synthesis of chloromethylvinylcyclopropanecarboxylic acid

Agric. Biol. Chem., 49 (3), 751 -760, 1985 751

Synthesis of ChloromethylvinylcyclopropanecarboxylicAcid Derivatives1

Shigeki Muramatsu, Yasuo Nakada and Junya Ide*Chemical Research Laboratories, Sankyo Co., Ltd.,

1-2-58 Hiromachi, Shinagawa-ku,Tokyo 140, Japan

Received August 16, 1984

The compound 3-(2-chloro- l -propenyl)-2,2-dimethylcyclopropanecarboxylate, which is a hy-brid structure of naturally occurring chrysanthemic acid and dichlorovinylcyclopropanecarbox-

ylate, was synthesized from several intermediates: (i) 5-methyl-4-hexen-2-one ethylene ketal (8),(ii) 2-methyl-5,5-dichloro-2-hexene (24), (iii) 5-methyl-2-chloro-2,4-hexadiene (27), (iv) ethyl

4,6-dichloro-3,3-dimethyl-5-heptenoate (35).

Synthetic pyrethroids such as permethrinand decamethrin (NRDC 161),2) which have 3-dihalovinyl-2,2-dimethylcyclopropanecar-boxylic acid as an acid component, exhibit

high insecticidal activity and low mamma-lian toxicity as well as photostability, quali-ties of which enable them to be used as agri-cultural insecticides. These pyrethroids, how-

ever, show high toxicity to fish,3) which pro-hibits their application in an aquatic environ-ment. However, phenothrin4) (discovered

by the Sumitomo group), has a naturally oc-curring chrysanthemic acid component andshows relatively low fish-toxicity.5) Our in-

terest has focused on developing a new type ofpyrethroid which can be used in an aquaticenvironment. In the preceding paper,1} wereported on the synthesis of 3-(2-halo-l-propenyl)-2,2-dimethylcyclopropanecar-boxylic acid esters, which are hybrid struc-tures of chrysanthemic acid and dihalovinyl-2,2-dimethylcyclopropanecarboxylic acid. Thecompound 3-(2-halo-1-propenyl)-2,2-dimeth-

ylcyclopropanecarboxylic acid has four dia-stereoisomers: i.e., (;E)-trans, (Z)-trans, (E)-cis

and (Z)-cis isomers with respect to the stereo-chemistry of the 2-halo-l-propenyl side chainand to the cyclopropane ring. The structureof each of these stereoisomers has been con-firmed by 13C-NMR6) and 'H-NMR spectralanalyses.^ Previously, we reported5} that m-phenoxybenzyl esters of 3-(2-chloro-l-pro-penyl)-2,2-dimethylcyclopropanecarboxylicacid showed comparably less insecticidal ac-

tivity than those of dihalovinyl cyclopropane-carboxylic acids against household pests suchas the housefly and cockroach, whereas the

activity of these esters against green-rice leaf-hopper in paddy fields was as potent as thecorresponding esters of dihalovinyl cyclopro-panecarboxylic acids. In addition, the fish-toxicity of the esters of 2-chloro-l-propenylcyclopropanecarboxylic acid was significant-

ly low, which may enable their applicationto paddy fields. The trans isomer 1 was shownto be more potent to green-rice leafhopper andless toxic to fish than the cis isomer 2. In thispaper, we wish to describe several efficientsyntheses of 2-chloro-l-propenyl cyclopro-panecarboxylates.

t

Studies on Halomethylvinyl Cyclopropanecarboxylic Acids and Their Esters. Part IV.1' Halomethylvinylcyclopropanecarboxylic acid refers to 3-(2-halo- l -propenyl)-2,2-dimethylcyclopropanecarboxylic acid.

* To whomcorrespondence should be addressed.

752 S. Muramatsu, Y. Nakada and J. Ide

Permethrin

CH3CH3

Hn /\/COO'^>Ct(^-%H

CH3 QH3CN

CH^ CH> SH

(i) The use of 5-methyl-4-hexen-2-one ethyleneketal (8) as a key intermediateseoButylaldehyde (3) was treated with ace-tylacetone (4) in the presence of piperidine togive 5-methyl-3-acetyl-3-hexen-2-one (5) in a

48% yield. Treatment of the diacetyl derivative5 in acetic acid under reflux afforded the enolfrom 6,7) *1 which was fairly stable at roomtemperature without tautomerization to thediacetyl derivative 5, presumably due to theformation of the six-membered ring by hy-drogen bonding. The structures of 5 and 6were confirmed form NMRspectra. The vinylproton of 5 showed a doublet peak at6.52ppm (7= 10.5Hz) coupling with the me-thin proton of the isopropyl group, whereas

the corresponding proton of 6 appeared at5.78ppm as a broad singlet.Deacetylation of 6 was conducted by treat-ment with zinc(II) acetate in methanol toafford the /?,y-unsaturated enone 7,7) whichexhibited methylene protons at 2.97ppm(d,.7= 7.0 Hz). Ketalization of 7 with ethyleneglycol in the presence of a catalytic amount of/?-toluenesulfonic acid in benzene under refluxfor 2.5 hr gave the corresponding ketal 8. Thisketal 8 was ultimately found to be preparedefficiently by direct ketalization of the com-mercially available a,/?-unsaturated ketone of5-methyl-3-hexen-2-one (9), with concomitantdouble bond migration under prolonged refluxfor 7 hr under ketalization conditions.

Crlav

c h>á"° * <ccocHH: ^^ á":>c" =<"ncá":-^^ cd>ccHH-J> ^^6CH3X XCOCH3

3 ACH3X ^COCH3

5

CHaH+CH3.CH3 V/VCH3 H+ CH3

CHa 0 HO-^s^OH CH3/^q^q ^ HO^s^OH CHs

WXCyclopropanation of 8 with ethyl diazo-

acetate in the presence of CuSO4afforded amixture of the trans and cis cyclopropanederivatives (10 and ll) in a 42% yield and52:48 ratio. Treatment of the enolate de-rivative 6 with ethyl diazoacetate gave nocyclopropane adduct, but the tetra-substitutedfuran derivative 16 in a 25% yield. Cyclo-propanation of the /?,y-unsaturated enone7 with ethyl diazoacetate was also unsuccess-ful.

