Related Compounds, part 1, edited by Patai, S., New York, Interscience Publications, Inc., 1980, p 223.

5. Hanford, W.E., Sauer, J.C., Organic Reactions, edited by Adams, R., Vol. 3, Wiley Interscience, Lodon, 1946, Chapter 3, p 108.

6. Pople, T.A., Gorden, M., J. Am. Chem. Soc., 89, 4253 (1967).

7. Weimann, L.J., Christoffersen, R.E., J. Am. Chem. Soc., 95, 2074 (1973).

8. Hopkinson, A.C., Csizmadia, I.G., Can. J. Chem., 52, 546 (1974).

9. Houk, K.N., Strozier, R.W., Hall, T.A., Tetrahedron Letters, 897 (1974).

10. Brady, W.T., Waters, O.H., J. Org. Chem., 32, 3703 ( 1967). ~~

11. Cragg, G.L.M.,_J. Chem. Soc., (C), 1829 (1970).

12. Montaigne, R., Ghosez, L., Angew. Chem. (Intern. Ed. Engl.),_L, 221 ( 1968).

13. Ghosez, L., Montaigne, R., Roussel, A., Vanlierde, H., Mollet, P., Tetrahedron, 27, 615 (1971).

14. Ghosez, L., Montaigne, R., Mollet, P., Tetrahedron Letters, 135 (1966). '

15. Asao, T., Machiguchi, T., Kitamura, T., Kitahara, Y. , _J_. Chem. Soc. , (D), 89 (1970).

16. Bartlett, P. D., Ando, T., J. Am. Chem. Soc., 92, 7518 (1970).

11

12

17. Fleming, I., Chem. Ind., (Lond.), 449 (1975).

18. Conia, J.M., Salaun, J.R., Acc. Chem. Res., 5, 33 (1772).

19. Bak, D.A., Brady, W.T., J. Org. Chem., 44, 107 (1979).

20. Tanaka, T., Yoshikoshi, A., Tetrahedron, 27, 4889 (1971).

21. Fletcher, V.R., Hassner, A., Tetrahedron Letters. 1071 (1970).

22. Kato, M., Kido, F. , Bull. Chem. Soc. Jpn, 47, 1516 (1974). '

23. Chapleo, C.B., Roberts, S.M., J_. Chem. Soc. , Chem. Comm., 680 (1979).

24. Arlt, D., Jautellat, M., Lantzsch, R., Angew. Chem. (Intern. Ed. Engl.), JO, 703 (1981).

25. Scharf, H.D., Mattay, J., Chem. Ber., 111, 2206 (1978).

26. Stetter, P.L., Roman, S.A., Edwards, C.L., Tetrahedron Letters, 4701 (1972).

27. Corey, E.J., Jautelat M., J. Am. Chem. Soc., 89, 3912 (1967).

28. Payne, G.B., _J. Org. Chem., 32, 3351 (1967).

29. Devos, M.J., Krief, A., Tetrahedron Letters, 1891 (1979).

30. Julia, M., Julia, S. , Jeanmart, C., C. R. Acad. Sci., 251, 149 (1960).

31. Conia, J.M., Salaun, J.R., Acc. Chem. Res., 5. 33 (1972).

32. Martin, P., Greuter, H., Bellus, D., J. Am. Chem. Soc., 101 , 5853 ( 1979). ~

33. Matsui, M., Kitahara, T., Agric. Biol. Chem., 31. 1143 (1967).

34. Ohno, N., Fujimoto, K., Agric. Biol. Chem., 38,

13

881 (1974).

35. Staudinger, H., Ruzicka, L. , Helv. Chim. Acta.. 7. 448 (1924).

36. Camphell, I.G.M., Harper, S.H., J. Chem. Soc., 283 (1945). ~

37. Julia, M., Julia, S., Jeanmart, C., langlois, M., Bull. Soc. Chem. Fr., 2243 (1962).

38. Matsui, M., Uchiyama, M., Aqric. Biol. Chem., 26. 532 ( 1962). —

39. Takeda, A., Sakai, T., Shinohara, S., Tsuboi, S., Bull. Chem. Soc. Jpn., 50, 1133 (1977).

40. Bellus, D., Greuter, H. , Martin, P., Pestic. Sci., 11, 141 (1980).

41. Elliott, M., Janes, N.F., Chem. Soc. Rev., 8. 473 (1979). —

42. Holan, G., Walser, R.A., US-Pat. 4226591 (1980). CSIRD.

43. Greuter, H., Bissig, P., Martin, P., Flucker, V., Gsell, L., Pestic. Sci., 11, 148 (1980).

44. Davis, R.H., Serale, R.J.G., DOS 2447735 (1975).

45. Davis, R.H., Serale, R.J.G., US-Pat. 4118510 (1978). Shell Oil Company.

46. Addor, R.W., Schrider, M.S., DOS 2605828 (1976). Am. Cyanamid Co.

47. Faroog, S., Drabek, J., Gsell, L., Karrer, F., Meyer, N., DOS 2642861 (1977). Ciba-Gegy

48. Brown, D.G., US-Pat. 4203918 (19801. Am. Cyanamid Co.

49. Fujimoto, K., Ohno, N., Mizutani, T., DOS 2365555 (1974). Sumitomo Chem. Co.

50. Wheeler, T.N., Ayad, H.M., J. Agric. Food Chem., 32, 85 (1984). ~ —

CHAPTER II

EXPERIMENTAL

Proton nuclear magnetic resonance (^H-NMR) spectra were

recorded on a 60 MHz Hitachi Perkin-Elmer R-24B spectrometer

employing deuteriochloroform as solvent, with tetramethyl-

silane as the internal standard. Carbon-13 NMR spectra were

recorded on a 90 MHz Jeol—FX—900 spectrometer. Deuterio-

chloroform was used as a lock solvent, and all chemical

shifts are reported in parts per million. The infrared (IR)

spectra were obtained on a Perkin-Elmer 1330 infrared

spectrophotometer. All melting points were determined on a

Thomas Hoover capillary melting point apparatus. Elemental

analyses were carried out by Midwest Microlab, Indiana.

The chromatographic separations were performed on Davisil

silica gel 62, Davision Chemical, using hexane/ethyl acetate

or ethyl acetate/petroleum ether as eluting solvents.

Hexanes, ether, triethylamine, and benzene were dried

by distilling from sodium-potassium alloy. All reagents

were distilled or recrystallized prior to use. Zinc was

activated by copper sulfate. The biological activity of all

the pyrethroid esters was evaluated on the female housefly

(Musca domestica) and the male German cockroach (Blattella

14

15

germanica) by Johnson Wax company. An topical application

of each candidate pyrethroid ester was made to determine

a value. Each ester was tested both unsynergized,

and synergized with piperonyl butoxide, an oxidative

inhibitor and with NIA-16388, an esterase inhibitor. Both

synergists were applied at the 1:4 toxicant/synergist ratio

to block the two major metabolic pathways known for pyre-

throid detoxifiction.

2 r2-Dichloro-4,4-dimethyl-3-(2-methylpropenyl)cyclo-

butanone, 2a, and 2,2-Dichloro-3,3-dimethyl-4-(2-methyl-

propenyl)cyclobutanone, 2a'. A solution of 25 mmol of

freshly distilled trichloroacetyl chloride and 25 mmol of

POCl^ in 250 ml of anhydrous ether was added over a 10 hr

period to a stirring mixture of 0.10 mol of 2,5-dimethyl-

2,4-hexadiene and 25 mmol of activated zinc (1.64 g) in

250 ml of ether at ambient temperature. After the addition

was complete, the reaction mixture was stirred for an

additional 12 hr. The excess zinc was removed by filtration

and the solution concentrated to about 50 ml and then

stirred with 100 ml of pentane. The solution was decanted

from the zinc chloride etherate and washed with water and

a saturated solution of NaHCO . The solvent was removed J

under reduced pressure and the residue vacuum distilled

at 55-58 C (0.2 mm) to yield 3.1 g (55%); the ratio of

2a/2a' = 3 as evidenced by the ^H-NMR. The IR and *H-NMR

data were identical with reported values (1). ^ C - N M R

16

(CDC1 ), R, 201.3 (s), 195.0 (s), 140.0 (s), 116.1 (d), 3 U

113.6 (d), 91.7 (s), 87.6 (s), 63.3 (d), 60.4 (s), 56.1 (d),

46.0 (s), 25.9 (q), 24.9 (q), 23.6 (q), 21.7 (q), 20.1 (q),

18.9 (q), and 18.6 (q).

2-Chloro-4,4-dimethyl-3-(2-methylpropenyl)cyclo-

butanone, 3a, and 2-Chloro-3,3-dimethyl-4-(2-methyl-

propenyl)cyclobutanone, 3a'. A 4.0 g (18 mmol) portion

of cycloadduct, 2a and 2a', in 50 ml of acetic acid and

5 ml of water was added in portions to 18 mmol of zinc

dust over a 1 hr period and then the mixture was stirred for

24 hr at ambient temperature. A 150 ml portion of ether

was added to the reaction mixture and the mixture washed

with water and a NaHCOg solution. The ether solution was

dried over anhydrous MgSO^, the solvent removed under reduced

pressure, and the residue vacuum distilled at 58-60°C

(0.1 mm) to yield 2.8 g (82%) of 3a and 3a'; IR (film),

1780 cm"1; 1 H-NMR (CDC13), £, 5.3 (d, 2 H, J = 8 Hz), 4.7 (m,

2 H), 3.8 (d, 1 H, J = 6 Hz), 3.0 (m, 1 H), 1.6-1.9 (m,6 H), 13

1.0-1.6 (m, 6 H); C-NMR (CDCI3 ), §, 210.7 (s), 205.5 (s),

138.2 (s), 136.6 (s), 119.5 (d), 117.9 (d), 114.8 (d), 114.1

(d), 69.6 (d), 68.7 (d), 64.7 (d), 63.1-18.3 (overlapped).

cis and trans-Chrysanthemic Acids, 4a. A 2.0 g mix-

ture of monochlorocycloadduct 3a and 3a' was treated with

2 eq of KOH in 50 ml of water at ambient temperature for

24 hrs. The reaction solution was then washed with CHCI3

to remove unreacted cyclobutanone and/or nonacidic products.

17

The aqueous reaction solution was then acidified with 2 N

HC1 and extracted with chloroform, dried over anhydrous

MgSO^ and evaporated under reduced pressure. The residue

was vacuum distilled at 95-96°C (0.25 mm) or 138-139°C (10mm)

to yield 1.3 g (73%) of cis - and trans -chrysanthemic

acids; (trans/cis = 3). The trans — acid was crystallized

from ethyl acetate at - 1 0 c (2 days), washed with petroleum

ether and recrystallized from ethyl acetate, m.p. 54°C.

The filtrate was cooled to —78 C to yield the cis —acid,

m.p. 115-116° C (the m.p. and 1 H - N M R data of cis - and

trans -chrysanthemic acids are identical with those in the

13

literature) (2). C-NMR ( C D C ^ ) , £, (cis-isomer), 177.8

(s), 134.9 (s), 117.9 (d), 33.2 (d), 31.2 (d), 28.8 (q),

27.2 (s), 25.6 (q), 18.2 (q), 14.7 (q); (trans-isomer),

178.9 (s), 135.7 (s), 120.7 (d), 34.6 (d), 33.4 (d), 29.5

(s), 25.6 (q), 22.1 (q), 20.3 (q), 18.3 (q).

2,2-Dichloro-3-(2-methylpropenyl)cyclobutanone, 2b.

From 50 mmol (5.6 ml) of trichloroacety1 chloride, 5 g (60

mmol) of 4-methyl-l,3-pentadiene, lb, 50 mmol (4.6 ml) of

5 g (78 mmol) of zinc in 500 ml of ether was

obtained 6.8 g (71%) of dichloroketene cycloadduct, 2b, at

65-67 C (0.2 mm); IR (film), 1800 cm ^ H-NMR (CDCI3),

5.2 (d, 1 H, J = 6 Hz), 2.9-3.9 (m, 3 H), 1.9 (m, 3 H), 1.8

(m, 3 H); 13C-NMR ( C D C ^ ) , £, 192.7 (s), 139.5 (s), 120.5

(d), 90.1 (s), 65.1 (q), 62.6 (d), 48.7 (q), 44.3 (q).

