Syntheses of the insect juvenile hormone

摘要

1972 361Syntheses of the Insect Juvenile HormoneBy J. S. Cochrane and J. R. Hanson," School of Molecular Sciences, University of Sussex, Brighton BNl 9QJTwo syntheses of the insect juvenile hormone are described.SussexTHE morphogenetic activity of the insect juvenilehormone (VIII) ensures the appearance and maintenanceof the features characteristic of the larval as opposedto the adult stages of insect development. The hormonealso has gonadotrophic effects in the control of ovarianand egg development in the adult female, whilst incertain insects it also activates the prothoracic g1and.lConsequently when its structure was published,2 itappeared to be an appropriate synthetic objective,particularly as the descriptions of its biological activityhad obvious implications in the control of insect popula-tion.At the outset of our work in 1967, there were noV. B. Wigglesworth, Nature, 1965, 208, 522.H. Roller, K. H. Dahm, C. C. Sweely, and R. M. Trost, Angew.For reviews see C. E. Berkoff, Quart. Rev., 1969, 23, 372;G. W. Canon, R. C. Ellis, and J . R. Leal, Org. Synth., 1963,Chem. Internat. Edn., 1967, 6, 179.B. M. Trost, Accounts Chem. Res., 1970, 3, 120.Coll. vol. Ibsol;', p. 597.reported syntheses, but since then a number of syntheseshave a~peared.~ We report two syntheses, whichallow structural variation in the alkyl residues, thechain length, and, in the second case, the stereo-chemistry .The first synthesis was non-stereospecific but allowsfor some structural variation (see Scheme 1). Cyclo-propyl inethyl ketone (I), which is readily availablefrom ethyl acetoacetate and ethylene oxide,* under-went a Grignard reaction to give 2-cyclopropylbutan-2-01 (II).5 Acid-catalysed cleavage 6 9 7 of the cyclo-propane ring gave l-bromo-4-methylhex-3-ene (111).5 T.A. Favorskaya, J . Gen. Chem. (U.S.S.R.), 1947, 17, 541(Chem. Abs., 1948, 42, 1210).hl. Julia, S. Julia, and R. Guegan, Bull, Soc. china. France,1960, 1072; M. Julia, Fr.P. 76,016/1962 (Chem. Abs., 1963, 59,11,252).7 S. Sarel, J. Yovell, and M. Sarel-Imber, Angew. Chenz.Intevnat. Edn., 1968, 7 , 577J.C.S. Perkin IG.1.c. showed that this contained 25-5y0 of the cis- and74.5 of the trans-isomer. A further Grignard re-action between the bromide (111) and ethyl cyclopropylI I MeCO*dHCH,amp;H, amp; Me(Et)C(OH) *CHCH,CH,(1) (11)j i iMe (Et)C:CHCH,*CH,Br (111)r---l Me(Et)C:CHCH,*CH,CEt(OH) CH*CH,*CH,(IV) I ii t iiiMe(Et)C:CH*CH,CH,C( Et) :CHCH,CH,Br(V)Me (Et) C:CH-CH,CH,*C(Et) :CHCH,.CH,COMe(VI) Ivi Me(Et) C:CHCH,*CH,*C(Et) :CHCH,*CH,*C(Me) :CHCO,M e(VII)viiI 1 Me (Et) amp;O.CH.CH,*CH,*C(Et) :CH*CH,CH,C(Me) :CHCO,MeSCHEME 1Reagents: i,.EtMgBr; ii, 48 HBr; iii, dry NaCN-Me,SO;iv, MeMgI ; VI, (EtO),P(O)CH,*CO,Me-NaH; vii, N-bromo-succinimide-H,O-NaOPr' .(VIII)ketone gave the cyclopropyl alcohol (IV).The syn-thesis of cyclopropyl ethyl ketone 8-10 from cyclo-propyl methyl ketone is outlined in Scheme 2. TheJ ii 1-16H,*CH,-kHCOEt CH,*CH,CH*COClSCHEME 2Reagents : i, NaBrO-H,O ; ii, Et,Cd.alternative route from ethyl 3-oxopentanoate was lesssatisfactory.Opening of the cyclopropane ring incompound (IV) with 48 hydrobromic acid gave theprimary bromide (V), which was shown by g.1.c. tocontain 59 of the cis- and 41 of the trans-3-ene.However this did not readily react under Grignardconditions. It was therefore converted into its nitrile,which was treated with methyl magnesium iodide togive 6-ethyl-lO-rnethyldodeca-5,9-dien-2-one (VI) as a8 M. Julia, S. Julia, and S. Tchen, Bull. SOC. chim. France,1961, 1849.9 G. H. Jeffery and A. I. Vogel, J . Chem. SOC., 1948, 1804.10 L. I. Smith and E . R. Rogier, J . Amer. Chem. SOC., 1961, 73,l1 K. Mori, B. Stalla-Bourdillon, M. Ohki, M. Matsui, and12 W. S. Wadsworthand W.D. Emmons, J . Amer. Chem. SOC.,4047.W. S. Bowers, Tetrahedron, 1969, 25, 1667.1961, 83, 