Deketalization of a mixture of the trans and

cis isomers (10 and ll) by HCl-catalysis inacetone gave the corresponding trans and cisketones (12 and 13) in 90% yields. Each ofthese isomers was separated by silica gel col-umnchromatography. The NMRspectra as-signed to the trans isomer 12 exhibited a

doublet peak at 2.43ppm (7=7.5Hz) due tothe methylene group on the cyclopropane ring;the corresponding doublet peak in the cisisomer 13 appeared in a lower field, at2.78ppm (J=6.0Hz). This may be due to theanisotropy effect of the ethoxycarbonyl group

** Uehara et aL1] has reported that the enol form 6 was obtained directly by condensation of3 with 4. In our case,however, only the non-enol form 5 was found under the same reaction conditions as Uehara's or under heating at80~ 85°C for 30min (see Experimental).

Synthesis of Chloromethylvinyl Pyrethroids 753

of the cis isomer 13 being on the same side ofthe cyclopropane ring. The structure andstereochemistry of the trans isomer 12 wasconfirmed with an authentic sample derivedfrom rnms-3-(2-chloro-l-propenyl)-2.2-di-

methylcyclopropanecarboxylic acid (14a)1} byacid-hydrolysis of the 2-chloro-1-propenylgroup followed by esterification. Conversionof the ketone moiety of 12 and 13 to thedichloromethylene moiety was examined by

using a variety of chlorinating agents. A chlo-rination reaction of the carbonyl group withphosphorus pentachloride under a variety ofreaction conditions gave a mixture of thedesired dichlorinated products 17 or 19 in

addition to further dehydrochlorinated prod-ucts 14 or 15 in insufficient yields. Thisreaction was accompanied by a significantamount of the undesirable exomethylene de-rivative 18 or 20 in both cases of the trans andcis isomers (12 and 13). Ultimately, efficient

dichlorination of the carbonyl group was at-tained by using dichloromethyl methyl ether8)in the presence of zinc(II) chloride in meth-

ylene chloride in both the cases of 12 and 13.The trans ketone 12 was treated with 1,1-dichloromethyl methyl ether and zinc(II)chloride in methylene chloride at 5°C to givethe dichlorinated product 17 and the furtherdehydrochlorinated trans isomer 14!) (a mix-ture of E and Z in the ratio 78:22), deter-mined by GLC (3% PEG 20m, 135°C), in an82% yield. Chlorination of the cis ketone 13under similar reaction conditions furnishedthe dichlorinated derivative 19 and the de-hydrochlorinated cis isomer 15 in the ratioof 54:46 in a 46% yield. The dichlorinatedtrans 17 and the cis isomer 19 were shownby spectroscopic data and GLC to be identi-cal to a corresponding authentic sample pre-pared by the method reported in the precedingpaper.1} The dichloro derivatives of the trans

and cis isomers (17 and 19) were converted totheir trans- and c/^-2-chloro-l-propenyl de-

rivatives (14 and 15), by treatment with DBUand sodium hydroxide, respectively, as re-

ported in the preceding paper.n

CHa QH3 CH3 QH3

g_NiCHCOOEt_^ PohX CQOEt + o}H X.»CH/Nx >H CH/ N/' >COOEt

12 II

CH3 qH3 CH3 CH3

---> gH>Av'CooEt + ,o,y*v"CH3'AV^ >H CH3A/ NCOOEt

12 ll

C^QHa ch H CHi

H/\.COOH 1)Hf-H2O.10 6 N^HC°OEt , 3V-IT CH3CH3>^-A;H 2)H-EtOH - ~ EtOOcAOAcH3

CH3 CH3 CH3 CH3 < CH3 QH3 ^2 CtzCHOCH3) CIClfciy\#.COOEt + HX^^OOEt I u PH/\yCOOEt-ch3;\/ nh ch3v ^-\h LCH2=\>>^ Nh J

17 Cl^^H u 1_8

CH3CHa CH3 QH3 < CH3 QH3 >

13CUCH0CH3, cmX) + hiX,h CH qij/VtiCHa^X/ NCOOEt CH3\-/ NCOOEt I ~N/ NCOOEtJ19 Cl H1_5 20

(ii) The use of 2-methyl-5,5-dichloro-2-hexene(24) as a key intermediate

Cyclopropanation of ethyl diazoacetate to2-methyl-5,5-dichloro-2-hexene (24) may leaddirectly to 17 and/or 19 for the synthesis of 2-

chloro- 1 -propenyl cyglopropanecarboxylate.In the preceding paper,1} an addition reactionof 1,1,1-trichloroethane to 3,3-dimethyl-4-pentenoate was successfully performed byusing iron(II) chloride as the catalyst and


hexamethylphosphoramide (HMPA) as a li-gand. This procedure was applied to the re-levant synthesis. An addition reaction of 1,1,1-trichloroethane to commercially available 2-methyl-3-buten-2-ol (21) in the presence ofiron(II) chloride and HMPAin a sealed tubeat 120°C gave the desirable adduct 22 in a 62%yield. Treatment of the chloroalcohol 22 withsodium hydride in DMFor 1 n sodium hy-droxide at room temperature afforded theepoxide 23 in 98% and 77% yields, respec-tively. Deoxygenation of the epoxide 23 usingzinc dust in the presence of sodium iodide andsodium acetate in aqueous acetic acid pro-ceeded smoothly to give 2-methyl-5,5-

dichloro-2-hexene (24) in a 79% yield. The useof McMurry's reagent (4TiGl3-LiAlH4)9) fordeoxygenation of 23 resulted in a poor yield(36%). This olefin (24) was alternatively pre-pared from the /?,y-unsaturated ketone 7 bydichlorination of the carbonyl group withphosphorus pentachloride; however, the yieldwas insufficient. The NMR spectrum of 24

showed three methyl groups at 1.60, 1.71 and2.02ppm, and a methylene group at 2.86ppm(d, /=7.0Hz).