18

2-Chloro-3-(2-methylpropenyl)cyclobutanone, 3b.

From 5 g (26 mmol) of dichloroketene cycloadduct, 2b, and

1.7 g of zinc in 50 ml of acetic acid and 5 ml of water

after 20hr at ambient temperature there was obtained 3.2 g

(79%) of monochlorocycloadduct, 3b, at 52-54°C (0.1 mm);

IR (film), 1790 cm - 1; !H-NMR (CDCl^, £, 5.2 (m, 1 H), 4.6

(m, 1 H), 2.6-3.7 (m, 3 H, endo - and exo -), 1.85 (s, 3 H),

and 1.75 (s, 3 H); 13C-NMR (CDC^), g, (endo- and exo -)

199.7 (s), 198.1 (s), 136.5 (s), 136.4 (s), 124.1 (d),

121.0 (d), 67.1 (d), 65.2 (d), 50.0 (t), 48.9 (t), 35.5 (d),

29.5 (d), 25.3 (q), 25.2 (q), 18.1 (q).

3~(2-Methylpropenyl)cyclobutanone, 3c. From 2 g (10

mmol) of dichlorocyclobutanone, 2b, and 6 g (10 mmol) of

zinc in 30 ml of acetic acid and 2 ml of water at ambient

temperature after 80 hrs there was obtained 1.2 g (90%) of

nonchlorinated cyclobutanone, 3c, at 42° C (3.5 mm); IR

(film), 1775 cm - 1; 1 H-NMR (CDC13), §, 5.2 (d, 1 H, J = 6.3

Hz), 2.6-3.4 (m, 5 H), 1.7 (s, 3 H), 1.65 (s, 3 H); 1 3C-NMR

(CDC13), §, 205.6 (s), 132.4 (s), 128.0 (d), 53.7 (t), 24.8

(q), 21.9 (d), 17.5 (q).

2-(2-Methylpropenyl)cyclopropanecarboxylic Acid, 4b.

From 2 g (12 mmol) of monochlorocyclobutanone, 3b, and 1.6 g

(30 mmol) of KOH in 50 ml of water at ambient temperature

after 24 hrs there was obtained 1.2 g (75%) of acid, 4b, at

8 5-86°C (0.1 mm), trans/cis = 10; IR (film), 1680 cm"1;

*H-NMR (CDC13), g, 12.3 (bs, 1 H), 4.6 (dd, 1 H, J = 8.9 Hz,

19

J = 1.2 Hz), 2.06 (m, 1 H), 1.48 (m, 3 H), 1.4 (m, 3 H),

1.35 (m, 2 H), and 0.9 (m, 1 H); 1 3C-NMR (CDCI3 ), £, trans -

acid: 180.1 (s), 134.0 (s), 124.0 (d), 24.9 (q), 22.3 (d),

21.5 (d), 17.8 (q), 16.3 (q); cis-acid: 178.7 (s), 134.0

(s), 120.7 (d), 20.8 overlapped with 20.3 overlapped with

14.5 (the cis -and trans -acids were not separated).

Anal. Calcd. for C8H12 02: C, 68.54; H, 8.63. Found:

C, 68.23; H, 8.69.

1,4-Dimethyl-l, 3-cyclohexadiene :

(A) Dehydration of 1,4-Dimethyl-3-cyclohexenol.

1,4-Dimethyl-3-cyclohexenol (10 g, 8 mmol) was added to a

solution of 6 ml of concentrated hydrochloric acid in 60

ml of water and refluxed for 14 hrs. Upon cooling to room

temperature, this mixture was extracted with two 30 ml

portions of ether. The combined ether extracts were ex-

tracted with water until neutral and then the ether

solution was dried over anhydrous MgSO^. The ether was

evaporated to give a mixture of 1,4-dimethyl-l,3-cyclo-

hexadiene, 14b, and 1,4-dimethyl-l,4-cyclohexadiene, 14a:

7.7 g (89%); the ratio of 14b/14a = 70/30 as evidenced by

^H-NMR and ^C-NMR spectra.

A portion of this mixture, 3 g, was passed through a

20% impregnated silver nitrate silica gel column (3)

(height 40 cm, diameter 20mm) using petroleum ether to

elute 1,4-dimethyl-l,4-cyclohexadiene. The desired 1,4-di-

methyl-1,3-cyclohexadiene was eluted with petroleum

20

ether containing ether (20%) to give 2.1 g. The 1H-NMR

and 1 3C-NMR spectra were identical with those in the

literature (4).

(B) Isomerization of 1,4-Dimethyl-l,4-cyclohexa-

diene. 1,4-Dimethyl-l,4-cyclohexadiene (10 g) was

refluxed with 6 ml of concentrated hydrochloric acid in 60

ml of water for 14 hr. This mixture was worked up as

described above and passed through the silica gel column

impregnated with silver nitrate to give pure 1,4-dimethyl-

1t3-cyclohexadiene (6.3 g) as evidenced by the ^H-NMR and

C-NMR spectral data (4).

General Procedure for Cycloadditions of Haloqenated

Ketenes with Cycloalkadiene Derivatives. To a solution

of 0.25 mol of triethylamine and 0.25 mol of the cyclo-

alkadiene derivative in 300 ml of hexane was added 0.25 mol

of the appropriate acid chloride (dichloroacetyl chloride

for dichloroketene cycloadditions and ££—chloropropionyl

chloride for methylchloroketene cycloadditions) in 100 ml

of hexane. The addition was made dropwise over a period of

2 hr with stirring. After the addition was complete, the

stirring was continued for 1 h and then the amine salt was

filtered and the filtrate washed with two 150 ml portions

of water. The filtrate was dried over MgSO and the 4

solvent removed under reduced pressure and the residue

vacuum distilled to yield the cycloaddition product.

21

7 f7-Dichloro-4-isopropylidenebicyclo(3.2.0)hept-2-en-

6-one. A solution of 13.8 g (93 mmol) of dichloroacetyl

chloride in 10 ml of hexane was added dropwise to a warm

(40) solution of 10 g (94 mmol) of 6,6-dimethylfulvene

and 9.5 g (94 mmol) of triethylamine in 500 ml of hexane

during a 5 hr period. The amine salt was removed under

reduced pressure and the residue vacuum distilled at 9 ^ C

(0.25 mm) or 10CP C (0.7 mm) to yield 18.2 g (89%); (5)

IR (film), 1802 cm" 1; H-NMR (CDClg), £ , 6.5 (m, 1 H)f

5.9 (m, 1 H), 4.7 (m, 1 H), 4.1 (m, 1 H), 1.8 (s, 6 H);

1 3 C-NMR (CDC13), g, 193.9 (s), 136.2 (d), 133.4 (s), 129.7

(s), 129.4 (d), 87.7 (s), 62.3 (d), 58.1 (d), 21.9 (q),

20.8 (q).

7,7-Dichloro-4-diethylmethylenebicyclo(3.2.0)hept-

en-6-one. A 50 g (0.37 mol) portion of 6,6-diethyl-

fulvene, (6) 36 ml (0.37 mol) of dichloroacetyl chloride

and 51.ml (0.37 mol) of triethylamine gave 60 g (66%) of

the cycloadduct; bp 12CP C (0.2 mm), IR (film), 1800 cm" 1,

1 H-NMR (CDClg ) , 1.0 (m, 6 H), 2.2 (q, 4 H), 4.1 (m, 1 H),

4.8 (d, 1 H, J = 6 Hz), 5.9 (m, 1 H), 6.6 (d, 1 H, J = 6 Hz);

13

C-NMR (CDC 13 ), £, 193.7 (s), 141.3 (s), 136.1 (d), 132.9

(s), 129.7 (d), 87.4 (s), 62.1 (d), 58.0 (d), 26.4 (t),

24.8 (t), 13.3 (q), 12.3 (q).

7-Chloro-7-methyl-4-diethylmethylenebicyclo(3.2.0)-

hept-2-en-6-one. A solution of 28 g (0.2 mol) of 6,6-di-

ethyIfulvene, 20.2 g (0.2 mol) of triethylamine and 25.4 g

22

(0.2 mol) of 2-chloropropanoyl chloride in hexane was re-

fluxed for 24 hrs. The crude cycloadduct in hexane was

passed through a silica gel column to give 27 g (60%); IR

(film), 1800 cm"1; 1H-NMR (CDC1 3),£, 1.0 (m, 6 H), 1.5

(s, 3 H), 2.2 (q, 4 H), 3.7 (d, 1 H, J = 7 Hz), 4.7 (d, 1 H,

13

J = 7 Hz), 5.9 (s, 1 H), 6.6 (d, 1 H, J = 6 Hz); C-NMR

(CDCI3 ), £, 202 (s), 139.7 (s), 135.9 (d), 131.7 (s), 130.6

(d), 77.9 (s), 63.4 (d), 53.8 (d), 26.6 (t), 24.9 (t), 19.5

(q), 13.6 (q), 12.5 (q).

7,7-Dichloro-4-cyclopentylidenebicyclo(3.2.0)hept-2-en-

6-one. From 30 g (0.22mol) of 6,6-tetramethylenefulvene,

(6) 33.4 g (0.22 mol) Of dichloroacetyl chloride and 22.2 g

(0.22 mol) of triethylamine in refluxing hexane, there was

obtained 33 g (61%); b.p. 130°C (0.15 mm); IR (film), 1800

cm"1; 1 H-NMR (CDCI3), $, 2.0-3.0 (m, 8 H), 4.2-4.4 (m, 2 H),

5.8 (m, 2 H).

7-Chloro-7-methyl-4-isopropylidenebicyclo(3.2.0)hept-2-

en-6-one. From 15 g (0.14mol) of 6,6-dimethylfulvene, (7)

14.5 g (0.14 mol) of triethylamine and 18 g (0.14 mol) of 2-

chloropropanoy1 chloride, there was obtained 19.6 g (70%);

b.p. 92-4 °C (0.25 mm); IR (film), 1790 cm"1; 1 H-NMR (CDC1 3 ),

5, 1.5 (s, 3 H), 1.8 (s, 6 H), 3.7 (m, 1 H), 4.7 (m, 1H), 5,8 13

(m, 1 H), 6.5 (d, 1 H, J = 6 Hz); C-NMR (CDCI3 ), £ , 202,9

(s), 135.9 (d), 130.3 (d), 78.2 (s), 63.6 (d), 53.9 (d), 22.2

(q), 20.9 (q), 19.6 (q).

23

2,3-Benzo-7,7-dichloro-4-isopropylidenebicyclo(3.2.0)-

heptan-6-one. From 40 g (0.25 mol) of dimethylbenzofulvene,

37.7 g (0.25 mol) of dichloroacetyl chloride, and 25.2 g

(0.25 mol) of triethylamine, there was obtained 26.7 g (40%);

m.p. 105-7 'b after recryst. from hexane; IR (film), 1800

cm"1; 1 H-NMR (CDC1 ), §, 2.0 (s, 3 H), 2.1 (s, 3 H), 4.4 (d,

13

1 H, J = 9 Hz), 5.0 (d, 1 H, J = 9 Hz), 7.5 (m, 4 H); C-NMR

(CDC13), £, 194.1 (s), 142.1 (s), 132.7 (s), 129.4 (s),

128.9 (d), 128.5 (d), 126.9 (d), 124.7 (d), 88.3 (s), 64.4

(d), 55.5 (d), 25.2 (q), 21.5 (q).

7-Chloro-7-methyl-4-diphenylmethylenebicyclo(3.2.0)-

hept-2-en-6-one. From 14 g (0.06 mol) of 6,6-diphenyl-

fulvene (8), 6 g (0.06 mol) of triethylamine and 7.6 g

(0.06 mol) of 2-chloropropanoyl chloride, there was obtained

7.6 g (40%); m.p. 117-8°C, recryst. from acetone; IR (film),

1780 cm"1; !H-NMR (CDC1 ) , 1.55 (s, 3 H), 3.9 (m, 1 H),

4.8 (d, 1 H, J = 7 Hz), 6.0 (m, 1 H), 6.45 (d, 1 H, J = 13

6 Hz), 7.2 (m, 10 H); C-NMR (CDC1 ),£, 202.1 (s), 125-141 o

(m), 77.8 (s), 65.8 (d), 54.8 (d), 19.3 (q).