1733.mixture of stereoisomers : cis-5,cis-9 15.5 ; cis-5,trans-943.4 ; trans-5,cis-9 10.8 ; and trans-5,trans-9 30.3(by g.1.c.). This ketone is an intermediate in a numberof other syntheses of the juvenile hormone.ll Reactionof this ketone with the anion derived from diethylmethox ycarbon ylmet hylphosphonat e gave the ester(VII).12 G.1.c. showed that this contained 9.8 of thetram-2 ,trans-6,cis- 1 O-isomer, which possesses the juvenilehormone backbone. However 28.9 of all-trans-isomerwas also produced, the epoxide of which differs fromjuvenile hormone in biological activity by a factor ofonly ca. 3. Epoxidation l3 gave a mixture of stereo-isomers which showed n.m.r. and mass spectra, g.1.c.behaviour, and biological activity comparable to thepublished data14 for the hormone admixed with itsstereoisomers.After this work was completed, acomparable sequence was briefly outlined in a flowdiagram by another gr0~p.l5Our second approach made use of an olefin synthesisdescribed16 by Corey et al. and used in his juvenilehormone synthesis l3 which permits the stereospecificconstruction of cis-trans double-bond isomers. 1,3-Di-chlorobut-2-ene was converted in two steps into but-2-yn-1-01 (IX) (see Scheme 3). trans-Addition ofhydrogen iodide by treatment with a heterogeneousmixture of lithium aluminium hydride and sodiummethoxide (2 : 1) followed by addition of iodine at-78" gave 3-iodobut-2-en-1-01.Alkylation of thisiodo-alcohol with diethyl copper lithium gave cis-3-methylpent-2-en-1-01 (X) in 15 yield from (IX).Although this route is stereospecific, alcohol (X) wasnot converted into the bromide (XI), since the lowoverall yield of alcohol precluded its incorporation into auseful synthesis. Hence, the pentenol (X) was alsosynthesised non-stereospecifically and used as a mix-ture of isomers. Treatment of ethyl methyl ketone withvinylmagnesium bromide gave 3-methylpent-l-en-3-01,~'MeCiC.CH,*OH Me(Et) C:CH.CH,*OH(IX) (XIi ii iiiEtCOMe 2 Me(Et)C:CH.CH,Br +(XI) Me (Et) C:CH*CH,*CH,*COEtSCHEME 3which on acid hydrolysis gave l-bromo-3-methylpent-2-ene (XI) (see Schemes 3 and 4). This was used, undercarefully defined conditions, to alkylate ethyl 3-oxopent-anoate to afford the ketone (XII) : cis-(27y0) and trans-(73) at C-6 (g.1.c.).The second portion of the insectjuvenile hormone molecule was prepared from tetra-1s E. J. Corey, J. A. Katzenellenbogen, W. H. Gilman, s. Q.Roman, a n d B . W. Erickson, J . Amer. Chem. SOC., 1968, 90, 5618.14 K. H. Dahn, H. Roller, and B. M. Trost, Life Sciences, PartTI, 1968, 7, 129.l5 B. H. Braun, M. Jacobsen, M. Schwarz, P. E. Sonnet,N. Wakabayashi, and R. M. Waters, J . Econ. Entomol., 1968, 61,866.E. J. Corey, J. A. Katzenellenbogen, and G. H. Posner,J . Amer. Chem. SOC., 1967, 89. 4245.l7 D. Papa, F. J. Villani, and H. F. Ginsberg, J . Amer. Chem.SOC., 1954, 76, 44461972 363hydro-2-furylmethanol, which was converted into pent-4-yn-1-01 (XIII) via the alkyl chloride and treatment ofthat with sodamide in liquid ammonia (see Scheme 4).18In our first experiment the terminal ethynyl group wasselectively protected as its trimethylsilyl derivative : l9~CH,CH,.CH,.LHCH,-OHiv, vvi 1 HOCH,CH,.CH,CiC.SiMe, HO*CH2CH,*CH2.CiCH( X W (XIII)vii, viii(XVJtPh,6*CH2CH,*CH,*CiC*SiMe3 I-Me (Et) C:CHCH,*CH,C( Et) :CH.CH,*CH,*CiCR(VIII) (XVI) 1(XVII)Me(Et) C:CHCH,CH,C(Et) :CHCH2*CH,CICCH,-OH+Ph,P*CH,.CH,*CH,*C~CCH,*OH I-SCHEME 4Reagents for Schemes 3 and 4: i, CH,:CH*MgBr; ii, 48HBr; iii, MeCH,CO*CH,*CO,Et; iv, SOC1,; v, NaNH,-NH,(liq) ;vi, ethynyl Grignard reagent-Me,SiCl; vii, (PhO),PMeI-;viii, PPh,; ix, (XI1)-NaH-Me,SO.