Cyclopropanation of 24 with ethyl diazo-acetate gave the corresponding trans and ciscyclopropane derivatives (17 and 19) in theratio of 48:52 in a 44% yield, which wereseparated by silica gel chromatography. The

NMRspectra of the trans and cis isomers (17and 19) were identical with those of authenticsamples.

Cl ClClCH3^y%CH CCI3CH3 CH3\/l\XcH NaH

CHs^OH CHa^OH 3or1N NaOH *

21 22

CH3\/°\ C\5l ATlCla-LlAlHtor CH;CH3/ N/^CHsZn-Nal-AcONa ' CH:

l3>=\y<CH3?c^-

C H3 V^^/CH3CH3'

7

:><XCv-ri3 yn3 LH3 CM3

CH3CH3CHsCHs

(iii) Cyclopropanation of 5-methyl-2-chloro-2,4-hexadiene (27)Commercially available 1,3-dichloro-2-

butene (25) is intrinsically the synton for thechloromethylvinyl moiety of the target com-

pounds. Therefore, this compoundwas attrac-tive as a starting material for the synthesis ofthe relevant cyclopropanecarboxylic acid.Treatment of 25 with sodium iodide in DMFgave the corresponding iodide, which withoutisolation was converted to the phosphoniumsalt 26 by reaction with triphenylphosphine inbenzene. The phosphorane generated by treat-ment of the phosphonium salt 26 with butyllithium in THFwas reacted with acetone togive 5-methyl-2-chloro-2,4-hexadiene (27) in a47% yield. Cyclopropanation of 27 with ethyldiazoacetate gave the corresponding cyclopro-panecarboxylate (15.3% yield), which consist-ed of the {E)-trans, {Z)-trans, (E)-cis and (Z)-cis isomers.

'^teCHCHiCL -

> C">CHCHPPh,I --iliU

CH3v_ rHr yCH3 NaCHCOOEt

U CHs'å HU"+Clv CHa'XH15

(iv) Cyclization of ethyl 4,6-dichloro-3,3-dimethyl-5-heptenoate (35).

Ethyl 3,3-dimethyl-4-oxobutanoate (30) wasprepared in a 27% yield by alkylation of 1-(N,7V-diisobutyl)amino-2-methyl- 1 -propene(28) with ethyl bromoacetate in acetonitrile,followed by hydrolysis with aqueous aceticacid. Alternatively, the aldehyde (30) was ob-tained from ethyl 3,3-dimethyl-4-pentenoate

(29)5) by osmium tetroxide-sodium periodateoxidation in a 48% yield. Elongation of the C-3 unit to the aldehyde (30) was accomplishedwith propargyl bromide in the presence of Al-Hg amalgam in THF10) to afford ethyl 3,3-dimethyl-4-hydroxyhept-6-ynoate (31) in a

45% yield, together with the lactonized prod-uct (32) in a 24% yield.

The alcohol (31) was converted to the en-

yne derivative (33) by mesylation, followed by


treatment with potassium tert-butoxide in a54% yield. Hydration of the en-yne derivative(33) was achieved by using mercury(II) chlo-ride and boron trifluoride etherate to afford

the a,/?-unsaturated ketone derivative (34) in a76% yield.Treatment of the enone derivative (34) withdichloromethyl methyl ether in dichloro-

methane in the presence of a catalytic amountof zinc(II) chloride afforded ethyl 3,3-dimeth-yl-4,6-dichloro-5-heptenoate (35) in a 61%

yield. The mass spectrum of 35 showed mo-lecular peaks at m/z (relative intensity) valuesof: 256 (1), 254 (5.2) and 252 (7.5), suggest-ing the dichloro derivative. The NMRspec-trum of 35 showed a doublet peak at 5.07,assignable to the proton on the chlorinatedmethin group, and a slightly broad doubletpeak of the vinyl proton at 5.75ppm, due tothe allyl coupling with the methyl group ob-served at 2.20ppm as a slightly broad singletpeak. The coupling constant between themethin proton and the vinyl proton showed10.5Hz. This NMRspectrum closely resem-bled that of ethyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate (39), previously synthesized inour laboratory,11] in which the proton on

the chlorinated methin group and the vinylproton appeared at 4.98 and 5.61ppm, re-spectively; the coupling constant betweenthese protons showed 10.5Hz. Huff et al.12)have reported a structurally similar com-pound, i.e., ethyl 3,3-dimethyl-4,6,7-trichloro-

7,7-difmoro-5-heptenoate (40), in which theproton on the chlorinated methylene groupappeared at 5.00ppm and the vinyl protonat 5.88 ppm, and with a coupling constant be-tween these protons of 10.0Hz.These NMRspectra suggested that chlori-nation of the a,/?-unsaturated ketone (34) didnot afford any other plausible product of ethyl3, 3-dimethyl-6,6-dichloro-4-heptenoate (38).*2Cyclization of 35 could be effected by treat-ment with sodium tert-butoxidQ in benzene toafford a 91 :9 mixture of the (Z)-trans- and(Z)-cw-cyclopropane derivatives (36 and 37) ina 76%yield, whose stereochemical assignmentwas confirmed by spectral data and GLCcomparing with those of authentic samplespreviously synthesized in our laboratory.nThis result suggests that the stereochemistry ofthe double bond in the chloride 35 should be

(Z )-configuration.