8,8-Dichloro-3,6-dimethylbicyclo(4.2.0)octa-2-en-7-

one. To a mixture of 5 g (0.046 mol) of 1,4-dimethyl-l,3-

cyclohexadiene (9) and 3.5 g of activated zinc in 250 ml of

ether was added over a 6 hr period a solution of freshly

distilled 5.2 ml (0.046 mol) of trichloroacetyl chloride and

4.3 ml (0.046 mol) of phosphoryl chloride in 250 ml of an-

hydrous ether at ambient temperature. After the addition was

24

complete, the mixture was stirred for an additional 2 hrs.

The excess zinc was removed by filtration and the solution

concentrated to about 50 ml and then mixed with 150 ml of

hexane. The solution was decanted from the zinc chloride

etherate and washed with a solution of sodium bicarbonate

and water until neutral. The solvent was removed under

reduced pressure and residue vacuum distilled, b.p. 69-72°C

(0.10 mm), to give 6 g (59%); 1 H-NMR (CDC13), § , 1.0-3.0 (m,

13

11 H), 5.25 (m, 1 H); C-NMR (CDCI3 ), £ , 193.0 (s), 139.4

(s), 124.4 (d), 84.2 (s), 65.1 (d), 20-40 (m).

General Procedure of the Reduction of the Dichloro-

ketene Cycloadducts. To a solution of 0.1 mol of the di-

chlorocyclobutanone derivatives in 300 ml of acetic acid is

added 0.1 mol of zinc dust in portions over a 1 hr period.

The mixture is then stirred at ambient temperature for 24

hr. A 200 ml portion of ether is added to the reaction

mixture and then it is washed with water until neutral.

The ether solution is then dried over anhydrous MgSO and 4

the solvent is removed under reduced pressure. The residue

was used without further purification in the next step

(ring contraction step).

7-Chloro-3-methylbicyclo(3.2.0)hept-2-en-6-one. From

6 g (0.031 mol) of 7,7-dichloro-3-methylbicyclo(3.2.0)hept-

2-en-6-one and 2.0 g of zinc in 30 ml of acetic acid was ob-0 -1

t a m e d 4.2 g (86.5%), bp 63 C (0.1 mm); IR (film), 1780 cm ; 1 H-NMR (CDC1 ), g, 1.7 (s, 3 H), 2.4 (m, 2 H), 3.6 (m, 2 H),

25

13 4.8 (dd, 1 H, J = 6 Hz, J = 6 Hz), 5.1 (m, 1 H); C-NMR

(CDC1 ) , § , 204.7 (s), 146.0 (s), 121.9 (d), 65.1 (d), 58.6

(d), 45.8 (d), 39.1 (t), 16.3 (q).

7-Chlorobicyclo(3.2.0)hept-2-en-6-one. From 10 g of

7,7-dichloro-bicyclo(3.2.0)hept-2-en-6-one and 3.7 g of zinc

in 50 ml of acetic acid there was obtained 7.2 g (90%); IR

(film), 1790 cm"1; 1H-NMR (CDC13) , £, 2.5 (m, 2 H), 3.7 (m,

13

2 H), 4.9 (m, 1 H), 5.6 (m, 2 H); C-NMR (CDC13), §, 204.3

(s), 135.3 (d), 128.0 (d), 65.2 (d), 58.0 (d), 45.7 (d), 35.3

(t).

7-Chloro-4-i sopropy1idenebicyclo(3.2.0)hept-2-en-6-one.

From 10 g (46 mmol) of 7,7-dichloro-4-isopropylidenebicyclo-

(3.2.0)hept-2-en-6-one and 3.0 g (46 mmol) of zinc in 100 ml

of acetic acid and 10 ml of water at ambient temperature, o

after 24 hrs there was obtained 6.8 g (82%), m.p. 63 C (from

petroleum ether); IR (film), 1780 cm 1 H - N M R (CDCl^), §, 6.1

(m, 1 H), 5.9 (m, 1 H), 5.0 (m, 1 H), 4.4 (m, 1 H), 3.95 (m, 13

1 H), 1.8 (s, 6 H); C-NMR (CDCI3), 201.9 (s), 135.7 (d),

135.1 (s), 129.9 (d), 127.4 (s), 64.4 (d), 63.1 (d), 44.3

(d), 21.7 (q), 20.6 (q).

7-Chloro-4-diethylmethylenebicyclo(3.2.0)hept-2-en-6-

one. From 50 g (0.20 mol) of 7,7-dichloro-4-diethyl-

methylenebicyclo(3.2.0)hept-2-en-6-one and 13.3 g of zinc

in 240 ml of acetic acid, there was obtained 38.7 g (92%), o - 1 1

b.p. 110 C (0.25mm); IR (film), 1790 cm ; H-NMR (CDClj),^,

1.05 (m, 6 H), 2.25 (q, 4 H), 4.0 (m, 1 H), 4.5 (m, 1 H), 5.0

26

(dd, 1 H, J = 9 Hz, J = 5 Hz), 5.95 (m, 1 H), 6.55 (m, 1 H);

13 C-NMR (CDC1 ), £, 201.4 (S), 141.4 (s), 138.8 (s), 135.4

(d), 130.2 (d), 64.0 (d), 62.6 (d), 44.1 (d), 26.0 (t), 24.6

(t), 13.1 (q), 12.3 (q).

7-Chloro-4-cyclopentylidenebicyclo(3.2.0)hept-2-en-6-

one. From 25 g (0.102 mol) of 7,7-Dichloro-4-cyclo-

pentylidenebicyclo(3.2.0)hept-2-en-6-one and 6.7 g of zinc

in 150 ml of acetic acid, there was obtained 15.9 g (75%),

O

m.p. 132 C (recryst. from hexane/benzene); IR (film), 1790

cm-1; 1 H-NMR (CDC1 ) , 1.8-3.1 (m, 8 H), 4.0 (m, 2 H), 5.1

(m, 1H), 5.7 (m, 2 H); 13C-NMR (CDC^ ), g, 204.5 (s), 144.8

(s), 139.2 (s), 130.4 (d), 122.3 (d), 65.2 (d), 58.3 (d),

46.0 (d), 35.6 (t), 33.1 (t), 32,7 (t), 23.1 (t).

2,3-Benzo-7-chlorobicyclo(3.2.0)heptan-6-one. From

21.6 g (0.095 mol) of 2,3-benzo-7,7-dichlorobicyclo(3.2.0)-

heptan-6—one and 6.2 g of zinc in 200 ml of acetic acid,

there was obtained 16.4 g (90%) of white solid, m.p. 112°C

after recryst. from hexane. The reaction solution was

treated with 200 ml of chloroform rather than ether as noted

above in general procedure; IR (film), 1790 cm ^ H-NMR

(CDClj ), §, 2.9-4.4 (m, 4 H), 5.2 (dd, J = 9 Hz, J = 3 Hz),

7.2 (m, 4 H); 13 C-NMR (CDC1 ), 203.7 (s), 143.5 (s), 137.6

(s), 128.1 (d), 127.9 (d), 126.5 (d), 125.1 (d), 65.3 (d),

58.6 (d), 44.7 (d), 34.5 (t).

2,3-Benzo-7-chloro-4-isopropylidenebicyclo(3.2.0)hept-

ane-one. From 1.24 g of zinc and 5 g (0.019 mol) of

27

2,3-benzo-7,7-dichloro-4-isopropylidenebicyclo(3.2.0)heptan-

e - o n e in 50 ml of acetic acid and using a chloroform extract

instead of ether, there was obtained 4.2 g (95%), m.p. 168-

170 C; IR (film), 1790 cm"1; 1H-NMR (CDC^ ), £, 2.0 (s, 2 H),

2.1 (s, 3 H), 4.3 (m, 1 H), 4.7 (m, 1 H), 5.2 (dd, 1 H, J =

9 Hz, J = 3 Hz), 7.4 (m, 4 H); 13C-NMR (CDC1 ), £, 203.0 (s),

142.1 (s), 140.1 (s), 130.7 (s), 127.8 (d), 126.5 (d), 124.7

(d), 64.4 (d), 38.5 (d), 25.2 (q), 21.5 (q).

8-Chloro-3,6-dimethylbicyclo(4.2.0)octa-2-en-7-one.

From 4 g (0.018 mol) of 8,8-dichloro-3,6-dimethylbicyclo-

(4.2.0)octa-2-en-7-one and 1.15 g of zinc in 100 ml of acetic

acid, there was obtained 3.1 g (93%); IR (film), 1785 cm"1 ;

!H-NMR (CDCI3), §, 1.0-2.5 (m, 10 H), 2.7 (m, 1 H), 4.5 (m,

1 H), 5.3 (m, 1 H); 13C-NMR (CDC13), g, 199.0 (s), 139.4 (s),

124.4 (d), 68.8 (d), 20-40 (m).

General Procedure for the Bicyclo(n.1.0)alkenecar-

boxylic Acid. A mixture of 0.05 mol of the corresponding

monochlorocyclobutanone and 0.10 mol of sodium hydroxide in 50

ml of water was refluxed for 6 hr. Upon cooling, the mix-

ture was washed with 100 ml of chloroform to remove any un-

reacted cyclobutanone and/or nonacidic products. The

aqueous solution was acidified with 2 N HC1 and extracted

with 200 ml of ether or chloroform. The extract was dried

over anhydrous MgSO^ and then the solvent was removed under

reduced pressure. The residue was vacuum distilled or

recrystallized. (The crude acids could be used for the

28

ester preparation without further purification). The

spectral data and the yield of a variety of different new

acids are described below.

4-Isopropylidenebicyclo(3.1.0)hex-2-en-6-carboxylic

Acid. A yield of 86% was obtained with m.p. 135-137°C

(recryst. from hexane/benzene); IR (film), 1680 cm" 1; ^H-NMR

(CDC13), £, 6.15 (dd, 1 H, J = 7.5 Hz, J = 1.2 Hz), 5.8 (m,

1 H), 2.65 (dd, 2 H, J = 9.6 Hz, J = 1.2 Hz), 2.0 (d, 1 H,

13

J = 3 Hz), 1.9 (s, 6 H); C-NMR (CDC13), £, 169.5 (s), 137.1

(s), 130.2 (d), 126.7 (s), 30.1 (d), 29.6 (d), 25.1 (d), 21.6

(q), 20.8 (q).

Anal. Calcd. for C j q H ^ O ^ : C, 73.17; H, 7.31. Found:

C, 73.09; H, 7.45.

3-Methylbicyclo(3.1.0)hex-2-en-6-carboxylic Acid. A

yield of 65% was obtained with b.p. 130°C (0.1 mm); cis/trans

= 1; H—NMR (CDC10), 1.1—2.7 (m, 16 H), 5.2 (m, 1 H), 5.5

13

(m, 1 H); C-NMR (CDC13), £, 179.8 (s), 177.0 (s), 144.6 (s),

141.4 (s), 125.3 (d), 119.3 (d), 40.1 (t), 35.5 (d), 32.9 (d),

31.0 (d), 27.4 (d), 23.3 (t), 22.9 (t), 15.8 (q), 15.6 (q).

Anal. Calcd. for CqHjqC^: C, 69.54; H, 7.29. Found: C,

69.28; H, 7.32.

The trans isomer crystallized from the cis/trans mixture

after 5 days under -10°C. After recrystallization from pe-

troleum ether a 25% yield was obtained (based on the mono-

chlorocyclobutanone) with a m.p. of 85-87°C; 1 H-NMR (CDC13), 5/ 1.65 (s, 3 H), 2.0-2.7 (m, 5 H), 5.2 (s, 1 H),; 13

C-NMR

29

(CDC^), g, 177.0 (s), 144.5 (s), 119.2 (d), 36.8 (t), 32.7

(d), 23.1 (d), 22.9 (d), 15.5 (q).