(XVIII)4-the alcohol was then converted into its iodide with tri-phenyl phosphite methiodide 2o and thence with tri-phenyl phosphine into the phosphonium salt (XV).AWittig reaction between this salt and the ketone (XII)gave the acetylene (XVI; R = SiMe,) as a mixture ofstereoisomers. We were unable to carry out this reactionin good yield. Sodium hydride in pure 21j22 dimethylsulphoxide gave the best coupling. The silyl groupwas removed with aqueous silver nitrate 23 and theacetylene was recovered from its silver salt by treatmentwith potassium cyanide. To improve the yield, analternative sequence was developed in which the ethynylgroup was not protected ( c j . ref. 24). Pent-4-yn-1-011(XIII) TsOCH,CH,*CH,C~CH __tICH,*CH,CH,.CiCH 1 iiiii(XVI; R = H) f-- Ph36CH,CH,CH2*CiCH I-SCHEME 5Reagents: i, NaI-Me,CO; ii, PPh,-C,H,, 24 h ; iii, (XI1)-NaOEt-HCO *NMe,.(XIII) was converted into its toluene-p-sulphonate andthence into its iodide in 60 overall yield from thealcohol (see Scheme 5 ) .25 5-Iodopent-l-yne was thenE.R. H. Jones, G. Eglinton, and M. C. Whiting, Org. Synth.,l9 M. I;. Shostakovskii, A. S. Atavia, and N. V. Egorov,2o J. Landauer and H. Rydon, J . Chem. SOC., 1953, 2224.21 E. J . Corey and R. Greenwold, J . Org. Chem., 1963, 28,1963, Coll. vol. IV, p. 755.J. Gen. Chem. (U.S.S.R.), 1965, 35, 813.1128.treated with triphenylphosphine to give the correspond-ing phosphonium salt. A Wittig reaction with 7-methyl-non-6-en-3-one (XII) proceeded in only 30 yield despiteconsiderable variation in the conditions.Treatment ofa methyl ketone such as 6-rnethylhept-5-en-Z-one underidentical conditions gave a 73 yield of the coupledproduct. The presence of an acetylene also affects thereaction since coupling of 7-methylnon-6-en-3-one with(4,4-ethylenedioxypenty1)triphenylphosphonium iodideunder these conditions proceeded in 82 yield.Hydroxymethylation of the Grignard derivative ofthe acetylene (XVI; R = H) gave the ethynyl alcohol(XVII), which was converted into the juvenile hormoneby Corey's procedure : l3 trans-addition of hydrogeniodide by treatment with lithium aluminium hydride-sodium methoxide-iodine, followed by alkylation of theresulting iodo-olefin with dimethylcopper lithium,afforded an allylic alcohol with the carbon skeleton ofthe hormone.The alcohol was oxidised under mildconditions, first with freshly prepared manganesedioxide to the aldehyde and then with methanolicsodium cyanide-manganese dioxide-acetic acid to themethyl ester (VII). G.1.c. showed that this contained21.7 of the required stereoisomer. The mixturewas then converted into the terminal epoxide as de-scribed before. The product showed n.m.r. and massspectra comparable to the published spectra of thenatural material.An alternative approach started from the ethynylalcohol (XVIII). This was prepared by treating theprop-2-ynyltetrahydropyranyl ether with l-bromo-3-chloropropane. The halogen atoms were replaced byiodine with sodium iodide in acetone.These conditionsled to partial removal of the protecting group. Treat-ment with triphenylphosphine and complete removalof the protecting group with toluene-$-sulphonic acidgave the required alcohol. However the Wittig re-actions were not successful and this approach wasabandoned.EXPERIMENTAL1.r. spectra were recorded with a Unicam SP 200 spectro-meter for Nujol mulls or neat Iiquids and U.V. spectrawith a Unicam SP 800 spectrometer for ethanolic solutions.N.m.r. spectra were recorded on Varian T60, A60A, andHA100 spectrometers for solutions in deuteriochloroform.Mass spectra were determined with an A.E.I. MS9 orHitachi-Perkin-Elmer RMU-6 spectrometer. G.1.c. wascarried out with a Perkin-Elmer F11 or a Pye 104 machine.Silica gel (B.D.H.) or alumina (Spence grade H) was usedfor column chromatography.Kieselgel G (Merck) wasused for analytical (0.25 mm) and preparative layer chrom-atography. M.p.s were determinrd on a Kofler hot-stageapparatus.Materials.