å cl!>=CH-<rIu-^^COn ?H CH3v _ XHiC=CHL 28 ^^^L^:CH3VCH0 HC=CCH2Br? CH3wCHCH2C=CH+CH,^ \~\\£2^^ CH3^CH2COOEt CH3/^CH2COOEt \,0

CH3VCH=CH2 OsOi^^^ 30 31 å g

CH3^CH2COOEt - ~~ 3 2^9

^Buo'k1 CH3n/CH^CH-C;CH _h1c, CH3VCH3CHCOCH3Cl2CHOCH3 } CHa^CHCteCCHa" 'CH3^CH2COOEt HgCU CH3^CH2COOEt ZnCli CH3^CH2COOEt

33 3A 35

CH3CH3 CH3CH3

tBuOK } Hy\XOOEt + H/\,HCl>(f NH Cl>< XOOEt

36 37.

a ci i cici qiCH3s^Vs;CH3 CH3N/(i:H-CH=CCl2 CH3VCH-CH=C-CF2 CH3^XhC13 CH3wKH

CH3^CH2COOEt CHs^CHzCOOEt CHa^CHiCOOEt CHs^CHzCOOEt CHs^C^COOEt38 39 AO 41 42.

EXPERIMENTAL

All boiling points are uncorrected. IR spectra were

measured on a JASCOIR-A2 spectrometer. NMRspectrawere obtained from a Varian high resolution NMRspec-trometers, models A-60, EM-390 and HA-100, or a

*2 This observation was clearly distinguished from the trans-coupling constant values of 15.0 and 16.0Hz in thevinyl protons of ethyl 3,3-dimethyl-6,6,6-trichloro-4-hexenoate (41)13) and ethyl 3,3-dimethyl-6,6,7-trichloro-7,7-

difluoro-4-heptenoate (42).12) The vinyl protons at C-4 and C-5 of 42 appeared at 5.59 and 6.44ppm, respectively.


Hitachi R-24 high resolution NMRspectrometer usingtetramethylsilane as an internal standard. Chemical

shifts are expressed in ppm. Analytical determination byGLCwas performed on a Gaschro Kogyo Inc. KOR-70model gas chromatograph. Mass spectra were recordedon a Japan Electron Optics Lab. JMS-01SG spectrom-eter.

3-Acetyl-5-methyl-3-hexen-2-one (5). To a solution of

isobutyl aldehyde (3) (10.8 g, 0.15 mol) and acetylacetone(4) (15g, 0.15mol) was added piperidine (128mg,1.5mmol) at 0°C. After being heated for 30min at

80 ~ 85°C, the resulting water was distilled azeotropicallyby adding 200ml of benzene. The oily residue was sub-mitted to distillation in vacuo to afford 10g of 5in a 48%yield, bp 90~92°C/10mmHg. NMR (CDC13)<5: 1.09 (6H,d,.7=6.5Hz, 2xCH3), 2.33 (6H, s, 2xCH3), 2.10-2.90

(1H, m, -CH-), 6.52 (1H, d, J=10.5Hz, =CH-).

3-Acetyl-5-methyl-4-hexen-2-one (6). A solution of 5

(572 mg, 2.6 mmol) in 150ml of acetic acid was refluxed for4hr. After removing the acetic acid at atmospheric pres-sure, the residue was distilled in vacuo to afford 23g of 6in a 69% yield, bp 72~73°C/10mmHg. NMR (CDC13)(5:

1.50 (3H, s, CH3), 1.79 (3H, s, CH3), 1.97 (6H, s, 2xCH3),

5.78 (1H, broad s, =CH-), 16.37 (1H, s, =C-OH).

5-Methyl-4-hexen-2-one (7). A solution of 6 (20g,

0.13 mol) and zinc(II) acetate (572mg, 2.6mmol) in 100mlof methanol was refluxed for 40hr. After cooling, the

mixture was diluted with ether, and the solution waswashed with water and dried over Na2SO4. After remov-ing the solvent, the residue was distilled in vacuo to afford10.8g of7 in a 74% yield, bp 68~69°C/35mmHg. NMR

(CDC13)& 1.57 (3H, s, CH3), 1.69 (3H, s, CH3), 2.04 (3H,

s, CH3), 2.97 (2H, d, J=7.0Hz, CH2CO), 5.18 (1H, broadt, J=7.0Hz, =CH-).

5-Methyl-4-hexen-2-one ethylene ketal (8).a) A mixture of 5-methyl-3-hexen-2-one (7) (2.24g,20mmol), ethylene glycol (3.1g, 50mmol) and p-toluenesulfonic acid (50mg) in 20ml of benzene was

refluxed for 7hr with continous removal of water as abenzene azeotrope. After cooling, the reaction mixturewas washed with aq. NaHCO3solution and water, anddried over Na2SO4. After removing the solvent, the res-idue was purified by column chromatography on silica gel

(hexane-ethyl acetate=9: l) to afford 2.64g of 8 in an85% yield. IRv^cm"1: 1450, 1375, 1050; NMR

(CDC13)<5: 1.23 (3H, s, CH3), 1.57 (3H, s, CH3), 1.68 (3H,

s, CH3), 2.29 (2H, d, J=7.0Hz, -CH2-), 3.92 (4H, s,

OCH2CH2O), 5.22 (1H, t, /=7.0Hz, CH=); MS m/z:

156 (M+), 141, 87.

b) A mixture of 5-methyl-4-hexen-2-one (9)*3 (4.34g,39mmol), ethylene glycol (6.0g, 97mmol) and p-

toluenesulfonic acid (20 mg) in 20 ml benzene was refluxedfor 2.5 hr with continuous removal of water as a benzeneazeotrope and worked up in the usual way. The crudeproduct was chromatographed on silica gel to give 5.84gof8 in a 90% yield.