4-Diethylmethylenebicyclo(3.1.0)hex-2-en-6-carboxylic

O

Acid. A 51% yield was obtained at b.p. 120 C (0.1mm);

cis/trans = 1; 1H-NMR (CDC13), £, 1.0 (m, 12 H), 2.2-2.9 (m,

14 H), 6.2-6.4 (m, 4 H); 1 3 C-NMR (CDC13), g, 179.2 (s), 175.3

(s), 140.9 (s), 137.7 (s), 135.4 (s), 133.2 (d), 131.2 (d),

128.8 (s), 128.4 (d), 25-34 (m), 13.4 (q), 12.4 (q), 12.2 (q).

Anal. Calcd. for c1 2

Hi6 02 : C ' 7 5 , 0 ; H ' 8 * 3 3 * Found: C,

74.82; H, 8.50.

4-Diethylmethylene-6-methylbicyclo(3.1.0)hex-2-en-6-

carboxylic acid. A 56% yield was obtained with m.p. 132-

134°C after recrystallization from hexane/benzene; ^H-NMR

(CDC13), £, 1.2 (m, 9 H), 2.2 (q, 4 H), 2.8 (s, 2 H), 5.8

(d, 1 H, J = 6 Hz), 6.3 (d, 1 H, J = 6 Hz); 1 3C-NMR (CDC^ ),

5, 182.1 (s), 144.2 (s), 135.8 (s), 132.2 (d), 130.2 (d), 39.7

(d), 34.7 (d), 31.4 (s), 26.5 (t), 25.8 (t), 14.1 (q), 12.9

(q), 7.28 (q).

Anal. Calcd. for ci3 Hig°2 5 C ' 75.73; H, 8.37. Found: C,

75.53; H, 8.93.

4-Cyclopentylidenebicyclo(3.1.0)hex-2-en-6-carboxylic

Acid. A 55% yield was obtained with m.p. 116 °C after

recrystallization from petroleum ether; *H-NMR (CDCl^),

1.5-3.0 (m, 22 H), 5.5 (m, 4 H); 13C-NMR (CDC13), 179.3

(s), 176.5 (s), 143.8 (s), 140.9 (s), 139.5 (s), 139.3 (s),

127.5 (d), 127.2 (d), 126.2 (d), 120.7 (d), 23-36 (m).

30

Anal. Calcd. for ci2 H14°2 : C ' 7 5 ' 7 8 ' H ' 7» 3 7» Found:

C, 75.50; H, 7.34.

5-Isopropylidene-6-methylbicyclo(3.1.0)hex-2-en-6-

carboxylic Acid. A 65% yield was obtained with a m.p. of

107-108°C after recrystallization from petroleum ether;

1H-NMR (CDC^ ), £ , 0.9 (s, 3 H), 1.85 (s, 6 H), 2.85 (s,

2 H), 5.8 (d, 1 H, J = 6 Hz), 6.2 (d, 1 H, J = 6 Hz); 1 3C-

NMR (CDC1 3),§, 182.1 (s), 136.5 (s), 132.3 (d), 131.7 (s),

129.9 (d), 39.9 (d), 34.9 (d), 31.1 (s), 21.9 (q), 20.9 (q),

7.28 (q).

Anal. Calcd. for C1 1

H1 4 ° 2

: C ' 74.15; H, 7.86. Found:

C, 74.18; H, 8.02.

4-Diphenylmethylene-6-methylbicyclo(3.1.0)hex-2-en-6-

carboxylic Acid. A yield of 40% was obtained with a m.p.

230°C after recrystallization from hexane/benzene; *H-NMR

(CDClj), 5, 1.8 (s, 3 H) , 3.4 (s, 2 H ) r 6.8-7.6 (m, 12 H);

13 C-NMR (DMSO-c^), 168.4 (s), 154.0 (s), 141.5 (s), 140.4

(s), 137.0 (d) , 134.1 (s), 129.7 (d), 129.0 (d), 128.2 (d),

128.1 (d), 126.9 (d), 116.3 (s), 36-41 (m), 16.1 (s).

Anal. Calcd. for C2i t\8°2 : C ' 8 3 , 4 0 ? H ' 5» 9 6» Found:

C, 8 3.65; H, 6.08.

2,3-Benzobicyclo(3.1.0)hexan-6-carboxylic Acid. A

yield of 65% was obtained with a m.p. 134°C after recrystal-

lization from hexane/benzene; cis/trans = 1; 1H-NMR (CDCl^),

1.1-3.4 (m, 10 H), 7.2 (m, 8 H); 13C-NMR (CDC13), 179.1

(s), 176.0 (s), 145.0 (s), 143.1 (s), 141.5 (s), 126.5 (d),

31

126.4 (d), 125.9 (d), 125.2 (d), 124.5 (d), 123.9 (d), 123.8

(d), 35.2 (t), 35.1 (t), 32.9 (d), 32.1 (d), 30.5 (d), 27.1

(d), 24.6 (d), 24.0 (d).

Anal. Calcd. for C-qH^qC^: C, 75.80; H, 5.74. Found:

C, 75.70; H, 5.75.

2,3-Benzo-4-isopropylidenebicyclo(3.1.0)hexan-6-

O carboxylic Acid. A yield of 52% with m.p. 193-195 C was

obtained after recrystallization from hexane/benzene; ^H-NMR

(CDC1 ), 1.9 (s, 3 H), 2.0 (s, 3 H), 2.1-3.3 (m, 3 H),

^ 13

7.2 (m, 4 H); C-NMR (DMSO-dg), $ , 169.6 (s), 142.3 (s),

141.7 (s), 132.6 (s), 129.7 (s), 126.1 (d), 125.6 (d), 125.1

(d), 123.4 (d), 28.9 (d), 28.7 (d), 28.3 (d), 24.4 (q) , 21.3

(q).

Anal. Calcd. for C ^ H ^ 0 2 : C, 78.50; H, 6.54. Found:

C, 78.37; H, 6.39. 3,6-Dimethylbicyclo(4.1.0)hept-2-en-7-carboxy1ic Acid.

A yield, of 50% of an oil was obtained; ^H-NMR (CDCI3 ),

13

1.2-2.5 (m, 12 H), 5.3 (m, 1 H); C-NMR (CDCI3 ), £ , 178.1

(s), 132.2 (s), 119.8 (d), 23-33 (m), 22.9 (q), 18.3 (q).

This acid was used to prepare the pyrethroid ester without

further purification.

General Procedure for Pyrethroid Esters. The active

m-phenoxybenzy1 alcohol, 5-benzyl-3-furylmethyl alcohol and

3',4',5',6'-tetrahydrophthalimidomethyl alcohol were used

for the pyrethroid ester preparations. To a refluxing so-

lution of 50 ml of benzene containing 0.08 mol of freshly

32

distilled thionyl chloride was added 0.02 mol of the py-

rethroid acid in 50 ml of benzene over a 30 min. period.

The solution was refluxed for 3 hr and cooled to ambient

temperature. The excess thionyl chloride and benzene were

removed under reduced pressure to give the corresponding

acid chloride as evidenced by IR and ^ H-NMR spectrum.

To a 50 ml benzene solution containing 0.03 mol of the

appropriate alcohol and 0.02 mol of pyridine, was added the

above described acid chloride in 25 ml of benzene over a 15

min period at ambient temperature. The mixture was stirred

for 6 hr and the pyridine salt removed by filtration. The

solvent was removed under reduced pressure and the residue

passed through a silica gel column. The esters could be

eluted with hexane/ethyl acetate (10/1) solvent system.

The spectral data and yields of a variety of different

pyrethroid esters which were prepared from the above des-

cribed pyrethroid acids are described below.

m-Phenoxybenzyl Bicyclo(3.1.0)hex-2-en-6-carboxylate.

There was obtained a colorless oil in an 84% yield; cis/trans

-1 1

= 1; IR (film), 1700 cm ; H-NMR (CDC^ ), $, 0.9-2.5 (m,

10 H), 5.1 (d, 4 H, J = 6 Hz), 5.9 (m, 4 H), 7.2 (m, 18 H);

13C-NMR (CDC13),<5, 172.1 (s), 168.3 (s), 157.0 (s), 156.6

(s), 138.1 (s), 137.9 (s), 132-126 (m), 122.9 (d), 122.2 (d),

118.6 (d), 117.8 9d), 65.0 (t), 64.7 (t), 35.7 (d), 34.1 (d),

32.5 (d), 31.2 (d), 29.8 (d), 25.8 (d), 22.6 (t), 21.8 (t).

Anal. Calcd. for C H n : C, 78.43; H, 5.88. Found: 2u 18 3

33

C, 78.38; H, 5.60.

5-Benzyl-3-furylmethyl Bicyclo(3.1.0)hex-2-en-6-

carboxylate. An 87% yield of a colorless oil was obtained

(cis/trans = 1); IR (film), 1700 cm"*; 1 H-NMR (CDC1 ), £ ,

0.9-2.5 (m, 10 H), 4.8 (s, 4 H), 5.6 (d, 4 Hf J = 6 Hz),

5.9-6.0 (m, 6 H), 7.2 (m, 12 H); 13 C-NMR (CDC1 ), $, 172.7 3

(s), 168.8 (s), 155.2 (s), 140.0 (s), 137.5 (d), 132-121.2

(m), 121.0 (s), 107.0 (d), 57.6 (t), 57.1 (t), 35.8-31.3 (m),

30.0 (d), 25.9 (d), 22.8 (d), 21.9 (d).

Anal. Calcd. C, 77.50; H, 6.12. Found:

C, 77.20; H, 5.99.

m-Phenoxybenzyl 3-Methylbicyclo(3.1.0)hex-2-en-6-

carboxylates. A 79% yield of a colorless oil was obtained

(cis/trans = 1); IR (film), 1700 cm"*; * H-NMR (CDC1 ), j§, 3

1.0-2.3 (m, 16 H), 5.0 (s, 4 H), 5.4 (m, 2 H), 7.2 (m, 18 H);

1 3C-NMR (CDClg),^, 172.6 (s), 172.3 (s), 157.2 (s), 156.6

(s), 144.4 (s), 141.0 (s), 140.7 (s), 138.5 (s), 129-105 (m),

65.0 (t), 64.5 (t), 39-26 (m), 15.5 (q), 12.1 (q).

Anal. Calcd. for ^ : c, 78.75; H, 6.25. Found:

C, 78.45; H, 5.97.

5-Benzyl-3-furylmethyl 3-Methylbicyclo(3.1.0)hex-2-

en-6-carboxylate. An 87% yield of a colorless oil was

obtained (cis/trans = 1); IR (film), 1700 cm" 1; 1 H-NMR

(00013), 1 * 0 - 3 ' 0 ( m/ 16 H), 3.9 (m, 4 H), 4.8 (m, 4 H),

5.2-6.0 (m, 4 H), 7.2 (m, 12 H); 13C-NMR (CDClj), <5, 172.5

(s), 171.5 (s), 155.1 (s), 140-139 (m), 137.4 (d), 128-121

34

(m), 106.9 (s), 57.3 (t), 56.8 (t), 39-22 (m), 15.5 (q).

Anal. Calcd. for °3 : C ' 77.92; H, 6.49. Found:

C, 78.10; H, 6.60.

trans-3',4',5',6'-Tetrahydrophthalimidomethyl 3-

Methylbicyclo(3.1.0)hex-2-en-6-carboxylate. An 88% yield

of a colorless oil was obtained; IR (film), 1700 cm"*;

1H-NMR (CDC13), 5, 1.7-2.4 (m, 16 H), 5.4 (m, 3 H);

13

C-NMR (CDCI3), £, 168.7 (s), 168.1 (s), 143.5 (s), 142.0

(s), 119.4 (d), 59.5 (t), 36.4 (t), 31.7 (d), 22.7-19.6 (m) ,

15.1 (q).

Anal. Calcd. for C 1 7H 1 9NQj: C, 67.77; H, 6.31. Found:

C, 67.88; H, 6.48.