-Cyclopropyl methyl ketone had b.p. 11 1-112" at 760 mmHg (lit.,4 110-112deg; at 760 mmHg).22 G. G. Price and M. C. Whiting, Chem. and Ind., 1963, 775.23 H. M. Schmidt and J. F. Arens, Rec. Trav. chim., 1967, 86,24 K. Sato, S. Inoue, and S. Ota, J . Org. Chem., 1970, 35, 565.25 G. Eglinton and M. C. Whiting, J . Chem. SOC., 1950, 3650.1138J.C.S. Perkin I2-Cyclopropylbutan-2-01 (11) was prepared from cyclo-propyl methyl ketone with ethylmagnesium iodide andhad b.p. 142-143" a t 760 mmHg (lit.,5 141.5-143" a t760 mmHg).l-Bromo-4-methylhex-3-ene (111) was pre-pared from 2-cyclopropylbutan-2-01 with 48 hydro-bromic acid 6 9 7 and had b.p. 95-96' a t 100 mmHg. (lit.,6114-116" at 120 mmHg) (Found: C, 47.0; H, 7.5. Calc.for C,H,,Br; C, 47.3; H, 7-4), v,,, 2950, 1660, and 860cm-l, 7 9.00 (3H, t, J 7 Hz), 8-40 (trans) and 8-33 (cis)(3H, s), 7-99 (trans) and 7.96 (cis) (2H, q, J 7 Hz), 7.42(2H, q, J 7 Hz), and 4.88 (lH, m, w+ 16 Hz).G.1.c. was carried out on a Carbowax 20M (50 f t x 0.02in) column in series with a Carbowax 1540 (50 f t x 0.02in) column with nitrogen as carrier gas, at a flow rate of8 ml min-l a t 80'. The cis-isomer (25.5) had a retentiontime (Rt of 41.1 min and the trans-isomer (74.5) 43-2 min.had b.p. 55" a t 2 mmHg(lit.,g 97" at 27 mmHg) ; the acid chloride had b.p.120' a t760 mmHg (1it.,lo 114-119" at 760 mmHg) and cyclo-propyl ethyl ketone had b.p. 130-131" a t 760 mmHg(lit.,8 130" a t 760 mmHg).3-Cyclopropyl-7-methylnon-6-en-3-ol (IV) .-l-Bromo-4-methylhex-3-ene (28.4 g) and magnesium (3.88 g) in ether(65 ml) were heated under reflux for 1 h. Cyclopropylethyl ketone (14-5 g) in ether (75 ml) was added below 10".The mixture was left overnight and then hydrolysed withcold aqueous ammonium chloride (100 ml). The productwas recovered in ether and, on distillation, afforded 3-c-yclo-propy1-7-methyZnon-6-en-3-01(28 g), b.p. 82-85' a t 2 mmHg(Found: C, 79.1; H, 12.0. C,,Hamp; requires C, 79.6;H, 12.2), vmax 3480 cm-l, T 9-70 (4H, m), 8.40 (3H, s),and 4.90 (lH, m, w4 16 Hz).l-Brorno-4-ethyl-8-methyldeca-3,7-diene (V) .-Ice-cold48 hydrobromic acid (67 ml) was slowly added to avigorously shaken suspension of the foregoing alcohol(28 g) in ice (30 g) .After 30 min the product was recoveredin light petroleum and the extract was thoroughly rinsedwith aqueous sodium chloride and sodium hydrogencarbonate. The solvent was evaporated and the residuedistilled to afford l-bromo-4-ethyl-8-methyldeca-3,7-diene(26 g), b.p. 85-88' a t 0.8 mmHg, vmx. 1660 and 840 cm-l,7 8.95 (6H, t, J 7 Hz), 8-39 (trans) and 8-33 (cis) (3H, s),6.68 (2H, t, J 7 Hz), and 4-86 (2H, m).5-Ethyl-9-methylundeca-4,8-dienonitrile.-The foregoingbromide (10-3 g) (prepared immediately prior to use) anddry sodium cyanide (4 g) in freshly purified dimethylsulphoxide (30 ml) were heated a t 50" for 30 min and thena t 90" for 30 min.The mixture was extracted with lightpetroleum. The extract was washed thoroughly withwater, dried, and the solvent was evaporated. The residuewas distilled to afford the nitrile (7.3 g), b.p. 88-92" a t1.3 mmHg (Found: C, 82.1; H, 11.1. C,,H,,N requiresC, 81.9; H, 11-3y0), vmxe 2280, 1660, and 860 cm-l, T 8-95(6H, t, J 7 Hz), 8.39 (trans) and 8-33 (cis) (3H, s), and4.83 (2H, m, w4 16 Hz).6-EthyZ-lO-nzethyldodeca-5,9-dien-2-one (VI) .-The pre-ceding nitrile (7-3 g) in ether (100 ml) was added dropwiseto a Grignard solution prepared from methyl iodide (25.6 g)and magnesium (4 g) in ether (80 ml). The mixture wasstirred for 48 h and then hydrolysed with ice-cold aqueousammonium chloride (50 ml) .Concentrated hydrochloricacid (20 ml) was added and the mixture was heated a t45" for 1 h. The mixture was thoroughly extracted withether and the extract washed with aqueous sodium hydro-gen carbonate and water and dried. The solvent wasCyclopropanecarboxylic acidevaporated and the residue distilled to afford amp;ethyl-IO-methyldodeca-5,9-dien-2-one (6.1 g), b.p. 94-95" at0-4 mmHg (1it.,l1 b.p. 85" at 0.05 mmHg) (Found: C,80.7; H, 11.8. Calc. for C,,H,,O: C, 81.0; H, 11-8y0),v,, 1710 and 860 cm-l, T 9.01 (6H, t, J 7 Hz), 8.39 (trans)and 8-33 (cis) (3H, s), and 4-85 (2H, in, 16 Hz). G.1.c.Carbowax 20M (50 f t x 0.02 in), nitrogen gas flow rate8 ml rnin-l a t 100deg; showed the following results :Isomer R,/min ()cis-9,cis-5 25-2 15.5tvans-9, cis-5 25.8 43.4cis-9,trans-5 26.6 10.8trans-9,trans-5 27.2 30.3Methyl 7-Ethyl-3,1 l-dimethyZtridecu-2,6,lO-tvienoate (VII).