Ethyl trans- and cis-2,2-dimethyl-3-{2,2-ethylenedi-oxypropyl)cyclopropanecarboxylate (10 and ll). To astirred solution of 8 (3.39g, 22mmol), 30mg of pow-dered copper and 8mg of anhydrous copper(II) sulfateat 95-100°C under a nitrogen atmosphere was added

slowly dropwise ethyl diazoacetate (2.0 g, 17.5 mmol) overa period of 1.5hr, the mixture being heated for anadditional lOmin at the same temperature. After cooling,the reaction mixture was separated by columnchromatog-raphy on silica gel to afford 804mg of the trans isomer 10,446mg of the cis isomer ll, 447mg ofa mixture of 10 andll (42% total yield) and 1.58g of the starting material 8.10. IRvS^cm"1: 1725, 1175, 1110; NMR(CDC13)<§: 1.07(3H, s, CH3), 1.15 (3H, s, CH3), 1.18 (3H, t, 7=7.0Hz,

CH2CH3), 1.26 (3H, s, CH3), 1.0-1.95 (4H, m, -CHCH-and CH2), 3.91 (4H, s, OCH2CH2O), 4.10 (2H, q, J=

7.0Hz, OCH2CH3); MSm/z: 242(M+), 227, 197, 169, 153,87.

ll. IRvSlScm"1: 1720, 1420, 1380, 1175, 1110; NMR

(CDC13)<5: 1.09 (3H, s, CH3), 1.15 (3H, s, CH3), 1.17 (3H,

t, /=7.0Hz, OCH2CH3), 1.24 (3H, s, CH3), 1.04-1.80

(2H, m, CH-CH), 1.93 (2H, d, 7=6.0Hz, CH2), 3.87 (4H,s, OCH2CH2O), 4.03 (2H, q,.7=7.0Hz, OCH2CH3); MSm/z: 242 (M+), 227, 197, 169, 153, 87.

Reaction of 3-acetyl-5-methyl-4-hexen-2-one (6) withethyl diazoacetate. To a stirred solution of 6 (1.54g,

9.2mmol), powdered copper (20mg) and anhydrouscopper(II) sulfate (40mg) at 95- 100°C under a nitrogenatmosphere was added slowly dropwise ethyl diazoacetate(395mg, 3.5mmol), heating the result for 15min. After

cooling, the mixture was purified by column chromatog-raphy (hexane-ethyl acetate=9 : 1) on silica gel to give191 mg of 2,4-dimethyl-3-(2-methyl-l-propenyl)-5-ethoxycarbonylfuran (16) in a 25% yield and 1.1 g of thestarting material (6).

IRv^cm-1: 1700, 1615, 1555, 1160, 1085; NMR

(CDC13)<S: 1.30 (3H, t,J=7.0Hz, OCH2CH3), 1.48 (3H, s,CH3), 1.82 (3H, s, CH3), 2.ll (6H, s, 2xCH3), 4.30 (2H, q,

7=7.0Hz, OCH2CH3), 5.23 (1H, broad s, =CH-); MSm/z: 222 (M+), 177, 150.

Ethyl trans- and cis-2,2-dimethyl-3-{2-oxopropyl)-

cyclopropanecarboxylate (12 and 13). A solution of a

mixture of 10 and ll (2.9g, 12mmol) and 100mg of cone,hydrochloric acid in 30ml ofacetone was stirred for 1 hr atroom temperature. After the reaction mixture had beenconcentrated in vacuo, the residue was diluted with waterand extracted with ether. The extracts were washed with

Commercially available from Aldrich Chemical Co.


water, saturated aq. NaHCO3solution and water, anddried over Na2SO4. After removing the solvent, the res-idue was purified by column chromatography on silica gel(hexane-ethyl acetate=85: 15) to afford 1.061 g of the

trans isomer 12, 973mg of the cis isomer 13 and 113mg ofa mixture of 12 and 13 in a 90% yield.

12. IRv^cm"1: 1720, 1155, 1115; NMR (CDC13)<5:

1.06 (3H, s, CH3), 1,18 (3H, s, CH3), 1.18 (3H, t, 7=

7.0Hz, OCH2CH3), 1.19 (1H, d, 7=5.0Hz, CHCO), 1.57(1H, dt, 7=5.0 and 7.5Hz, CHCH2), 2.09 (3H, s,

COCH3), 2.43 (2H, d, 7=7.5Hz, CH2), 4.08 (2H, q, 7=

7.0Hz, OCH2CH3); MSm/z: 198 (M+) 180, 152, 141, 125,113.

13. IRv^cm"1: 1720, 1375, 1175, 1130, 1090; NMR

(CDC13)(5: 1.08 (3H, s, CH3), 1.13 (3H, s, CH3), 1.16 (3H,

t, 7=7.0Hz, OCH2CH3), 1.04-1.80 (2H, m, CH-CH),2.06 (3H, s, COCH3), 2.78 (2H, d, J=6.0Hz, CH2), 4.02(2H, q, 7=7.0Hz, OCH2CH3); MS m/z: 198 (M+), 197,152, 141, 125, 113, 109.

Ethyl trans-3- (2 , 2- dich lo rop ropyt) - 2, 2- dime thylcyclo -propanecarboxylate (17). To a mixture of zinc(II)chloride (6mg) and dichloromethyl methyl ether(138mg, 1.2mmol) was added dropwise 12 (198mg,1mmol) at 0~5°C, the mixture being stirred for 5min.The resultant mixture was directly submitted to columnchromatography on silica gel to give 207 mg of a mixtureof 17 and 14, whose structural confirmation and productratio were determined by comparing with the GLC (3%PEG 20M, 135°C) of authentic samples, giving the ratio of78 : 5 : 17 for 17, (E)-trans and (Z)-trans of14, respectively.

Ethyl cis-2, 2-dime thyl-3- {2, 2-dichloropropyl)cyclo -propanecarboxylate (19). In a similar manner to thatfor 17, the cis keto ester 18 (198mg, 1mmol) waschlorinated by dichloromethyl methyl ether to giveHOmgof a mixture of the dichloride 19 and 15, whosestructural confirmation and product ratio were deter-mined by comparing with the GLC (3% PEG 20M,135°C) of authentic samples, giving the ratio of 54 : 12 : 34for 17, (E)-cis and (Z)-cis of 15, respectively.