5-Benzyl-3-furylmethyl 4-Diethylmethylene-6-methyl-

bicyclo(3.1.0)hex-2-en-6-carboxylate. An 80% yield of a

colorless oil was obtained; IR (film), 1700 cm *; * H-NMR

(CDCI3 ), §, 0.9 (m, 9 H), 2.2 (m, 4 H), 2.8 (m, 2 H), 3.9

(s, 2 H), 4.9 (s, 2 H), 6.2 (m, 3 H), 7.2 (m, 6 H); ^C-NMR

(CDC1 ), £, 174.6 (s), 155.3 (s), 143.3 (s), 139.8 (s), o

137.6-126 (m), 121.4 (s), 106.9 (d), 58.1 (t), 38.8 (t),

34-25 (m), 14.0 (q), 12.7 (q), 7.51 (q).

Anal. Calcd. for C25 H28^3: c ' 79.78; H, 7.45. Found:

C, 79.92; H, 7.56.

m-Phenoxybenzyl 4-Diethylmethylene-6-methylbicyclo-

(3.1.0)hex-2-en-6-carboxylate. A yield of 84% of a color-

less oil was obtained; IR (film), 1700 cm S 1 H-NMR (CDCl^

8 , 1.0 (m, 9 H), 2.3 (m, 4 H), 2.8 (m, 2 H), 5.1 (s,2 H),

35

13

6.7 (m, 1 H), 7.1 (m, 9 H); C-NMR (CDC13 ) , §, 174.5 (s),

157.5 (s), 156.8 (s), 143.5 (s), 138.4 (s), 135.8 (s), 132.0

(d), 130-117 (m), 65.5 (t), 38.9 (d), 34.0 (d), 31.6 (s),

26.4 (t), 25.6 (t), 13.9 (q), 12.8 (q), 7.49 (q). Anal. Calcd. for C26H28°3: c» 80.40; H, 1.21. Found:

C, 80.23; H, 7.26.

m-Phenoxybenzyl 2,3-Benzobicyclo(3.1.0)hexan-6-carboxy-

late. A colorless oil in an 84% yield was obtained

(cis/trans = 1); IR (film), 1700 cm \ ^H-NMR (CDCI3), §,

1.0-3.2 (m, 10 H), 4.8 (s, 2 H), 5.1 (s, 2 H), 7.2 (m, 26 H);

13 C-NMR (CDC1 ),§, 171.8 (s), 168 7 (s), 157.2 (s), 157.0

(s) , 156.9 (s), 156.7 (s), 144.3 (s), 143.1 (s), 141.4 (s),

139.3 (s), 137-122 (m) , 118.6 (d), 118.0 (d), 65.5 (t), 64.9

(t), 35-30 (m), 26.3 (s), 24-23 (m).

Anal. Calcd. for C H 0 : C, 80.80; H, 5.61. Found: 24 20 3

C, 80.47; H, 5.71.

5-Benzyl-3-furylmethyl 2,3-Benzobicyclo(3.1.0)hexan-

6-carboxylate. An 85% yield of a colorless oil was -1 1

obtained (cis/trans =1); IR (film), 1700 cm ; H-NMR

(CDC1 ), 5, 1.2-3.5 (m, 10 H), 3.9 (s, 4 H), 4.6 (s, 2 H), 3

4.9 (s, 2 H), 5.7 (s, 1 H), 6.0 (s, 1 H), 7.2 (m, 20 H);

13 C-NMR (CDC1 3>,5, 172.0 «.), 168.8 (s), 155.3 <s>, 155.2

(s), 143.1 (s), 141.7 (s), 138.4 (s), 137.4 (s), 129-120 (m),

107.0 (d), 57.7 (t), 57.0 (t), 34-23 (m).

Anal. Calcd. for C H 0 : C, 80.20; H, 5.81. Found: 23 20 3

C, 80.04; H, 5.76.

3 6

5-Benzyl-3-furylmethyl 3,6-Dimethylbicyclo(4.1.0)-

hept-2-en-7-carboxylate. A yield of 82% of a colorless

-1 i oil was obtained; IR (film), 1700 cm ; 1 H-NMR (CDC1 ), ft,

3 u

1.2-2.3 (m, 12 H), 3.9 (s, 2 H), 4.8 (s, 2 H), 5.3-5.9

(m, 3 H), 7.2 (m, 6 H); 1 3C-NMR (CDC1 ), £ , 172.2 (s), 154.9

(s), 139.8 (d), 137.2 (s), 133-117 (m), 106.9 (d), 57.0 (t),

33.9 (t), 32-18 (m).

Anal. Calcd. for H24°3 ! H ' 7.14. Found:

C, 78.67; H, 7.29.

7-Isopropylidenebicyclo(4.2.0)octane. To a solution

of 4.7 g (37 mmol) of bicyclo(4.2.0)octan-7-one (1) and 60

ml of dimethyl sulfoxide was added 28 g (64 mmol) of (iso-

propyl)triphenylphosphonium iodide and 7.1 g (64 mmol) of

t-BuOK over 1 h period. The solution was stirred overnight

o

and then heated for 15 h at 90 C. The resultant solution

was extracted with petroleum ether, after removing the

solvent, the residue was passed through silica gel column

by using petroleum ether as eluting solvent to give 2.3 g -1 i

(40%) of pure olefin. IR (film), 1600 cm ; 1 H-NMR (CDCl^ ),

5, 1.1-2.9 (m, 18 H); 1 3C-NMR ( C D C ^ ) , ^ , 135.1 (s), 120.8

(s), 39.9 (d), 32.7 (t), 28-18 (m).

2,2-Dichloro-3,3-dimethy1-5,6-tetramethylenespiro-

(3,3)heptan-l-one. To a solution of 1.7 g (11.3 mmol) of

7-isopropylidenebicyclo(4.2.0)octane and 2 g of activated

zinc in 100 ml ether was added over a 6 h period a solution

of 1.7 ml (15 mmol) trichloroacety1 chloride, after work up,

37

there was obtained 2.4 g (81%); IR (film), 1800 cm"1; 1H-NMR

(CDCI3 ), £, 1.3-2.8 (m, 18 H); 13C_NMR ( C D Ci )f e 201.6 3 u

(s), 91.5 (s), 68.9 (s), 47.4 (s), 39.4 (d), 20-30 (m).

2-Chloro-3,3-dimethyl-5,6-tetramethylenespiro(3,3)-

heptan-l-one. To a solution of 2.0 g of 2,2-dichloro-

3,3-dimethyl-5,6-tetramethylenespiro(3,3)heptan-l-one and

50 ml of acetic acid was added 0.5 g of zinc. After

stirring overnight and work up, there was obtained 1.5 g

(90%); IR (film), 1780 cm"l; 1 H-NMR (CDCI3), £, 1.0-2.8 13

(m, 18 H), 4.4 (s, 1 H); C-NMR (CDCI3 ), £, 205.2 (s), 69.7

(d), 47.2 (s), 20-30 (m).

2,2-Dimethyl-4,5-tetramethylenespiro(2,3)hexan-l-

carboxylic acid. A solution of 1.2 g of 2-chloro-3,3-

dimethyl-5,6-tetramethylenespiro(3,3)heptan-l-one in

15 ml of water containing 1 g of NaOH was stirred for

6 h. After work up there was obtained 0.8 g (80%); IR

(film), 1680 cm'1; !H-NMR (CDCI3), £, 1.1-2.9 (m, 19 H), 13

9.9 (s, 1 H); C-NMR (CDCI3 ), 178.9 (s), 44.4 (s),

44.2 (s), 14.9-36 (m).

5-Benzyl-3-furylmethyl 2,2-Dimethyl-4,5-tetra-

methylenespiro(2,3)hexan-l-carboxylate. The 2,2-di-

methyl-4,5-tetramethylenespiro(2,3)hexan-l-carboxy1ic

acid was converted to the acid chloride and then reacted

with 5-benzyl-3-furylmethyl alcohol by following the

described general procedure. Thus, a 70% of a colorless

ester was obtained; IR (film), 1700 cm *; 1 H-NMR (CDClg ),

38

£, 1.0-2.4 (m, 19 H), 3.7 (s, 2 H), 4.7 (s, 2 H), 7.0

(m, 6 H); 13C-NMR (CDCI3), £, 171.5 (s), 155.2 (s), 139.8

(s), 137.5 (d), 128.4 (d), 128.2 (d), 126.2 (d), 121.4 (s),

107.0 (d), 56.9 (t), 42.8 (s), 15-36 (m).

Anal. Calcd. for C, 79.36; H, 7.93. Found:

C, 79.29; H, 7.74.


1. Brady, W.T., Bak, D.A., J_. Org. Chem. , 4£, 107 (1979).

2. Bramwell, A.F., Crombie, L. , Hemesley, R., Pattenden, G., Elliott, M., Jones, N.F., Tetrahedron, 25, 1727 (1969).

3. DeVries, B., Chem. and Ind., 1049 (1962).

4. Ruttimann, A., Wick, A., Eschenomosh, A., Helv. Chim. Acta., 58, 1450 (1975). "

5. Asao, T., Machiguchi, T., Kitamura, T., Kitahara, Y., Chem. Comm., 89 (1970).

6. Meuche, A., Helv. Chim. Acta., 49, 1278 (1966).

7. Crane, A., Boord, C.E., Henne, A.L., J. Am. Chem. Soc., 67, 1237 (1945). — '

8. Harmony, R.E., Barta, W.D., Gupta, S.K., J. Chem. Soc.. (C), 3645 (1971). ~

9. Brady, W.T., Norton, S.J., Ko, J., Synthesis, 1985 (in press).

39

CHAPTER III

RESULTS AND DISCUSSION

Chrysanthemic acid and certain analogues have been

known for many years to be effective components of

pyrethroid esters which are potent insecticides (1). In

this dissertation we describe a simple yet versatile

synthesis of pyrethroid acids from conjugated dienes which

we believe will offer an attractive alternative to existing

pyrethroid acid syntheses. The procedure is based on the

finding that 2,2-dichloro-3-vinylcyclobutanones, readily

available cycloaddition products from dichloroketene and

conjugated dienes, will undergo a selective reductive

removal of one chlorine atom. The resultant monochloro-

cyclobutanones undergo a facile Favorskii-type ring con-

traction to the pyrethroid acids.

In previous studies in this laboratory on dichloro-

ketene-hindered olefin cycloadditions, the dichloroketene

cycloadducts of 2,5-dimethyl-2,4-hexadiene, 2a and 2a' were

prepared (2). These cycloaddition products are now an

important precursor to chrysanthemic acid, 4a. Dichloro-

ketene is generated _in situ from trichloroacetyl chloride

with zinc in ether containing phosphorous oxychloride (a

40

41

s l i g h t m o d i f i c a t i o n of e x i s t i n g l i t e r a t u r e p r o c e d u r e ) ( 2 , 3)

in t h e p r e s e n c e of t h e d i e n e . Both r e g i o i s o m e r s a r e o p i n e d ;

la , R

2a, R = CH b, R = H

3a, R = CH. b, R = H "

+ ci3ccoci

Zn/POCl.

2a ' , R = CH,

Zn/HOAc

V

3a ' , R = CH.

'OH

4a, R

.COOH

42

2,2-dichloro-4,4-dimethyl-3-(2-methylpropenyl)cyclobutanone,

2a, in 40% yield and 2,2-dichloro-3,3-dimethyl-4-(2-methyl-

propenyl)cyclobutanone, 2a', in 15% yield. Theoretically,

orbital interaction of the LUMO of the ketene and the HOMO

of the olefin allows two dipolar transition states in which

2a forms from an allylic cation-type transition state, 2e,

and 2a' forms from a tertiary carbon cation-type transition

state, 2f, as illustrated. Since the allylic cation-type

transition state is more stable than the tertiary carbon-

cation-type transition state, the yield of the regioisomer,

2a, is higher. Apparently the energy difference between

these two transition states is not sufficient to eliminate

the pathway leading to 2a'.