-Diethy1 methoxycarbonylmethylphosphonate (7 g ) wasadded dropwise to a stirred suspension of sodium hydride(50 suspension in oil; 1.6 g) in anhydrous benzene(20 ml) and the mixture was stirred for 30 min a t roomtemperature until hydrogen was no longer expelled and aclear grey solution was obtained. 6-Ethyl-lO-methyl-dodeca-5,9-dien-2-one (6-5 g ) in anhydrous benzene (20 nil)was then added dropwise and the mixture was stirred atroom temperature for 20 h.Water (5 ml) was addedand the mixture was extracted with light petroleum.The extract was washed with water, dried, and evaporated.The residue was purified by p.1.c.in benzene to give methyl7-ethyl-3,l l-dimethyltrideca-2,6,1O-trienoate (6-2 g, RF0.68; starting material RF 0.43) (Found: C, 77.6; H,10.7 ; m/e, 278. Calc. for C,,H,,O,: C, 77.7; H, 11.8 ;M, 278), vm, 1725, 1655, and 840 cm-l, 7 9-04 and 9.02(3H, t, J 7 Hz), 8.40 (trans) and 8.33 (cis) (3H, s, trans : cis2.8 : l), 7-83 (3H, d, J 1 Hz), 6.29 (3H, s), 4-88 (2H, m), and4-29 (lH, s). G.1.c. Carbowax 20M (50 f t x 0.02 in),nitrogen; 3 ml min-l and l42" showed the followingresults :IsomerC(10), W), C(2)c c ct c cc t ct t cc c tt c tc t ttR,/min50.452.855.257-662.466.068.672.3(I3.48.62.77.49.630-59.828.9c = cis, t = trans.Methyl 10,l l-Epoxy-7-ethyl-3,l l-dirnethyltrideca-2,6-dieno-ate (VIII).-The preceding ester (1.31 g) in dimethoxy-ethane (5 ml) was added dropwise a t 0" to a solution ofN-bromosuccinimide (0.88 g) in water (3 ml) and di-methoxyethane (20 ml).After 1 hr a t 0", a solution ofsodium (0-23 g) in propan-2-01 (8 ml) was slowly addedand the mixture was stirred for 30 min. The solution wasextracted with ether-light petroleum (3 : 1 v/v; 200 ml).The extract was washed with water, dried, and evaporated.The residue was purified by p.1.c. hexane-ether ( 4 : l)to give methyl 10,l l-epoxy-7-ethyl-3,l l-dimethyltrideca-2,6-dienoate ,914 (0.7 g) (RF 0-42), (Found: C, 73.0; H,10.2; rn/e 294. Calc. for C1SH3003; C, 73.4; H, 10.3;M , 294), vmx.1725, 1655, 1220, and 1145 cm-l 7 9.15-8.85 (6H, m), 8.77 (trans) and 8-74 (cis) (3H, s), 8-60-8-326 Hz), 6-32 (3H, s ) , 4-85 (lH, m), and 4-32 (lH, s).(4H), 8.22-7.80 (12H), 7.84 (3H, d, J 1 Hz), 7.30 (lH, t, 1972 365An alternative but less efficient procedure with tetra-hydrofuran and methanolic sodium methoxide gave theepoxide in 25 yield. The hormone was tested againstRhodnius prolixus, Schistocerca gregaria, and Galleriainellonella in collaboration with Dr. G. Ellis-Pratt.trans-3-lodobut-2-en-l-ol.-Lithium aluminium hydride(3.8 g) and sodium methoxide (10-8 g) in dry tetrahydro-furan (1 1) were heated under reflux under nitrogen for 30min. But-2-yn-1-01 (3.55 g) was added to the cooledmixture, which was then heated under reflux for a further3 h.The solution was cooled to -78" and finely powderediodine (80 g) was added. The mixture was then stirredovernight a t -78". The solvent was evaporated off andwater (10 ml) was added. The mixture was extracted withether, washed with water, aqueous sodium thiosulphate,and water, and dried. The solvent was evaporated offand the product was chromatographed on silica gel to afford3-iodobut-2-en-1-01 (3-0 g), (mle 198. C,H,IO requiresill, 198) as an unstable oil, vmaZ 3300 and 1650 cm-l, T 7.5(3H, m), 7.00 (lH, s ) , 5.90 (2H, m), and 4-30 (lH, m).cis-3-Methylpent-2-en-1-01 (X).