3,5,5-Trichloro-2-methyl-2-hexanol (22). A mixture of 2-methyl-3-buten-2-ol (21)*4 (30g, 0.35mol), trichloro-ethane (140g, 1.05mol), iron(II) chloride 4H2O (7.0g,0.035mol) and hexamethylphosphoramide (34.0g,0.19mol) placed in a sealed tube of stainless steel washeated for 7hr at 1 10- 115°C. After cooling, the reactionmixture was diluted with ether and the insoluble materialswere filtered off. The filtrate was concentrated in vacuo andthe oily residue was distilled to give 48g of 22 in a 62%yield, bp 106~109°C/10mmHg. IRvScm"1: 3560,

3500, 685, 650, 600; NMR (CDC13) 6: 1.25 (6H, s, 2xCH3),2.18 (3H, s, CH3), 2.50 (1H, dd, 7=8.5 and 17.0Hz,

CHH-), 3.05 (1H, dd, 7=2.0 and 17.0Hz, -CHH-), 4.04

(1H, dd, 7=2.0 and 8.5Hz, -CH-).

5,5-Dichloro-2,3-epoxy-2-methylhexane (23).a) To a suspension of sodium hydride (55%, 97mg,2.2mmol) in 5ml of DMFwas added dropwise a solutionof22 (440mg, 2mmol) in 3ml ofDMF at room tempera-ture, the mixture being stirred for 2.5hr. The reactionmixture was diluted with ether, washed with water anddried over Na2SO4. After removing the solvent, the res-idue was purified by column chromatography on silica gel(hexane-ethyl acetate= 10:0.5-10: 1) to give 360mg ofthe epoxide 23 in a 98% yield. IRv^cm"1: 2900, 1380,1250, 850, 700, 680, 650; NMR (CDC13)<5: 1.30 (3H, s,CH3), 1.33 (3H, s, CH3) 2.23 (3H, s, CH3), 2.27 (1H, dd,

.7=6.0 and 15.0Hz, -CHH-) 2.60 (1H, dd, 7=4.0 and15.0Hz, -CHH-), 3.07 (1H, dd, 7=4.0 and 6.0Hz-CH-).b) Amixture of22(319.5mg, 1.45mmol) and 1 nNaOH(1.72ml, 1.72mmol) was stirred for 2.5hr at room tem-perature. The reaction mixture was diluted with ether,washed with water and dried over Na2SO4. After remov-ing the solvent, the residue was purified by columnchromatography on silica gel to give 202 mg of23 in a 77%yield.

2-Methyl-5,5-dichloro-2-hexene (24).

a) To a solution of the epoxide 23 (366mg, 2mmol) in1 ml of acetic acid and 0.1 ml of water was added sodiumiodide (510mg, 3.4mmol) and sodium acetate (165mg,2mmol). To the mixture was added zinc dust (510mg,7.8mmol) portion-wise at 10~ 12°C, the mixture beingstirred for 4 hr at room temperature. The resulting mixturewas diluted with hexane and the insoluble materials werefiltered off. The filtrate was washed with saturated aq.NaCl solution and dried over Na2SO4. After removing thesolvent, the residue was purified by column chromatog-raphy on silica gel (hexane) to give 260mg of 24 in a 79%yield.NMR (CDC13)<5: 1.60 (3H, s, CH3), 1.71 (3H, s, CH3),2.02 (3H, s, CH3), 2.86 (2H, d, 7=7.0Hz, CH2), 5.32 (1H,m, -CH=).

,b) To a suspension of McMurry's reagent(4TiCl3-LiAlH4, 548mg, 3.34mmol) in 5ml of THF wasadded a solution of the epoxide 23 (366mg, 2mmol) in5ml of THF, the mixture being refluxed for 10hr. Theresulting mixture was filtered, and the filtrate was dilutedwith 30ml of ether, washed with water and dried overNa2SO4. After removing the solvent, the residue was

purified by column chromatography on silica gel (hexane)to give 120mg of the hexene 24 in a 36% yield.c) To a solution ofPC15 (1.92g, 9.2mmol) in 20ml ofCC14 was added 7 (900mg, 8mmol) at between -5 and0°C. The reaction mixture was stirred for 30minat thattemperature and then for 30 min at roomtemperature. Thereaction mixture was poured onto ice and extracted withether. The extracts were washed with water and dried over

*4 Commercially available from Aldrich Chemical Co.


Na2SO4. After removing the solvent, the residue waspurified by column chromatography on silica gel (hexane)

to give 517mg of24 in a 39% yield.

Cyclopropanation of 2-methyl-5,5-dichloro-2-hexene(24). To a suspension of 24 (835mg, 5mmol) and pow-dered copper (40mg) at 100~105°C under a nitrogen

atmosphere was added slowly dropwise ethyl diazoacetate(285mg, 2.5mmol) over a period of 1.3 hr, the result beingstirred for an additional 15 min. The reaction mixture waspurified by column chromatography on silica gel to give280mg of a mixture of the trans and cis isomers (17 and19) (17: 19=48:52, by GLC on carbowax 20M at 140°C)in a 44% yield.

S- Chloro-2-butenyl triphenylphosphonium iodide (26). Toa solution of l,3-dichloro-2-butene (25)*5 (3.75g,

0.03mol) in 100ml of DMFwas added sodium iodide(4.95g, 0.033mol) at 0°C, the mixture being stirred for

6hr at room temperature. The reaction mixture was

poured into ice-cooled water and extracted with ether. Theextracts were washed with aq. Na2S2O3 solution and driedover Na2SO4. The solvent was removed in vacuo to afford3.7g of the iodide.

To a solution of the crude iodide (3.7g, 0.017mol) in50ml of benzene was added portion-wise triphenyl phos-phine (5.2 g, 0.02 mol) under stirring at room temperature.After stirring for 1 hr, the precipitate was filtered from thesolution and washed with benzene to give 6.45g of thephosphonium salt (26) in a 78% yield.