.S +

CI

CI

2e 2f

A key step in the synthesis of chrysanthemic acid is

the reductive removal of only one chlorine atom (3-15) in 2a

and 2a' by treating the dichloroketene cycloaddition product

with one equivalent of zinc dust in acetic acid. After 24

43

h at ambient temperature, a mixture of monochlorocyclobutan-

ones, 3a and 3a', is obtained in 82% yield. The structures

of 3a and 3a' were determined by ^H-NMR and 13 C-NMR spectro-

metry. The reduction step is not regiospecific and yields

two stereomers for each regioisomer of the cycloadduct thus

accounting for the four signals for the carbon bearing the

chlorine atom in the 13C-NMR spectrum. The mechanism of the

zinc reduction is shown below (8, 16):

.0*.

'CI

HOAc

^C1

44

The Favorskii-type ring contraction reaction is a regio-

specific reaction (17-27) and the four monochlorocyclo-

butanones yield cis - and trans -chrysanthemic acid, 4a, in

73% yield. The cis -acid was obtained from cis -chloro-

cyclobutanone and the trans, -acid was obtained from trans -

chlorocyclobutanone. The isomeric chrysanthemic acids may

be separated by crystallization from ethyl acetate (28).

'OH

trans

COOH

trans

'OH

CIS

In order to verify the versatility of this synthetic

sequence, 4-methyl-l,3-pentadiene, lb, was also used to

prepare the pyrethroid acid analogue, 4b. Obviously the

allylic cation-type dipolar transition state would be much

45

more stable than the primary carbon cation-type dipolar

transition state; thus, only one regioisomer of dichloro-

ketene cycloadduct, 2b, is observed. To prove that 2b is

in fact the regioisomer obtained, the cycloaddition product

was reduced with an excess of zinc/acetic acid to remove

both chlorine atoms to yield 3c. The symmetric structure

of 3c was mainly characterized by the appearance of only 7

carbon peaks in the completely decoupled 1 3 C-NMR spectrum

as illustrated.

excess Zri >

HOAc 21 .9

128.0

205.6

2b 3c

The advantages of this three-step reaction sequence

are that the reagents are readily available, the procedure

is simple and requires only mild conditions, and the reaction

can be performed with a wide variety of conjugated dienes.

This method should compete quite favorably with existing pro-

cedures in the literature in terms of simplicity and availa-

bility of starting compounds for a broad range of pyrethroid

46

acids (29-32).

Although the natural pyrethrins have been widely used

as effective insecticides, a major disadvantage of the

natural pyrethrins, especially for the use against agri-

cultural pests, lies in the lack of stability in the

presence of air and sunlight. In order to overcome this

drawback, the synthesis of new systems of pyrethroid acids

and the structure-activity studies have received much more

attention in the literature in recent years (33, 34). A

variety of new synthetic pyrethroid esters have been syn-

thesized and reported as effective insecticides with a

higher activity and stability compared to the natural

pyrethrins.

in our efforts to develop a new system of pyrethroid

insecticides, we found that the bicyclo(n.1.0)alkenecar-

boxylates are quite similar to the natural pyrethroids and

also can be synthesized by utilizing our recently developed

synthetic method described above (35). Thus, alkylcyclo-

pentadienes were used as starting materials for the dichloro-

ketene cycloadditions. The alternate method of generating

dichloroketene from dichloroacetyl chloride with triethyl-

amine was used in this in a i m cycloaddition to provide the

cycloaddition products, 3-alkyl-7,7-dichlorobicyclo(3.2.0)-

hept-2-en-6-ones, in 70-75% yield. Monodechlorination and

the Favorskii-type ring contraction resulted in the formation

of 3-alkylbicyclo(3.1.0)hex-2-en-6-carboxylic acids, 6a-6c.

R = H, CH 3

C I 2 C = C = O

Zn HOAc

6a, R 6b, R 6c, R

= H CH- (trans) CH3 (cis)

While the zinc reduction step is generally not regio-

specific, the reduction of 3-alkyl-7,7-dichlorobicyclo-

(3.2.0)hept-2-en-6-one results in only one regioisomer, the

endo -chlorocyclobutanone, 5, which is also the same

regioisomer as obtained from the reduction when tri-n-butyl-

tin hydride is employed (36, 37). Apparently in this bi-

cyclic system the exo -chloro substituent is much more

susceptible to reductive removal. The subseguent Favorskii-

type ring contraction of the end° -chlorocyclobutanone

affords both cis- and trans- substituted bicyclof3.1.0)-

alkenecarboxylic acids <ci_s/trans = 1). The Favorskii ring

48

contraction is a regiospecific reaction (38, 39). Hence,

the formation of approximately equal amounts of the cis -

and trans -isomers of the c y c l o p r o p a n e c a r b o x y l t c acids is due

to the epimerization of monochlorocyclobutanone under the

basic reaction conditions (40) prior to the ring contraction

reaction as illustrated.

'OH

CI

trans

C00H

CIS

A variety of dialkylfulvenes derived from cyclopenta-

diene were also used as precursors in this synthetic sequence

49

to prepare the new

8d, 8e.

pyrethroid-1ike acids as illustrated, 8a,

C12C=C=0

R = CHg, CgHgs Zn HOAc

COOH - Q H

8a, R = CH-j

8d, R = C2H5

86, R =

In addition to dichloroketene, methylchloroketene was

used in the cycloaddition step with several disubstituted

fulvenes as illustrated, 8b,8c,8f. In the methylchloroketene

cycloadditions, only the endo -methyl- exo -chloro-cyclo-

butanones, 7, were obtained which underwent a regiospecific

50

C=C=0

8b, R = C H 3 8f, R = Ph

8c, R = C2Hg

ring contraction to yield only one regioisomer of the pyre-

throid acid, the endo -methyl isomer (41). Since the endo -

methyl- exo -chlorocyclobutanones cannot undergo the endo -

and exo -chloroepimerization as noted above for the mono-

chlorocyclobutanones, these regioisomers gave only the

trans -cyclopropanecarboxylic acids after ring contraction

(Only one regioisomer was found as evidenced by the C-NMR

spectrum). In an extension of this study, the cyclopenta-

diene derivatives, indene and dimethylbenzofulvene, were also

used to prepare the corresponding analogues of bicyclo(3.1.0)-

alkenecarboxylic acids, 9 and 10, by following the same

scheme. Thus, eleven new bicyclo(3.1.0)alkenecarboxylic acids

were prepared sucessfully as listed in Table I.

51

TABLE I

NEW BICYCLO(3.1.0)ALKENECARBOXYLIC ACIDS SYNTHESIZED

0 ^ m [ Q

6 8

Compound R Ri Physical State

6a H H mp 112

6b Me H mp 85-7 (trans)

6c Me H oil (cis)

8a Me H mp 135-7

8b Me Me mp 107-8

8c Et Me mp 132-4

8d Et H bp 120/0.1 mm

8e 0 = H mp 116

8f . Ph Me mp 230

9 - H mp 134

10 — H mp 193-5

In the synthesis of the pyrethroid esters of the above

described acids^ the acids were converted to pyrethroid

esters by conversion to the corresponding acid chlorides by

treatment with thionyl chloride or oxalyl chloride. The

52

acid chlorides were then allowed to react with active pyre-

throid alcohols in benzene solution containing pyridine to

give the pyrethroid esters. The three active pyrethroid

alcohols used were m-phenoxybenzyl alcohol, 5-benzyl-3-furyl-

methyl alcohol and 3•,4',5•,6•-tetrahydrophthalimidomethyl

alcohol. The insecticidal activity test results of six

representative esters against the housefly (Musca domestica)

and German cockroach (Blattell germanica) are listed in

Table II. All of the candidate pyrethroids synthesized are

non-toxic to the housefly when applied either unsynergized or

synergized with piperonyl butoxide. Housefly toxicity is

demonstrated at the 5 Aig/insect level by several of the

pyrethroids only when synergized with the esterase inhibitor

NIA 16388. These results indicate that metabolic hydrolysis

is the major detoxification route for these pyrethroids.

However, for the application of 0.5 Ail/insect this level of

housefly toxicity results in less than 1% the activity of the

permethrin standard. Neither the unsynergized nor syner-

gized formulations of the new pyrethroids demonstrate any

activity when applied on German cockroach.

Since the bicyclo(3.1.0)alkenecarboxylates had shown

little insecticidal activity, we continued our efforts to

find a new system with a specific configuration which is

more similar to the naturally occurring pyrethroid. After

a careful consideration, we found that the 3,6-dimethyl-

bicyclo(4.1.0)hept-2-en-7-carboxylic acid, 11, is worthy

5 3

TABLE II

TEST RESULTS OF NEW BICYCLO(3.1.0)ALKENECARBOXYLATES

Housefly LD50 >uq(1) Roach LD50 >ug( 1)

Toxicant 1.0 PB(1:4) N(l:4) 1.0 PB(1:4)N(1:4)

Pyrethrins 0.125 0.132 <0.5 <0.5

COGS

00R-,

NA NA 1.6 NA NA NA

NA NA 1.4 NA NA NA

00 R

COOP,

. C 0 0 R

COORi

1 NA NA 2.6 NA NA NA

NA 1.85 1.90 NA NA NA

NA 1.84 1.90 NA NA NA

NA NA 2.90 NA NA NA

(1) 1.0 = unsynergized, PB = piperonyl butoxide, N - NIA 16388,

NA = no activity.

-CH9 R = 2 0 ^

V •CH

2 // \

^0

54

of particular note. This acid is very similar to the natural

chrysanthemic acid except it is locked in one particular

conformation, 12, and lacks the freedom of rotation about the

vinyl group as in the natural acid as illustrated. It was

COOH

11

COOH COOH

12

anticipated that this acid could give some very specific

information about the conformational requirements of the

pyrethroid acid as it binds to the target site in the

insect.

In order to synthesize this particular acid, 1,4-di-

methyl-1,3-cyclohexadiene was the ideal precursor for our

three-step synthetic sequence. Unfortunately, the two most

often cited references for the preparation of this diene

require several steps and suffer from difficulty of yield

reproducibility and starting material availability (42, 43)

55

Therefore, we developed a simple and efficient procedure

for the preparation of pure 1,4-dimethyl-l,3-cyclohexadiene

uncontaminated with 1,4—dimethyl—1,4—cyclohexadiene from

readily available compounds. Thus, 4—methyl-3—cyclohexen—1—

one, 13a, was prepared by the Birch Reduction and hydrolysis

of commerically available p-methylanisole as previously

described (44). 1,4-Dimethyl-3-cyclohexenol, 13b, was

readily available from 13a by the usual method of adding

methylmagnesium iodide to the ketone in good yield (45).

Several different precedures were tried for the dehydration

process (46, 47), and the optimum procedure was found to be

refluxing the alcohol with 3-5% aqueous hydrochloric acid

for two hours. Both 1,4-dimethyl-l,4-cyclohexadiene, 14a,

and 1,4-dimethyl-l,3-cyclohexadiene, 14b, were formed in a

90% yield in a ratio of 45/55 respectively based on the

^ H-NMR spectrum. Upon heating the dehydration mixture for

14 hr, the ratio of dienes changed to 14b/14a of 70/30.

Apparently, isomerization of 14a to the more thermodynamic-

ally stable 14b occurred during this heating period. The

separation of 14a from 14b is difficult by fractional dis-

tillation but a silica gel column impregnated with silver

nitrate was found to be very suitable for the separation of

these two isomers using a petroleum ether/ether solvent

system (48). The overall yield of pure 14b from 13a is

about 50%.

OCH-

Li/NH,

EtOH

56

13b

14a

.OH

CH 3MgI

H + / A

+ AgNO,

SiO,

13a

30 70 1 4 b

In further studies on the isomerization of 14a to 14b,

the pure 14a was prepared by the Birch Reduction of p-xylene

in near quantitative yield (49). Refluxing the pure 14a

under the same acidic conditions as described above for 14

hr resulted in a ratio of 14b/14a of 70/30 as evidenced by

1 H-NMR spectrum. Obviously, 14a is being isomerized to 14b

under the acidic conditions described at about 100 C in 14

hr to the extent of 70%. Efforts to increase the percentage

of 14b above 70% were unsucessful.

The overall yield of pure 14b from p-xylene is 63%.

Clearly, the method of choice for the preparation of 14b is

the isomerization of pure 14a prepared by the Birch Reduction

57

of p-xylene because only two steps are involved and the

better overall yield. The key to this preparative procedure

is the efficient separation of 14b from 14a by the silver

nitrate impregnated silica gel column. We have utilized this

procedure to prepare several grams of pure 14b free from any

14a.

