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  • 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 3O H

    (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 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-

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