2-Methyl-5-chloro-2,4-hexadiene (27). To a suspension

ofphosphonium salt (26) (19.15g, 53.8mmol) in 300ml ofTHF was added dropwise butyl lithium (35ml of 1.62m

solution in hexane, 56.7mmol) at -78°C, stirring being

continued for 15min at -78°C. Acetone (6.5g, 112mmol)was added dropwise to the resulting ylide solution at

- 78°C. After stirring overnight at room temperature, thereaction mixture was diluted with hexane and the insolublematerials were removed by filtration. The filtrate was

washed with ether and dried over Na2SO4. After removingthe solvent, the residue was purified by column chroma-tography on silica gel (hexane) to afford 3.3g of 27 in a47% yield. NMR (CDC13)<S: 1.84(3H, s, CH3), 1.92 (3H, s,

CH3), 2.26 (3H, s, CH3), 5.91-6.45 (2H, m,

=CH-CH=).

Reaction of 2-chloro-5-methyl-2,4-hexadiene (27) withethyl diazoacetate. To a suspension of27 (653 mg, 5 mmol)and powdered copper (40mg) at 95~100°C under anitrogen atmosphere was added slowly dropwise ethyl

diazoacetate (285 mg, 2.5 mmol), the result being stirredfor 10min. After cooling, the reaction mixture was pu-rified by column chromatography on silica gel

(hexane-ethyl acetate=2 : 1) to give 83mg of a mixture of

14and 15in a 15.3%yield.

Ethyl 3,3-dimethyl-4-oxobutanoate (30).

a) A mixture of isobutylaldehyde (20.7g, 0.29mol) anddiisobutylamine (18.5g, 0.143mol) was refluxed for 7hr

with continuous removal of the water. The reaction mix-ture was subjected directly to distillation to afford 20.4 g ofl-A^A^diisobutylamino-2-methyl-l-propene (28), bp68~80°C/20mmHg in a 78% yield. A solution of theresulting enamine 28 (3.6g, 0.02mol) and ethyl bro-moacetate (5.0g, 0.03mol) in 50ml of acetonitrile was

refluxed for 22hr. After cooling, 4.5ml of water and 1.5 mlof acetic acid were added to the reaction mixture, and themixture was further refluxed for 2hr. After cooling, thereaction mixture was poured into ice-cooled water andextracted with ether. The extracts were washed suc-cessively with saturated aq. NaHCO3solution and water,and dried over MgSO4.After evaporating the solvent, theoily residue was purified by column chromatography onsilica gel (hexane-ethyl acetate=10: 1-6: 1) to afford0.86g of the aldehyde 30 in a 27% yield. IRvS^cm"1:2830,.2720, 1730, 1210; NMR (CDC13)<§: 1.13 (6H, s,

2xCH3), 1.21 (3H, t, 7=7.0Hz, OCH2CH3), 2.43 (2H, s,

CH2CO) 4.00 (2H, q, J=7.0Hz, OCH2CH3), 9.51 (1H, s,

CHO). MS m/z: 158 (M+), 130, 113, 87.b) To a solution of ethyl 3,3-dimethyl-4-pentenoate (29)(3.1 g, 0.02mol) in 20ml of water and 60ml ofdioxane wasadded 0.12g of osmium tetroxide at room temperature.After stirring for 5min, sodium periodate (10.7g,

0.05 mol) was added to the mixture, which was then stirredfor 1.5hr. The resulting precipitates were removed byfiltration and the filtrate was extracted with ether. Theextracts were washed successively with saturated aq.NaHCO3 solution and water, and dried over MgSO4.After removing the solvent, the residue was purified by

column chromatography on silica gel to give 1.5g of thealdehyde 30 in a 48% yield.

Ethyl 3,3-dimethyl-4-hydroxy-6-heptynoate (31). To asuspension of aluminium ribbon (1.96g, 0.07mol) in

100ml of THF, which was activated with a catalyticamount of iodine and mercury(II) chloride, was addeddropwise a solution of propargyl bromide (13.0g,0.llmol) in 15ml of THF at 40°C, the mixture beingrefluxed for 2hr. To the reaction mixture was added asolution of the aldehyde 30 (7.65g, 0.048mol) in 10ml ofTHFat between -70 and -60°C, the resultant mixturebeing stirred for 50min at -60°C. The reaction mixturewas quenched with saturated aq. NH4C1 solution andallowed to warmto the ambient temperature. The result-ing mixture was poured into ice-cooled water and extrac-ted with ether. The extracts were washed with water anddried over Na2SO4. After removing the solvent in vacuo,the residue was purified by column chromatography onsilica gel (hexane-ethyl acetate = 8 : 2) to afford 4.3 g of the

*5 Commercially available from Tokyo Kasei Kogyo Go., Ltd. (Japan).


alcohol 31 and 1.8g of the lactone 32 in 45% and 24%yields, respectively.

31. IRv^cm-^SOO, 3290, 2100, 1730, 1220; NMR

(CDC13)(5: 0.97 (3H, s, CH3), 1.00 (3H, s, CH3), 1.22 (3H,t, /=7.5Hz, OCH2CH3), 2.01 (1H, t, /=15Hz, CeeCH),

2.20-2.40 (4H, m, -CH2C~ and -CH2CO), 2.73 (1H, d,

.7=4.0Hz, -OH), 3.50-3.80 (1H, m, -CHOH), 4.13 (2H,q, 7=7.5Hz, OCH2CH3); MS ra/z: 198 (M+), 159, 130,113. 32. IRv^cm-1: 3280, 2120, 1780, 1150- NMR

(CDC13)<5: 1.14(3H, s, CH3), 1.27 (3H, s, CH3), 2.08 (1H,

t, 7=3.0Hz, C=CH), 2.42 (2H, s, CH2CO), 2.57 (2H, dd,7=3.0 and 6.8Hz, CH2C=), 4.30 (1H, t,.7=6.8Hz,-OCH); MS m/z: 113 (M+ -39(-CH2-C=CH)).

Ethyl 3,3-dimethyl-4-hepten-6-ynoate (33). To a solutionof the alcohol 31 (0.60g, 3mmol) in 5ml of pyridine wasadded dropwise methanesufonyl chloride (0.70 g, 6 mmol)at room temperature, the reaction mixture being stirredfor an additional 1 hr. The resulting mixture was poured

into ice-cooled water and extracted with ether. The ex-tracts were washed successively with water, saturated aq.NaHCO3 solution and water, and dried over Na2SO4.