14b

Na/NH.

EtOH

AgNO,

SiO,

70

14a

H + / A

N|/

+

30

The advantages of this isomerization procedure for the

preparation of 1,4-dimethyl-l,3-cyclohexadiene over existing

literature procedures are that the starting compounds are

58

readily available, the procedure is simple, short and re-

quires only mild conditions to produce the pure diene on a

preparative scale.

The 1,4-dimethyl-l,3-cyclohexadiene obtained by this

method was allowed to react with dichloroketene to give the

cycloadduct, 8,8-dichloro-3,6-dimethylbicyclo(4.2.0)octa-2-

en-7-one. This cycloaddition product upon reduction and

ring contraction gave the expected 3,6-dimethylbicyclo-

(4.1.0)hept-2-en-7-carboxylic acid, 11, in 50% yield. The

pyrethroid acid derived from 1,4-dimethyl-l,4-cyclohexadiene

was also prepared. These acids were converted to esters of

ci2c=c=o

Zn HOAc

C00H OH

11

59

5-benzyl-3-furylmethyl alcohol and tested against the common

housefly and German cockroach. The esters revealed little

activity as indicated in Table III.

TABLE III

TEST RESULTS OF DIMETHYLBICYCLO(4.1.0)HEPTENECARBOXYLATES

Housefly LD50Aig(l) Roach LD50 /uq(1)

Toxicant 1.0 PB(1:4) N(l:4) 1.0 PB(1:4) N(l:4)

Pyrethrins 1.6 0.125 0.16 0.132

*C00R

>5.0 5.2 1.6 NA NA NA

C00R

> 5 . 0 > 5 . 0 > 5 . 0 NA NA NA

(1) 1.0 = unsynergized, PB = piperonyl butoxide, N = NIA 16388, NA - no a c t i v i t y .

R = - C , V V

Apparently, this particular conformation of the acid

is of little consequence as it binds to the target site in

the insect. Certainly this locked conformation would be

the least stable of the conformations that the naturally

occurring chrysanthemic acid could assume. These results

led us to believe that substituted spirocyclopropanecar-

boxylic acid systems, 15, with the structure similar to

60

the more stable conformer, 16, of natural pyrethroid acid,

would be good candidates for pyrethroids and should provide

a higher toxicity against insects.

C00H

16 15

After an examination of the literature, it was found

that only a limited number of simple spirocarboxylic acids

have been synthesized as pyrethroid insecticides. All of

these spirocarboxylic acids were derived from commercial

available olefins. Apparently, the limited development in

the synthesis of spiro-pyrethroid acids is due to the lack

of availability of the appropriate olefins. In our efforts

to synthesize some new spiro-pyrethroids, we found that a

variety of bicyclic olefins can be derived from the cyclo-

addition product of cycloalkenes and dichloroketene fairly

easy in good yield. Thus, cyclohexene was allowed to react

with dichloroketene to give the corresponding cyclobutanone,

61

After a reductive removal of the two chlorine atoms, and a

Wittig reaction, there was obtained 7-isopropylidenebicyclo-

(4.2.0)octane. This olefin was cycloadded to dichloro-

ketene, selectively monodechlorinated and ring contracted

to yield 2,2-dimethyl-5,6-tetramethylenespiro(2,3)hexan-l-

carboxylic acid, 17. Molecular models of this cyclopropane-

carboxylic acid do in fact reveal a locked conformation

quite similar to the expected most stable conformation of

the natural chrysanthemic acids.

ci2c=c=o Zn/HOAc

CI excess

PPh 3V t-BuO~K+

COOH

17

62

The pyrethroid esters of this acid demonstrate a tox-

icity against the housefly of about 0.5 times as active as

pyrethrin. On German cockroaches these esters demonstrated

a minimal amount of toxicity and only when synergized with

the esterase inhibitor - Niagara 16388 as indicated in

Table IV. Although the bicyclic spiro pyrethroids syn-

thesized are not as active as natural pyrethrin, this test

result obviously showed that the bicyclic spiro-pyrethroids

are more insecticidally active than the synthesized bicyclic

pyrethroids as we expected.

TABLE IV

TEST RESULTS OF BICYCLO SPIRO PYRETHROIDS

Toxicant Synergist Housefly LD50 yuq Roach LD50 /uq

Pyrethrin PB 0 > 1 5 0 3 5

2.60 >5.0

PB 0.34 5.0

NI 0.27 2.55

2.16 >5.0

PB 0.35 5.0

; NI 0. 28 1.7

(1) PB = piperonyl butoxide, NI = NIA 16388.

COOR C00R'

R ^ 2 T ~ \ \ ft \ R" - _CH

/

63

In summary, the results described in this study

indicate that the newly developed synthetic sequence

for pyrethroid acids is a significant improvement over

existing syntheses in the literature. This synthesis

has the advantage of utilizing readily available

starting compounds, the procedure is simple and requires

only mild conditions and the reaction can be performed with

a wide variety of conjugated dienes. The scope of the

synthesis was examined by studying various conjugated dienes

and the results were very positive with good to excellent

yields being obtained of the cyclopropanecarboxylic acids

for all three steps.

The new cyclopropanecarboxylic acids that were syn-

thesized were used to study structure-activity relationships

of pyrethroid insecticides. The bicyclo pyrethroids have

structures similar to the naturally occurring pyrethroid

acid except for a methyl group on carbon 3 or 5. However,

the test results revealed little activity against the

housefly and cockroach. In an effort to more closely mimic

the natural pyrethroid, 3,6-dimethylbicyclo(4.1.0)hept-2-en-

7-carboxylic acid was synthesized by our new synthesis.

This acid, with methyl groups on carbon atom 3 and 6,

closely resembles the natural pyrethroid acid and was

expected to provide information concerning the structural

requirements as it binds to the target site in the insect.

1,4-Dimethyl-l,3-cyclohexadiene was required as the

64

conjugated diene for the synthesis of the above described

acid. It was necessary to develop a new synthesis of this

diene free from any 1,4-dimethyl-l,4-cyclohexadiene. This

preparation involved the Birch Reduction of p-xylene to

1,4-dimethy1-1,4-cyclohexadiene, isomerization of this diene

to a mixture of 1,4-dimethyl-l,3-cyclohexadiene and 1,4-

dimethyl-1,4-cyclohexadiene and then an efficient separation

of the dienes by a silica gel column chromatography im-

pregnated with silver nitrate.

The test results of the pyrethroid esters derived from

3,6-dimethylbicyclo(4.1.0)hept-2-en-7-carboxylic acid

revealed a low toxicity. It is important to note that this

cyclopropanecarboxylic acid is identical to the naturally

occurring chrysanthemic acid except it is locked in a single

conformation and this conformation would be expected to be

the least stable conformation. Therefore, these results

indicate for the first time that this conformer is not the

active form of the pyrethroid.

A new cyclopropanecarboxylic acid was designed and

synthesized with a rigid structure which closely resembles

the more stable conformer of the natural pyrethroid acid.

This acid was a spiro acid and was prepared from an iso-

propylidenecyclobutane derivative. Consistent with our

expectations the pyrethroid ester derived from this spiro

acid revealed a much greater toxicity against the housefly

and cockroach.

65

Clearly, based on the insecticidal activity test

results, it can be concluded that the pyrethroid ester

derived from the more stable conformer of the natural

pyrethroid acid provides the greater toxicity against the

insects tested. These results also suggest that in the

synthesis of potent new pyrethroid acids, the acids should

have structures that mimic the major conformation of the

natural pyrethroid acid.


1. Elliott, M., Jones, N.F., Chem. Soc. Rev. , 7, 473 (1978).

2. Brady, W.T., Bak, D.A. , J_. Org • Chem. , 44, 107 (1979).

3. Krepski, L.R., Hassner, A., J. Org. Chem., 43, 2879 (1978).

4. Ghosez, L., Montaigne, R., Mollet, P., Tetrahedron Letters, 135 (1966).

5. Moppett, C.E., Sutherland, J.K., J. Chem. Soc., (C), 3040 (1968). '

6. Jensen, F.R., Gale, L.H., Rodgers, J.E., J. Am. Chem. Soc., 90, 5793 (1968). —

7. Jefford, C.W., Kirkpatrick, D., Delay, F., J. Am. Chem. Soc. , 94, 8905 ( 1972).

8. Zimmerman, H.E., Mais, A., J. Am. Chem. Soc., 81, 3644 (1959).

9. Brady, W.T., Hoff, E.F., Roe, R.J., Parry, F.H.J., J_. Am. Chem. Soc., 91 , 5679 ( 1969).

10. Sydnes, L.K., Acta. Chem. Scand., 32, 47 (1978).

11. Kuivila, H.G., Menapace, L.W., J. Org. Chem., 28, 2165 (1963).

12. Greene, F.D., Lowry, N.N., jJ. Org. Chem., 32, 882 (1967)

13. Yamanaka, H., Oshima, R., Teramura, K., J. Org. Chem., 37, 1734 (1972). ~ "

14. Kuivila, H.G., Acc. Chem. Res. , JL_, 299 ( 1968).

15. Kuivila, H.G., Beumel, O.F.J., jJ. Am. Chem. Soc., 83 1246 (1961).

16. Dryden, H.L.J. , Webber, G.M., Wieczorek, J.J., _J_. Am. Chem. Soc., 86., 2257 (1964).

17. Conia, J.M., Salaun, J.R., Acc. Chem. Res., J5, 33

66

67

(1972).

18. Bordwell, F.G., Acc. Chem. Res., 3, 281 (1970).

19. Conia, J.M., Ripoll, J.L., Bull. Soc. Chim. Fr., 763 (1963).

20. Salaun, J., Conia, J.M., Bull. Soc. Chim. Fr., 3735 (1968).

21. Bordwell, F.G., Scamehorn, R.G., Am. Chem. Soc., 90, 6751 (1968).

22. Brook, P.R., Duke, A.J., _J. Chem. Soc., 1013 (1973).

23. Conia, J.M., Salaun, J., Bull. Soc. Chim. Fr., 1957 (1964).

24. Bordwell, F.G., Scamehorn, R.G., Springer, W.R., J. Am. Chem. Soc., 91, 2087 (1969).



27. Brook, P.R., Duke, A.J., Griffiths, J.G., Roberts, S.M., Rey, M., Dreiding, A.S., Helv. Chim. Acta.. 60, 1528 (1977).