-3-Iodobut-2-en-l-ol (2.9g) in ether (20 nil) was added dropwise to a solution ofdiethylcopper lithium from copper(1) iodide (14.6 g), ethyliodide (48 g), and lithium (20 g) in ether (180 ml) a t -30".The mixture was stirred for 2 h at -30" and then treatedwith ethyl iodide (10 g) a t 0" for 18 h.Methanol (2.0 ml)and then water (5 ml) were added and the inorganic saltswere filtered off. The solvent was evaporated and thecrude residue was chromatographed on silica gel. Distill-ation of the fractions eluted with 14 ethyl acetate-lightpetroleum afforded cis-3-methylpent-2-en-1-01 (0-65 g),b.p. 86-87' a t 2 mmHg, vmx. 3300 and 1660 cm-l T 8-995.82 (2H, d, J 8 Hz), and 5-50 (lH, m).7-Methylnon-6-en-3-one was prepared from ethyl 3-0x0-pentanoate 26 and l-bromo-3-methylpent-2-ene. It hadb.p. 66' at 1.5 mmHg (1it.,l1 98" a t 18 mmHg) (Found:C, 77.9; H, 11.7y0; m/e, 204.Calc. for CloHl8O: C, 77.9;H, 11.80/o; 11.1, 204), vmX. 1705 and 860 cm-l T 9.03 and8-95 (3H, t, J 7 Hz), 8.41 (trans) and 8.36 (cis) (3H, s ) , and4-98 (lH, m, q 16 Hz). G.1.c. Ucon oil HB2000 (50 f t x0.02 in) ; nitrogen; 3 ml min-l; 70'1 showed the cis-isomer27:amp; (R, 33.8 min) and the trans-isomer 73 (14.2 min).5-TrimethylsilyZpent-4-yn-l-ol (XIV) .-Pent-4-yn-l-o1 l 8(43 g) in ether (100 ml) was added to an ice-cold solutionprepared from ethyl bromide (113.6 g) and magnesium(25 g) in ether (240 ml). After stirring for 2 h, copper(1)chloride (1.2 g) was added, followed by chlorotrimethylsilyl-silane (60 g) in ether (100 ml). The mixture was heatedunder gentle reflux for 14 h, cooled, and hydrolysed withhydrochloric acid (5).The aqueous layer was extractedwith ether and the combined extracts were washed withaqueous sodium hydrogen carbonate, dried, and evaporated.Distillation of the residue afforded 5-trimethylsilylpent-4-yn-1-02, an oil, b.p. 66' at 1.5 mmHg (Found: C, 61.4; H,10.2. C,H,,OSi requires C, 61.5; H, 10.27(0), vmlC 3410,2180, and 1250 cm-l, T 10-00 (9H, s), 7.82 (2H, t, J 6 Hz),6.50 (2H, t, J 6 Hz), and 5.60 (lH, s).5-Iodo-l-trimethylszZylpent-l-yne.-A mixture of 5-tri-methylsilylpent-4-yn-1-01 (1 5-6 g) and triphenyl phosphitemethiodide (51.3 g) was stirred a t 85' for 2 h under nitrogen.The fractions which distilled below 74" a t 2-2 mmHg werecollected, taken up in ether, washed with aqueous sodiumhydroxide (504,) and water, and dried. Distillation afforded5-iodo-l-trimetJzyZsilyZ~ent-l-yne, b.p.64" a t 1.8 mmHg,(3H, t, J 7 Hz), 8.29 (3H, s), 8.15-7.60 (2H), 7.18 (lH, s),v,, 2180, 1250, 760, and 677 cm-1, T 10.00 (9H, s), 7-75(2H, t, J 6 Hz), and 6.72 (2H, t, J 6 Hz). This was usedimmediately to prepare the phosphonium salt.Tri~henyl-(5-trimethylsiZyl~ent-4-ynyl)Phosphonium Io-dide (XV) .-Triphenylphosphine (20 g) and 5-iOdO- l-tri-methylsilylpent- 1-yne (22 g) in ethanol ( 100 ml) wereheated under reflux for 12 h. The ethanol was evaporatedoff in vacuo and the product was poured into ethyl acetate( 150 ml) to give triphenyl- (5-trimethylsiZyZpent-4-ynyl) -phosphoniurn iodide, m.p. 233-234" (from chloroforni-ethyl acetate) (Found: C, 59.1; H, 5.8. C,6H,,IPSirequires C, 59.1; H, 5.7), vmx.2175 and 1250 cm-l, 710.00 (9H, s), 7.42 (2H, t , J 6 Hz), 6.00-6.75 (2H), and2.60-2.22 (15H). This product was stored over phos-phorus pentoxide under vacuum.6-EthyZ-lO-rnethyZdodeca-5,9-dien-l-yne (XVI ; R = H) .-( a ) Sodium hydride (50 dispersion in oil; 4.8 g) waswashed free of oil by flushing with dry pentane undernitrogen. Dimethyl sulphoxide (rigorously purified im-mediately prior to use,,) (50 ml) and tetrahydrofuran(purified from sodium and benzophenone) (75 ml) wereadded and the mixture was stirred a t 0" for 1 h (until allthe hydrogen was expelled and a clear grey solutionremained). Triphenyl- (5-trimethylsilylpent-4-yny1)phos-phonium iodide (52-8 g) was added to give a deep redsolution. 