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.
CHAPTER BIBLIOGRAPHY
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.
CHAPTER BIBLIOGRAPHY
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).
25. Conia, J.M., Salaun, J., Bull. Soc. Chim. Fr., 2751 (1965).
26. Conia, J.M., Salaun, J., Bull. Soc. Chim. Fr., 1773 (1963).
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).
48. DeVries, B., Chem. and Ind., 1049 (1962).
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).
38. DeVries, B., Chem. and Ind., 1049 (1962).
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).