28. Inoue, Y., Katauda, A., Nishimura, A., Kitagawa, K., Ohno, M., Botynu Kagaku, 10, 111 (1951).

29. Martel, J., Huynh, C., Bull. Soc. Chim. Fr., 985 (1967).

30. Julia, M., Guy-Rouault, M. , Bull. Soc. Chim_. Pr. , 1411 (1967).

31. Aratani, T., Yoneyoshi, Y., Nagase, T., Tetrahedron Letters, 1707 (1975).

32. Martin, P., Greuter, H., Bellus, D, J_. Am. Chem. Soc. , 101, 5853 (1979).

33. Plummer, E.L., Stewart, R.R., J. Agric. Food Chem., 32. 1116 (1984). ~~

34. Ayad, H.M., Wheeler, T.N., J. Agric. Food Chem., 32, 85 (1984).

68

35. Brady, W.T., Norton, S.J., Ko, J., Synthesis, 1002 (1983). .

36. Rey, M., Huber, U.A., Dreiding, A.S., Tetrahedroon Letters, 32, 3583 (1968).

37. Brady, W.T., Hoff, E.F.J., J. Org. Chem., 35, 3733 (1970). '

38. Salaun, J., Conia, J.M., Bull. Soc. Chim. Fr. , 3735 (1968).

39. Conia, J.M., Salaun, J.R., Acc. Chem. Res., 5, 33 (1972).

40. Rey, M., Roberts, S.M., Dreiding, A.S., Helv. Chim. Acta. , 65., 703 ( 1982).

41. Brady, W.T., Hieble, J.P., _J_. Am. Chem. Soc. , 94, 4278 (1972).

42. Dauben, W.G., Hart, D.J., Ipaktschi, J., Kozikowski, A.P., Tetrahedron Letters, 4425 (1973).

43. Ruttimann, A., Wick, A., Eschenomosh, A., Helv. Chim. Acta., 18, 1450 (1975).

44. Faulkner, A.J., Wolinsky, L.E., J. Org. Chem., 40, 389 (1975).

45. Hanaya, K., Kudo, H., Gohre, K., Imaizumi, S., Nippon Kaqaku Kaishi 1006 (1979).

46. Manson, R.S., Tetrahedron Letters, 567 (1971).

47. Wheeler, O.H., _J. Or£. Chem., 20, 1672 (1955).


49. Fehnel, E.A., J. Am. Chem. Soc., 94, 3961 (1972).

BIBLIOGRAPHY

1. Addor, R.W., Schrider, M.S., DOS 2605828 (1976). Am. Cyanamid Co.

2. Aratani, T., Yoneyoshi, Y., Nagaase, T., Tetrahedron Letters, 1707 (1975).

3. Arlt, D., Jautellat, M., Lantzsch, R., Anqew. Chem. (Intern. Ed. Engl.), 20_, 703 ( 1981).

4. Asao, T., Machiguchi, T., Kitamura, T., Kitahara, Y. , Chem. Soc. , (D) , 89 ( 1970).

5. Ayad, H.M., Wheeler, T.N., £. Agric. Food Chem., 32, 85 (1984).

6. Bak, D.A., Brady, W.T., £. Org. Chem., 44, 107 (1979)

7. Bartlett, P.D., Ando, T. , J_. Am. Chem. Soc. , 92, 7518 (1970).

8. Bellus, D. , Greuter, H., Martin, P., Pestic. Sci. , 11, 141 (1980).

9. Bordwell, F.G., Acc. Chem. Res., 3, 281 (1970).

10. Bordwell, F.G., Scamehorn, R.G., J_. Am. Chem. Soc. , 90, 6751 (1968).

11. Bordwell, F.G., Scamehorn, R.G., Springer, W.R.,_J. Am. Chem. Soc., 91, 2087 (1969).

12. Brady, W.T., Hieble, J.P., J_. _Am. Chem. Soc. , 94, 4278 (1972).

13. Brady, W.T., Hoff, E.F.J., Roe, R.J., Parry, F.H.J., J. Am. Chem. Soc., 91, 5679 (1969).

14. Brady, W.T., Hoff, E.F.J., _J. Org. Chem., 35, 3733 (1970).

15. Brady, W.T., Norton, S.J., Ko, J., Synthesis, 1002 (1983).

16. Brady, W.T., Norton, S.J., Ko, J., Synthesis, 1985 (in press).

69

70

17. Brady, W.T. , Synthesis, 8, 415 (1971).

18. Brady, W.T., Tetrahedron, 37, 1939 (1981).

19. Brady, W.T., Waters, O.H., J_. Org. Chem. , 32, 3703

(1967).

20. Bramwell, A.F., Crombie, L., Hemesley, R., Pattenden, G., Elliott, M., Jones, N.F., Tetrahedron, 25., 1727

(1969).

21. Brook, P.R., Duke, A.J., _J_. Chem. Soc. , 1013 (1973).

22. Brook, P.R., Duke, A.J., Griffiths, J.G., Roberts, S.M., Rey, M., Dreiding, A.S., Helv. Chim. Acta.., j>U,

1528 (1977).

23. Brown, D.G., ns-Pat. 4203918 (1980). Am. Cyanamid Co.

24. Camphell, I.G.M., Harper, S.H., J_. Chem. Soc., 283

(1945).

25. Chapleo, C.B., Roberts, S.M.,_J_. Chem. Soc. , Chem. Comm., 680 (1979).

26. Conia, J.M., Ripoll, J.L., Bull. Soc. Chim. Fr., 763

(1963).

27. Conia, J.M., Salaun, J.R., Acc. Chem. Res. , .5, 33

(1972).

28. Conia, J.M., Salaun, J., Bull. Soc. Chim. _Fr., 1957

( 1964) .

29. Conia, J.M., Salaun, J., Bull. Soc. Chim. _Fr_. , 1773

(1963).

30. Conia, J.M., Salaun, J., Bull. Soc. Chim. _Fr., 2751

(1965).

31. Corey, E.J., Jautelat, M., J_. Am. Chem. Soc., _89,

3912 (1967).

32. Cragg, G.L.M., J_* Chem. Soc., (C), 1829 (1970).

33. Crane, A., Brood, C.E., Henne, A.L., _J. Am. Chem. Soc_. , 67, 1237 (1945).

34. Dauben, W.G., Hart, D.J., Ipaktschi, J., Kozikowski, A.P., Tetrahedron Letters, 4425 (1973).

35. Davis, R.H., Searle, R.J.G., US-Pat. 4118510 (1978).

71

Shell Oil Company.

36. Davis, R.H., Serale, R.J.G, DOS 2447735 (1975).

37. Devos, M.J., Krief, A., Tetrahedron Letters, 1891

( 1979).


39. Dryden, H.L.J. , Webber, G.M., Wieczorek, J.J., J_. Am. Chem. Soc. , 8j6, 2257 (1964).

40. Elliott, M., Jones, N.F., Chem. Soc. Rev., _8, 473 (1979).

41. Elliott, M., Jones, N.F., Chem. Soc. Rev., J7, 473 (1978).

42. Faroog, S., Drabek, J., Gsell, L., Karrer, F., Meyer, N., DOS 2642861 (1977). Ciba-Gegy.

43. Faulkner, A.J., Wolinsky, L.E., £. Org. Chem., 40, 389 (1975).

44. Fehnel, E.A., _J. Am. Chem. Soc. , 94., 3961 (1972).

45. Fleming, I., Chem. Ind., (Lond.,), 449 (1975).

46. Fletcher, V.R., Hassner, A., Tetrahedron Letters,

1071 (1970).

47. Fujimoto, K. , Ohno, N. , Mizutani, T. , DOS 2365555_ (1974). Sumimoto Chem. Co.

48. Ghosez, L., Montaigne, R., Roussel, A., Vanlierde, H., Mollet, P.. Tetrahedron Letters, 135 (1966).

49. Ghosez, L., Montaigne, R., Roussel, A., Vanlierde, H., Mollet, P., Tetrahedron, 27, 615 (1971).

50. Greene, F.D., Lowry, N.N., J. Org. Chem., 32, 882

(1967). ~

51. Greuter, H., Bissig, P., Martin, P., Flucker, V. , Gsell, L., Pestic. Sci., 11, 148 (1980).

52. Hanaya, K., Kudo, H., Gohre, K., Imaizumi, S., Nippon Kagaku Kaishi, 1006 (1979).

53. Hanford, W.E., Sauer, J.C., Organic Reactions, edited by Adams, R., Vol. 3, Wiley Interscience, Lodon, 1946, Chapter 3, p 108.

72

54. Harmony, R.E., Barta, W.D., Gupta, S.K., _J_. Chem. Soc. , (C), 3645 (1971).

55. Holan, G., Walser, R.A., US-Pat. 4226591 (1980).

56. Hopkinson, A.C., Csizmadia, I.G., Can. jJ. Chem., 52, 546 (1974).

57. Houk, K.N., Strozier, R.W., Hall, T.A., Tetrahedron Letters, 897 (1974).

58. Inoue, Y., Katauda, A., Nishimura, A., Kitagawa, K., Ohno, M., Botynu Kagaku, 10, 111 (1951).

59. Jefford, C.W., Kirapatrick, D. , Delay, F., J_. Am. Chem. Soc., 94, 8905 (1972).

60. Jensen, F.R., Gale, L.H., Rodgers, J.E., J . Am. Chem. Soc., 90, 5793 (1968).

61. Julia, M., Guy-Rouault, M., Bull. Soc. Chim. _Fr., 1411

(1967).

62. Julia, M., Julia, S., Jeanmart, C., C. R. Acad. Sci., 251, 149 (1960).

63. Julia, M., Julia, S., Jeanmart, C., Langlois, M., Bull. Soc. Chim. Fr., 2243 (1962).

64. Kato, M., Kido, F. , Bull. Soc. Chim. Jpn. , 4J7' 1516 (1974).

65. Krepski, L.R., Hassner, A., jJ. Org. Chem. , _43, 2879 (1978).

66. Kuivila, H.G., Acc. Chem. Res., 1_, 299 (1968).

67. Kuivila, H.G., Beumel, O.F.J. , J_. _Am. Chem. Soc. , 1246 (1961).

68. Kuivila, H.G., Menapace, L.W., J. Org. Chem. , 28_, 2165 (1963).

69. Manson, R.S., Tetrahedron Letters, 567 (1971).

70. Marte 1, J• , Huynh, C. , Bui 1. Soc. Chim. F_r_« , 985 (1967).

71. Martin, P., Greuter, H., Bellus, D. , J_. _Am. Chem. Soc., 101, 5853 (1979).

73

72. Matsui, M., Kitahara, T., Agric. Biol. Chem., 3 U 1143

(1967). .

73. Matsui, M.f Uchiyama, M. , Agric. Biol. Chem., 26, 532

(1962).

74. Meuche, A., Helv. Chim. Acta., 49, 1278 (1966).

75. Montaigne, R. , Ghosez, L., Angew. Chem. (Intern. Ed. Engl.), 7, 221 (1968).

76. Moppett, C.E., Sutherland, J.K., J_. Chem. Soc., (C), 3040 (1968).

77. Ohno, N., Fujimoto, K., Agric. Biol. Chem., 38,

881 (1974).

78. Payne, G.B., J_. Org. Chem. , 32, 3351 (1967).

79. Plummer, E.L., Stewart, R.R.,_J. Agric. Food Chem., 32, 1116 (1984).

80. Pople, T.A., Gorden, M., J_. Am. Chem. Soc., 89, 4253

(1967).

81. Rey, M. , Roberts, S.M., Dreiding, A.S., Helv_. Chim. Acta., 65, 703 (1982).

82. Rey, M., Huber, U.A., Dreiding, A.S., Tetrahedron

Letters, 32, 3583 (1968).

83. Ruden, R.A., J. Org. Chem., 39, 2607 (1974).

84. Ruttiman, A., Wick, A., Eschenomosh, A., Helv. Chim..

Acta., 58' 1 4 5 0 ( 1 9 7 5>-

85. Salaun, J., Conia, J.M., Bull. Soc. Chim_. Fr. r 3735

(1968).

86. Scharf, H.D., Mattay, J., Chem. Ber., 111, 2206

(1978).

87. Staudinger, H., Ruzicka, L., Helv. Chim. Acta., 7, 448 (1924).

88. Stetter, P.L., Roman, S.A., Edwards, C.L., Tetrahedron Letters, 4701 (1972).

89. Sydnes, L.K., Acta. Chem. Scand., 32, 47 (1978).

90. Taketa, T., Sakai, T., Shinohara, S., Tsuboi, S., Bull Soc. Chem. Jpn., 50, 1133 (1977).

74

91. Tanka, T., Yoshikoshi, A., Tetrahedron, 27, 4889 (1971).

92. Ward, R.S., The Chemistry Of Ketene, Allene, and Related Compounds, part 1, edited by Patai, S., New York, Interscience Publications, Inc., 1980, p 223.

93. Weimann, L.J., Christof fersen, R.E., J . Am. Chem. Soc. , 95, 2074 (1973).

94. Wheeler, T.N., Ayad, H.M., J. Agric. Food Chem., 32, 85 (1984). —

95. Wheeler, O.H., J. Org. Chem., 20, 1672 (1955).

96. Yamanaka, H., Oshima, R., Teramura, K., J_. Org. Chem. , 37, 1734 (1972).

97. Zimmerman, H.E., Mais, A., J. Am. Chem. Soc., 81, 3644 (1959).

Download - SYNTHETIC APPLICATIONS OF KETENE CYCLOADDITIONS; …/67531/metadc331031/... · SYNTHETIC APPLICATIONS OF KETENE CYCLOADDITIONS; NATURAL AND NOVEL PYRETHROID INSECTICIDES DISSERTATION

Top Related