After removing the solvent, purification of the residue bycolumn chromatography on silica gel (hexane-ethylacetate=10: 3.5) afforded 0.5g of the mesylate in a 61%yield. IRv^cm-1: 3270, 2110, 1730, 1340, 1170; NMR

(CDC13)(S: 1.12 (6H, s, 2xCH3), 1.25 (3H, t,.7=7.0Hz,

OCH2CH3), 2.ll (1H, t, 7=2.0Hz, CeeCH), 2.38 (2H, s,

CH2CO), 2.50-2.80 (2H, m, -CH2C=), 3.18 (3H, s,

SO2CH3), 4.18 (2H, q, J=7.0Hz, OCH2CH3), 4.92 (1H,

dd, /=5.2Hz, CH-CH2); MS m/z: 261 (M+), 237(M+ -39 (-CH2CeeCH)).

A solution of the mesylate (O.lOg, 0.35mmol) in 0.5mlof THFwas added dropwise to a suspension of potassiumter/-butoxide (0.081 g, 0.7mmol) in 1 ml of THF at 0°C,and the mixture stirred for 1 hr at room temperature. Thereaction mixture was poured into ice-cooled water andextracted with ether. The extracts were washed with waterand dried over MgSO4. After removing the solvent, theresidue was purified by column chromatography on silicagel (hexane-ethyl acetate= 10 : 1) to give 0.057g of the en-yne product (33) in an 88% yield. IRv^cm"1: 3280,2100, 1730, 1200; NMR (CDCl3)cS: 1.12 (6H, s, 2xCH3),1.21 (3H, t5.7=7.5Hz, OCH2CH3), 2.28 (2H, s, CH2CO),

2.82 (1H, d, /=2.0H, CeeCH), 4.13 (2H, q, 7=7.5Hz,OCH2CH3), 5.49 (dd,.7=2.0 and 16.0Hz, =CH-), 6.34

(1H,d,J=16.0Hz,-CH=); MSm/z: 180(M+), 141, 135,91.

Ethyl 3,3-dimethyl-6-oxo-4-heptenoate (34). To a sus-

pension of mercury(II) oxide (0.13 g), boron trifluorideetherate (0.05ml) and trichloroacetic acid (0.002g) in

10ml of methanol was added dropwise a solution of theen-yne (33) (0.23 g, 1.3mmol) in 5 ml of methanol at roomtemperature, the reaction mixture being stirred for 30 min.Thereaction mixture was poured into ice-cooled waterand extracted with ether. The extracts were washed sue-

cessively with saturated aq. NaHCO3solution and water,and dried over Na2SO4.The solvent was evaporated andthe residue was chromotographed on silica gel(hexane-ethyl acetate= 100 : 20-100 : 50) to afford 0.19gof34ina 76%yield. IRvá"á"cm"1: 1730, 1700, 1680, 1630,1200; NMR (CDC13)<5: 1.12 (6H, s, 2xCH3), 1.16 (3H, t,

J=7.0Hz, OCH2CH3), 2.23 (3H, s, COCH3), 2.25 (2H, s,CH2CO), 3.9.6 (2H, q, 7=7.0Hz, OCH2CH3), 5.92 (1H, d,7=16.5Hz,-CH=), 6.73 (1H, d,7=16.5Hz, =CH-CO);MSm/z: 198 (M+), 183, 155, 153, 121, 120, 119.

Ethyl 4,6-dichloro-3,3-dimethyl-5-heptenoate (35). To a

solution of dichloromethyl methyl ether (0.19 g, 1.6 mmol)and zinc(II) chloride (0,018g, 0.13 mmol) in lml of di-chloromethane was added dropwise a solution of 34(0.157g, 0.8mmol) in 0.5ml of dichloromethane at 0°C,and the reaction mixture being stirred for 30min at0°C. The reaction mixture was poured into ice-cooledwater and extracted with ether. The extracts werewashed successively with saturated aq. NaHCO3 solu-tion and water, and dried over Na2SO4. After removingthe solvent, the residue was purified by column chroma-tography on silica gel (hexane-ethyl acetate=200 : 12) toafford 0.121g of35 in a 61% yield. IRv^cm"1: 1730,1660, 1150; NMR (CDC13)<5: 1.14 (6H, s, 2xCH3), 1.27

(3H, t, 7=6.5Hz, OCH2CH3), 2.20 (3H, s, CH3), 2.35

(1H, d, 7=14.0Hz, -CHHCO), 2.52 (1H, d, 7=

14.0Hz, -CHHCO2), 4.20 (2H, q, 7=6.5Hz, OCH2CH3),5.07 (1H, d, /=10.5Hz, -CHC1), 5.75 (1H, d, 7=10.5Hz, =CH); MS m/z: 256, 254, 252 (35C1 M+).

Cyclization of ethyl 3,3-dimethyl-4,6-dichloro-5-

heptenoate (35). To a solution of35 (170mg, 0.67mmol) in2ml of benzene was added potassium ter/-butoxide(200mg, 1.78mmol) at 0°C and the reaction mixture wasstirred for 30min at room temperature. The resultingmixture was poured into ice-cooled water and extractedwith ether. The extracts were washed with water and driedover MgSO4.After removing the solvent, the residue waspurified by column chromotography on silica gel(hexane-ethyl acetate=3:2-l : 1) to afford MOmg of amixture of the (Z)-isomers 36 and 37 (36:37=91 :9) in a76% yield.

The structural confirmation and product ratio wereconfirmed by the spectral data and GLC(3% PEG 20M,135°C) of authentic samples.

Acknowledgments. The authors wish to express theirgratitude to Dr. K. Murayama, director of the ResearchInstitute, and Dr. N. Soma, director of the PatentDepartment, for their encouragement throughout thiswork.

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synthesis of chloromethylvinylcyclopropanecarboxylic acid

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