7-Methylnon-6-en-3-one (15.4 g) was added andthe mixture was stirred for 3 days a t 4".The tetrahydro-furan was evaporated off below 10" and the mixture wasthen poured on ice (100 g), stirred for 1 h, and extractedwith pentane (10 x 100 ml). The extracts were washedwith water, dried, and evaporated to give an oil (14.3 g),which was chromatographed on silica gel. Elution withlight petroleum afforded an oil (3.8 g), vmx. 2180 and 1250cm-l. Elution with 5 ethyl acetate-light petroleumgave 7-methylnon-6-en-3-one (9.1 g). The oil was dissolvedin ethanol (15 ml) and a solution of silver nitrate (2.34 g)in water (6 ml) and ethanol (18 ml) was added dropwise.After 1 h potassium cyanide (4.4 g) in water (7 ml) was addedand the mixture was stirred for 45 min.The ethanol wasevaporated in Ztacuo and the aqueous residue thoroughlyextracted with pentane. The extract was washed withwater, dried, and evaporated to give an oil which waschromatographed on silica gel. Elution with light petrol-eum afforded 6-ethyl-lO-methyldodeca-5,9-dien- 1-yne (1.9 g)(Found: C, 87-8; H, 11.9; m/e, 204. C1,H,, requiresC, 88.1; H, 11.8; M , 204), vmx. 3290, 2120, and 860cm-l, T 9.04 and 9.03 (3H each t, J 7 Hz), 8.41 (trans)and 8.34 (cis) (3H, s; trans : cis 2.62 : l), and 4.87 (lH, m,5-Iodopent-1-yne was prepared by the method ofEglinton et al.,, and had b.p. 47" at 7 mmHg (lit.,,, 84-89" a t 43 mmHg) (Found: C, 31.3; H, 3-8. Calc. forC,H,I : C, 31.0; H, 3.6). The triphenylphosphoniumsalt was prepared as before; m.p.199-200" (lit.,24194-195") (Found: C, 60-3; H, 5.1. Calc. for C,,H,,IP:C, 60.5; H, 4.9y0), vmx. 3260 and 1600 cm-l, T 7-85 (lH, t,J 2 Hz), 7-38 (2H, t, J 6 Hz), 6-50-5-90 (2H, m), and1.95-2.40 (15H, m).(b) Dimethylformamide (purified over barium oxide)(150 ml) was added dropwise to sodium ethoxide (4.07 g)a t 0" under nitrogen and stirred for 1 h. Triphenyl(pent-4-yny1)phosphonium iodide (27.4 g) was slowly added andthe mixture was then stirred for 2 h a t 0". 7-Methylnon-26 G. Anderson, I. Halverstadt, W. Miller, and 0. Roblin,J . Amer. Chem. Soc., 1945, 87, 2197.W+ 16 Hz)J.C.S. Perkin I6-en-3-one (4.62 g ) was added dropwise during 1 h and themixture was stirred at 40" for 48 h. The mixture wasconcentrated in vucuo to 50 ml, poured on ice (150 g),and extracted with pentane (10 x 100 ml).The extractswere washed with water, dried, and evaporated to give anoil which was carefully chromatographed on silica gel.Elution with light petroleum gave successively 6-ethyl-IO-methyldodeca-l,2,5,9-tetraene as an oil (0.95 g) (Found:C, 87-9; H, ll-6y0; mle, 204. C15H24 requires C, 88.1;H, 11.8; M , 204), vmx. 1960 and 860 cm-l, T 9-18 (3H, t,J 7 Hz), 9.09 (3H, t, J 7 Hz), 8-41 (trans) and 8-34 (cis)(3H, s ; trans : cis 2.62 : l), and 5.45-4.80 (5H), 6-ethyl-1 O-methyldodeca-5,9-dien-l-yne (2-2 g) , identical withthe material obtained before, and 7-methylnon-6-en-3-one7-Ethyl-ll-methyltrideca-6,1O-dien-2-yn-l-ol (XVII) .-6-Ethyl- 1 O-methyldodeca-5, 9-dien- 1-yne (1 -7- g) in ether(5 ml) was added to a solution of ethylmagnesium iodidefrom magnesium (0-22 g) and ethyl iodide (1.5 g) inether (20 ml) .The mixture was heated under reflux undernitrogen for 6 h ; acetone-solid carbon dioxide was thecoolant in the condenser. Gaseous formaldehyde wasslowly introduced by passing dry nitrogen through a flaskcontaining paraformaldehyde (1 g) (dried over phosphoruspentoxide for 2 weeks) at 180". The mixture was heatedunder reflux for 6 h and then hydrolysed with 5 hydro-chloric acid, and the product was recovered in ether.The solvent was evaporated off and the residue distilled togive 7-ethyl-1 l-methyltrideca-6,1O-dien-2-yn- 1-01 (1.2 g) asan oil, b.p. 115' at 0.09 mmHg (Found: C, 82-4; H,11-6. Cl6HZ6O requires C, 82.0; H, 11*5y0), vmx.3380,2220, 1665, and 840 cm-l, 7 9.04 (3H, t, J 7 Hz), 9.03 (3H, t,J 7 Hz), 8.41 (trans) and 8-34 (cis) (3H, s; trans : cis2.7 : l), 5.79 (2H, s), and 4.87 (2H, m, z q 16 Hz).7-Ethyl-3,1 l-dimethyltrideca-2,6,10-trien-l-o1.- Lithiumaluminium hydride (475 mg) and sodium methoxide (1.35 g)were heated under reflux in tetrahydrofuran (125 ml)under nitrogen for 30 min. The foregoing alcohol (XVII)(1 g) in tetrahydrofuran (5 ml) was added and the solutionwas heated under reflux for 3 h. The mixture was cooledto -778' and iodine was added in small portions until apermanent brown colour remained. Stirring was continuedfor 14 h at -78". The solvent was evaporated off andaqueous sodium thiosulphate was added. The mixturewas extracted with ether and the extract washed withwater, dried, and evaporated to give the iodo-alcohol (1 g)as a yellow oil.This was dissolved in ether (5 ml) andadded to a solution of dimethylcopper lithium fromcopper(1) iodide (2-92 g) in ether (10 ml) and stirred at 0"for 24 h. Water (1 ml) was added and the mixture wasextracted with ether. The extracts were washed withwater and dried. The solvent was evaporated off and theresidue distilled to give an oil which was purified by p.1.c.(silica gel; 25 ethyl acetate-light petroleum) : theproduct had Rp 0.20 and the iodo-alcohol RF 0.25. 7-Ethyl-3,l l-dimethyltrideca-2,6,10-trien-l-ol (260 mg) was recoveredas an oil (Found: C, 81.3; H, 12-0y0; m/e, 250. Cl,H,,O27 J. Attenburrow, A.F. B. Cameron, J. H. Chapman, R. M.Evans, B. A. Hems, A. B. A. Jensen, and T. Walker, J . Chem.Soc., 1952, 1094.(1.6 euro;9.requires C, 81.5; H, 12.0; M , 250), 7 9.04 (3H, t, J 7 Hz),9.03 (3H, t, J 7 Hz), 8.41 (trans) and 8-34 (cis) (6H, s;trans : cis 1.84 : l), 5-84 (2H, d, J 6 Hz), 4.87 (2H, m), and4.64 (lH, m).Methyl 7-Ethyl-3,1 l-dimethyltrideca-2,6,10-trienoate (VII) .-7-Ethyl-3,1 l-dimethyltrideca-2,6,l0-trien-l-ol (1 20 mg)in hexane (0.5 ml) was added to fresh manganese dioxide z7(1-5 g) in hexane ( 8 ml) and stirred at 0" for 30 min. Thesolvent was evaporated off. Sodium cyanide (164 mg),glacial acetic acid (60 mg), and manganese dioxide (1.5 g.)in methanol (15 ml.) were added and the mixture wasstirred at 25" for 14 h. Water (0.5 ml) was added and thesolution was extracted with ether.Evaporation ofthe solvent and chromatography of the product on silica gelafforded methyl 7-ethyl-3,1 l-dimethyltrideca-2,6,1O-trieno-ate (53 mg) (Found: C, 77.6; H, 10.7; m/e, 278. Calc.for Cl8H3,O2: C, 77-6; H, 10.8; M , 278), v,, 1720and 830 cm-l, 7 9.04 (3H, t, J Hz), 9.03 (3H, t, J 7 Hz),8.41 (trans) and 8-34 (cis) (3H, s), 7.82 (3H, d, J 1 Hz),6.30 (3H, s), 4.88 (2H, m), and 4.30 (lH, s ) . G.1.c. Carbo-wax 20M (50 f t x 0.02 in) ; nitrogen; 3 ml min-l; 142'1showed :RJmin (Average)50.4 0-552-8 0.555.2 ( 157.6 162-4 20.466.1 26-669.1 21.772.6 31.3G = cis, t = transThe terminal epoxide was prepared as described earlierand used in the same test system.(6-Hydroxyhex-4-ynyl)tri~henyl~hosphonium Iodide(XVIII) .- l-(Tetrahydro-2-pyranyloxy)-6-chlorohex-2yne 28 b.p. 117 "C a t 0.25 mmHg (lit.,,* 110-114 at 0-14mmHg) (10 g) and sodium iodide (7.7 g) were heatedunder reflux for 6 h in freshly purified acetone (50 ml).The solution was filtered and the solvent was evaporatedoff. The iodo-acetylene (1 g ) and triphenylphosphine(880 mg) were heated under reflux in dry benzene (20 ml)for 24 h and the solvent was evaporated off. The residuewas taken up in ether (50 ml) and heated under refluxwith toluene-p-sulphonic acid (110 mg) for 30 min. Theproduct was collected and washed thoroughly with hotbenzene to give (6-hydroxyhex-4-ynyl)triphenylphosphoniumiodide (0.76 g ) as white flakes, m.p. 190-192" (fromchloroform-ethyl acetate) (Found: C, 59.4; H, 5.0.C,,HZ4IOP requires C, 59-3; H, 4.9), v,, 3380, 1590,745, and 690 cm-l, T 5-82 (2H, t, J 2 Hz) and 1.85-2.50(15H, m).We thank I.C.I. (Plant Protection Ltd.) for financialsupport and for permission to publish this work.1/1309 Received, July 27th, 19711m A. I. Rachlin, N. Wasyliw, and M. W. Goldberg, J. Org.Chem., 1961, 26, 2688